Multiple Myeloma

Multiple myeloma (MM) accounts for 1% to 2% of all cancers and slightly more than 17% of hematologic malignancies in the United States.¹ MM is characterized by the neoplastic proliferation of immunoglobulin (Ig)-producing plasma cells with ≥ 10% clonal plasma cells in the bone marrow or biopsy-proven bony or soft tissue plasmacytoma, plus presence of related organ or tissue impairment or presence of a biomarker associated with near-inevitable progression to end-organ damage.²

Background

Up to 97% of patients with MM will have a monoclonal (M) protein produced and secreted by the malignant plasma cells, which can be detected by protein electrophoresis of the serum and an aliquot of urine from a 24-hour collection combined with immunofixation of the serum and urine. The M protein in MM usually consists of IgG 50% of the time and light chains 16% of the time. Patients who lack detectable M protein are considered to have nonsecretory myeloma. MM presents with end-organ damage, which includes hypercalcemia, renal dysfunction, anemia, or lytic bone lesions. Patients with MM frequently present with renal insufficiency due to cast nephropathy or light chain deposition disease.³

MM is thought to evolve from monoclonal gammopathy of uncertain significance (MGUS), an asymptomatic premalignant stage of clonal plasma cell proliferation with a risk of progression to active myeloma at 1% per year.^4,5 Epidemiologic data suggest that people who develop MM have a genetic predisposition, but risk factors may develop or be acquired, such as age, immunosuppression, and environmental exposures. To better assess what causes transformation from MGUS to MM, it is important to identify agents that may cause this second hit.⁶

In November 1961, President John F. Kennedy authorized the start of Operation Ranch Hand, the US Air Force’s herbicide program during the Vietnam War. Twenty million gallons of various chemicals were sprayed in Vietnam, eastern Laos, and parts of Cambodia to defoliate rural land, depriving guerillas of their support base. Agent Orange (AO) was one of these chemicals; it is a mixed herbicide with traces of dioxin, a compound that has been associated with major health problems among exposed individuals.⁷ Several studies have evaluated exposure to AO and its potential harmful repercussions. Studies have assessed the link between AO and MGUS as well as AO to various leukemias, such as chronic lymphocytic leukemia.^8,9 Other studies have shown the relationship between AO exposure and worse outcomes in persons with MM.¹⁰ To date, only a single abstract from a US Department of Veterans Affairs (VA) medical center has investigated the relationships between AO exposure and MGUS, MM, and the rate of transformation. The VA study of patients seen from 2005 to 2015 in Detroit, Michigan, found that AO exposure led to an increase in cumulative incidence rate of MGUS/MM, suggesting possible changes in disease biology and genetics.¹¹

In this study, we aimed to determine the incidence of transformation of MGUS to MM in patients with and without exposure to AO. We then analyzed survival as a function of AO exposure, transformation, and clinical and sociodemographic variables. We also explored the impact of psychosocial variables and hematopoietic stem cell transplantation (HSCT), a standard of treatment for MM.

Methods

This retrospective cohort study assembled electronic health record (EHR) data from the Veterans Health Administration Corporate Data Warehouse (CDW). The VA Central Texas Veterans Healthcare System Institutional Review Board granted a waiver of consent for this record review. Eligible patients were Vietnam-era veterans who were in the military during the time that AO was used (1961-1971). Veterans were included if they were being cared for and received a diagnosis for MGUS or MM between October 1, 2009, and September 30, 2015 (all prevalent cases fiscal years 2010-2015). Cases were excluded if there was illogical death data or if age, race, ethnicity, body mass index (BMI), or prior-year diagnostic data were missing.

Measures

Patients were followed through April 2020. Presence of MGUS was defined by the International Classification of Diseases, Ninth Revision (ICD-9) diagnosis code 273.1. MM was identified by ICD-9 diagnosis codes 203.00, 203.01, and 203.02. The study index date was the earliest date of diagnosis of MGUS or MM in fiscal years 2010-2015. It was suspected that some patients with MM may have had a history of MGUS prior to this period. Therefore, for patients with MM, historical diagnosis of MGUS was extracted going back through the earliest data in the CDW (October 1999). Patients diagnosed with both MGUS and MM were considered transformation patients.

Other measures included age at index date, sex, race, ethnicity, VA priority status (a value 1 to 8 summarizing why the veteran qualified for VA care, such as military service-connected disability or very low income), and AO exposure authenticated per VA enrollment files and disability records. Service years were separated into 1961 to 1968 and 1969 to 1971 to match a change in the formulation of AO associated with decreased carcinogenic effect. Comorbidity data from the year prior to first MGUS/MM diagnosis in the observation period were extracted. Lifestyle factors associated with development of MGUS/MM were determined using the following codes: obesity per BMI calculation or diagnosis (ICD-9, 278.0), tobacco use per diagnosis (ICD-9, 305.1, V15.82), and survival from MGUS/MM diagnosis index date to date of death from any cause. Comorbidity was assessed using ICD-9 diagnosis codes to calculate the Charlson Comorbidity Index (CCI), which includes cardiovascular diseases, diabetes mellitus, liver and kidney diseases, cancers, and metastatic solid tumors. Cancers were omitted from our adapted CCI to avoid collinearity in the multivariable models. The theoretical maximum CCI score in this study was 25.^12,13 Additional conditions known to be associated with variation in outcomes among veterans using the VA were indicated, including major depressive disorder, posttraumatic stress disorder (PTSD), alcohol use disorder (AUD), substance use disorder (SUD), and common chronic disease (hypertension, lipid disorders).¹⁴

Statistical Analysis

Sample characteristics were represented by frequencies and percentages for categorical variables and means and SDs (or medians and ranges where appropriate) for continuous variables. A χ² test (or Fisher exact test when cell counts were low) assessed associations in bivariate comparisons. A 2-sample t test (or Wilcoxon rank sum test as appropriate) assessed differences in continuous variables between 2 groups. Kaplan-Meier curves depicted the unadjusted relationship of AO exposure to survival. Cox proportional hazards survival models examined an unadjusted model containing only the AO exposure indicator as a predictor and adjusted models were used for demographic and clinical factors for MGUS and patients with MM separately.

Predictors were age in decades, sex, Hispanic ethnicity, race, nicotine dependence, obesity, overweight, AUD, SUD, major depressive disorder, PTSD, and the adapted CCI. When modeling patients with MM, MGUS was added to the model to identify the transformation group. The interaction of AO with transformation was also analyzed for patients with MM. Results were reported as hazard ratios (HR) with their 95% CI.

Results

We identified 18,215 veterans diagnosed with either MGUS or MM during fiscal years 2010-2015 with 16,366 meeting inclusion criteria. Patients were excluded for missing data on exposure (n = 334), age (n = 12), race (n = 1058), ethnicity (n = 164), diagnosis (n = 47), treatment (n = 56), and BMI (n = 178). All were Vietnam War era veterans; 14 also served in other eras.

The cohort was 98.5% male (Table 1). Twenty-nine percent were Black veterans, 65% were White veterans, and 4% of individuals reported Hispanic ethnicity. Patients had a mean (SD) age of 66.7 (5.9) years (range, 52-96). Most patients were married (58%) or divorced/separated (27%). All were VA priority 1 to 5 (no 6, 7, or 8); 50% were priority 1 with 50% to 100% service-connected disability. Another 29% were eligible for VA care by reason of low income, 17% had 10% to 40% service-connected disability, and 4% were otherwise disabled.

Disscussion

Elucidating the pathophysiology and risk of transformation from MGUS to MM is an ongoing endeavor, even 35 years after the end of US involvement in the Vietnam War. Our study sought to understand a relationship between AO exposure, risk of MGUS transforming to MM, and associated mortality in US Vietnam War veterans. The rate of transformation (MGUS progressing to active MM) is well cited at 1% per year.¹⁵ Here, we found 12% of our cohort had undergone this transformation over 10 years.

Vietnam War era veterans who were exposed to AO during the Operation Ranch Hand period had 2.4 times greater risk of developing MGUS compared with veterans not exposed to AO.⁸ Our study was not designed to look at this association of AO exposure and MGUS/MM as this was a retrospective review to assess the difference in outcomes based on AO exposure. We found that AO exposure is associated with a decrease in mortality in contrast to a prior study showing worse survival with individuals with AO exposure.¹⁰ Another single center study found no association between AO exposure and overall survival, but it did identify an increased risk of progression from MGUS to MM.¹¹ Our study did not show increased risk of transformation but did show positive effect on survival.

Black individuals have twice the risk of developing MM compared with White individuals and are diagnosed at a younger age (66 vs 70 years, respectively).¹⁶ Interestingly, Black race was a protective factor in our study. Given the length of time (35 years) elapsed since the Vietnam War ended, it is likely that most vulnerable Black veterans did not survive until our observation period.

HSCT, as expected, was a protective factor for veterans undergoing this treatment modality, but it is unclear why such a small number (8%) underwent HSCT as this is a standard of care in the management of MM. Obesity was also found to be a protective factor in a prior study, which was also seen in our study cohort.⁸

Limitations

This study was limited by its retrospective review of survivors among the Vietnam-era cohort several decades after the exposure of concern. Clinician notes and full historical data, such as date of onset for any disorder, were unavailable. These data also relied on the practitioners caring for the veterans to make the correct diagnosis with the associated code so that the data could be captured. Neither AO exposure nor diagnoses codes were verified against other sources of data; however, validation studies over the years have supported the accuracy of the diagnosis codes recorded in the VA EHR.

Conclusions

Because AO exposure is a nonmodifiable risk factor, focus should be placed on modifiable risk factors (eg, nicotine dependence, alcohol and substance use disorders, underlying comorbid conditions) as these were associated with worse outcomes. Future studies will look at the correlation of AO exposure, cytogenetics, and clinical outcomes in these veterans to learn how best to identify their disease course and optimize their care in the latter part of their life.

Acknowledgments

This research was supported by the Central Texas Veterans Health Care System and Baylor Scott and White Health, both in Temple and Veterans Affairs Central Western Massachusetts Healthcare System, Leeds.

Multiple myeloma (MM) accounts for 1% to 2% of all cancers and slightly more than 17% of hematologic malignancies in the United States.¹ MM is characterized by the neoplastic proliferation of immunoglobulin (Ig)-producing plasma cells with ≥ 10% clonal plasma cells in the bone marrow or biopsy-proven bony or soft tissue plasmacytoma, plus presence of related organ or tissue impairment or presence of a biomarker associated with near-inevitable progression to end-organ damage.²

Background

Up to 97% of patients with MM will have a monoclonal (M) protein produced and secreted by the malignant plasma cells, which can be detected by protein electrophoresis of the serum and an aliquot of urine from a 24-hour collection combined with immunofixation of the serum and urine. The M protein in MM usually consists of IgG 50% of the time and light chains 16% of the time. Patients who lack detectable M protein are considered to have nonsecretory myeloma. MM presents with end-organ damage, which includes hypercalcemia, renal dysfunction, anemia, or lytic bone lesions. Patients with MM frequently present with renal insufficiency due to cast nephropathy or light chain deposition disease.³

MM is thought to evolve from monoclonal gammopathy of uncertain significance (MGUS), an asymptomatic premalignant stage of clonal plasma cell proliferation with a risk of progression to active myeloma at 1% per year.^4,5 Epidemiologic data suggest that people who develop MM have a genetic predisposition, but risk factors may develop or be acquired, such as age, immunosuppression, and environmental exposures. To better assess what causes transformation from MGUS to MM, it is important to identify agents that may cause this second hit.⁶

In November 1961, President John F. Kennedy authorized the start of Operation Ranch Hand, the US Air Force’s herbicide program during the Vietnam War. Twenty million gallons of various chemicals were sprayed in Vietnam, eastern Laos, and parts of Cambodia to defoliate rural land, depriving guerillas of their support base. Agent Orange (AO) was one of these chemicals; it is a mixed herbicide with traces of dioxin, a compound that has been associated with major health problems among exposed individuals.⁷ Several studies have evaluated exposure to AO and its potential harmful repercussions. Studies have assessed the link between AO and MGUS as well as AO to various leukemias, such as chronic lymphocytic leukemia.^8,9 Other studies have shown the relationship between AO exposure and worse outcomes in persons with MM.¹⁰ To date, only a single abstract from a US Department of Veterans Affairs (VA) medical center has investigated the relationships between AO exposure and MGUS, MM, and the rate of transformation. The VA study of patients seen from 2005 to 2015 in Detroit, Michigan, found that AO exposure led to an increase in cumulative incidence rate of MGUS/MM, suggesting possible changes in disease biology and genetics.¹¹

In this study, we aimed to determine the incidence of transformation of MGUS to MM in patients with and without exposure to AO. We then analyzed survival as a function of AO exposure, transformation, and clinical and sociodemographic variables. We also explored the impact of psychosocial variables and hematopoietic stem cell transplantation (HSCT), a standard of treatment for MM.

Methods

This retrospective cohort study assembled electronic health record (EHR) data from the Veterans Health Administration Corporate Data Warehouse (CDW). The VA Central Texas Veterans Healthcare System Institutional Review Board granted a waiver of consent for this record review. Eligible patients were Vietnam-era veterans who were in the military during the time that AO was used (1961-1971). Veterans were included if they were being cared for and received a diagnosis for MGUS or MM between October 1, 2009, and September 30, 2015 (all prevalent cases fiscal years 2010-2015). Cases were excluded if there was illogical death data or if age, race, ethnicity, body mass index (BMI), or prior-year diagnostic data were missing.

Measures

Patients were followed through April 2020. Presence of MGUS was defined by the International Classification of Diseases, Ninth Revision (ICD-9) diagnosis code 273.1. MM was identified by ICD-9 diagnosis codes 203.00, 203.01, and 203.02. The study index date was the earliest date of diagnosis of MGUS or MM in fiscal years 2010-2015. It was suspected that some patients with MM may have had a history of MGUS prior to this period. Therefore, for patients with MM, historical diagnosis of MGUS was extracted going back through the earliest data in the CDW (October 1999). Patients diagnosed with both MGUS and MM were considered transformation patients.

Other measures included age at index date, sex, race, ethnicity, VA priority status (a value 1 to 8 summarizing why the veteran qualified for VA care, such as military service-connected disability or very low income), and AO exposure authenticated per VA enrollment files and disability records. Service years were separated into 1961 to 1968 and 1969 to 1971 to match a change in the formulation of AO associated with decreased carcinogenic effect. Comorbidity data from the year prior to first MGUS/MM diagnosis in the observation period were extracted. Lifestyle factors associated with development of MGUS/MM were determined using the following codes: obesity per BMI calculation or diagnosis (ICD-9, 278.0), tobacco use per diagnosis (ICD-9, 305.1, V15.82), and survival from MGUS/MM diagnosis index date to date of death from any cause. Comorbidity was assessed using ICD-9 diagnosis codes to calculate the Charlson Comorbidity Index (CCI), which includes cardiovascular diseases, diabetes mellitus, liver and kidney diseases, cancers, and metastatic solid tumors. Cancers were omitted from our adapted CCI to avoid collinearity in the multivariable models. The theoretical maximum CCI score in this study was 25.^12,13 Additional conditions known to be associated with variation in outcomes among veterans using the VA were indicated, including major depressive disorder, posttraumatic stress disorder (PTSD), alcohol use disorder (AUD), substance use disorder (SUD), and common chronic disease (hypertension, lipid disorders).¹⁴

Statistical Analysis

Sample characteristics were represented by frequencies and percentages for categorical variables and means and SDs (or medians and ranges where appropriate) for continuous variables. A χ² test (or Fisher exact test when cell counts were low) assessed associations in bivariate comparisons. A 2-sample t test (or Wilcoxon rank sum test as appropriate) assessed differences in continuous variables between 2 groups. Kaplan-Meier curves depicted the unadjusted relationship of AO exposure to survival. Cox proportional hazards survival models examined an unadjusted model containing only the AO exposure indicator as a predictor and adjusted models were used for demographic and clinical factors for MGUS and patients with MM separately.

Predictors were age in decades, sex, Hispanic ethnicity, race, nicotine dependence, obesity, overweight, AUD, SUD, major depressive disorder, PTSD, and the adapted CCI. When modeling patients with MM, MGUS was added to the model to identify the transformation group. The interaction of AO with transformation was also analyzed for patients with MM. Results were reported as hazard ratios (HR) with their 95% CI.

Results

We identified 18,215 veterans diagnosed with either MGUS or MM during fiscal years 2010-2015 with 16,366 meeting inclusion criteria. Patients were excluded for missing data on exposure (n = 334), age (n = 12), race (n = 1058), ethnicity (n = 164), diagnosis (n = 47), treatment (n = 56), and BMI (n = 178). All were Vietnam War era veterans; 14 also served in other eras.

The cohort was 98.5% male (Table 1). Twenty-nine percent were Black veterans, 65% were White veterans, and 4% of individuals reported Hispanic ethnicity. Patients had a mean (SD) age of 66.7 (5.9) years (range, 52-96). Most patients were married (58%) or divorced/separated (27%). All were VA priority 1 to 5 (no 6, 7, or 8); 50% were priority 1 with 50% to 100% service-connected disability. Another 29% were eligible for VA care by reason of low income, 17% had 10% to 40% service-connected disability, and 4% were otherwise disabled.

Disscussion

Elucidating the pathophysiology and risk of transformation from MGUS to MM is an ongoing endeavor, even 35 years after the end of US involvement in the Vietnam War. Our study sought to understand a relationship between AO exposure, risk of MGUS transforming to MM, and associated mortality in US Vietnam War veterans. The rate of transformation (MGUS progressing to active MM) is well cited at 1% per year.¹⁵ Here, we found 12% of our cohort had undergone this transformation over 10 years.

Vietnam War era veterans who were exposed to AO during the Operation Ranch Hand period had 2.4 times greater risk of developing MGUS compared with veterans not exposed to AO.⁸ Our study was not designed to look at this association of AO exposure and MGUS/MM as this was a retrospective review to assess the difference in outcomes based on AO exposure. We found that AO exposure is associated with a decrease in mortality in contrast to a prior study showing worse survival with individuals with AO exposure.¹⁰ Another single center study found no association between AO exposure and overall survival, but it did identify an increased risk of progression from MGUS to MM.¹¹ Our study did not show increased risk of transformation but did show positive effect on survival.

Black individuals have twice the risk of developing MM compared with White individuals and are diagnosed at a younger age (66 vs 70 years, respectively).¹⁶ Interestingly, Black race was a protective factor in our study. Given the length of time (35 years) elapsed since the Vietnam War ended, it is likely that most vulnerable Black veterans did not survive until our observation period.

HSCT, as expected, was a protective factor for veterans undergoing this treatment modality, but it is unclear why such a small number (8%) underwent HSCT as this is a standard of care in the management of MM. Obesity was also found to be a protective factor in a prior study, which was also seen in our study cohort.⁸

Limitations

This study was limited by its retrospective review of survivors among the Vietnam-era cohort several decades after the exposure of concern. Clinician notes and full historical data, such as date of onset for any disorder, were unavailable. These data also relied on the practitioners caring for the veterans to make the correct diagnosis with the associated code so that the data could be captured. Neither AO exposure nor diagnoses codes were verified against other sources of data; however, validation studies over the years have supported the accuracy of the diagnosis codes recorded in the VA EHR.

Conclusions

Because AO exposure is a nonmodifiable risk factor, focus should be placed on modifiable risk factors (eg, nicotine dependence, alcohol and substance use disorders, underlying comorbid conditions) as these were associated with worse outcomes. Future studies will look at the correlation of AO exposure, cytogenetics, and clinical outcomes in these veterans to learn how best to identify their disease course and optimize their care in the latter part of their life.

Acknowledgments

This research was supported by the Central Texas Veterans Health Care System and Baylor Scott and White Health, both in Temple and Veterans Affairs Central Western Massachusetts Healthcare System, Leeds.

Multiple myeloma (MM) accounts for 1% to 2% of all cancers and slightly more than 17% of hematologic malignancies in the United States.¹ MM is characterized by the neoplastic proliferation of immunoglobulin (Ig)-producing plasma cells with ≥ 10% clonal plasma cells in the bone marrow or biopsy-proven bony or soft tissue plasmacytoma, plus presence of related organ or tissue impairment or presence of a biomarker associated with near-inevitable progression to end-organ damage.²

Background

Up to 97% of patients with MM will have a monoclonal (M) protein produced and secreted by the malignant plasma cells, which can be detected by protein electrophoresis of the serum and an aliquot of urine from a 24-hour collection combined with immunofixation of the serum and urine. The M protein in MM usually consists of IgG 50% of the time and light chains 16% of the time. Patients who lack detectable M protein are considered to have nonsecretory myeloma. MM presents with end-organ damage, which includes hypercalcemia, renal dysfunction, anemia, or lytic bone lesions. Patients with MM frequently present with renal insufficiency due to cast nephropathy or light chain deposition disease.³

MM is thought to evolve from monoclonal gammopathy of uncertain significance (MGUS), an asymptomatic premalignant stage of clonal plasma cell proliferation with a risk of progression to active myeloma at 1% per year.^4,5 Epidemiologic data suggest that people who develop MM have a genetic predisposition, but risk factors may develop or be acquired, such as age, immunosuppression, and environmental exposures. To better assess what causes transformation from MGUS to MM, it is important to identify agents that may cause this second hit.⁶

In November 1961, President John F. Kennedy authorized the start of Operation Ranch Hand, the US Air Force’s herbicide program during the Vietnam War. Twenty million gallons of various chemicals were sprayed in Vietnam, eastern Laos, and parts of Cambodia to defoliate rural land, depriving guerillas of their support base. Agent Orange (AO) was one of these chemicals; it is a mixed herbicide with traces of dioxin, a compound that has been associated with major health problems among exposed individuals.⁷ Several studies have evaluated exposure to AO and its potential harmful repercussions. Studies have assessed the link between AO and MGUS as well as AO to various leukemias, such as chronic lymphocytic leukemia.^8,9 Other studies have shown the relationship between AO exposure and worse outcomes in persons with MM.¹⁰ To date, only a single abstract from a US Department of Veterans Affairs (VA) medical center has investigated the relationships between AO exposure and MGUS, MM, and the rate of transformation. The VA study of patients seen from 2005 to 2015 in Detroit, Michigan, found that AO exposure led to an increase in cumulative incidence rate of MGUS/MM, suggesting possible changes in disease biology and genetics.¹¹

In this study, we aimed to determine the incidence of transformation of MGUS to MM in patients with and without exposure to AO. We then analyzed survival as a function of AO exposure, transformation, and clinical and sociodemographic variables. We also explored the impact of psychosocial variables and hematopoietic stem cell transplantation (HSCT), a standard of treatment for MM.

Methods

This retrospective cohort study assembled electronic health record (EHR) data from the Veterans Health Administration Corporate Data Warehouse (CDW). The VA Central Texas Veterans Healthcare System Institutional Review Board granted a waiver of consent for this record review. Eligible patients were Vietnam-era veterans who were in the military during the time that AO was used (1961-1971). Veterans were included if they were being cared for and received a diagnosis for MGUS or MM between October 1, 2009, and September 30, 2015 (all prevalent cases fiscal years 2010-2015). Cases were excluded if there was illogical death data or if age, race, ethnicity, body mass index (BMI), or prior-year diagnostic data were missing.

Measures

Patients were followed through April 2020. Presence of MGUS was defined by the International Classification of Diseases, Ninth Revision (ICD-9) diagnosis code 273.1. MM was identified by ICD-9 diagnosis codes 203.00, 203.01, and 203.02. The study index date was the earliest date of diagnosis of MGUS or MM in fiscal years 2010-2015. It was suspected that some patients with MM may have had a history of MGUS prior to this period. Therefore, for patients with MM, historical diagnosis of MGUS was extracted going back through the earliest data in the CDW (October 1999). Patients diagnosed with both MGUS and MM were considered transformation patients.

Other measures included age at index date, sex, race, ethnicity, VA priority status (a value 1 to 8 summarizing why the veteran qualified for VA care, such as military service-connected disability or very low income), and AO exposure authenticated per VA enrollment files and disability records. Service years were separated into 1961 to 1968 and 1969 to 1971 to match a change in the formulation of AO associated with decreased carcinogenic effect. Comorbidity data from the year prior to first MGUS/MM diagnosis in the observation period were extracted. Lifestyle factors associated with development of MGUS/MM were determined using the following codes: obesity per BMI calculation or diagnosis (ICD-9, 278.0), tobacco use per diagnosis (ICD-9, 305.1, V15.82), and survival from MGUS/MM diagnosis index date to date of death from any cause. Comorbidity was assessed using ICD-9 diagnosis codes to calculate the Charlson Comorbidity Index (CCI), which includes cardiovascular diseases, diabetes mellitus, liver and kidney diseases, cancers, and metastatic solid tumors. Cancers were omitted from our adapted CCI to avoid collinearity in the multivariable models. The theoretical maximum CCI score in this study was 25.^12,13 Additional conditions known to be associated with variation in outcomes among veterans using the VA were indicated, including major depressive disorder, posttraumatic stress disorder (PTSD), alcohol use disorder (AUD), substance use disorder (SUD), and common chronic disease (hypertension, lipid disorders).¹⁴

Statistical Analysis

Sample characteristics were represented by frequencies and percentages for categorical variables and means and SDs (or medians and ranges where appropriate) for continuous variables. A χ² test (or Fisher exact test when cell counts were low) assessed associations in bivariate comparisons. A 2-sample t test (or Wilcoxon rank sum test as appropriate) assessed differences in continuous variables between 2 groups. Kaplan-Meier curves depicted the unadjusted relationship of AO exposure to survival. Cox proportional hazards survival models examined an unadjusted model containing only the AO exposure indicator as a predictor and adjusted models were used for demographic and clinical factors for MGUS and patients with MM separately.

Predictors were age in decades, sex, Hispanic ethnicity, race, nicotine dependence, obesity, overweight, AUD, SUD, major depressive disorder, PTSD, and the adapted CCI. When modeling patients with MM, MGUS was added to the model to identify the transformation group. The interaction of AO with transformation was also analyzed for patients with MM. Results were reported as hazard ratios (HR) with their 95% CI.

Results

We identified 18,215 veterans diagnosed with either MGUS or MM during fiscal years 2010-2015 with 16,366 meeting inclusion criteria. Patients were excluded for missing data on exposure (n = 334), age (n = 12), race (n = 1058), ethnicity (n = 164), diagnosis (n = 47), treatment (n = 56), and BMI (n = 178). All were Vietnam War era veterans; 14 also served in other eras.

The cohort was 98.5% male (Table 1). Twenty-nine percent were Black veterans, 65% were White veterans, and 4% of individuals reported Hispanic ethnicity. Patients had a mean (SD) age of 66.7 (5.9) years (range, 52-96). Most patients were married (58%) or divorced/separated (27%). All were VA priority 1 to 5 (no 6, 7, or 8); 50% were priority 1 with 50% to 100% service-connected disability. Another 29% were eligible for VA care by reason of low income, 17% had 10% to 40% service-connected disability, and 4% were otherwise disabled.

Disscussion

Elucidating the pathophysiology and risk of transformation from MGUS to MM is an ongoing endeavor, even 35 years after the end of US involvement in the Vietnam War. Our study sought to understand a relationship between AO exposure, risk of MGUS transforming to MM, and associated mortality in US Vietnam War veterans. The rate of transformation (MGUS progressing to active MM) is well cited at 1% per year.¹⁵ Here, we found 12% of our cohort had undergone this transformation over 10 years.

Vietnam War era veterans who were exposed to AO during the Operation Ranch Hand period had 2.4 times greater risk of developing MGUS compared with veterans not exposed to AO.⁸ Our study was not designed to look at this association of AO exposure and MGUS/MM as this was a retrospective review to assess the difference in outcomes based on AO exposure. We found that AO exposure is associated with a decrease in mortality in contrast to a prior study showing worse survival with individuals with AO exposure.¹⁰ Another single center study found no association between AO exposure and overall survival, but it did identify an increased risk of progression from MGUS to MM.¹¹ Our study did not show increased risk of transformation but did show positive effect on survival.

Black individuals have twice the risk of developing MM compared with White individuals and are diagnosed at a younger age (66 vs 70 years, respectively).¹⁶ Interestingly, Black race was a protective factor in our study. Given the length of time (35 years) elapsed since the Vietnam War ended, it is likely that most vulnerable Black veterans did not survive until our observation period.

HSCT, as expected, was a protective factor for veterans undergoing this treatment modality, but it is unclear why such a small number (8%) underwent HSCT as this is a standard of care in the management of MM. Obesity was also found to be a protective factor in a prior study, which was also seen in our study cohort.⁸

Limitations

This study was limited by its retrospective review of survivors among the Vietnam-era cohort several decades after the exposure of concern. Clinician notes and full historical data, such as date of onset for any disorder, were unavailable. These data also relied on the practitioners caring for the veterans to make the correct diagnosis with the associated code so that the data could be captured. Neither AO exposure nor diagnoses codes were verified against other sources of data; however, validation studies over the years have supported the accuracy of the diagnosis codes recorded in the VA EHR.

Conclusions

Because AO exposure is a nonmodifiable risk factor, focus should be placed on modifiable risk factors (eg, nicotine dependence, alcohol and substance use disorders, underlying comorbid conditions) as these were associated with worse outcomes. Future studies will look at the correlation of AO exposure, cytogenetics, and clinical outcomes in these veterans to learn how best to identify their disease course and optimize their care in the latter part of their life.

Acknowledgments

This research was supported by the Central Texas Veterans Health Care System and Baylor Scott and White Health, both in Temple and Veterans Affairs Central Western Massachusetts Healthcare System, Leeds.

Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease: treatment with chimeric antigen-receptor (CAR) T cells.

Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells; in some cases, they manage to eradicate the disease completely.

About half of patients with leukemia or lymphoma and about a third of those with multiple myeloma who receive this treatment have a complete remission and achieve a functional “cure.”

But not all patients who could benefit from this therapy are able to get it. Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.

The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.

The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minn., and medical director for the cellular therapy program. It was published as an abstract at the annual meeting of the American Society of Clinical Oncology recently, although it was not presented there.

“We wanted to find out just how widespread this problem is,” Dr. Lin said, adding: “There had been nothing in the literature thus far about it.”

The team contacted 20 centers across the United States and received responses from 17. Results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy. An additional 25% were able to enter a CAR T clinical trial. The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.

For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
 

Shortage affecting mostly myeloma patients

The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.

The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).

“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50-60 eligible patients.”

Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market: idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb. “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Dr. Shah said.

A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022. While that helped provide centers with a few more slots, it wasn’t sufficient to cut waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.

“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the department of lymphoma/myeloma in the division of cancer medicine at the University of Texas MD Anderson Cancer Center, Houston.

“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”

“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance.

He noted that, as with other cancer centers, for multiple myeloma they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Dr. Maloney.

“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
 

Complex causes behind bottleneck

The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.

While the biggest impact of shortages has been on patients with multiple myeloma, Dr. Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree.

“This is multifactorial as to why, but most of the issues arise from manufacturing,” Dr. Patel said in an interview. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do.”

On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.

Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.

There are also problems regarding supply. Manufacture and delivery of CAR T is complicated and takes time to scale up, Dr. Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”

The shortages and delays likely involve two main factors. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting, and manufacturing is extremely complicated and not easily scaled up,” he said.

“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Dr. Frigault commented.

Delays in access to myeloma CAR T-cell therapy are also affecting patient care at Fox Chase Cancer Center in Philadelphia. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase. “For Carvykti, there are only 32 certified centers in [the] U.S., and access is very limited.”

Dr. Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR T products used for lymphomas.”
 

Pharma companies trying to meet the demand

This news organization reached out to the manufacturers of CAR T products. All have reported that they are doing what they feasibly can to ramp up production.

“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.

“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.

“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”

Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” according to a Novartis spokesperson.

The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.

“Data presented at [the] American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility, our flagship CAR T manufacturing site, had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.

Legend and Janssen, the companies behind Carvykti, one of the two approved cell products for myeloma, which launched earlier in 2022, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.

“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”

With regard to the industry-wide supply shortage of lentivirus, Legend and Janssen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
 

Incredibly exciting potential

Given the immense potential of CAR T-cell therapy, the supply shortage that myeloma patients are experiencing is all the more poignant and distressing. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.

“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.

But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.

A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.

The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.

At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”

A version of this article first appeared on Medscape.com.

Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease: treatment with chimeric antigen-receptor (CAR) T cells.

Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells; in some cases, they manage to eradicate the disease completely.

About half of patients with leukemia or lymphoma and about a third of those with multiple myeloma who receive this treatment have a complete remission and achieve a functional “cure.”

But not all patients who could benefit from this therapy are able to get it. Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.

The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.

The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minn., and medical director for the cellular therapy program. It was published as an abstract at the annual meeting of the American Society of Clinical Oncology recently, although it was not presented there.

“We wanted to find out just how widespread this problem is,” Dr. Lin said, adding: “There had been nothing in the literature thus far about it.”

The team contacted 20 centers across the United States and received responses from 17. Results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy. An additional 25% were able to enter a CAR T clinical trial. The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.

For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
 

Shortage affecting mostly myeloma patients

The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.

The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).

“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50-60 eligible patients.”

Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market: idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb. “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Dr. Shah said.

A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022. While that helped provide centers with a few more slots, it wasn’t sufficient to cut waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.

“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the department of lymphoma/myeloma in the division of cancer medicine at the University of Texas MD Anderson Cancer Center, Houston.

“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”

“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance.

He noted that, as with other cancer centers, for multiple myeloma they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Dr. Maloney.

“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
 

Complex causes behind bottleneck

The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.

While the biggest impact of shortages has been on patients with multiple myeloma, Dr. Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree.

“This is multifactorial as to why, but most of the issues arise from manufacturing,” Dr. Patel said in an interview. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do.”

On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.

Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.

There are also problems regarding supply. Manufacture and delivery of CAR T is complicated and takes time to scale up, Dr. Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”

The shortages and delays likely involve two main factors. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting, and manufacturing is extremely complicated and not easily scaled up,” he said.

“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Dr. Frigault commented.

Delays in access to myeloma CAR T-cell therapy are also affecting patient care at Fox Chase Cancer Center in Philadelphia. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase. “For Carvykti, there are only 32 certified centers in [the] U.S., and access is very limited.”

Dr. Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR T products used for lymphomas.”
 

Pharma companies trying to meet the demand

This news organization reached out to the manufacturers of CAR T products. All have reported that they are doing what they feasibly can to ramp up production.

“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.

“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.

“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”

Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” according to a Novartis spokesperson.

The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.

“Data presented at [the] American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility, our flagship CAR T manufacturing site, had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.

Legend and Janssen, the companies behind Carvykti, one of the two approved cell products for myeloma, which launched earlier in 2022, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.

“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”

With regard to the industry-wide supply shortage of lentivirus, Legend and Janssen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
 

Incredibly exciting potential

Given the immense potential of CAR T-cell therapy, the supply shortage that myeloma patients are experiencing is all the more poignant and distressing. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.

“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.

But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.

A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.

The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.

At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”

A version of this article first appeared on Medscape.com.

Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease: treatment with chimeric antigen-receptor (CAR) T cells.

Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells; in some cases, they manage to eradicate the disease completely.

About half of patients with leukemia or lymphoma and about a third of those with multiple myeloma who receive this treatment have a complete remission and achieve a functional “cure.”

But not all patients who could benefit from this therapy are able to get it. Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.

The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.

The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minn., and medical director for the cellular therapy program. It was published as an abstract at the annual meeting of the American Society of Clinical Oncology recently, although it was not presented there.

“We wanted to find out just how widespread this problem is,” Dr. Lin said, adding: “There had been nothing in the literature thus far about it.”

The team contacted 20 centers across the United States and received responses from 17. Results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy. An additional 25% were able to enter a CAR T clinical trial. The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.

For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
 

Shortage affecting mostly myeloma patients

The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.

The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).

“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50-60 eligible patients.”

Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market: idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb. “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Dr. Shah said.

A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022. While that helped provide centers with a few more slots, it wasn’t sufficient to cut waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.

“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the department of lymphoma/myeloma in the division of cancer medicine at the University of Texas MD Anderson Cancer Center, Houston.

“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”

“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance.

He noted that, as with other cancer centers, for multiple myeloma they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Dr. Maloney.

“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
 

Complex causes behind bottleneck

The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.

While the biggest impact of shortages has been on patients with multiple myeloma, Dr. Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree.

“This is multifactorial as to why, but most of the issues arise from manufacturing,” Dr. Patel said in an interview. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do.”

On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.

Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.

There are also problems regarding supply. Manufacture and delivery of CAR T is complicated and takes time to scale up, Dr. Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”

The shortages and delays likely involve two main factors. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting, and manufacturing is extremely complicated and not easily scaled up,” he said.

“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Dr. Frigault commented.

Delays in access to myeloma CAR T-cell therapy are also affecting patient care at Fox Chase Cancer Center in Philadelphia. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase. “For Carvykti, there are only 32 certified centers in [the] U.S., and access is very limited.”

Dr. Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR T products used for lymphomas.”
 

Pharma companies trying to meet the demand

This news organization reached out to the manufacturers of CAR T products. All have reported that they are doing what they feasibly can to ramp up production.

“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.

“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.

“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”

Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” according to a Novartis spokesperson.

The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.

“Data presented at [the] American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility, our flagship CAR T manufacturing site, had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.

Legend and Janssen, the companies behind Carvykti, one of the two approved cell products for myeloma, which launched earlier in 2022, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.

“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”

With regard to the industry-wide supply shortage of lentivirus, Legend and Janssen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
 

Incredibly exciting potential

Given the immense potential of CAR T-cell therapy, the supply shortage that myeloma patients are experiencing is all the more poignant and distressing. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.

“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.

But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.

A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.

The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.

At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”

A version of this article first appeared on Medscape.com.

New results with quadruple drug therapy in the frontline treatment of multiple myeloma (MM) are prompting experts to speculate that stem cell transplantation may soon be able to take a back seat in the treatment of newly diagnosed disease.

“It is not a big leap of faith to imagine that, in the near future, with the availability of quadruplets and T-cell therapies, the role of high-dose melphalan and autologous stem cell transplant will be diminished,” said Dickran Kazandjian, MD, and Ola Landgren, MD, PhD, of the myeloma division, Sylvester Comprehensive Cancer Center, University of Miami.

They commented in a editorial in JAMA Oncology, prompted by a paper describing new results with a novel quadruple combination of therapies. These treatments included the monoclonal antibody elotuzumab (Empliciti) added onto the established backbone of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (known as KRd).

“Regardless of what the future holds for elotuzumab-based combinations, it is clear that the new treatment paradigm of newly diagnosed MM will incorporate antibody-based quadruplet regimens,” the editorialists commented.

“Novel immunotherapies are here to stay,” they added, “as they are already transforming the lives of patients with multiple MM and bringing a bright horizon to the treatment landscape.”
 

Study details

The trial of the novel quadruplet regimen was a multicenter, single-arm, phase 2 study that involved 46 patients with newly diagnosed multiple myeloma, explain first author Benjamin A. Derman, MD, of the University of Chicago Medical Center, and colleagues.

These patients had a median age of 62; more than two-thirds were male (72%) and White (70%). About half (48%) had high-risk cytogenetic abnormalities.

All patients were treated with 12 cycles of the quadruple therapy Elo-KRd regimen. They underwent bone marrow assessment of measurable residual disease (MRD; with 10-5 sensitivity) after cycle 8 and cycle 12.

“An MRD-adapted treatment approach is rational because it may identify which patients can be administered shorter courses of intensive therapy without compromising efficacy,” the authors explained.

Patients who had MRD negativity at both time points did not receive further Elo-KRd, while patients who converted from MRD positivity to negativity in between cycles 8 and 12 received 6 additional cycles of Elo-KRd. Those who remained MRD positive or converted to positivity after 12 cycles received an additional 12 cycles of Elo-KRd.

Following Elo-KRd treatment, all patients transitioned to triple therapy with Elo-Rd (with no carfilzomib), for indefinite maintenance therapy or until disease progression.

For the primary endpoint, the rate of stringent complete response and/or MRD-negativity after cycle 8 was 58% (26 of 45), meeting the predefined definition of efficacy. 

Importantly, 26% of patients converted from MRD positivity after cycle 8 to negativity at a later time point, while 50% of patients reached 1-year sustained MRD negativity.

Overall, the estimated 3-year, progression-free survival was 72%, and the rate was 92% for patients with MRD-negativity at cycle 8. The overall survival rate was 78%.

The most common grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively), and one patient had a grade 5 MI. Three patients discontinued the treatment because of intolerance.

“An MRD-adapted design using elotuzumab and weekly KRd without autologous stem cell transplantation showed a high rate of stringent complete response (sCR) and/or MRD-negativity and durable responses,” the authors wrote.

“This approach provides support for further evaluation of MRD-guided de-escalation of therapy to decrease treatment exposure while sustaining deep responses.”

To better assess the difference of the therapy versus treatment including stem cell transplantation, a phase 3, randomized trial is currently underway to compare the Elo-KRd regimen against KRd with autologous stem cell transplant in newly diagnosed MM.

“If Elo-KRd proves superior, a randomized comparison of Elo versus anti-CD38 mAb-based quadruplets would help determine the optimal combination of therapies in the frontline setting,” the authors noted.
 

Randomized trial anticipated to clarify benefit

In their editorial, Dr. Kazandjian and Dr. Landgren agreed with the authors that the role of elotuzumab needs to be better clarified in a randomized trial setting.

Elotuzumab received FDA approval in 2015 based on results from the ELOQUENT-2 study, which showed improved progression-free survival and overall survival with the addition of elotuzumab to lenalidomide and dexamethasone in patients with multiple myeloma who have previously received one to three other therapies.

However, the editorialists pointed out that recently published results from the randomized ELOQUENT-1 trial of lenalidomide and dexamethasone with and without elotuzumab showed the addition of elotuzumab was not associated with a statistically significant difference in progression-free survival.

The editorialists also pointed out that, in the setting of newly diagnosed multiple myeloma, another recent, similarly designed study found that the backbone regimen of carfilzomib, lenalidomide, and dexamethasone – on its own – was also associated with a favorable MRD-negative rate of 62%.

In addition, several studies involving novel quadruple treatments with the monoclonal antibody daratumumab (Darzalex) instead of elotuzumab, have also shown benefit in newly diagnosed multiple myeloma, resulting in high rates of MRD negativity.

Collectively, the findings bode well for the quadruple regimens in the treatment of MM, the editorialists emphasized.

“Importantly, with the rate of deep remissions observed with antibody-based quadruplet therapies, one may question the role of using early high-dose melphalan and autologous stem cell transplant in every patient, especially in those who have achieved MRD negativity with the quadruplet alone,” they added.

The study was sponsored in part by Amgen, Bristol-Myers Squibb, and the Multiple Myeloma Research Consortium. Dr. Derman reported advisory board fees from Sanofi, Janssen, and COTA Healthcare; honoraria from PleXus Communications and MJH Life Sciences. Dr. Kazandjian declares receiving advisory board or consulting fees from Bristol-Myers Squibb, Sanofi, and Arcellx outside the submitted work. Dr. Landgren has received grant support from numerous organizations and pharmaceutical companies. Dr. Landgren has also received honoraria for scientific talks/participated in advisory boards for Adaptive Biotech, Amgen, Binding Site, Bristol-Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer, and served on independent data monitoring committees for international randomized trials by Takeda, Merck, Janssen, and Theradex.

A version of this article first appeared on Medscape.com.

New results with quadruple drug therapy in the frontline treatment of multiple myeloma (MM) are prompting experts to speculate that stem cell transplantation may soon be able to take a back seat in the treatment of newly diagnosed disease.

“It is not a big leap of faith to imagine that, in the near future, with the availability of quadruplets and T-cell therapies, the role of high-dose melphalan and autologous stem cell transplant will be diminished,” said Dickran Kazandjian, MD, and Ola Landgren, MD, PhD, of the myeloma division, Sylvester Comprehensive Cancer Center, University of Miami.

They commented in a editorial in JAMA Oncology, prompted by a paper describing new results with a novel quadruple combination of therapies. These treatments included the monoclonal antibody elotuzumab (Empliciti) added onto the established backbone of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (known as KRd).

“Regardless of what the future holds for elotuzumab-based combinations, it is clear that the new treatment paradigm of newly diagnosed MM will incorporate antibody-based quadruplet regimens,” the editorialists commented.

“Novel immunotherapies are here to stay,” they added, “as they are already transforming the lives of patients with multiple MM and bringing a bright horizon to the treatment landscape.”
 

Study details

The trial of the novel quadruplet regimen was a multicenter, single-arm, phase 2 study that involved 46 patients with newly diagnosed multiple myeloma, explain first author Benjamin A. Derman, MD, of the University of Chicago Medical Center, and colleagues.

These patients had a median age of 62; more than two-thirds were male (72%) and White (70%). About half (48%) had high-risk cytogenetic abnormalities.

All patients were treated with 12 cycles of the quadruple therapy Elo-KRd regimen. They underwent bone marrow assessment of measurable residual disease (MRD; with 10-5 sensitivity) after cycle 8 and cycle 12.

“An MRD-adapted treatment approach is rational because it may identify which patients can be administered shorter courses of intensive therapy without compromising efficacy,” the authors explained.

Patients who had MRD negativity at both time points did not receive further Elo-KRd, while patients who converted from MRD positivity to negativity in between cycles 8 and 12 received 6 additional cycles of Elo-KRd. Those who remained MRD positive or converted to positivity after 12 cycles received an additional 12 cycles of Elo-KRd.

Following Elo-KRd treatment, all patients transitioned to triple therapy with Elo-Rd (with no carfilzomib), for indefinite maintenance therapy or until disease progression.

For the primary endpoint, the rate of stringent complete response and/or MRD-negativity after cycle 8 was 58% (26 of 45), meeting the predefined definition of efficacy. 

Importantly, 26% of patients converted from MRD positivity after cycle 8 to negativity at a later time point, while 50% of patients reached 1-year sustained MRD negativity.

Overall, the estimated 3-year, progression-free survival was 72%, and the rate was 92% for patients with MRD-negativity at cycle 8. The overall survival rate was 78%.

The most common grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively), and one patient had a grade 5 MI. Three patients discontinued the treatment because of intolerance.

“An MRD-adapted design using elotuzumab and weekly KRd without autologous stem cell transplantation showed a high rate of stringent complete response (sCR) and/or MRD-negativity and durable responses,” the authors wrote.

“This approach provides support for further evaluation of MRD-guided de-escalation of therapy to decrease treatment exposure while sustaining deep responses.”

To better assess the difference of the therapy versus treatment including stem cell transplantation, a phase 3, randomized trial is currently underway to compare the Elo-KRd regimen against KRd with autologous stem cell transplant in newly diagnosed MM.

“If Elo-KRd proves superior, a randomized comparison of Elo versus anti-CD38 mAb-based quadruplets would help determine the optimal combination of therapies in the frontline setting,” the authors noted.
 

Randomized trial anticipated to clarify benefit

In their editorial, Dr. Kazandjian and Dr. Landgren agreed with the authors that the role of elotuzumab needs to be better clarified in a randomized trial setting.

Elotuzumab received FDA approval in 2015 based on results from the ELOQUENT-2 study, which showed improved progression-free survival and overall survival with the addition of elotuzumab to lenalidomide and dexamethasone in patients with multiple myeloma who have previously received one to three other therapies.

However, the editorialists pointed out that recently published results from the randomized ELOQUENT-1 trial of lenalidomide and dexamethasone with and without elotuzumab showed the addition of elotuzumab was not associated with a statistically significant difference in progression-free survival.

The editorialists also pointed out that, in the setting of newly diagnosed multiple myeloma, another recent, similarly designed study found that the backbone regimen of carfilzomib, lenalidomide, and dexamethasone – on its own – was also associated with a favorable MRD-negative rate of 62%.

In addition, several studies involving novel quadruple treatments with the monoclonal antibody daratumumab (Darzalex) instead of elotuzumab, have also shown benefit in newly diagnosed multiple myeloma, resulting in high rates of MRD negativity.

Collectively, the findings bode well for the quadruple regimens in the treatment of MM, the editorialists emphasized.

“Importantly, with the rate of deep remissions observed with antibody-based quadruplet therapies, one may question the role of using early high-dose melphalan and autologous stem cell transplant in every patient, especially in those who have achieved MRD negativity with the quadruplet alone,” they added.

The study was sponsored in part by Amgen, Bristol-Myers Squibb, and the Multiple Myeloma Research Consortium. Dr. Derman reported advisory board fees from Sanofi, Janssen, and COTA Healthcare; honoraria from PleXus Communications and MJH Life Sciences. Dr. Kazandjian declares receiving advisory board or consulting fees from Bristol-Myers Squibb, Sanofi, and Arcellx outside the submitted work. Dr. Landgren has received grant support from numerous organizations and pharmaceutical companies. Dr. Landgren has also received honoraria for scientific talks/participated in advisory boards for Adaptive Biotech, Amgen, Binding Site, Bristol-Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer, and served on independent data monitoring committees for international randomized trials by Takeda, Merck, Janssen, and Theradex.

A version of this article first appeared on Medscape.com.

New results with quadruple drug therapy in the frontline treatment of multiple myeloma (MM) are prompting experts to speculate that stem cell transplantation may soon be able to take a back seat in the treatment of newly diagnosed disease.

“It is not a big leap of faith to imagine that, in the near future, with the availability of quadruplets and T-cell therapies, the role of high-dose melphalan and autologous stem cell transplant will be diminished,” said Dickran Kazandjian, MD, and Ola Landgren, MD, PhD, of the myeloma division, Sylvester Comprehensive Cancer Center, University of Miami.

They commented in a editorial in JAMA Oncology, prompted by a paper describing new results with a novel quadruple combination of therapies. These treatments included the monoclonal antibody elotuzumab (Empliciti) added onto the established backbone of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (known as KRd).

“Regardless of what the future holds for elotuzumab-based combinations, it is clear that the new treatment paradigm of newly diagnosed MM will incorporate antibody-based quadruplet regimens,” the editorialists commented.

“Novel immunotherapies are here to stay,” they added, “as they are already transforming the lives of patients with multiple MM and bringing a bright horizon to the treatment landscape.”
 

Study details

The trial of the novel quadruplet regimen was a multicenter, single-arm, phase 2 study that involved 46 patients with newly diagnosed multiple myeloma, explain first author Benjamin A. Derman, MD, of the University of Chicago Medical Center, and colleagues.

These patients had a median age of 62; more than two-thirds were male (72%) and White (70%). About half (48%) had high-risk cytogenetic abnormalities.

All patients were treated with 12 cycles of the quadruple therapy Elo-KRd regimen. They underwent bone marrow assessment of measurable residual disease (MRD; with 10-5 sensitivity) after cycle 8 and cycle 12.

“An MRD-adapted treatment approach is rational because it may identify which patients can be administered shorter courses of intensive therapy without compromising efficacy,” the authors explained.

Patients who had MRD negativity at both time points did not receive further Elo-KRd, while patients who converted from MRD positivity to negativity in between cycles 8 and 12 received 6 additional cycles of Elo-KRd. Those who remained MRD positive or converted to positivity after 12 cycles received an additional 12 cycles of Elo-KRd.

Following Elo-KRd treatment, all patients transitioned to triple therapy with Elo-Rd (with no carfilzomib), for indefinite maintenance therapy or until disease progression.

For the primary endpoint, the rate of stringent complete response and/or MRD-negativity after cycle 8 was 58% (26 of 45), meeting the predefined definition of efficacy. 

Importantly, 26% of patients converted from MRD positivity after cycle 8 to negativity at a later time point, while 50% of patients reached 1-year sustained MRD negativity.

Overall, the estimated 3-year, progression-free survival was 72%, and the rate was 92% for patients with MRD-negativity at cycle 8. The overall survival rate was 78%.

The most common grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively), and one patient had a grade 5 MI. Three patients discontinued the treatment because of intolerance.

“An MRD-adapted design using elotuzumab and weekly KRd without autologous stem cell transplantation showed a high rate of stringent complete response (sCR) and/or MRD-negativity and durable responses,” the authors wrote.

“This approach provides support for further evaluation of MRD-guided de-escalation of therapy to decrease treatment exposure while sustaining deep responses.”

To better assess the difference of the therapy versus treatment including stem cell transplantation, a phase 3, randomized trial is currently underway to compare the Elo-KRd regimen against KRd with autologous stem cell transplant in newly diagnosed MM.

“If Elo-KRd proves superior, a randomized comparison of Elo versus anti-CD38 mAb-based quadruplets would help determine the optimal combination of therapies in the frontline setting,” the authors noted.
 

Randomized trial anticipated to clarify benefit

In their editorial, Dr. Kazandjian and Dr. Landgren agreed with the authors that the role of elotuzumab needs to be better clarified in a randomized trial setting.

Elotuzumab received FDA approval in 2015 based on results from the ELOQUENT-2 study, which showed improved progression-free survival and overall survival with the addition of elotuzumab to lenalidomide and dexamethasone in patients with multiple myeloma who have previously received one to three other therapies.

However, the editorialists pointed out that recently published results from the randomized ELOQUENT-1 trial of lenalidomide and dexamethasone with and without elotuzumab showed the addition of elotuzumab was not associated with a statistically significant difference in progression-free survival.

The editorialists also pointed out that, in the setting of newly diagnosed multiple myeloma, another recent, similarly designed study found that the backbone regimen of carfilzomib, lenalidomide, and dexamethasone – on its own – was also associated with a favorable MRD-negative rate of 62%.

In addition, several studies involving novel quadruple treatments with the monoclonal antibody daratumumab (Darzalex) instead of elotuzumab, have also shown benefit in newly diagnosed multiple myeloma, resulting in high rates of MRD negativity.

Collectively, the findings bode well for the quadruple regimens in the treatment of MM, the editorialists emphasized.

“Importantly, with the rate of deep remissions observed with antibody-based quadruplet therapies, one may question the role of using early high-dose melphalan and autologous stem cell transplant in every patient, especially in those who have achieved MRD negativity with the quadruplet alone,” they added.

The study was sponsored in part by Amgen, Bristol-Myers Squibb, and the Multiple Myeloma Research Consortium. Dr. Derman reported advisory board fees from Sanofi, Janssen, and COTA Healthcare; honoraria from PleXus Communications and MJH Life Sciences. Dr. Kazandjian declares receiving advisory board or consulting fees from Bristol-Myers Squibb, Sanofi, and Arcellx outside the submitted work. Dr. Landgren has received grant support from numerous organizations and pharmaceutical companies. Dr. Landgren has also received honoraria for scientific talks/participated in advisory boards for Adaptive Biotech, Amgen, Binding Site, Bristol-Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer, and served on independent data monitoring committees for international randomized trials by Takeda, Merck, Janssen, and Theradex.

A version of this article first appeared on Medscape.com.

As a class of drugs, proteasome inhibitors are known to rarely cause drug-induced thrombotic microangiopathy (DITMA). In particular, carfilzomib is a second-generation, irreversible proteasome inhibitor approved for the treatment of relapsed, refractory multiple myeloma (MM) in combination with other therapeutic agents.¹ Although generally well tolerated, carfilzomib has been associated with serious adverse events such as cardiovascular toxicity and DITMA.^2-4 Thrombotic microangiopathy (TMA) is a life-threatening disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and end-organ damage.⁵ Its occurrence secondary to carfilzomib has been reported only rarely in clinical trials of MM, and the most effective management of the disorder as well as the concurrent risk factors that contribute to its development remain incompletely understood.^6,7 As a result, given both the expanding use of carfilzomib in practice and the morbidity of TMA, descriptions of carfilzomib-induced TMA from the real-world setting continue to provide important contributions to our understanding of the disorder.

At our US Department of Veterans Affairs (VA) medical center, 2 patients developed severe carfilzomib-induced TMA within days of one another. The presentation of simultaneous cases was highly unexpected and offered the unique opportunity to compare clinical features in real time. Here, we describe our 2 cases in detail, review their presentations and management in the context of the prior literature, and discuss potential insights gained into the disease.

Case Presentation

Case 1

A 78-year-old male patient was diagnosed with monoclonal gammopathy of undetermined significance in 2012 that progressed to Revised International Staging System stage II IgG-κ MM in 2016 due to worsening anemia with a hemoglobin level < 10 g/dL (Table 1). He was treated initially with 8 cycles of first-line bortezomib, lenalidomide, and dexamethasone, to which he achieved a partial response with > 50% reduction in serum M-protein. He then received 3 cycles of maintenance bortezomib until relapse, at which time he was switched to second-line therapy consisting of carfilzomib 20 mg/m² on days 1 and 2 and 56 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 56 mg/m² on days 1, 2, 8, 9, 15, and 16 for subsequent cycles plus dexamethasone 20 mg twice weekly every 28 days.

After the patient received cycle 3, day 1 of carfilzomib, he developed subjective fevers, chills, and diarrhea. He missed his day 2 infusion and instead presented to the VA emergency department, where his vital signs were stable and laboratory tests were notable for the following levels: leukocytosis of20.3 K/µL (91.7% neutrophils), hemoglobin 12.4 g/dL (prior 13.5 g/dL), platelet count 171 K/µL, and creatinine 1.39 mg/dL (prior 1.13 g/dL). A chest X-ray demonstrated diffuse bilateral opacities concerning for edema vs infection, and he was started empirically on vancomycin, piperacillin-tazobactam, and azithromycin. His outpatient medications, which included acyclovir, aspirin, finasteride, oxybutynin, ranitidine, omega-3 fatty acids, fish oil, vitamin D, and senna, were continued as indicated.

On hospital day 2, the patient’s platelet count dropped to 81 K/µL and creatinine level rose to 1.78 mg/dL. He developed dark urine (urinalysis [UA] 3+ blood, 6-11 red blood cells per high power field [RBC/HPF]) and had laboratory tests suggestive of hemolysis, including lactic dehydrogenase (LDH) > 1,200 IU/L (reference range, 60-250 IU/L), haptoglobin < 30 mg/dL (reference range, 44-215 mg/dL), total bilirubin 3.2 mg/dL (reference range, 0.2-1.3 mg/dL; indirect bilirubin, 2.6 mg/dL), and a peripheral blood smear demonstrating moderate microangiopathy (Figure 1).

Case 2

A 59-year-old male patient, diagnosed in 2013 with ISS stage I IgG-κ MM after presenting with compression fractures, completed 8 cycles of cyclophosphamide, bortezomib, and dexamethasone before undergoing autologous hematopoietic stem cell transplantation with complete response (Table 1). He subsequently received single-agent maintenance bortezomib until relapse nearly 2 years later, at which time he started second-line carfilzomib 20 mg/m² on days 1 and 2 and 27 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 27 mg/m² on days 8, 9, 15, and 16 for cycles 2 to 8, lenalidomide 25 mg on days 1 to 21, and dexamethasone 40 mg weekly every 28 days. Serum free light chain levels normalized after 9 cycles, and he subsequently began maintenance carfilzomib 70 mg/m² on days 1 and 15 plus lenalidomide 10 mg on days 1 to 21 every 28 days.

On the morning before admission, the patient received C6D17 of maintenance carfilzomib, which had been delayed from day 15 because of the holiday. Later that evening, he developed nausea, vomiting, and fever of 101.3 °F. He presented to the VA emergency department and was tachycardic (108 beats per minute) and hypotensive (86/55 mm Hg). Laboratory tests were notable for hemoglobin level 9.9 g/dL (prior 11.6 g/dL), platelet count 270 K/µL, and creatinine level 1.86 mg/dL (prior 1.12 mg/dL). A respiratory viral panel was positive for influenza A, and antimicrobial agents were eventually broadened to piperacillin-tazobactam, azithromycin, and oseltamivir. His outpatient medications, which included acyclovir, zoledronic acid, sulfamethoxazole/trimethoprim, aspirin, amlodipine, atorvastatin, omeprazole, zolpidem, calcium, vitamin D, loratadine, ascorbic acid, and prochlorperazine, were continued as indicated.

On hospital day 2, the patient’s platelet count declined from 211 to 57 K/µL. He developed tea-colored urine (UA 2+ blood, 0-2 RBC/HPF) and had laboratory tests suggestive of hemolysis, including LDH 910 IU/L (reference range, 60-250 IU/L), total bilirubin 3.3 mg/dL (reference range, 0.2-1.3 mg/dL; no direct or indirect available), and a peripheral blood smear demonstrating moderate microangiopathy. Although haptoglobin level was normal at this time (206 mg/dL; reference range, 44-215 mg/dL), it decreased to 42 mg/dL by the following day. Additional workup included a negative direct Coombs and a DIC panel showing elevated fibrinogen (596 mg/dL; reference range, 200-400 mg/dL) and mildly elevated INR (1.16). Blood cultures remained negative, and a 22-pathogen GI PCR panel identified no viral or bacterial pathogens, including E coli O157:H7. C3 (114 mg/dL; reference range, 90-180 mg/dL) and C4 (40 mg/dL; reference range, 16-47 mg/dL) complement levels were both normal.

Based on these findings, empiric treatment was started with plasma exchange and pulse-dosed steroids. The patient received 3 cycles of plasma exchange until the results of the ADAMTS13 activity ruled out TTP (63% enzyme activity). Over the next 6 days, his platelet count reached a nadir of 6 K/µL and creatinine level peaked at 10.36 mg/dL, necessitating the initiation of hemodialysis. Given severe renal insufficiency, a diagnosis of atypical HUS was again considered, and eculizumab 900 mg was administered on days 9 and 16 with stabilization of renal function. By the time of discharge on day 17, the patient’s creatinine level had decreased to 4.17 mg/dL and platelet count was 164 K/µL. Creatinine level normalized to 1.02 mg/dL by day 72.

Outpatient genetic testing through the BloodCenter of Wisconsin Diagnostic Laboratories was negative for gene mutations associated with atypical HUS. Approximately 1 month after discharge, the patient resumed maintenance lenalidomide alone without reinitiation of proteasome inhibitor therapy.

Discussion

In this case series, we describe the uncommon drug-related adverse event of TMA occurring in 2 patients with MM after receiving carfilzomib. Although the incidence of TMA disorders is low, reaching up to 2.8% in patients receiving carfilzomib plus cyclophosphamide and dexamethasone in the phase 2 CARDAMON trial, our experience suggests that a high index of suspicion for carfilzomib-induced TMA is warranted in the real-world setting.⁸ TMA syndromes, including TTP, HUS, and DITMA, are characterized by microvascular endothelial injury and thrombosis leading to thrombocytopenia and microangiopathic hemolytic anemia.^5,9 Several drug culprits of DITMA are recognized, including quinine, gemcitabine, tacrolimus, and proteasome inhibitors (bortezomib, carfilzomib, ixazomib).^10-12 In a real-world series of patients receiving proteasome inhibitor therapy, either carfilzomib (n=8) or bortezomib (n=3), common clinical features of DITMA included thrombocytopenia, microangiopathic hemolytic anemia, gastrointestinal symptoms, and renal insufficiency with or without a need for hemodialysis.² Although DITMA has been described primarily as an early event, its occurrence after 12 months of proteasome inhibitor therapy has also been reported, both in this series and elsewhere, thereby suggesting an ongoing risk for DITMA throughout the duration of carfilzomib treatment.^2,13

The diagnosis of DITMA can be challenging given its nonspecific symptoms that overlap with other TMA syndromes. Previous studies have proposed that for a drug to be associated with DITMA, there should be: (1) evidence of clinical and/or pathologic findings of TMA; (2) exclusion of alternative causes of TMA; (3) no other new drug exposures other than the suspected culprit medication; and (4) a lack of recurrence of TMA in absence of the drug.¹⁰ In the case of patients with MM, other causes of TMA have also been described, including the underlying plasma cell disorder itself and stem cell transplantation.¹⁴ In the 2 cases we have described, these alternative causes were considered unlikely given that only 1 patient underwent transplantation remotely and neither had a previous history of TMA secondary to their disease. With respect to other TMA syndromes, ADAMTS13 levels > 10% and negative stool studies for E coli O157:H7 suggested against TTP or typical HUS, respectively. No other drug culprits were identified, and the close timing between the receipt of carfilzomib and symptom onset supported a causal relationship.

Because specific therapies are lacking, management of DITMA has traditionally included drug discontinuation and supportive care for end-organ injury.⁵ The terminal complement inhibitor, eculizumab, improves hematologic abnormalities and renal function in patients with atypical HUS but its use for treating patients with DITMA is not standard.¹⁵ Therefore, the decision to administer eculizumab to our 2 patients was driven by their severe renal insufficiency without improvement after plasma exchange, which suggested a phenotype similar to atypical HUS. After administration of eculizumab, renal function stabilized and then gradually improved over weeks to months, a time course similar to that described in cases of patients with DITMA secondary to other anticancer therapies treated with eculizumab.¹⁶ Although these results suggest a potential role for eculizumab in proteasome inhibitor–induced TMA, distinguishing the benefit of eculizumab over drug discontinuation alone remains challenging, and well-designed prospective investigations are needed.

Conclusions

DITMA is a known risk of proteasome inhibitors and is listed as a safety warning in the prescribing information for bortezomib, carfilzomib, and ixazomib.¹² Given the overall rarity of this adverse event, the simultaneous presentation of our 2 cases was unexpected and underscores the need for heightened awareness in clinical practice. In addition, while no underlying complement mutations were identified, eculizumab was used in both cases to successfully stabilize renal function. Further research investigating the efficacy of eculizumab and the role of complement activation in proteasome inhibitor–induced TMA will be valuable.

Acknowledgments

The authors would like to thank the patients whose histories are reported in this manuscript as well as the physicians and staff who provided care during the hospitalizations and beyond. We also thank Oscar Silva, MD, PhD, for his assistance in reviewing and formatting the peripheral blood smear images.

As a class of drugs, proteasome inhibitors are known to rarely cause drug-induced thrombotic microangiopathy (DITMA). In particular, carfilzomib is a second-generation, irreversible proteasome inhibitor approved for the treatment of relapsed, refractory multiple myeloma (MM) in combination with other therapeutic agents.¹ Although generally well tolerated, carfilzomib has been associated with serious adverse events such as cardiovascular toxicity and DITMA.^2-4 Thrombotic microangiopathy (TMA) is a life-threatening disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and end-organ damage.⁵ Its occurrence secondary to carfilzomib has been reported only rarely in clinical trials of MM, and the most effective management of the disorder as well as the concurrent risk factors that contribute to its development remain incompletely understood.^6,7 As a result, given both the expanding use of carfilzomib in practice and the morbidity of TMA, descriptions of carfilzomib-induced TMA from the real-world setting continue to provide important contributions to our understanding of the disorder.

At our US Department of Veterans Affairs (VA) medical center, 2 patients developed severe carfilzomib-induced TMA within days of one another. The presentation of simultaneous cases was highly unexpected and offered the unique opportunity to compare clinical features in real time. Here, we describe our 2 cases in detail, review their presentations and management in the context of the prior literature, and discuss potential insights gained into the disease.

Case Presentation

Case 1

A 78-year-old male patient was diagnosed with monoclonal gammopathy of undetermined significance in 2012 that progressed to Revised International Staging System stage II IgG-κ MM in 2016 due to worsening anemia with a hemoglobin level < 10 g/dL (Table 1). He was treated initially with 8 cycles of first-line bortezomib, lenalidomide, and dexamethasone, to which he achieved a partial response with > 50% reduction in serum M-protein. He then received 3 cycles of maintenance bortezomib until relapse, at which time he was switched to second-line therapy consisting of carfilzomib 20 mg/m² on days 1 and 2 and 56 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 56 mg/m² on days 1, 2, 8, 9, 15, and 16 for subsequent cycles plus dexamethasone 20 mg twice weekly every 28 days.

After the patient received cycle 3, day 1 of carfilzomib, he developed subjective fevers, chills, and diarrhea. He missed his day 2 infusion and instead presented to the VA emergency department, where his vital signs were stable and laboratory tests were notable for the following levels: leukocytosis of20.3 K/µL (91.7% neutrophils), hemoglobin 12.4 g/dL (prior 13.5 g/dL), platelet count 171 K/µL, and creatinine 1.39 mg/dL (prior 1.13 g/dL). A chest X-ray demonstrated diffuse bilateral opacities concerning for edema vs infection, and he was started empirically on vancomycin, piperacillin-tazobactam, and azithromycin. His outpatient medications, which included acyclovir, aspirin, finasteride, oxybutynin, ranitidine, omega-3 fatty acids, fish oil, vitamin D, and senna, were continued as indicated.

On hospital day 2, the patient’s platelet count dropped to 81 K/µL and creatinine level rose to 1.78 mg/dL. He developed dark urine (urinalysis [UA] 3+ blood, 6-11 red blood cells per high power field [RBC/HPF]) and had laboratory tests suggestive of hemolysis, including lactic dehydrogenase (LDH) > 1,200 IU/L (reference range, 60-250 IU/L), haptoglobin < 30 mg/dL (reference range, 44-215 mg/dL), total bilirubin 3.2 mg/dL (reference range, 0.2-1.3 mg/dL; indirect bilirubin, 2.6 mg/dL), and a peripheral blood smear demonstrating moderate microangiopathy (Figure 1).

Case 2

A 59-year-old male patient, diagnosed in 2013 with ISS stage I IgG-κ MM after presenting with compression fractures, completed 8 cycles of cyclophosphamide, bortezomib, and dexamethasone before undergoing autologous hematopoietic stem cell transplantation with complete response (Table 1). He subsequently received single-agent maintenance bortezomib until relapse nearly 2 years later, at which time he started second-line carfilzomib 20 mg/m² on days 1 and 2 and 27 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 27 mg/m² on days 8, 9, 15, and 16 for cycles 2 to 8, lenalidomide 25 mg on days 1 to 21, and dexamethasone 40 mg weekly every 28 days. Serum free light chain levels normalized after 9 cycles, and he subsequently began maintenance carfilzomib 70 mg/m² on days 1 and 15 plus lenalidomide 10 mg on days 1 to 21 every 28 days.

On the morning before admission, the patient received C6D17 of maintenance carfilzomib, which had been delayed from day 15 because of the holiday. Later that evening, he developed nausea, vomiting, and fever of 101.3 °F. He presented to the VA emergency department and was tachycardic (108 beats per minute) and hypotensive (86/55 mm Hg). Laboratory tests were notable for hemoglobin level 9.9 g/dL (prior 11.6 g/dL), platelet count 270 K/µL, and creatinine level 1.86 mg/dL (prior 1.12 mg/dL). A respiratory viral panel was positive for influenza A, and antimicrobial agents were eventually broadened to piperacillin-tazobactam, azithromycin, and oseltamivir. His outpatient medications, which included acyclovir, zoledronic acid, sulfamethoxazole/trimethoprim, aspirin, amlodipine, atorvastatin, omeprazole, zolpidem, calcium, vitamin D, loratadine, ascorbic acid, and prochlorperazine, were continued as indicated.

On hospital day 2, the patient’s platelet count declined from 211 to 57 K/µL. He developed tea-colored urine (UA 2+ blood, 0-2 RBC/HPF) and had laboratory tests suggestive of hemolysis, including LDH 910 IU/L (reference range, 60-250 IU/L), total bilirubin 3.3 mg/dL (reference range, 0.2-1.3 mg/dL; no direct or indirect available), and a peripheral blood smear demonstrating moderate microangiopathy. Although haptoglobin level was normal at this time (206 mg/dL; reference range, 44-215 mg/dL), it decreased to 42 mg/dL by the following day. Additional workup included a negative direct Coombs and a DIC panel showing elevated fibrinogen (596 mg/dL; reference range, 200-400 mg/dL) and mildly elevated INR (1.16). Blood cultures remained negative, and a 22-pathogen GI PCR panel identified no viral or bacterial pathogens, including E coli O157:H7. C3 (114 mg/dL; reference range, 90-180 mg/dL) and C4 (40 mg/dL; reference range, 16-47 mg/dL) complement levels were both normal.

Based on these findings, empiric treatment was started with plasma exchange and pulse-dosed steroids. The patient received 3 cycles of plasma exchange until the results of the ADAMTS13 activity ruled out TTP (63% enzyme activity). Over the next 6 days, his platelet count reached a nadir of 6 K/µL and creatinine level peaked at 10.36 mg/dL, necessitating the initiation of hemodialysis. Given severe renal insufficiency, a diagnosis of atypical HUS was again considered, and eculizumab 900 mg was administered on days 9 and 16 with stabilization of renal function. By the time of discharge on day 17, the patient’s creatinine level had decreased to 4.17 mg/dL and platelet count was 164 K/µL. Creatinine level normalized to 1.02 mg/dL by day 72.

Outpatient genetic testing through the BloodCenter of Wisconsin Diagnostic Laboratories was negative for gene mutations associated with atypical HUS. Approximately 1 month after discharge, the patient resumed maintenance lenalidomide alone without reinitiation of proteasome inhibitor therapy.

Discussion

In this case series, we describe the uncommon drug-related adverse event of TMA occurring in 2 patients with MM after receiving carfilzomib. Although the incidence of TMA disorders is low, reaching up to 2.8% in patients receiving carfilzomib plus cyclophosphamide and dexamethasone in the phase 2 CARDAMON trial, our experience suggests that a high index of suspicion for carfilzomib-induced TMA is warranted in the real-world setting.⁸ TMA syndromes, including TTP, HUS, and DITMA, are characterized by microvascular endothelial injury and thrombosis leading to thrombocytopenia and microangiopathic hemolytic anemia.^5,9 Several drug culprits of DITMA are recognized, including quinine, gemcitabine, tacrolimus, and proteasome inhibitors (bortezomib, carfilzomib, ixazomib).^10-12 In a real-world series of patients receiving proteasome inhibitor therapy, either carfilzomib (n=8) or bortezomib (n=3), common clinical features of DITMA included thrombocytopenia, microangiopathic hemolytic anemia, gastrointestinal symptoms, and renal insufficiency with or without a need for hemodialysis.² Although DITMA has been described primarily as an early event, its occurrence after 12 months of proteasome inhibitor therapy has also been reported, both in this series and elsewhere, thereby suggesting an ongoing risk for DITMA throughout the duration of carfilzomib treatment.^2,13

The diagnosis of DITMA can be challenging given its nonspecific symptoms that overlap with other TMA syndromes. Previous studies have proposed that for a drug to be associated with DITMA, there should be: (1) evidence of clinical and/or pathologic findings of TMA; (2) exclusion of alternative causes of TMA; (3) no other new drug exposures other than the suspected culprit medication; and (4) a lack of recurrence of TMA in absence of the drug.¹⁰ In the case of patients with MM, other causes of TMA have also been described, including the underlying plasma cell disorder itself and stem cell transplantation.¹⁴ In the 2 cases we have described, these alternative causes were considered unlikely given that only 1 patient underwent transplantation remotely and neither had a previous history of TMA secondary to their disease. With respect to other TMA syndromes, ADAMTS13 levels > 10% and negative stool studies for E coli O157:H7 suggested against TTP or typical HUS, respectively. No other drug culprits were identified, and the close timing between the receipt of carfilzomib and symptom onset supported a causal relationship.

Because specific therapies are lacking, management of DITMA has traditionally included drug discontinuation and supportive care for end-organ injury.⁵ The terminal complement inhibitor, eculizumab, improves hematologic abnormalities and renal function in patients with atypical HUS but its use for treating patients with DITMA is not standard.¹⁵ Therefore, the decision to administer eculizumab to our 2 patients was driven by their severe renal insufficiency without improvement after plasma exchange, which suggested a phenotype similar to atypical HUS. After administration of eculizumab, renal function stabilized and then gradually improved over weeks to months, a time course similar to that described in cases of patients with DITMA secondary to other anticancer therapies treated with eculizumab.¹⁶ Although these results suggest a potential role for eculizumab in proteasome inhibitor–induced TMA, distinguishing the benefit of eculizumab over drug discontinuation alone remains challenging, and well-designed prospective investigations are needed.

Conclusions

DITMA is a known risk of proteasome inhibitors and is listed as a safety warning in the prescribing information for bortezomib, carfilzomib, and ixazomib.¹² Given the overall rarity of this adverse event, the simultaneous presentation of our 2 cases was unexpected and underscores the need for heightened awareness in clinical practice. In addition, while no underlying complement mutations were identified, eculizumab was used in both cases to successfully stabilize renal function. Further research investigating the efficacy of eculizumab and the role of complement activation in proteasome inhibitor–induced TMA will be valuable.

Acknowledgments

The authors would like to thank the patients whose histories are reported in this manuscript as well as the physicians and staff who provided care during the hospitalizations and beyond. We also thank Oscar Silva, MD, PhD, for his assistance in reviewing and formatting the peripheral blood smear images.

As a class of drugs, proteasome inhibitors are known to rarely cause drug-induced thrombotic microangiopathy (DITMA). In particular, carfilzomib is a second-generation, irreversible proteasome inhibitor approved for the treatment of relapsed, refractory multiple myeloma (MM) in combination with other therapeutic agents.¹ Although generally well tolerated, carfilzomib has been associated with serious adverse events such as cardiovascular toxicity and DITMA.^2-4 Thrombotic microangiopathy (TMA) is a life-threatening disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and end-organ damage.⁵ Its occurrence secondary to carfilzomib has been reported only rarely in clinical trials of MM, and the most effective management of the disorder as well as the concurrent risk factors that contribute to its development remain incompletely understood.^6,7 As a result, given both the expanding use of carfilzomib in practice and the morbidity of TMA, descriptions of carfilzomib-induced TMA from the real-world setting continue to provide important contributions to our understanding of the disorder.

At our US Department of Veterans Affairs (VA) medical center, 2 patients developed severe carfilzomib-induced TMA within days of one another. The presentation of simultaneous cases was highly unexpected and offered the unique opportunity to compare clinical features in real time. Here, we describe our 2 cases in detail, review their presentations and management in the context of the prior literature, and discuss potential insights gained into the disease.

Case Presentation

Case 1

A 78-year-old male patient was diagnosed with monoclonal gammopathy of undetermined significance in 2012 that progressed to Revised International Staging System stage II IgG-κ MM in 2016 due to worsening anemia with a hemoglobin level < 10 g/dL (Table 1). He was treated initially with 8 cycles of first-line bortezomib, lenalidomide, and dexamethasone, to which he achieved a partial response with > 50% reduction in serum M-protein. He then received 3 cycles of maintenance bortezomib until relapse, at which time he was switched to second-line therapy consisting of carfilzomib 20 mg/m² on days 1 and 2 and 56 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 56 mg/m² on days 1, 2, 8, 9, 15, and 16 for subsequent cycles plus dexamethasone 20 mg twice weekly every 28 days.

After the patient received cycle 3, day 1 of carfilzomib, he developed subjective fevers, chills, and diarrhea. He missed his day 2 infusion and instead presented to the VA emergency department, where his vital signs were stable and laboratory tests were notable for the following levels: leukocytosis of20.3 K/µL (91.7% neutrophils), hemoglobin 12.4 g/dL (prior 13.5 g/dL), platelet count 171 K/µL, and creatinine 1.39 mg/dL (prior 1.13 g/dL). A chest X-ray demonstrated diffuse bilateral opacities concerning for edema vs infection, and he was started empirically on vancomycin, piperacillin-tazobactam, and azithromycin. His outpatient medications, which included acyclovir, aspirin, finasteride, oxybutynin, ranitidine, omega-3 fatty acids, fish oil, vitamin D, and senna, were continued as indicated.

On hospital day 2, the patient’s platelet count dropped to 81 K/µL and creatinine level rose to 1.78 mg/dL. He developed dark urine (urinalysis [UA] 3+ blood, 6-11 red blood cells per high power field [RBC/HPF]) and had laboratory tests suggestive of hemolysis, including lactic dehydrogenase (LDH) > 1,200 IU/L (reference range, 60-250 IU/L), haptoglobin < 30 mg/dL (reference range, 44-215 mg/dL), total bilirubin 3.2 mg/dL (reference range, 0.2-1.3 mg/dL; indirect bilirubin, 2.6 mg/dL), and a peripheral blood smear demonstrating moderate microangiopathy (Figure 1).

Case 2

A 59-year-old male patient, diagnosed in 2013 with ISS stage I IgG-κ MM after presenting with compression fractures, completed 8 cycles of cyclophosphamide, bortezomib, and dexamethasone before undergoing autologous hematopoietic stem cell transplantation with complete response (Table 1). He subsequently received single-agent maintenance bortezomib until relapse nearly 2 years later, at which time he started second-line carfilzomib 20 mg/m² on days 1 and 2 and 27 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 27 mg/m² on days 8, 9, 15, and 16 for cycles 2 to 8, lenalidomide 25 mg on days 1 to 21, and dexamethasone 40 mg weekly every 28 days. Serum free light chain levels normalized after 9 cycles, and he subsequently began maintenance carfilzomib 70 mg/m² on days 1 and 15 plus lenalidomide 10 mg on days 1 to 21 every 28 days.

On the morning before admission, the patient received C6D17 of maintenance carfilzomib, which had been delayed from day 15 because of the holiday. Later that evening, he developed nausea, vomiting, and fever of 101.3 °F. He presented to the VA emergency department and was tachycardic (108 beats per minute) and hypotensive (86/55 mm Hg). Laboratory tests were notable for hemoglobin level 9.9 g/dL (prior 11.6 g/dL), platelet count 270 K/µL, and creatinine level 1.86 mg/dL (prior 1.12 mg/dL). A respiratory viral panel was positive for influenza A, and antimicrobial agents were eventually broadened to piperacillin-tazobactam, azithromycin, and oseltamivir. His outpatient medications, which included acyclovir, zoledronic acid, sulfamethoxazole/trimethoprim, aspirin, amlodipine, atorvastatin, omeprazole, zolpidem, calcium, vitamin D, loratadine, ascorbic acid, and prochlorperazine, were continued as indicated.

On hospital day 2, the patient’s platelet count declined from 211 to 57 K/µL. He developed tea-colored urine (UA 2+ blood, 0-2 RBC/HPF) and had laboratory tests suggestive of hemolysis, including LDH 910 IU/L (reference range, 60-250 IU/L), total bilirubin 3.3 mg/dL (reference range, 0.2-1.3 mg/dL; no direct or indirect available), and a peripheral blood smear demonstrating moderate microangiopathy. Although haptoglobin level was normal at this time (206 mg/dL; reference range, 44-215 mg/dL), it decreased to 42 mg/dL by the following day. Additional workup included a negative direct Coombs and a DIC panel showing elevated fibrinogen (596 mg/dL; reference range, 200-400 mg/dL) and mildly elevated INR (1.16). Blood cultures remained negative, and a 22-pathogen GI PCR panel identified no viral or bacterial pathogens, including E coli O157:H7. C3 (114 mg/dL; reference range, 90-180 mg/dL) and C4 (40 mg/dL; reference range, 16-47 mg/dL) complement levels were both normal.

Based on these findings, empiric treatment was started with plasma exchange and pulse-dosed steroids. The patient received 3 cycles of plasma exchange until the results of the ADAMTS13 activity ruled out TTP (63% enzyme activity). Over the next 6 days, his platelet count reached a nadir of 6 K/µL and creatinine level peaked at 10.36 mg/dL, necessitating the initiation of hemodialysis. Given severe renal insufficiency, a diagnosis of atypical HUS was again considered, and eculizumab 900 mg was administered on days 9 and 16 with stabilization of renal function. By the time of discharge on day 17, the patient’s creatinine level had decreased to 4.17 mg/dL and platelet count was 164 K/µL. Creatinine level normalized to 1.02 mg/dL by day 72.

Outpatient genetic testing through the BloodCenter of Wisconsin Diagnostic Laboratories was negative for gene mutations associated with atypical HUS. Approximately 1 month after discharge, the patient resumed maintenance lenalidomide alone without reinitiation of proteasome inhibitor therapy.

Discussion

In this case series, we describe the uncommon drug-related adverse event of TMA occurring in 2 patients with MM after receiving carfilzomib. Although the incidence of TMA disorders is low, reaching up to 2.8% in patients receiving carfilzomib plus cyclophosphamide and dexamethasone in the phase 2 CARDAMON trial, our experience suggests that a high index of suspicion for carfilzomib-induced TMA is warranted in the real-world setting.⁸ TMA syndromes, including TTP, HUS, and DITMA, are characterized by microvascular endothelial injury and thrombosis leading to thrombocytopenia and microangiopathic hemolytic anemia.^5,9 Several drug culprits of DITMA are recognized, including quinine, gemcitabine, tacrolimus, and proteasome inhibitors (bortezomib, carfilzomib, ixazomib).^10-12 In a real-world series of patients receiving proteasome inhibitor therapy, either carfilzomib (n=8) or bortezomib (n=3), common clinical features of DITMA included thrombocytopenia, microangiopathic hemolytic anemia, gastrointestinal symptoms, and renal insufficiency with or without a need for hemodialysis.² Although DITMA has been described primarily as an early event, its occurrence after 12 months of proteasome inhibitor therapy has also been reported, both in this series and elsewhere, thereby suggesting an ongoing risk for DITMA throughout the duration of carfilzomib treatment.^2,13

The diagnosis of DITMA can be challenging given its nonspecific symptoms that overlap with other TMA syndromes. Previous studies have proposed that for a drug to be associated with DITMA, there should be: (1) evidence of clinical and/or pathologic findings of TMA; (2) exclusion of alternative causes of TMA; (3) no other new drug exposures other than the suspected culprit medication; and (4) a lack of recurrence of TMA in absence of the drug.¹⁰ In the case of patients with MM, other causes of TMA have also been described, including the underlying plasma cell disorder itself and stem cell transplantation.¹⁴ In the 2 cases we have described, these alternative causes were considered unlikely given that only 1 patient underwent transplantation remotely and neither had a previous history of TMA secondary to their disease. With respect to other TMA syndromes, ADAMTS13 levels > 10% and negative stool studies for E coli O157:H7 suggested against TTP or typical HUS, respectively. No other drug culprits were identified, and the close timing between the receipt of carfilzomib and symptom onset supported a causal relationship.

Because specific therapies are lacking, management of DITMA has traditionally included drug discontinuation and supportive care for end-organ injury.⁵ The terminal complement inhibitor, eculizumab, improves hematologic abnormalities and renal function in patients with atypical HUS but its use for treating patients with DITMA is not standard.¹⁵ Therefore, the decision to administer eculizumab to our 2 patients was driven by their severe renal insufficiency without improvement after plasma exchange, which suggested a phenotype similar to atypical HUS. After administration of eculizumab, renal function stabilized and then gradually improved over weeks to months, a time course similar to that described in cases of patients with DITMA secondary to other anticancer therapies treated with eculizumab.¹⁶ Although these results suggest a potential role for eculizumab in proteasome inhibitor–induced TMA, distinguishing the benefit of eculizumab over drug discontinuation alone remains challenging, and well-designed prospective investigations are needed.

Conclusions

DITMA is a known risk of proteasome inhibitors and is listed as a safety warning in the prescribing information for bortezomib, carfilzomib, and ixazomib.¹² Given the overall rarity of this adverse event, the simultaneous presentation of our 2 cases was unexpected and underscores the need for heightened awareness in clinical practice. In addition, while no underlying complement mutations were identified, eculizumab was used in both cases to successfully stabilize renal function. Further research investigating the efficacy of eculizumab and the role of complement activation in proteasome inhibitor–induced TMA will be valuable.

Acknowledgments

The authors would like to thank the patients whose histories are reported in this manuscript as well as the physicians and staff who provided care during the hospitalizations and beyond. We also thank Oscar Silva, MD, PhD, for his assistance in reviewing and formatting the peripheral blood smear images.

There is not enough evidence to recommend for or against taking most vitamin and mineral supplements to prevent heart disease, stroke, and cancer, a new report by the U.S. Preventive Services Task Force concludes.

However, there are two vitamins – vitamin E and beta-carotene – that the task force recommends against for the prevention of heart disease, stroke, and cancer. Evidence shows that there is no benefit to taking vitamin E and that beta-carotene can increase the risk for lung cancer in people already at risk, such as smokers and those with occupational exposure to asbestos.

sodapix/thinkstockphotos.com

These are the main findings of the USPSTF’s final recommendation statement on vitamin, mineral, and multivitamin supplementation to prevent cardiovascular disease and cancer. The statement was published in JAMA.

“This is essentially the same recommendation that the task force made in 2014,” USPSTF member John Wong, MD, professor of medicine at Tufts University, Boston, said in an interview.

“We recognize that over half of people in the U.S. take a vitamin supplement of some sort every day and 30% take a vitamin/mineral combination. We wanted to review the evidence again to see if there was any benefit in terms of reducing the risk of cardiovascular disease or cancer or increasing the chances of living longer,” Dr. Wong explained.

“We looked hard for evidence, reviewing 84 studies in total. But we did not find sufficient evidence in favor of taking or not taking vitamins, with the two exceptions of beta-carotene and vitamin E, which we recommend against taking,” he noted.

Although there is evidence of some harm with beta-carotene, the main reason behind the recommendation against taking vitamin E is the consistent evidence of no benefit, Dr. Wong explained.

“While the evidence for some other vitamins is conflicting, there is more consistent evidence of no benefit for vitamin E,” he said.

The bulk of new evidence since the last review in 2014 was predominately for vitamin D supplementation, but despite the inclusion of 32 new randomized, controlled trials and two cohort studies, pooled estimates for all-cause mortality were similar to those in the previous review, with confidence intervals only slightly crossing 1, and point estimates that suggest at most a very small benefit, the task force noted.

“Apart from beta-carotene and vitamin E, after reviewing 84 studies – including 78 randomized controlled trials – in over a million patients, we can find no clear demonstration of benefit or harm of taking vitamins in terms of developing cardiovascular disease or cancer or the effect on all-cause mortality. So, we don’t know whether people should take vitamins or not, and we need more research,” Dr. Wong added.

On the use of a multivitamin supplement, Dr. Wong noted that the complete body of evidence did not find any benefit of taking a multivitamin on cardiovascular or cancer mortality. But there was a small reduction in cancer incidence.

However, he pointed out that the three studies that suggested a reduction in cancer incidence all had issues regarding generalizability.

“The recently published COSMOS trial had an average follow-up of only 3.6 years, which isn’t really long enough when thinking about the prevention of cancer, one of the other studies only used antioxidants, and the third study was conducted only in U.S. male physicians. So those limitations regarding generalizability limited our confidence in making recommendations about multivitamins,” Dr. Wong explained.

But he noted that the task force did not find any significant harms from taking multivitamins.

“There are possible harms from taking high doses of vitamin A and vitamin D, but generally the doses contained in a multivitamin tablet are lower than these. But if the goal for taking a multivitamin is to lower your risk of cancer or cardiovascular disease, we didn’t find sufficient evidence to be able to make a recommendation,” he said.

Asked what he would say to all the people currently taking multivitamins, Dr. Wong responded that he would advise them to have a conversation with a trusted health care professional about their particular circumstances.

“Our statement has quite a narrow focus. It is directed toward community-dwelling, nonpregnant adults. This recommendation does not apply to children, persons who are pregnant or may become pregnant, or persons who are chronically ill, are hospitalized, or have a known nutritional deficiency,” he commented.
 

‘Any benefit likely to be small’

In an editorial accompanying the publication of the USPSTF statement, Jenny Jia, MD; Natalie Cameron, MD; and Jeffrey Linder, MD – all from Northwestern University, Chicago – noted that the current evidence base includes 52 additional studies not available when the last USPSTF recommendation on this topic was published in 2014.

The editorialists pointed out that for multivitamins, proving the absence of a benefit is challenging, but at best, current evidence suggests that any potential benefits of a multivitamin to reduce mortality are likely to be small.

They gave an example of a healthy 65-year-old woman with a 9-year estimated mortality risk of about 8%, and note that taking a multivitamin for 5-10 years might reduce her estimated mortality risk to 7.5% (based on an odds ratio of 0.94).

“In addition to showing small potential benefit, this estimate is based on imperfect evidence, is imprecise, and is highly sensitive to how the data are interpreted and analyzed,” they said.

The editorialists recommended that lifestyle counseling to prevent chronic diseases should continue to focus on evidence-based approaches, including balanced diets that are high in fruits and vegetables and physical activity.

However, they added that healthy eating can be a challenge when the American industrialized food system does not prioritize health, and healthy foods tend to be more expensive, leading to access problems and food insecurity.

The editorialists suggested that, rather than focusing money, time, and attention on supplements, it would be better to emphasize lower-risk, higher-benefit activities, such as getting exercise, maintaining a healthy weight, and avoiding smoking, in addition to following a healthful diet.
 

Possible benefit for older adults?

Commenting on the USPSTF statement, JoAnn Manson, MD, chief, division of preventive medicine, Brigham and Women’s Hospital, Boston, who led the recent COSMOS study, said that vitamin and mineral supplements should not be perceived as a substitute for a healthful diet.

“The emphasis needs to be on getting nutritional needs from a healthy diet that is high in plant-based and whole foods that don’t strip the vitamins and minerals through excessive processing,” she said. “Although it’s easier to pop a pill each day than to focus on healthful dietary patterns, the mixture of phytochemicals, fiber, and all the other nutrients in actual foods just can’t be packaged into a pill. Also, vitamins and minerals tend to be better absorbed from food than from supplements and healthy foods can replace calories from less healthy foods, such as red meat and processed foods.”

However, Dr. Manson noted that the evidence is mounting that taking a tablet containing moderate doses of a wide range of vitamins and minerals is safe and may actually have benefits for some people.

She pointed out that the COSMOS and COSMOS-Mind studies showed benefits of multivitamins in slowing cognitive decline in older adults, but the findings need to be replicated.  

“The USPSTF did see a statistically significant 7% reduction in cancer with multivitamins in their meta-analysis of four randomized trials and a borderline 6% reduction in all-cause mortality,” she noted. “Plus, multivitamins have been shown to be quite safe in several large and long-term randomized trials. I agree the evidence is not sufficient to make a blanket recommendation for everyone to take multivitamins, but the evidence is mounting that this would be a prudent approach for many older adults,” Dr. Manson said.

“Many people view multivitamins as a form of insurance, as a way to hedge their bets,” she added. “Although this is a rational approach, especially for those who have concerns about the adequacy of their diet, it’s important that this mindset not lead to complacency about following healthy lifestyle practices, including healthy eating, regular physical activity, not smoking, making sure that blood pressure and cholesterol levels are well controlled, and many other practices that critically important for health but are more challenging than simply popping a pill each day.”

A version of this article first appeared on Medscape.com.

There is not enough evidence to recommend for or against taking most vitamin and mineral supplements to prevent heart disease, stroke, and cancer, a new report by the U.S. Preventive Services Task Force concludes.

However, there are two vitamins – vitamin E and beta-carotene – that the task force recommends against for the prevention of heart disease, stroke, and cancer. Evidence shows that there is no benefit to taking vitamin E and that beta-carotene can increase the risk for lung cancer in people already at risk, such as smokers and those with occupational exposure to asbestos.

sodapix/thinkstockphotos.com

These are the main findings of the USPSTF’s final recommendation statement on vitamin, mineral, and multivitamin supplementation to prevent cardiovascular disease and cancer. The statement was published in JAMA.

“This is essentially the same recommendation that the task force made in 2014,” USPSTF member John Wong, MD, professor of medicine at Tufts University, Boston, said in an interview.

“We recognize that over half of people in the U.S. take a vitamin supplement of some sort every day and 30% take a vitamin/mineral combination. We wanted to review the evidence again to see if there was any benefit in terms of reducing the risk of cardiovascular disease or cancer or increasing the chances of living longer,” Dr. Wong explained.

“We looked hard for evidence, reviewing 84 studies in total. But we did not find sufficient evidence in favor of taking or not taking vitamins, with the two exceptions of beta-carotene and vitamin E, which we recommend against taking,” he noted.

Although there is evidence of some harm with beta-carotene, the main reason behind the recommendation against taking vitamin E is the consistent evidence of no benefit, Dr. Wong explained.

“While the evidence for some other vitamins is conflicting, there is more consistent evidence of no benefit for vitamin E,” he said.

The bulk of new evidence since the last review in 2014 was predominately for vitamin D supplementation, but despite the inclusion of 32 new randomized, controlled trials and two cohort studies, pooled estimates for all-cause mortality were similar to those in the previous review, with confidence intervals only slightly crossing 1, and point estimates that suggest at most a very small benefit, the task force noted.

“Apart from beta-carotene and vitamin E, after reviewing 84 studies – including 78 randomized controlled trials – in over a million patients, we can find no clear demonstration of benefit or harm of taking vitamins in terms of developing cardiovascular disease or cancer or the effect on all-cause mortality. So, we don’t know whether people should take vitamins or not, and we need more research,” Dr. Wong added.

On the use of a multivitamin supplement, Dr. Wong noted that the complete body of evidence did not find any benefit of taking a multivitamin on cardiovascular or cancer mortality. But there was a small reduction in cancer incidence.

However, he pointed out that the three studies that suggested a reduction in cancer incidence all had issues regarding generalizability.

“The recently published COSMOS trial had an average follow-up of only 3.6 years, which isn’t really long enough when thinking about the prevention of cancer, one of the other studies only used antioxidants, and the third study was conducted only in U.S. male physicians. So those limitations regarding generalizability limited our confidence in making recommendations about multivitamins,” Dr. Wong explained.

But he noted that the task force did not find any significant harms from taking multivitamins.

“There are possible harms from taking high doses of vitamin A and vitamin D, but generally the doses contained in a multivitamin tablet are lower than these. But if the goal for taking a multivitamin is to lower your risk of cancer or cardiovascular disease, we didn’t find sufficient evidence to be able to make a recommendation,” he said.

Asked what he would say to all the people currently taking multivitamins, Dr. Wong responded that he would advise them to have a conversation with a trusted health care professional about their particular circumstances.

“Our statement has quite a narrow focus. It is directed toward community-dwelling, nonpregnant adults. This recommendation does not apply to children, persons who are pregnant or may become pregnant, or persons who are chronically ill, are hospitalized, or have a known nutritional deficiency,” he commented.
 

‘Any benefit likely to be small’

In an editorial accompanying the publication of the USPSTF statement, Jenny Jia, MD; Natalie Cameron, MD; and Jeffrey Linder, MD – all from Northwestern University, Chicago – noted that the current evidence base includes 52 additional studies not available when the last USPSTF recommendation on this topic was published in 2014.

The editorialists pointed out that for multivitamins, proving the absence of a benefit is challenging, but at best, current evidence suggests that any potential benefits of a multivitamin to reduce mortality are likely to be small.

They gave an example of a healthy 65-year-old woman with a 9-year estimated mortality risk of about 8%, and note that taking a multivitamin for 5-10 years might reduce her estimated mortality risk to 7.5% (based on an odds ratio of 0.94).

“In addition to showing small potential benefit, this estimate is based on imperfect evidence, is imprecise, and is highly sensitive to how the data are interpreted and analyzed,” they said.

The editorialists recommended that lifestyle counseling to prevent chronic diseases should continue to focus on evidence-based approaches, including balanced diets that are high in fruits and vegetables and physical activity.

However, they added that healthy eating can be a challenge when the American industrialized food system does not prioritize health, and healthy foods tend to be more expensive, leading to access problems and food insecurity.

The editorialists suggested that, rather than focusing money, time, and attention on supplements, it would be better to emphasize lower-risk, higher-benefit activities, such as getting exercise, maintaining a healthy weight, and avoiding smoking, in addition to following a healthful diet.
 

Possible benefit for older adults?

Commenting on the USPSTF statement, JoAnn Manson, MD, chief, division of preventive medicine, Brigham and Women’s Hospital, Boston, who led the recent COSMOS study, said that vitamin and mineral supplements should not be perceived as a substitute for a healthful diet.

“The emphasis needs to be on getting nutritional needs from a healthy diet that is high in plant-based and whole foods that don’t strip the vitamins and minerals through excessive processing,” she said. “Although it’s easier to pop a pill each day than to focus on healthful dietary patterns, the mixture of phytochemicals, fiber, and all the other nutrients in actual foods just can’t be packaged into a pill. Also, vitamins and minerals tend to be better absorbed from food than from supplements and healthy foods can replace calories from less healthy foods, such as red meat and processed foods.”

However, Dr. Manson noted that the evidence is mounting that taking a tablet containing moderate doses of a wide range of vitamins and minerals is safe and may actually have benefits for some people.

She pointed out that the COSMOS and COSMOS-Mind studies showed benefits of multivitamins in slowing cognitive decline in older adults, but the findings need to be replicated.  

“The USPSTF did see a statistically significant 7% reduction in cancer with multivitamins in their meta-analysis of four randomized trials and a borderline 6% reduction in all-cause mortality,” she noted. “Plus, multivitamins have been shown to be quite safe in several large and long-term randomized trials. I agree the evidence is not sufficient to make a blanket recommendation for everyone to take multivitamins, but the evidence is mounting that this would be a prudent approach for many older adults,” Dr. Manson said.

“Many people view multivitamins as a form of insurance, as a way to hedge their bets,” she added. “Although this is a rational approach, especially for those who have concerns about the adequacy of their diet, it’s important that this mindset not lead to complacency about following healthy lifestyle practices, including healthy eating, regular physical activity, not smoking, making sure that blood pressure and cholesterol levels are well controlled, and many other practices that critically important for health but are more challenging than simply popping a pill each day.”

A version of this article first appeared on Medscape.com.

There is not enough evidence to recommend for or against taking most vitamin and mineral supplements to prevent heart disease, stroke, and cancer, a new report by the U.S. Preventive Services Task Force concludes.

However, there are two vitamins – vitamin E and beta-carotene – that the task force recommends against for the prevention of heart disease, stroke, and cancer. Evidence shows that there is no benefit to taking vitamin E and that beta-carotene can increase the risk for lung cancer in people already at risk, such as smokers and those with occupational exposure to asbestos.

sodapix/thinkstockphotos.com

These are the main findings of the USPSTF’s final recommendation statement on vitamin, mineral, and multivitamin supplementation to prevent cardiovascular disease and cancer. The statement was published in JAMA.

“This is essentially the same recommendation that the task force made in 2014,” USPSTF member John Wong, MD, professor of medicine at Tufts University, Boston, said in an interview.

“We recognize that over half of people in the U.S. take a vitamin supplement of some sort every day and 30% take a vitamin/mineral combination. We wanted to review the evidence again to see if there was any benefit in terms of reducing the risk of cardiovascular disease or cancer or increasing the chances of living longer,” Dr. Wong explained.

“We looked hard for evidence, reviewing 84 studies in total. But we did not find sufficient evidence in favor of taking or not taking vitamins, with the two exceptions of beta-carotene and vitamin E, which we recommend against taking,” he noted.

Although there is evidence of some harm with beta-carotene, the main reason behind the recommendation against taking vitamin E is the consistent evidence of no benefit, Dr. Wong explained.

“While the evidence for some other vitamins is conflicting, there is more consistent evidence of no benefit for vitamin E,” he said.

The bulk of new evidence since the last review in 2014 was predominately for vitamin D supplementation, but despite the inclusion of 32 new randomized, controlled trials and two cohort studies, pooled estimates for all-cause mortality were similar to those in the previous review, with confidence intervals only slightly crossing 1, and point estimates that suggest at most a very small benefit, the task force noted.

“Apart from beta-carotene and vitamin E, after reviewing 84 studies – including 78 randomized controlled trials – in over a million patients, we can find no clear demonstration of benefit or harm of taking vitamins in terms of developing cardiovascular disease or cancer or the effect on all-cause mortality. So, we don’t know whether people should take vitamins or not, and we need more research,” Dr. Wong added.

On the use of a multivitamin supplement, Dr. Wong noted that the complete body of evidence did not find any benefit of taking a multivitamin on cardiovascular or cancer mortality. But there was a small reduction in cancer incidence.

However, he pointed out that the three studies that suggested a reduction in cancer incidence all had issues regarding generalizability.

“The recently published COSMOS trial had an average follow-up of only 3.6 years, which isn’t really long enough when thinking about the prevention of cancer, one of the other studies only used antioxidants, and the third study was conducted only in U.S. male physicians. So those limitations regarding generalizability limited our confidence in making recommendations about multivitamins,” Dr. Wong explained.

But he noted that the task force did not find any significant harms from taking multivitamins.

“There are possible harms from taking high doses of vitamin A and vitamin D, but generally the doses contained in a multivitamin tablet are lower than these. But if the goal for taking a multivitamin is to lower your risk of cancer or cardiovascular disease, we didn’t find sufficient evidence to be able to make a recommendation,” he said.

Asked what he would say to all the people currently taking multivitamins, Dr. Wong responded that he would advise them to have a conversation with a trusted health care professional about their particular circumstances.

“Our statement has quite a narrow focus. It is directed toward community-dwelling, nonpregnant adults. This recommendation does not apply to children, persons who are pregnant or may become pregnant, or persons who are chronically ill, are hospitalized, or have a known nutritional deficiency,” he commented.
 

‘Any benefit likely to be small’

In an editorial accompanying the publication of the USPSTF statement, Jenny Jia, MD; Natalie Cameron, MD; and Jeffrey Linder, MD – all from Northwestern University, Chicago – noted that the current evidence base includes 52 additional studies not available when the last USPSTF recommendation on this topic was published in 2014.

The editorialists pointed out that for multivitamins, proving the absence of a benefit is challenging, but at best, current evidence suggests that any potential benefits of a multivitamin to reduce mortality are likely to be small.

They gave an example of a healthy 65-year-old woman with a 9-year estimated mortality risk of about 8%, and note that taking a multivitamin for 5-10 years might reduce her estimated mortality risk to 7.5% (based on an odds ratio of 0.94).

“In addition to showing small potential benefit, this estimate is based on imperfect evidence, is imprecise, and is highly sensitive to how the data are interpreted and analyzed,” they said.

The editorialists recommended that lifestyle counseling to prevent chronic diseases should continue to focus on evidence-based approaches, including balanced diets that are high in fruits and vegetables and physical activity.

However, they added that healthy eating can be a challenge when the American industrialized food system does not prioritize health, and healthy foods tend to be more expensive, leading to access problems and food insecurity.

The editorialists suggested that, rather than focusing money, time, and attention on supplements, it would be better to emphasize lower-risk, higher-benefit activities, such as getting exercise, maintaining a healthy weight, and avoiding smoking, in addition to following a healthful diet.
 

Possible benefit for older adults?

Commenting on the USPSTF statement, JoAnn Manson, MD, chief, division of preventive medicine, Brigham and Women’s Hospital, Boston, who led the recent COSMOS study, said that vitamin and mineral supplements should not be perceived as a substitute for a healthful diet.

“The emphasis needs to be on getting nutritional needs from a healthy diet that is high in plant-based and whole foods that don’t strip the vitamins and minerals through excessive processing,” she said. “Although it’s easier to pop a pill each day than to focus on healthful dietary patterns, the mixture of phytochemicals, fiber, and all the other nutrients in actual foods just can’t be packaged into a pill. Also, vitamins and minerals tend to be better absorbed from food than from supplements and healthy foods can replace calories from less healthy foods, such as red meat and processed foods.”

However, Dr. Manson noted that the evidence is mounting that taking a tablet containing moderate doses of a wide range of vitamins and minerals is safe and may actually have benefits for some people.

She pointed out that the COSMOS and COSMOS-Mind studies showed benefits of multivitamins in slowing cognitive decline in older adults, but the findings need to be replicated.  

“The USPSTF did see a statistically significant 7% reduction in cancer with multivitamins in their meta-analysis of four randomized trials and a borderline 6% reduction in all-cause mortality,” she noted. “Plus, multivitamins have been shown to be quite safe in several large and long-term randomized trials. I agree the evidence is not sufficient to make a blanket recommendation for everyone to take multivitamins, but the evidence is mounting that this would be a prudent approach for many older adults,” Dr. Manson said.

“Many people view multivitamins as a form of insurance, as a way to hedge their bets,” she added. “Although this is a rational approach, especially for those who have concerns about the adequacy of their diet, it’s important that this mindset not lead to complacency about following healthy lifestyle practices, including healthy eating, regular physical activity, not smoking, making sure that blood pressure and cholesterol levels are well controlled, and many other practices that critically important for health but are more challenging than simply popping a pill each day.”

A version of this article first appeared on Medscape.com.

CHICAGO – New results from a trial in patients with newly diagnosed multiple myeloma (MM) offer some answers to questions about which treatment route to choose.

The trial, known as DETERMINATION, found that newly diagnosed patients treated with a triplet of drugs had longer progression-free survival (PFS) if they received an autologous stem cell transplant (ASCT) soon after the drug therapy than if they simply had their stem cells collected for a possible future transplant.

Patients who received the triplet of lenalidomide, bortezomib, and dexamethasone (RVD) plus ASCT had a median PFS of 67.5 months, compared with 46.2 months for those who received RVD but did not have a transplant soon after.

However, patients were just as likely to be alive more than 6 years after treatment regardless of whether or not they underwent an immediate stem cell transplant.

In addition, treatment-related adverse events of grade 3 or above were higher in the group that received the transplant immediately after the triplet therapy.  

The results were presented during a plenary session at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.

“Our findings confirm the PFS benefit of transplantation as first-line treatment for patients with myeloma and confirms stem cell transplant as a standard of care with certain triplet therapy,” said lead author Paul G. Richardson, MD, professor of medicine, Harvard Medical School, and clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana Farber Cancer Institute, Boston.

Another finding from the trial was that the use of maintenance lenalidomide in both groups continuously until progression conferred substantial clinical benefit.

“We can also say that the use of lenalidomide maintenance therapy is also a standard of care,” he added.
 

Study details

In this trial, Dr. Richardson and colleagues randomly assigned 873 patients newly diagnosed with multiple myeloma to the RVD-alone group (n = 357) or the transplantation group (n = 365). All patients had received one cycle of RVD prior to randomization and then received two additional RVD cycles plus stem-cell mobilization followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Lenalidomide was administered to all patients until disease progression, unacceptable side effects, or both.

At a median follow-up of 76.0 months, the risk of disease progression or death was 53% higher among patients who received RVD alone versus the transplantation group (hazard ratio [HR], 1.53; P < .001). The median duration of PFS among patients with a high-risk cytogenetic profile was 55.5 vs. 17.1 months, favoring the transplantation group.

The percentage of patients who were alive without progression at 5 years was 58.4% vs 41.6%, respectively (HR, 1.66) and median duration of response was 56.4 vs 38.9 months, also favoring transplantation (HR, 1.45).

The estimated 5-year overall survival was similar between groups: 80.7% for transplantation and 79.2% for RVD alone (HR for death, 1.10; P > .99). For patients with a high-risk cytogenetic profile, 5-year survival was 63.4% versus 54.3%, respectively.

“This tells us that for patients who had kept transplant in reserve, they had the same overall survival as those who had had a transplant right away, despite there being such impressive initial disease control for the patients in whom transplant was used early,” Dr. Richardson said in a press release from his institution.

Patients who did not undergo immediate transplant received treatment when their disease progressed with newer and active therapies, such as monoclonal antibodies and/or next-generation novel agents, he noted. Only 28% of patients used the reserve option of a transplant.

“It demonstrates the extent to which patients now have options and that we have new data to guide them in balancing the pluses and minuses of each approach,” he added.

When looking at safety, the authors noted that the most common treatment-related adverse events of grade 3 or higher occurred in 279 patients (78.2%) in the RVD-alone group and 344 patients (94.2%) in the transplantation group. Of those patients, 60.5% and 89.9%, respectively, reported hematologic events of grade 3 or higher (P < .001). The 5-year cumulative incidence of invasive second primary cancers was similar in both cohorts (RVD-alone group, 4.9%; transplantation group, 6.5%).

However, while the risk of secondary cancers was similar between groups, Dr. Richardson noted that there was a higher incidence of acute myeloid leukemia and myelodysplastic syndromes in the transplant cohort.

“There was also a significant drop in quality of life across transplant procedures, but the good news is that it was recoverable rapidly,” he said. “What is also really important is that we have prospective, multicenter, national comparative data on toxicity. That’s very important for providing patients with a choice as they move forward with their treatment plan.”

He noted that treatment continues to evolve. “This study was designed in 2009, begun in 2010, and now there is mature data in 2022,” Dr. Richardson said. “This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies and novel next-generation therapies. The results from these studies are extremely exciting.

“Now more than ever, treatment for multiple myeloma can be adapted for each patient,” Dr. Richardson said. “Our study provides important information about the benefits of transplant in the era of highly effective novel therapies and continuous maintenance, as well as the potential risks, to help patients and their physicians decide what approach may be best for them. This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies, such as RVD combined with daratumumab.”
 

Lack of difference in overall survival

These new results further support an already established role of autologous hematopoietic stem cell transplantation in the management of patients with multiple myeloma, said Samer Al-Homsi, MD, clinical professor of medicine and director of the blood and marrow transplant program at Perlmutter Cancer Center, NYU Langone, New York, who was approached for comment.

“The treatment regimen is applicable to patients who are determined by an expert in transplantation to be fit to receive autologous hematopoietic transplantation,” he added. “Although this study, like many others, establishes hematopoietic stem cell transplantation as part of the standard of care in multiple myeloma, only a fraction of patients are actually offered this important modality of treatment for a variety of reasons, including provider bias,” he noted. “In fact, although improvement in supportive care has enhanced the safety of the procedure, many patients are denied this therapy.” 

Dr. Al-Homsi noted that the lack of difference in overall survival might be due to the fact that some patients (28%) in the RVD-alone group did end up undergoing transplantation at the time of progression. “Also, longer follow-up might reveal a difference in overall survival,” he said.

The toxicities are manageable, and the incidence of secondary malignancies was not significantly different between cohorts. “However,” he emphasized, “lenalidomide has been associated in other studies with increased incidence of secondary malignancies and it must be noted that this study used extended administration of lenalidomide until progression.” 

Support for this study was provided by grants to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute, the National Cancer Institute, R. J. Corman Multiple Myeloma Foundation, Celgene/Bristol Myers Squibb, and Millennium/Takeda Pharmaceutical. Dr. Richardson has reported relationships with Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm Therapeutics, Oncopeptides, Sanofi, Secura Bio, Takeda, and Bristol Myers Squibb. Dr. Al-Homsi has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

CHICAGO – New results from a trial in patients with newly diagnosed multiple myeloma (MM) offer some answers to questions about which treatment route to choose.

The trial, known as DETERMINATION, found that newly diagnosed patients treated with a triplet of drugs had longer progression-free survival (PFS) if they received an autologous stem cell transplant (ASCT) soon after the drug therapy than if they simply had their stem cells collected for a possible future transplant.

Patients who received the triplet of lenalidomide, bortezomib, and dexamethasone (RVD) plus ASCT had a median PFS of 67.5 months, compared with 46.2 months for those who received RVD but did not have a transplant soon after.

However, patients were just as likely to be alive more than 6 years after treatment regardless of whether or not they underwent an immediate stem cell transplant.

In addition, treatment-related adverse events of grade 3 or above were higher in the group that received the transplant immediately after the triplet therapy.  

The results were presented during a plenary session at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.

“Our findings confirm the PFS benefit of transplantation as first-line treatment for patients with myeloma and confirms stem cell transplant as a standard of care with certain triplet therapy,” said lead author Paul G. Richardson, MD, professor of medicine, Harvard Medical School, and clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana Farber Cancer Institute, Boston.

Another finding from the trial was that the use of maintenance lenalidomide in both groups continuously until progression conferred substantial clinical benefit.

“We can also say that the use of lenalidomide maintenance therapy is also a standard of care,” he added.
 

Study details

In this trial, Dr. Richardson and colleagues randomly assigned 873 patients newly diagnosed with multiple myeloma to the RVD-alone group (n = 357) or the transplantation group (n = 365). All patients had received one cycle of RVD prior to randomization and then received two additional RVD cycles plus stem-cell mobilization followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Lenalidomide was administered to all patients until disease progression, unacceptable side effects, or both.

At a median follow-up of 76.0 months, the risk of disease progression or death was 53% higher among patients who received RVD alone versus the transplantation group (hazard ratio [HR], 1.53; P < .001). The median duration of PFS among patients with a high-risk cytogenetic profile was 55.5 vs. 17.1 months, favoring the transplantation group.

The percentage of patients who were alive without progression at 5 years was 58.4% vs 41.6%, respectively (HR, 1.66) and median duration of response was 56.4 vs 38.9 months, also favoring transplantation (HR, 1.45).

The estimated 5-year overall survival was similar between groups: 80.7% for transplantation and 79.2% for RVD alone (HR for death, 1.10; P > .99). For patients with a high-risk cytogenetic profile, 5-year survival was 63.4% versus 54.3%, respectively.

“This tells us that for patients who had kept transplant in reserve, they had the same overall survival as those who had had a transplant right away, despite there being such impressive initial disease control for the patients in whom transplant was used early,” Dr. Richardson said in a press release from his institution.

Patients who did not undergo immediate transplant received treatment when their disease progressed with newer and active therapies, such as monoclonal antibodies and/or next-generation novel agents, he noted. Only 28% of patients used the reserve option of a transplant.

“It demonstrates the extent to which patients now have options and that we have new data to guide them in balancing the pluses and minuses of each approach,” he added.

When looking at safety, the authors noted that the most common treatment-related adverse events of grade 3 or higher occurred in 279 patients (78.2%) in the RVD-alone group and 344 patients (94.2%) in the transplantation group. Of those patients, 60.5% and 89.9%, respectively, reported hematologic events of grade 3 or higher (P < .001). The 5-year cumulative incidence of invasive second primary cancers was similar in both cohorts (RVD-alone group, 4.9%; transplantation group, 6.5%).

However, while the risk of secondary cancers was similar between groups, Dr. Richardson noted that there was a higher incidence of acute myeloid leukemia and myelodysplastic syndromes in the transplant cohort.

“There was also a significant drop in quality of life across transplant procedures, but the good news is that it was recoverable rapidly,” he said. “What is also really important is that we have prospective, multicenter, national comparative data on toxicity. That’s very important for providing patients with a choice as they move forward with their treatment plan.”

He noted that treatment continues to evolve. “This study was designed in 2009, begun in 2010, and now there is mature data in 2022,” Dr. Richardson said. “This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies and novel next-generation therapies. The results from these studies are extremely exciting.

“Now more than ever, treatment for multiple myeloma can be adapted for each patient,” Dr. Richardson said. “Our study provides important information about the benefits of transplant in the era of highly effective novel therapies and continuous maintenance, as well as the potential risks, to help patients and their physicians decide what approach may be best for them. This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies, such as RVD combined with daratumumab.”
 

Lack of difference in overall survival

These new results further support an already established role of autologous hematopoietic stem cell transplantation in the management of patients with multiple myeloma, said Samer Al-Homsi, MD, clinical professor of medicine and director of the blood and marrow transplant program at Perlmutter Cancer Center, NYU Langone, New York, who was approached for comment.

“The treatment regimen is applicable to patients who are determined by an expert in transplantation to be fit to receive autologous hematopoietic transplantation,” he added. “Although this study, like many others, establishes hematopoietic stem cell transplantation as part of the standard of care in multiple myeloma, only a fraction of patients are actually offered this important modality of treatment for a variety of reasons, including provider bias,” he noted. “In fact, although improvement in supportive care has enhanced the safety of the procedure, many patients are denied this therapy.” 

Dr. Al-Homsi noted that the lack of difference in overall survival might be due to the fact that some patients (28%) in the RVD-alone group did end up undergoing transplantation at the time of progression. “Also, longer follow-up might reveal a difference in overall survival,” he said.

The toxicities are manageable, and the incidence of secondary malignancies was not significantly different between cohorts. “However,” he emphasized, “lenalidomide has been associated in other studies with increased incidence of secondary malignancies and it must be noted that this study used extended administration of lenalidomide until progression.” 

Support for this study was provided by grants to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute, the National Cancer Institute, R. J. Corman Multiple Myeloma Foundation, Celgene/Bristol Myers Squibb, and Millennium/Takeda Pharmaceutical. Dr. Richardson has reported relationships with Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm Therapeutics, Oncopeptides, Sanofi, Secura Bio, Takeda, and Bristol Myers Squibb. Dr. Al-Homsi has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

CHICAGO – New results from a trial in patients with newly diagnosed multiple myeloma (MM) offer some answers to questions about which treatment route to choose.

The trial, known as DETERMINATION, found that newly diagnosed patients treated with a triplet of drugs had longer progression-free survival (PFS) if they received an autologous stem cell transplant (ASCT) soon after the drug therapy than if they simply had their stem cells collected for a possible future transplant.

Patients who received the triplet of lenalidomide, bortezomib, and dexamethasone (RVD) plus ASCT had a median PFS of 67.5 months, compared with 46.2 months for those who received RVD but did not have a transplant soon after.

However, patients were just as likely to be alive more than 6 years after treatment regardless of whether or not they underwent an immediate stem cell transplant.

In addition, treatment-related adverse events of grade 3 or above were higher in the group that received the transplant immediately after the triplet therapy.  

The results were presented during a plenary session at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.

“Our findings confirm the PFS benefit of transplantation as first-line treatment for patients with myeloma and confirms stem cell transplant as a standard of care with certain triplet therapy,” said lead author Paul G. Richardson, MD, professor of medicine, Harvard Medical School, and clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana Farber Cancer Institute, Boston.

Another finding from the trial was that the use of maintenance lenalidomide in both groups continuously until progression conferred substantial clinical benefit.

“We can also say that the use of lenalidomide maintenance therapy is also a standard of care,” he added.
 

Study details

In this trial, Dr. Richardson and colleagues randomly assigned 873 patients newly diagnosed with multiple myeloma to the RVD-alone group (n = 357) or the transplantation group (n = 365). All patients had received one cycle of RVD prior to randomization and then received two additional RVD cycles plus stem-cell mobilization followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Lenalidomide was administered to all patients until disease progression, unacceptable side effects, or both.

At a median follow-up of 76.0 months, the risk of disease progression or death was 53% higher among patients who received RVD alone versus the transplantation group (hazard ratio [HR], 1.53; P < .001). The median duration of PFS among patients with a high-risk cytogenetic profile was 55.5 vs. 17.1 months, favoring the transplantation group.

The percentage of patients who were alive without progression at 5 years was 58.4% vs 41.6%, respectively (HR, 1.66) and median duration of response was 56.4 vs 38.9 months, also favoring transplantation (HR, 1.45).

The estimated 5-year overall survival was similar between groups: 80.7% for transplantation and 79.2% for RVD alone (HR for death, 1.10; P > .99). For patients with a high-risk cytogenetic profile, 5-year survival was 63.4% versus 54.3%, respectively.

“This tells us that for patients who had kept transplant in reserve, they had the same overall survival as those who had had a transplant right away, despite there being such impressive initial disease control for the patients in whom transplant was used early,” Dr. Richardson said in a press release from his institution.

Patients who did not undergo immediate transplant received treatment when their disease progressed with newer and active therapies, such as monoclonal antibodies and/or next-generation novel agents, he noted. Only 28% of patients used the reserve option of a transplant.

“It demonstrates the extent to which patients now have options and that we have new data to guide them in balancing the pluses and minuses of each approach,” he added.

When looking at safety, the authors noted that the most common treatment-related adverse events of grade 3 or higher occurred in 279 patients (78.2%) in the RVD-alone group and 344 patients (94.2%) in the transplantation group. Of those patients, 60.5% and 89.9%, respectively, reported hematologic events of grade 3 or higher (P < .001). The 5-year cumulative incidence of invasive second primary cancers was similar in both cohorts (RVD-alone group, 4.9%; transplantation group, 6.5%).

However, while the risk of secondary cancers was similar between groups, Dr. Richardson noted that there was a higher incidence of acute myeloid leukemia and myelodysplastic syndromes in the transplant cohort.

“There was also a significant drop in quality of life across transplant procedures, but the good news is that it was recoverable rapidly,” he said. “What is also really important is that we have prospective, multicenter, national comparative data on toxicity. That’s very important for providing patients with a choice as they move forward with their treatment plan.”

He noted that treatment continues to evolve. “This study was designed in 2009, begun in 2010, and now there is mature data in 2022,” Dr. Richardson said. “This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies and novel next-generation therapies. The results from these studies are extremely exciting.

“Now more than ever, treatment for multiple myeloma can be adapted for each patient,” Dr. Richardson said. “Our study provides important information about the benefits of transplant in the era of highly effective novel therapies and continuous maintenance, as well as the potential risks, to help patients and their physicians decide what approach may be best for them. This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies, such as RVD combined with daratumumab.”
 

Lack of difference in overall survival

These new results further support an already established role of autologous hematopoietic stem cell transplantation in the management of patients with multiple myeloma, said Samer Al-Homsi, MD, clinical professor of medicine and director of the blood and marrow transplant program at Perlmutter Cancer Center, NYU Langone, New York, who was approached for comment.

“The treatment regimen is applicable to patients who are determined by an expert in transplantation to be fit to receive autologous hematopoietic transplantation,” he added. “Although this study, like many others, establishes hematopoietic stem cell transplantation as part of the standard of care in multiple myeloma, only a fraction of patients are actually offered this important modality of treatment for a variety of reasons, including provider bias,” he noted. “In fact, although improvement in supportive care has enhanced the safety of the procedure, many patients are denied this therapy.” 

Dr. Al-Homsi noted that the lack of difference in overall survival might be due to the fact that some patients (28%) in the RVD-alone group did end up undergoing transplantation at the time of progression. “Also, longer follow-up might reveal a difference in overall survival,” he said.

The toxicities are manageable, and the incidence of secondary malignancies was not significantly different between cohorts. “However,” he emphasized, “lenalidomide has been associated in other studies with increased incidence of secondary malignancies and it must be noted that this study used extended administration of lenalidomide until progression.” 

Support for this study was provided by grants to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute, the National Cancer Institute, R. J. Corman Multiple Myeloma Foundation, Celgene/Bristol Myers Squibb, and Millennium/Takeda Pharmaceutical. Dr. Richardson has reported relationships with Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm Therapeutics, Oncopeptides, Sanofi, Secura Bio, Takeda, and Bristol Myers Squibb. Dr. Al-Homsi has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A weekly subcutaneous dose of teclistamab resulted in high response rates among adults with relapsed or refractory multiple myeloma, based on data from 165 patients in the MajesTEC-1 study presented at the annual meeting of the American Society of Clinical Oncology.

“We have limited treatment options for triple-class exposed and refractory multiple myeloma patients, especially for use in the community,” coauthor Dr. Saad Z. Usmani, of Memorial Sloan Kettering Cancer Center, New York, said in an interview. “Teclistamab is a BCMA directed bispecific antibody that is showing high response rates at the recommended subcutaneous phase 2 doses (RP2D),” and has a strong safety profile, he explained.

Teclistamab tackles two targets – both CD3 on the surface of T cells and B-cell maturation antigen (BCMA) on the surface of myeloma cells – said Dr. Ajay K. Nooka of Emory University, Atlanta, in the meeting presentation. The study was published simultaneously in the New England Journal of Medicine.

After teclistamab showed promising efficacy and an acceptable level of side effects in phase 1, researchers enrolled 165 adults aged 33-84 years with relapsed or refractory multiple myeloma (MM). The patients had experienced at least three previous lines of therapy (LOT). All patients received a weekly subcutaneous injection of 1.5 mg/kg of body weight following step-up doses of 0.06 mg/kg and 0.3 mg/kg. The primary endpoint of the study was overall response.

The median age of the patients was 64 years; 58% were male, 81.2% were White. The median prior LOT was 5; all of the patients were triple-class exposed (100%); 70% were penta-drug exposed, 78% were triple-class refractory, and 30% penta-drug refractory.

The overall response rate (ORR) was 63% over a median follow-up period of approximately 14.1 months. In addition, 39.4% of patients had a complete response or better, and 26.7% had no minimal residual disease, for a negative minimal residual disease rate of 46.2% in patients with complete response. The median durations of response and progression-free survival were 18.4 months and 11.3 months, respectively.

“The ORR was consistent across clinically relevant subgroups, including high cytogenetic risk and penta-drug refractory subgroups,” Dr. Nooka said in his presentation.

The most common adverse event was cytokine release syndrome, which occurred in 72.1% of patients; however, only 0.6% of these events were grade 3, and none were grade 4. Other adverse events included neutropenia in 70.9% (64.2% of events were grade 3 or 4), anemia (52.1%, 37.0% of events were grade 3 or 4, respectively) and thrombocytopenia (40%, 21.2% of events were grade 3 or 4). Infections occurred in 76.4% of patients overall, 44.8% of which were grade 3 or 4, and neurotoxic events occurred in 24 patients (14.5%). The five cases of immune effector cell–associated neurotoxicity syndrome (CRS) were grade 1 or 2.

A total of 2 patients (1.2%) discontinued the study because of adverse events, but no discontinuations or dose reductions occurred as a result of neurotoxic events.

A total of 5 deaths attributed to teclistamab occurred during the study: 2 caused by COVID-19, 1 pneumonia, 1 hepatic failure, and 1 progressive multifocal leukoencephalopathy (PML).

The responses were durable and persisted over time, said Dr. Nooka. At the point of data cutoff, 64.4% of patients who responded maintained that response.

Overall, the data support teclistamab as “a promising new, off-the-shelf, T-cell redirecting therapy targeting BCMA for patients with relapsed or refractory MM,” with phase 3 studies ongoing and early access programs in progress, Dr. Nooka concluded.

 “The ORR and durability of response seen with teclistamab is very impressive when one sees the data for other single agents approved for relapsed/refractory MM in the past,” Dr. Usmani said in an interview. “I hope the current data will help get a regulatory approval for the triple class exposed MM population.”

However, potential barriers to widespread use of teclistamab in practice include logistics and a learning curve for practicing hematologists/oncologists, Dr. Usmani noted. “While the CRS appears to be grade 1 or 2 and very manageable, the logistics of giving bispecific antibodies in the community setting and managing CRS during the first cycle of therapy in the community will need to be worked out, and partnership with academic centers that have experience in managing these patients will be needed, he added.

As for additional research, “teclistamab is being combined with other MM therapies and being explored in earlier lines of treatment,” Dr. Usmani said.
 

Be ready to manage infections

Despite promising early findings, the use of teclistamab and other BCMA-targeting biospecific therapies is “not a free lunch” for refractory and relapsed MM patients, said discussant Dr. Madhav V. Dhodapkar of Emory University, Atlanta, during the discussion period after the ASCO presentation.

Although the risk of CRS and ICANS appears low, “infections are emerging as a major adverse event” that need to be recognized and managed, he said.

A distinct pattern of infections may be emerging, based on data from the current study and other studies of similar therapies, with infections such as Pneumocystis jirovecii (PJP) and cytomegalovirus (CMV) reactivation, Dr. Dhodapkar added.

He noted other considerations for studies of teclistamab and similar therapies, including the need to address both host-related and tumor-related factors, as well as seasonal and opportunistic threats such as COVID-19.

Future research questions include whether there is a role for pathogen-specific surveillance to help mitigate infection risk, including COVID-19 risk management strategies, he emphasized.

The study was funded by Janssen Research and Development.

Dr. Usmani disclosed relationships as a consultant or advisor, speakers’ bureau member, and/or recipient of research funding from serving as a consultant or advisor for Abbvie, Amgen, Bristol-Myers Squibb/Celgene, Celgene, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Merck, Oncopeptides, Seattle Genetics, Skyline Diagnostics, and Takeda. Lead author of the New England Journal paper Dr. Philippe Moreau disclosed relationships with companies including Abbvie, Amgen, Celgene, GlaxoSmithKline, Janssen-Cilag, Oncopeptides, and Sanofi. ASCO presenting author Dr. Nooka disclosed relationships with companies including Adaptive Biotechnologies, Amgen, BeyondSpring Pharmaceuticals, Bristol-Myers Squibb/Celgene, Genzyme, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Oncopeptides, Secura Bio, Arch Oncology, and Takeda.

A weekly subcutaneous dose of teclistamab resulted in high response rates among adults with relapsed or refractory multiple myeloma, based on data from 165 patients in the MajesTEC-1 study presented at the annual meeting of the American Society of Clinical Oncology.

“We have limited treatment options for triple-class exposed and refractory multiple myeloma patients, especially for use in the community,” coauthor Dr. Saad Z. Usmani, of Memorial Sloan Kettering Cancer Center, New York, said in an interview. “Teclistamab is a BCMA directed bispecific antibody that is showing high response rates at the recommended subcutaneous phase 2 doses (RP2D),” and has a strong safety profile, he explained.

Teclistamab tackles two targets – both CD3 on the surface of T cells and B-cell maturation antigen (BCMA) on the surface of myeloma cells – said Dr. Ajay K. Nooka of Emory University, Atlanta, in the meeting presentation. The study was published simultaneously in the New England Journal of Medicine.

After teclistamab showed promising efficacy and an acceptable level of side effects in phase 1, researchers enrolled 165 adults aged 33-84 years with relapsed or refractory multiple myeloma (MM). The patients had experienced at least three previous lines of therapy (LOT). All patients received a weekly subcutaneous injection of 1.5 mg/kg of body weight following step-up doses of 0.06 mg/kg and 0.3 mg/kg. The primary endpoint of the study was overall response.

The median age of the patients was 64 years; 58% were male, 81.2% were White. The median prior LOT was 5; all of the patients were triple-class exposed (100%); 70% were penta-drug exposed, 78% were triple-class refractory, and 30% penta-drug refractory.

The overall response rate (ORR) was 63% over a median follow-up period of approximately 14.1 months. In addition, 39.4% of patients had a complete response or better, and 26.7% had no minimal residual disease, for a negative minimal residual disease rate of 46.2% in patients with complete response. The median durations of response and progression-free survival were 18.4 months and 11.3 months, respectively.

“The ORR was consistent across clinically relevant subgroups, including high cytogenetic risk and penta-drug refractory subgroups,” Dr. Nooka said in his presentation.

The most common adverse event was cytokine release syndrome, which occurred in 72.1% of patients; however, only 0.6% of these events were grade 3, and none were grade 4. Other adverse events included neutropenia in 70.9% (64.2% of events were grade 3 or 4), anemia (52.1%, 37.0% of events were grade 3 or 4, respectively) and thrombocytopenia (40%, 21.2% of events were grade 3 or 4). Infections occurred in 76.4% of patients overall, 44.8% of which were grade 3 or 4, and neurotoxic events occurred in 24 patients (14.5%). The five cases of immune effector cell–associated neurotoxicity syndrome (CRS) were grade 1 or 2.

A total of 2 patients (1.2%) discontinued the study because of adverse events, but no discontinuations or dose reductions occurred as a result of neurotoxic events.

A total of 5 deaths attributed to teclistamab occurred during the study: 2 caused by COVID-19, 1 pneumonia, 1 hepatic failure, and 1 progressive multifocal leukoencephalopathy (PML).

The responses were durable and persisted over time, said Dr. Nooka. At the point of data cutoff, 64.4% of patients who responded maintained that response.

Overall, the data support teclistamab as “a promising new, off-the-shelf, T-cell redirecting therapy targeting BCMA for patients with relapsed or refractory MM,” with phase 3 studies ongoing and early access programs in progress, Dr. Nooka concluded.

 “The ORR and durability of response seen with teclistamab is very impressive when one sees the data for other single agents approved for relapsed/refractory MM in the past,” Dr. Usmani said in an interview. “I hope the current data will help get a regulatory approval for the triple class exposed MM population.”

However, potential barriers to widespread use of teclistamab in practice include logistics and a learning curve for practicing hematologists/oncologists, Dr. Usmani noted. “While the CRS appears to be grade 1 or 2 and very manageable, the logistics of giving bispecific antibodies in the community setting and managing CRS during the first cycle of therapy in the community will need to be worked out, and partnership with academic centers that have experience in managing these patients will be needed, he added.

As for additional research, “teclistamab is being combined with other MM therapies and being explored in earlier lines of treatment,” Dr. Usmani said.
 

Be ready to manage infections

Despite promising early findings, the use of teclistamab and other BCMA-targeting biospecific therapies is “not a free lunch” for refractory and relapsed MM patients, said discussant Dr. Madhav V. Dhodapkar of Emory University, Atlanta, during the discussion period after the ASCO presentation.

Although the risk of CRS and ICANS appears low, “infections are emerging as a major adverse event” that need to be recognized and managed, he said.

A distinct pattern of infections may be emerging, based on data from the current study and other studies of similar therapies, with infections such as Pneumocystis jirovecii (PJP) and cytomegalovirus (CMV) reactivation, Dr. Dhodapkar added.

He noted other considerations for studies of teclistamab and similar therapies, including the need to address both host-related and tumor-related factors, as well as seasonal and opportunistic threats such as COVID-19.

Future research questions include whether there is a role for pathogen-specific surveillance to help mitigate infection risk, including COVID-19 risk management strategies, he emphasized.

The study was funded by Janssen Research and Development.

Dr. Usmani disclosed relationships as a consultant or advisor, speakers’ bureau member, and/or recipient of research funding from serving as a consultant or advisor for Abbvie, Amgen, Bristol-Myers Squibb/Celgene, Celgene, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Merck, Oncopeptides, Seattle Genetics, Skyline Diagnostics, and Takeda. Lead author of the New England Journal paper Dr. Philippe Moreau disclosed relationships with companies including Abbvie, Amgen, Celgene, GlaxoSmithKline, Janssen-Cilag, Oncopeptides, and Sanofi. ASCO presenting author Dr. Nooka disclosed relationships with companies including Adaptive Biotechnologies, Amgen, BeyondSpring Pharmaceuticals, Bristol-Myers Squibb/Celgene, Genzyme, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Oncopeptides, Secura Bio, Arch Oncology, and Takeda.

A weekly subcutaneous dose of teclistamab resulted in high response rates among adults with relapsed or refractory multiple myeloma, based on data from 165 patients in the MajesTEC-1 study presented at the annual meeting of the American Society of Clinical Oncology.

“We have limited treatment options for triple-class exposed and refractory multiple myeloma patients, especially for use in the community,” coauthor Dr. Saad Z. Usmani, of Memorial Sloan Kettering Cancer Center, New York, said in an interview. “Teclistamab is a BCMA directed bispecific antibody that is showing high response rates at the recommended subcutaneous phase 2 doses (RP2D),” and has a strong safety profile, he explained.

Teclistamab tackles two targets – both CD3 on the surface of T cells and B-cell maturation antigen (BCMA) on the surface of myeloma cells – said Dr. Ajay K. Nooka of Emory University, Atlanta, in the meeting presentation. The study was published simultaneously in the New England Journal of Medicine.

After teclistamab showed promising efficacy and an acceptable level of side effects in phase 1, researchers enrolled 165 adults aged 33-84 years with relapsed or refractory multiple myeloma (MM). The patients had experienced at least three previous lines of therapy (LOT). All patients received a weekly subcutaneous injection of 1.5 mg/kg of body weight following step-up doses of 0.06 mg/kg and 0.3 mg/kg. The primary endpoint of the study was overall response.

The median age of the patients was 64 years; 58% were male, 81.2% were White. The median prior LOT was 5; all of the patients were triple-class exposed (100%); 70% were penta-drug exposed, 78% were triple-class refractory, and 30% penta-drug refractory.

The overall response rate (ORR) was 63% over a median follow-up period of approximately 14.1 months. In addition, 39.4% of patients had a complete response or better, and 26.7% had no minimal residual disease, for a negative minimal residual disease rate of 46.2% in patients with complete response. The median durations of response and progression-free survival were 18.4 months and 11.3 months, respectively.

“The ORR was consistent across clinically relevant subgroups, including high cytogenetic risk and penta-drug refractory subgroups,” Dr. Nooka said in his presentation.

The most common adverse event was cytokine release syndrome, which occurred in 72.1% of patients; however, only 0.6% of these events were grade 3, and none were grade 4. Other adverse events included neutropenia in 70.9% (64.2% of events were grade 3 or 4), anemia (52.1%, 37.0% of events were grade 3 or 4, respectively) and thrombocytopenia (40%, 21.2% of events were grade 3 or 4). Infections occurred in 76.4% of patients overall, 44.8% of which were grade 3 or 4, and neurotoxic events occurred in 24 patients (14.5%). The five cases of immune effector cell–associated neurotoxicity syndrome (CRS) were grade 1 or 2.

A total of 2 patients (1.2%) discontinued the study because of adverse events, but no discontinuations or dose reductions occurred as a result of neurotoxic events.

A total of 5 deaths attributed to teclistamab occurred during the study: 2 caused by COVID-19, 1 pneumonia, 1 hepatic failure, and 1 progressive multifocal leukoencephalopathy (PML).

The responses were durable and persisted over time, said Dr. Nooka. At the point of data cutoff, 64.4% of patients who responded maintained that response.

Overall, the data support teclistamab as “a promising new, off-the-shelf, T-cell redirecting therapy targeting BCMA for patients with relapsed or refractory MM,” with phase 3 studies ongoing and early access programs in progress, Dr. Nooka concluded.

 “The ORR and durability of response seen with teclistamab is very impressive when one sees the data for other single agents approved for relapsed/refractory MM in the past,” Dr. Usmani said in an interview. “I hope the current data will help get a regulatory approval for the triple class exposed MM population.”

However, potential barriers to widespread use of teclistamab in practice include logistics and a learning curve for practicing hematologists/oncologists, Dr. Usmani noted. “While the CRS appears to be grade 1 or 2 and very manageable, the logistics of giving bispecific antibodies in the community setting and managing CRS during the first cycle of therapy in the community will need to be worked out, and partnership with academic centers that have experience in managing these patients will be needed, he added.

As for additional research, “teclistamab is being combined with other MM therapies and being explored in earlier lines of treatment,” Dr. Usmani said.
 

Be ready to manage infections

Despite promising early findings, the use of teclistamab and other BCMA-targeting biospecific therapies is “not a free lunch” for refractory and relapsed MM patients, said discussant Dr. Madhav V. Dhodapkar of Emory University, Atlanta, during the discussion period after the ASCO presentation.

Although the risk of CRS and ICANS appears low, “infections are emerging as a major adverse event” that need to be recognized and managed, he said.

A distinct pattern of infections may be emerging, based on data from the current study and other studies of similar therapies, with infections such as Pneumocystis jirovecii (PJP) and cytomegalovirus (CMV) reactivation, Dr. Dhodapkar added.

He noted other considerations for studies of teclistamab and similar therapies, including the need to address both host-related and tumor-related factors, as well as seasonal and opportunistic threats such as COVID-19.

Future research questions include whether there is a role for pathogen-specific surveillance to help mitigate infection risk, including COVID-19 risk management strategies, he emphasized.

The study was funded by Janssen Research and Development.

Dr. Usmani disclosed relationships as a consultant or advisor, speakers’ bureau member, and/or recipient of research funding from serving as a consultant or advisor for Abbvie, Amgen, Bristol-Myers Squibb/Celgene, Celgene, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Merck, Oncopeptides, Seattle Genetics, Skyline Diagnostics, and Takeda. Lead author of the New England Journal paper Dr. Philippe Moreau disclosed relationships with companies including Abbvie, Amgen, Celgene, GlaxoSmithKline, Janssen-Cilag, Oncopeptides, and Sanofi. ASCO presenting author Dr. Nooka disclosed relationships with companies including Adaptive Biotechnologies, Amgen, BeyondSpring Pharmaceuticals, Bristol-Myers Squibb/Celgene, Genzyme, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Oncopeptides, Secura Bio, Arch Oncology, and Takeda.

We have a half-forgotten Indian immigrant to thank – a hospital night porter turned biochemist –for revolutionizing treatment of leukemia, the once deadly childhood scourge that is still the most common pediatric cancer.

Dr. Yellapragada SubbaRow has been called the “father of chemotherapy” for developing methotrexate, a powerful, inexpensive therapy for leukemia and other diseases, and he is celebrated for additional scientific achievements. Yet Dr. SubbaRow’s life was marked more by struggle than glory.

1995 Indian stamp; photo in public domain

Born poor in southeastern India, he nearly succumbed to a tropical disease that killed two older brothers, and he didn’t focus on schoolwork until his father died. Later, prejudice dogged his years as an immigrant to the United States, and a blood clot took his life at the age of 53.

Scientifically, however, Dr. SubbaRow (pronounced sue-buh-rao) triumphed, despite mammoth challenges and a lack of recognition that persists to this day. National Cancer Research Month is a fitting time to look back on his extraordinary life and work and pay tribute to his accomplishments.
 

‘Yella,’ folic acid, and a paradigm shift

No one appreciates Dr. SubbaRow more than a cadre of Indian-born physicians who have kept his legacy alive in journal articles, presentations, and a Pulitzer Prize-winning book. Among them is author and oncologist Siddhartha Mukherjee, MD, who chronicled Dr. SubbaRow’s achievements in his New York Times No. 1 bestseller, “The Emperor of All Maladies: A Biography of Cancer.”

As Dr. Mukherjee wrote, Dr. SubbaRow was a “pioneer in many ways, a physician turned cellular physiologist, a chemist who had accidentally wandered into biology.” (Per Indian tradition, SubbaRow is the doctor’s first name, and Yellapragada is his surname, but medical literature uses SubbaRow as his cognomen, with some variations in spelling. Dr. Mukherjee wrote that his friends called him “Yella.”)

Dr. SubbaRow came to the United States in 1923, after enduring a difficult childhood and young adulthood. He’d survived bouts of religious fervor, childhood rebellion (including a bid to run away from home and become a banana trader), and a failed arranged marriage. His wife bore him a child who died in infancy. He left it all behind.

In Boston, medical officials rejected his degree. Broke, he worked for a time as a night porter at Brigham and Women’s Hospital in Boston, changing sheets and cleaning urinals. To a poor but proud high-caste Indian Brahmin, the culture shock of carrying out these tasks must have been especially jarring.

Dr. SubbaRow went on to earn a diploma from Harvard Medical School, also in Boston, and became a junior faculty member. As a foreigner, Dr. Mukherjee wrote, Dr. SubbaRow was a “reclusive, nocturnal, heavily accented vegetarian,” so different from his colleagues that advancement seemed impossible. Despite his pioneering biochemistry work, Harvard later declined to offer Dr. SubbaRow a tenured faculty position.

By the early 1940s, he took a job at an upstate New York pharmaceutical company called Lederle Labs (later purchased by Pfizer). At Lederle, Dr. SubbaRow strove to synthesize the vitamin known as folic acid. He ended up creating a kind of antivitamin, a lookalike that acted like folic acid but only succeeded in gumming up the works in receptors. But what good would it do to stop the body from absorbing folic acid? Plenty, it turned out.
 

Discoveries pile up, but credit and fame prove elusive

Dr. SubbaRow was no stranger to producing landmark biological work. He’d previously codiscovered phosphocreatine and ATP, which are crucial to muscular contractions. However, “in 1935, he had to disown the extent of his role in the discovery of the color test related to phosphorus, instead giving the credit to his co-author, who was being considered for promotion to a full professorship at Harvard,” wrote author Gerald Posner in his 2020 book, “Pharma: Greed, Lies and the Poisoning of America.”

Houston-area oncologist Kirtan Nautiyal, MD, who paid tribute to Dr. SubbaRow in a 2018 article, contended that “with his Indian instinct for self-effacement, he had irreparably sabotaged his own career.”

Dr. SubbaRow and his team also developed “the first effective treatment of filariasis, which causes elephantiasis of the lower limbs and genitals in millions of people, mainly in tropical countries,” Dr. Nautiyal wrote. “Later in the decade, his antibiotic program generated polymyxin, the first effective treatment against the class of bacteria called Gram negatives, and aureomycin, the first “broad-spectrum’ antibiotic.” (Aureomycin is also the first tetracycline antibiotic.)

Dr. SubbaRow’s discovery of a folic acid antagonist would again go largely unheralded. But first came the realization that folic acid made childhood leukemia worse, not better, and the prospect that this process could potentially be reversed.
 

Rise of methotrexate and fall of leukemia

In Boston, Sidney Farber, MD, a Boston pathologist, was desperate to help Robert Sandler, a 2-year-old leukemia patient. Dr. Farber contacted his ex-colleague Dr. SubbaRow to request a supply of aminopterin, an early version of methotrexate that Dr. SubbaRow and his team had developed. Dr. Farber injected Robert with the substance and within 3 days, the toddler’s white blood count started falling – fast. He stopped bleeding, resumed eating, and once again seemed almost identical to his twin brother, as Dr. Mukherjee wrote in his book.

Leukemia had never gone into remission before. Unfortunately, the treatment only worked temporarily. Robert, like other children treated with the drug, relapsed and died within months. But Dr. Farber “saw a door open” – a chemical, a kind of chemotherapy, that could turn back cancer. In the case of folic acid antagonists, they do so by stopping cancer cells from replicating.

Methotrexate, a related agent synthesized by Dr. SubbaRow, would become a mainstay of leukemia treatment and begin to produce long-term remission from acute lymphoblastic leukemia in 1970, when combination chemotherapy was developed.

Other cancers fell to methotrexate treatment. “Previous assumptions that cancer was nearly always fatal were revised, and the field of medical oncology (treatment of cancer with chemotherapy), which had not previously existed, was formally established in 1971,” according to the National Cancer Institute’s history of methotrexate. This account does not mention Dr. SubbaRow.
 

Death takes the doctor, but his legacy remains

In biographies, as well as his own words, Dr. SubbaRow comes across as a prickly, hard-driving workaholic who had little interest in intimate human connections. “It is not good to ask in every letter when I will be back,” he wrote to his wife back in India, before cutting off ties completely in the early 1930s. “I will come as early as possible. ... I do not want to write anything more.”

It seems, as his biographer S.P.K. Gupta noted, that “he was quite determined that the time allotted to him on Earth should be completely devoted to finding cures for ailments that plagued mankind.”

Still, Dr. SubbaRow’s research team was devoted to him, and he had plenty of reasons to be bitter, such as the prejudice and isolation he encountered in the United States and earlier, in British-run India. According to Mr. Posner’s book, even as a young medical student, Dr. SubbaRow heeded the call of Indian independence activist Mohandas Gandhi. He “refused the British surgical gown given him at school and instead donned a traditional and simple cotton Khadi. That act of defiance cost SubbaRow the college degree that was necessary for him to get into the State Medical College.”

During the last year of his life, Dr. SubbaRow faced yet another humiliation: In his landmark 1948 study about aminopterin as a treatment for leukemia, his colleague Dr. Farber failed to credit him, an “astonishing omission” as Yaddanapudi Ravindranath, MBBS, a pediatric hematologist/oncologist at Wayne State University, Detroit, put it. “From everything I know, Dr. Farber spent the rest of his career apologizing and trying to make amends for it,” Dr. Ravindranath said in an interview.
 

A career cut short, and a lasting legacy

In 1948, at the age of 53, Dr. SubbaRow suddenly died. “Many think Dr. SubbaRow would have won [the] Nobel Prize had he lived a few years longer,” said Dr. Ravindranath.

Like Dr. SubbaRow, Dr. Ravindranath was born in Andhra Pradesh state, near the city of Chennai formerly known as Madras. “Being a compatriot, in a way I continue his legacy, and I am obviously proud of him,” said Dr. Ravindranath, who has conducted his own landmark research regarding methotrexate and leukemia.

Nearly 75 years after Dr. SubbaRow’s death, Indian-born physicians like Dr. Ravindranath continue to honor him in print, trying to ensure that he’s not forgotten. Methotrexate remains a crucial treatment for leukemia, along with a long list of other ailments, including psoriasis.

Recognition for “Yella” may have come late and infrequently, but a Lederle Laboratories research library named after him offered Dr. SubbaRow a kind of immortality. A plaque there memorialized him in stone as a scientist, teacher, philosopher, and humanitarian, featuring the quote: “Science simply prolongs life. Religion deepens it.”

By all accounts, Dr. SubbaRow was a man of science and faith who had faith in science.

We have a half-forgotten Indian immigrant to thank – a hospital night porter turned biochemist –for revolutionizing treatment of leukemia, the once deadly childhood scourge that is still the most common pediatric cancer.

Dr. Yellapragada SubbaRow has been called the “father of chemotherapy” for developing methotrexate, a powerful, inexpensive therapy for leukemia and other diseases, and he is celebrated for additional scientific achievements. Yet Dr. SubbaRow’s life was marked more by struggle than glory.

1995 Indian stamp; photo in public domain

Born poor in southeastern India, he nearly succumbed to a tropical disease that killed two older brothers, and he didn’t focus on schoolwork until his father died. Later, prejudice dogged his years as an immigrant to the United States, and a blood clot took his life at the age of 53.

Scientifically, however, Dr. SubbaRow (pronounced sue-buh-rao) triumphed, despite mammoth challenges and a lack of recognition that persists to this day. National Cancer Research Month is a fitting time to look back on his extraordinary life and work and pay tribute to his accomplishments.
 

‘Yella,’ folic acid, and a paradigm shift

No one appreciates Dr. SubbaRow more than a cadre of Indian-born physicians who have kept his legacy alive in journal articles, presentations, and a Pulitzer Prize-winning book. Among them is author and oncologist Siddhartha Mukherjee, MD, who chronicled Dr. SubbaRow’s achievements in his New York Times No. 1 bestseller, “The Emperor of All Maladies: A Biography of Cancer.”

As Dr. Mukherjee wrote, Dr. SubbaRow was a “pioneer in many ways, a physician turned cellular physiologist, a chemist who had accidentally wandered into biology.” (Per Indian tradition, SubbaRow is the doctor’s first name, and Yellapragada is his surname, but medical literature uses SubbaRow as his cognomen, with some variations in spelling. Dr. Mukherjee wrote that his friends called him “Yella.”)

Dr. SubbaRow came to the United States in 1923, after enduring a difficult childhood and young adulthood. He’d survived bouts of religious fervor, childhood rebellion (including a bid to run away from home and become a banana trader), and a failed arranged marriage. His wife bore him a child who died in infancy. He left it all behind.

In Boston, medical officials rejected his degree. Broke, he worked for a time as a night porter at Brigham and Women’s Hospital in Boston, changing sheets and cleaning urinals. To a poor but proud high-caste Indian Brahmin, the culture shock of carrying out these tasks must have been especially jarring.

Dr. SubbaRow went on to earn a diploma from Harvard Medical School, also in Boston, and became a junior faculty member. As a foreigner, Dr. Mukherjee wrote, Dr. SubbaRow was a “reclusive, nocturnal, heavily accented vegetarian,” so different from his colleagues that advancement seemed impossible. Despite his pioneering biochemistry work, Harvard later declined to offer Dr. SubbaRow a tenured faculty position.

By the early 1940s, he took a job at an upstate New York pharmaceutical company called Lederle Labs (later purchased by Pfizer). At Lederle, Dr. SubbaRow strove to synthesize the vitamin known as folic acid. He ended up creating a kind of antivitamin, a lookalike that acted like folic acid but only succeeded in gumming up the works in receptors. But what good would it do to stop the body from absorbing folic acid? Plenty, it turned out.
 

Discoveries pile up, but credit and fame prove elusive

Dr. SubbaRow was no stranger to producing landmark biological work. He’d previously codiscovered phosphocreatine and ATP, which are crucial to muscular contractions. However, “in 1935, he had to disown the extent of his role in the discovery of the color test related to phosphorus, instead giving the credit to his co-author, who was being considered for promotion to a full professorship at Harvard,” wrote author Gerald Posner in his 2020 book, “Pharma: Greed, Lies and the Poisoning of America.”

Houston-area oncologist Kirtan Nautiyal, MD, who paid tribute to Dr. SubbaRow in a 2018 article, contended that “with his Indian instinct for self-effacement, he had irreparably sabotaged his own career.”

Dr. SubbaRow and his team also developed “the first effective treatment of filariasis, which causes elephantiasis of the lower limbs and genitals in millions of people, mainly in tropical countries,” Dr. Nautiyal wrote. “Later in the decade, his antibiotic program generated polymyxin, the first effective treatment against the class of bacteria called Gram negatives, and aureomycin, the first “broad-spectrum’ antibiotic.” (Aureomycin is also the first tetracycline antibiotic.)

Dr. SubbaRow’s discovery of a folic acid antagonist would again go largely unheralded. But first came the realization that folic acid made childhood leukemia worse, not better, and the prospect that this process could potentially be reversed.
 

Rise of methotrexate and fall of leukemia

In Boston, Sidney Farber, MD, a Boston pathologist, was desperate to help Robert Sandler, a 2-year-old leukemia patient. Dr. Farber contacted his ex-colleague Dr. SubbaRow to request a supply of aminopterin, an early version of methotrexate that Dr. SubbaRow and his team had developed. Dr. Farber injected Robert with the substance and within 3 days, the toddler’s white blood count started falling – fast. He stopped bleeding, resumed eating, and once again seemed almost identical to his twin brother, as Dr. Mukherjee wrote in his book.

Leukemia had never gone into remission before. Unfortunately, the treatment only worked temporarily. Robert, like other children treated with the drug, relapsed and died within months. But Dr. Farber “saw a door open” – a chemical, a kind of chemotherapy, that could turn back cancer. In the case of folic acid antagonists, they do so by stopping cancer cells from replicating.

Methotrexate, a related agent synthesized by Dr. SubbaRow, would become a mainstay of leukemia treatment and begin to produce long-term remission from acute lymphoblastic leukemia in 1970, when combination chemotherapy was developed.

Other cancers fell to methotrexate treatment. “Previous assumptions that cancer was nearly always fatal were revised, and the field of medical oncology (treatment of cancer with chemotherapy), which had not previously existed, was formally established in 1971,” according to the National Cancer Institute’s history of methotrexate. This account does not mention Dr. SubbaRow.
 

Death takes the doctor, but his legacy remains

In biographies, as well as his own words, Dr. SubbaRow comes across as a prickly, hard-driving workaholic who had little interest in intimate human connections. “It is not good to ask in every letter when I will be back,” he wrote to his wife back in India, before cutting off ties completely in the early 1930s. “I will come as early as possible. ... I do not want to write anything more.”

It seems, as his biographer S.P.K. Gupta noted, that “he was quite determined that the time allotted to him on Earth should be completely devoted to finding cures for ailments that plagued mankind.”

Still, Dr. SubbaRow’s research team was devoted to him, and he had plenty of reasons to be bitter, such as the prejudice and isolation he encountered in the United States and earlier, in British-run India. According to Mr. Posner’s book, even as a young medical student, Dr. SubbaRow heeded the call of Indian independence activist Mohandas Gandhi. He “refused the British surgical gown given him at school and instead donned a traditional and simple cotton Khadi. That act of defiance cost SubbaRow the college degree that was necessary for him to get into the State Medical College.”

During the last year of his life, Dr. SubbaRow faced yet another humiliation: In his landmark 1948 study about aminopterin as a treatment for leukemia, his colleague Dr. Farber failed to credit him, an “astonishing omission” as Yaddanapudi Ravindranath, MBBS, a pediatric hematologist/oncologist at Wayne State University, Detroit, put it. “From everything I know, Dr. Farber spent the rest of his career apologizing and trying to make amends for it,” Dr. Ravindranath said in an interview.
 

A career cut short, and a lasting legacy

In 1948, at the age of 53, Dr. SubbaRow suddenly died. “Many think Dr. SubbaRow would have won [the] Nobel Prize had he lived a few years longer,” said Dr. Ravindranath.

Like Dr. SubbaRow, Dr. Ravindranath was born in Andhra Pradesh state, near the city of Chennai formerly known as Madras. “Being a compatriot, in a way I continue his legacy, and I am obviously proud of him,” said Dr. Ravindranath, who has conducted his own landmark research regarding methotrexate and leukemia.

Nearly 75 years after Dr. SubbaRow’s death, Indian-born physicians like Dr. Ravindranath continue to honor him in print, trying to ensure that he’s not forgotten. Methotrexate remains a crucial treatment for leukemia, along with a long list of other ailments, including psoriasis.

Recognition for “Yella” may have come late and infrequently, but a Lederle Laboratories research library named after him offered Dr. SubbaRow a kind of immortality. A plaque there memorialized him in stone as a scientist, teacher, philosopher, and humanitarian, featuring the quote: “Science simply prolongs life. Religion deepens it.”

By all accounts, Dr. SubbaRow was a man of science and faith who had faith in science.

We have a half-forgotten Indian immigrant to thank – a hospital night porter turned biochemist –for revolutionizing treatment of leukemia, the once deadly childhood scourge that is still the most common pediatric cancer.

Dr. Yellapragada SubbaRow has been called the “father of chemotherapy” for developing methotrexate, a powerful, inexpensive therapy for leukemia and other diseases, and he is celebrated for additional scientific achievements. Yet Dr. SubbaRow’s life was marked more by struggle than glory.

1995 Indian stamp; photo in public domain

Born poor in southeastern India, he nearly succumbed to a tropical disease that killed two older brothers, and he didn’t focus on schoolwork until his father died. Later, prejudice dogged his years as an immigrant to the United States, and a blood clot took his life at the age of 53.

Scientifically, however, Dr. SubbaRow (pronounced sue-buh-rao) triumphed, despite mammoth challenges and a lack of recognition that persists to this day. National Cancer Research Month is a fitting time to look back on his extraordinary life and work and pay tribute to his accomplishments.
 

‘Yella,’ folic acid, and a paradigm shift

No one appreciates Dr. SubbaRow more than a cadre of Indian-born physicians who have kept his legacy alive in journal articles, presentations, and a Pulitzer Prize-winning book. Among them is author and oncologist Siddhartha Mukherjee, MD, who chronicled Dr. SubbaRow’s achievements in his New York Times No. 1 bestseller, “The Emperor of All Maladies: A Biography of Cancer.”

As Dr. Mukherjee wrote, Dr. SubbaRow was a “pioneer in many ways, a physician turned cellular physiologist, a chemist who had accidentally wandered into biology.” (Per Indian tradition, SubbaRow is the doctor’s first name, and Yellapragada is his surname, but medical literature uses SubbaRow as his cognomen, with some variations in spelling. Dr. Mukherjee wrote that his friends called him “Yella.”)

Dr. SubbaRow came to the United States in 1923, after enduring a difficult childhood and young adulthood. He’d survived bouts of religious fervor, childhood rebellion (including a bid to run away from home and become a banana trader), and a failed arranged marriage. His wife bore him a child who died in infancy. He left it all behind.

In Boston, medical officials rejected his degree. Broke, he worked for a time as a night porter at Brigham and Women’s Hospital in Boston, changing sheets and cleaning urinals. To a poor but proud high-caste Indian Brahmin, the culture shock of carrying out these tasks must have been especially jarring.

Dr. SubbaRow went on to earn a diploma from Harvard Medical School, also in Boston, and became a junior faculty member. As a foreigner, Dr. Mukherjee wrote, Dr. SubbaRow was a “reclusive, nocturnal, heavily accented vegetarian,” so different from his colleagues that advancement seemed impossible. Despite his pioneering biochemistry work, Harvard later declined to offer Dr. SubbaRow a tenured faculty position.

By the early 1940s, he took a job at an upstate New York pharmaceutical company called Lederle Labs (later purchased by Pfizer). At Lederle, Dr. SubbaRow strove to synthesize the vitamin known as folic acid. He ended up creating a kind of antivitamin, a lookalike that acted like folic acid but only succeeded in gumming up the works in receptors. But what good would it do to stop the body from absorbing folic acid? Plenty, it turned out.
 

Discoveries pile up, but credit and fame prove elusive

Dr. SubbaRow was no stranger to producing landmark biological work. He’d previously codiscovered phosphocreatine and ATP, which are crucial to muscular contractions. However, “in 1935, he had to disown the extent of his role in the discovery of the color test related to phosphorus, instead giving the credit to his co-author, who was being considered for promotion to a full professorship at Harvard,” wrote author Gerald Posner in his 2020 book, “Pharma: Greed, Lies and the Poisoning of America.”

Houston-area oncologist Kirtan Nautiyal, MD, who paid tribute to Dr. SubbaRow in a 2018 article, contended that “with his Indian instinct for self-effacement, he had irreparably sabotaged his own career.”

Dr. SubbaRow and his team also developed “the first effective treatment of filariasis, which causes elephantiasis of the lower limbs and genitals in millions of people, mainly in tropical countries,” Dr. Nautiyal wrote. “Later in the decade, his antibiotic program generated polymyxin, the first effective treatment against the class of bacteria called Gram negatives, and aureomycin, the first “broad-spectrum’ antibiotic.” (Aureomycin is also the first tetracycline antibiotic.)

Dr. SubbaRow’s discovery of a folic acid antagonist would again go largely unheralded. But first came the realization that folic acid made childhood leukemia worse, not better, and the prospect that this process could potentially be reversed.
 

Rise of methotrexate and fall of leukemia

In Boston, Sidney Farber, MD, a Boston pathologist, was desperate to help Robert Sandler, a 2-year-old leukemia patient. Dr. Farber contacted his ex-colleague Dr. SubbaRow to request a supply of aminopterin, an early version of methotrexate that Dr. SubbaRow and his team had developed. Dr. Farber injected Robert with the substance and within 3 days, the toddler’s white blood count started falling – fast. He stopped bleeding, resumed eating, and once again seemed almost identical to his twin brother, as Dr. Mukherjee wrote in his book.

Leukemia had never gone into remission before. Unfortunately, the treatment only worked temporarily. Robert, like other children treated with the drug, relapsed and died within months. But Dr. Farber “saw a door open” – a chemical, a kind of chemotherapy, that could turn back cancer. In the case of folic acid antagonists, they do so by stopping cancer cells from replicating.

Methotrexate, a related agent synthesized by Dr. SubbaRow, would become a mainstay of leukemia treatment and begin to produce long-term remission from acute lymphoblastic leukemia in 1970, when combination chemotherapy was developed.

Other cancers fell to methotrexate treatment. “Previous assumptions that cancer was nearly always fatal were revised, and the field of medical oncology (treatment of cancer with chemotherapy), which had not previously existed, was formally established in 1971,” according to the National Cancer Institute’s history of methotrexate. This account does not mention Dr. SubbaRow.
 

Death takes the doctor, but his legacy remains

In biographies, as well as his own words, Dr. SubbaRow comes across as a prickly, hard-driving workaholic who had little interest in intimate human connections. “It is not good to ask in every letter when I will be back,” he wrote to his wife back in India, before cutting off ties completely in the early 1930s. “I will come as early as possible. ... I do not want to write anything more.”

It seems, as his biographer S.P.K. Gupta noted, that “he was quite determined that the time allotted to him on Earth should be completely devoted to finding cures for ailments that plagued mankind.”

Still, Dr. SubbaRow’s research team was devoted to him, and he had plenty of reasons to be bitter, such as the prejudice and isolation he encountered in the United States and earlier, in British-run India. According to Mr. Posner’s book, even as a young medical student, Dr. SubbaRow heeded the call of Indian independence activist Mohandas Gandhi. He “refused the British surgical gown given him at school and instead donned a traditional and simple cotton Khadi. That act of defiance cost SubbaRow the college degree that was necessary for him to get into the State Medical College.”

During the last year of his life, Dr. SubbaRow faced yet another humiliation: In his landmark 1948 study about aminopterin as a treatment for leukemia, his colleague Dr. Farber failed to credit him, an “astonishing omission” as Yaddanapudi Ravindranath, MBBS, a pediatric hematologist/oncologist at Wayne State University, Detroit, put it. “From everything I know, Dr. Farber spent the rest of his career apologizing and trying to make amends for it,” Dr. Ravindranath said in an interview.
 

A career cut short, and a lasting legacy

In 1948, at the age of 53, Dr. SubbaRow suddenly died. “Many think Dr. SubbaRow would have won [the] Nobel Prize had he lived a few years longer,” said Dr. Ravindranath.

Like Dr. SubbaRow, Dr. Ravindranath was born in Andhra Pradesh state, near the city of Chennai formerly known as Madras. “Being a compatriot, in a way I continue his legacy, and I am obviously proud of him,” said Dr. Ravindranath, who has conducted his own landmark research regarding methotrexate and leukemia.

Nearly 75 years after Dr. SubbaRow’s death, Indian-born physicians like Dr. Ravindranath continue to honor him in print, trying to ensure that he’s not forgotten. Methotrexate remains a crucial treatment for leukemia, along with a long list of other ailments, including psoriasis.

Recognition for “Yella” may have come late and infrequently, but a Lederle Laboratories research library named after him offered Dr. SubbaRow a kind of immortality. A plaque there memorialized him in stone as a scientist, teacher, philosopher, and humanitarian, featuring the quote: “Science simply prolongs life. Religion deepens it.”

By all accounts, Dr. SubbaRow was a man of science and faith who had faith in science.

The link between obesity and cancer has increasingly been emphasized in public health messages, but is the current message correct?

“Being overweight or having obesity increases your risk of getting cancer,” warns the U.S. Centers for Disease Control and Prevention. It warns that overweight/obesity is “linked with a higher risk of getting 13 types of cancer ... [which] make up 40% of all cancers diagnosed in the United States each year.”

But that message, which is also promulgated by many cancer organizations, is based on data from observational studies, which have many limitations.

A new study based on Mendelian randomization studies has come to a slightly different conclusion and has found a potential causal association with just six cancers.

In addition, it found an inverse relationship for breast cancer, in which early-life obesity was associated with a reduced risk of breast cancer, and the relationship with obesity was “complicated” for lung and prostate cancer.

The study, headed by Zhe Fang, MBBS, Harvard T. H. Chan School of Public Health, Boston, Mass., was published in the Journal of the National Cancer Institute

“For a seemingly straightforward question of whether excessive body fatness causes cancer, the answer may not be straightforward after all,” writes Song Yao, PhD, professor of oncology, Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., in an accompanying editorial

“How to craft a simple public health message to convey the complexity and nuances of the relationships may be a challenge to be grappled with going forward,” he added.

In an interview, Dr. Yao said that it “really depends on what kind of message you want to get out.”

“If you want to talk about cancer overall, as one disease, we all know that a clear association with obesity does not exist,” he said. “It’s not that simple.”

“You really cannot say that obesity increases cancer risk overall,” he said.

For some cancers included in the study, Dr. Yao continued, it was “very clear that obesity increased the risk ... but for some other cancer types, we either don’t have enough data yet or the association is not as consistent.”

This, he said, is especially the case for prostate and lung cancer.

All of this indicates that there is a complex relationship between obesity and cancer risk, he maintains.

“We always think obesity is bad, not only for cancer but also for more common conditions, like hypertension, diabetes, and cardiovascular disease,” Dr. Yao noted. This points to the link between obesity and chronic inflammation, he added.

However, there are also other hypotheses, including synthesis of estrogen in adipose tissue, which may explain the link between obesity and breast cancer risk in older women.

However, in younger women, obesity protects against breast cancer, and “we really don’t know why,” Dr. Yao said.

The new study used Mendelian randomization to examine these relationships. This is a “new tool that we have developed over the past 20 years or so, largely because there is so much data coming from genome-wide association studies,” Dr. Yao explained.

It has “advantages” over other methods, including observational studies. One of its strengths is that it is “not impacted by reverse causality,” because genetic risk does not change over time.

However, he said, it is “quite straightforward to think that the genetics do not change, but at the same time, the environment we live in throughout our life course changes,” and the impact of genetic variants may be “washed out.”

How genetics influences cancer risk may therefore change over time, and it is a “dynamic process,” Dr. Yao commented.

In addition, this approach has its own limitations, he said, because it depends on how much of the variation in a given measure can be attributed to genetic factors.
 

New conclusions

In their study, Dr. Fang and colleagues reviewed 204 meta-analyses of 2,179 individual estimates from 507 cohort or case-control studies. They found “strong evidence” that supports the association between obesity and 11 cancers.

These are esophageal adenocarcinoma, multiple myeloma, and cancers of the gastric cardia, colon, rectum, biliary tract system, pancreas, breast, endometrium, ovary, and kidney.

They note, however, that the associations “may be causal for some malignancies” but that the co-occurrence of obesity with various cancer risk factors means that others may be “susceptible to potential confounding bias.”

To overcome some of these limitations, the team looked to Mendelian randomization studies that examined the association between genetic variants linked to body mass index (BMI), indicating lifetime risk of high BMI, and cancer risk for a range of cancer types.

These Mendelian randomization studies were then compared with the results of large-scale conventional observational studies, as well as with evidence in reports from the International Agency for Research on Cancer and the World Cancer Research Fund–American Institute of Cancer Research, which also include experimental studies.

The researchers say that, overall, the Mendelian randomization studies “further establish the causality of obesity” with six cancer types: colorectal, endometrial, ovarian, kidney, and pancreatic cancer, and esophageal adenocarcinoma.

In addition, these studies further establish the inverse relationship of early-life obesity with breast cancer.

However, the approach could not confirm a positive association between obesity and gallbladder and gastric cardia cancer, as well as multiple myeloma.

“This could be due to low power,” the team suggests, “and larger studies are required.”

With respect to lung cancer, the Mendelian randomization identified a positive association with obesity that supports the inverse association identified in observational studies, that is, that obesity may reduce the risk for lung cancer.

The researchers suggest this may reflect reverse causality related to the loss of lean body mass before diagnosis, as well as confounding by smoking.

For prostate cancer, the evidence was “conflicting” and “implies a complicated role of obesity,” Dr. Zhang and colleagues comment.

The link between obesity and lower prostate-specific antigen levels, they suggest, may result in a detection bias by masking the presence of prostate cancer, or it “could be biological” in origin, owing to reduced androgen levels.

For six cancer types for which a causal relationship with obesity could be established, the effect estimates from the Mendelian randomization studies were stronger than those seen in conventional studies, with the magnitude of risk ranging from 1.14-fold for early-life obesity and breast cancer to 1.37-fold for adult obesity and esophageal adenocarcinoma.

In another editorial accompanying the new study, Graham A. Colditz, MD, DrPH, from Washington University School of Medicine, St. Louis, underlined that childhood and adolescent obesity and their contribution to cancer risk need further attention.

“To reap the reward from past research, we must act to implement effective strategies to reduce childhood and adolescent adiposity, reduce excess weight gain in adult years, and maintain a healthy weight,” he writes.

“This will require us to change the way we live, but COVID-19 has shown we can make changes to how we live and work. Let us keep the changes we have already made, or take on new ones, that will cut our collective cancer toll,” he implores.

No funding for the study was described. Dr. Colditz is supported by the Breast Cancer Research Foundation. No other relevant financial relationships were described.

A version of this article first appeared on Medscape.com.

The link between obesity and cancer has increasingly been emphasized in public health messages, but is the current message correct?

“Being overweight or having obesity increases your risk of getting cancer,” warns the U.S. Centers for Disease Control and Prevention. It warns that overweight/obesity is “linked with a higher risk of getting 13 types of cancer ... [which] make up 40% of all cancers diagnosed in the United States each year.”

But that message, which is also promulgated by many cancer organizations, is based on data from observational studies, which have many limitations.

A new study based on Mendelian randomization studies has come to a slightly different conclusion and has found a potential causal association with just six cancers.

In addition, it found an inverse relationship for breast cancer, in which early-life obesity was associated with a reduced risk of breast cancer, and the relationship with obesity was “complicated” for lung and prostate cancer.

The study, headed by Zhe Fang, MBBS, Harvard T. H. Chan School of Public Health, Boston, Mass., was published in the Journal of the National Cancer Institute

“For a seemingly straightforward question of whether excessive body fatness causes cancer, the answer may not be straightforward after all,” writes Song Yao, PhD, professor of oncology, Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., in an accompanying editorial

“How to craft a simple public health message to convey the complexity and nuances of the relationships may be a challenge to be grappled with going forward,” he added.

In an interview, Dr. Yao said that it “really depends on what kind of message you want to get out.”

“If you want to talk about cancer overall, as one disease, we all know that a clear association with obesity does not exist,” he said. “It’s not that simple.”

“You really cannot say that obesity increases cancer risk overall,” he said.

For some cancers included in the study, Dr. Yao continued, it was “very clear that obesity increased the risk ... but for some other cancer types, we either don’t have enough data yet or the association is not as consistent.”

This, he said, is especially the case for prostate and lung cancer.

All of this indicates that there is a complex relationship between obesity and cancer risk, he maintains.

“We always think obesity is bad, not only for cancer but also for more common conditions, like hypertension, diabetes, and cardiovascular disease,” Dr. Yao noted. This points to the link between obesity and chronic inflammation, he added.

However, there are also other hypotheses, including synthesis of estrogen in adipose tissue, which may explain the link between obesity and breast cancer risk in older women.

However, in younger women, obesity protects against breast cancer, and “we really don’t know why,” Dr. Yao said.

The new study used Mendelian randomization to examine these relationships. This is a “new tool that we have developed over the past 20 years or so, largely because there is so much data coming from genome-wide association studies,” Dr. Yao explained.

It has “advantages” over other methods, including observational studies. One of its strengths is that it is “not impacted by reverse causality,” because genetic risk does not change over time.

However, he said, it is “quite straightforward to think that the genetics do not change, but at the same time, the environment we live in throughout our life course changes,” and the impact of genetic variants may be “washed out.”

How genetics influences cancer risk may therefore change over time, and it is a “dynamic process,” Dr. Yao commented.

In addition, this approach has its own limitations, he said, because it depends on how much of the variation in a given measure can be attributed to genetic factors.
 

New conclusions

In their study, Dr. Fang and colleagues reviewed 204 meta-analyses of 2,179 individual estimates from 507 cohort or case-control studies. They found “strong evidence” that supports the association between obesity and 11 cancers.

These are esophageal adenocarcinoma, multiple myeloma, and cancers of the gastric cardia, colon, rectum, biliary tract system, pancreas, breast, endometrium, ovary, and kidney.

They note, however, that the associations “may be causal for some malignancies” but that the co-occurrence of obesity with various cancer risk factors means that others may be “susceptible to potential confounding bias.”

To overcome some of these limitations, the team looked to Mendelian randomization studies that examined the association between genetic variants linked to body mass index (BMI), indicating lifetime risk of high BMI, and cancer risk for a range of cancer types.

These Mendelian randomization studies were then compared with the results of large-scale conventional observational studies, as well as with evidence in reports from the International Agency for Research on Cancer and the World Cancer Research Fund–American Institute of Cancer Research, which also include experimental studies.

The researchers say that, overall, the Mendelian randomization studies “further establish the causality of obesity” with six cancer types: colorectal, endometrial, ovarian, kidney, and pancreatic cancer, and esophageal adenocarcinoma.

In addition, these studies further establish the inverse relationship of early-life obesity with breast cancer.

However, the approach could not confirm a positive association between obesity and gallbladder and gastric cardia cancer, as well as multiple myeloma.

“This could be due to low power,” the team suggests, “and larger studies are required.”

With respect to lung cancer, the Mendelian randomization identified a positive association with obesity that supports the inverse association identified in observational studies, that is, that obesity may reduce the risk for lung cancer.

The researchers suggest this may reflect reverse causality related to the loss of lean body mass before diagnosis, as well as confounding by smoking.

For prostate cancer, the evidence was “conflicting” and “implies a complicated role of obesity,” Dr. Zhang and colleagues comment.

The link between obesity and lower prostate-specific antigen levels, they suggest, may result in a detection bias by masking the presence of prostate cancer, or it “could be biological” in origin, owing to reduced androgen levels.

For six cancer types for which a causal relationship with obesity could be established, the effect estimates from the Mendelian randomization studies were stronger than those seen in conventional studies, with the magnitude of risk ranging from 1.14-fold for early-life obesity and breast cancer to 1.37-fold for adult obesity and esophageal adenocarcinoma.

In another editorial accompanying the new study, Graham A. Colditz, MD, DrPH, from Washington University School of Medicine, St. Louis, underlined that childhood and adolescent obesity and their contribution to cancer risk need further attention.

“To reap the reward from past research, we must act to implement effective strategies to reduce childhood and adolescent adiposity, reduce excess weight gain in adult years, and maintain a healthy weight,” he writes.

“This will require us to change the way we live, but COVID-19 has shown we can make changes to how we live and work. Let us keep the changes we have already made, or take on new ones, that will cut our collective cancer toll,” he implores.

No funding for the study was described. Dr. Colditz is supported by the Breast Cancer Research Foundation. No other relevant financial relationships were described.

A version of this article first appeared on Medscape.com.

The link between obesity and cancer has increasingly been emphasized in public health messages, but is the current message correct?

“Being overweight or having obesity increases your risk of getting cancer,” warns the U.S. Centers for Disease Control and Prevention. It warns that overweight/obesity is “linked with a higher risk of getting 13 types of cancer ... [which] make up 40% of all cancers diagnosed in the United States each year.”

But that message, which is also promulgated by many cancer organizations, is based on data from observational studies, which have many limitations.

A new study based on Mendelian randomization studies has come to a slightly different conclusion and has found a potential causal association with just six cancers.

In addition, it found an inverse relationship for breast cancer, in which early-life obesity was associated with a reduced risk of breast cancer, and the relationship with obesity was “complicated” for lung and prostate cancer.

The study, headed by Zhe Fang, MBBS, Harvard T. H. Chan School of Public Health, Boston, Mass., was published in the Journal of the National Cancer Institute

“For a seemingly straightforward question of whether excessive body fatness causes cancer, the answer may not be straightforward after all,” writes Song Yao, PhD, professor of oncology, Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., in an accompanying editorial

“How to craft a simple public health message to convey the complexity and nuances of the relationships may be a challenge to be grappled with going forward,” he added.

In an interview, Dr. Yao said that it “really depends on what kind of message you want to get out.”

“If you want to talk about cancer overall, as one disease, we all know that a clear association with obesity does not exist,” he said. “It’s not that simple.”

“You really cannot say that obesity increases cancer risk overall,” he said.

For some cancers included in the study, Dr. Yao continued, it was “very clear that obesity increased the risk ... but for some other cancer types, we either don’t have enough data yet or the association is not as consistent.”

This, he said, is especially the case for prostate and lung cancer.

All of this indicates that there is a complex relationship between obesity and cancer risk, he maintains.

“We always think obesity is bad, not only for cancer but also for more common conditions, like hypertension, diabetes, and cardiovascular disease,” Dr. Yao noted. This points to the link between obesity and chronic inflammation, he added.

However, there are also other hypotheses, including synthesis of estrogen in adipose tissue, which may explain the link between obesity and breast cancer risk in older women.

However, in younger women, obesity protects against breast cancer, and “we really don’t know why,” Dr. Yao said.

The new study used Mendelian randomization to examine these relationships. This is a “new tool that we have developed over the past 20 years or so, largely because there is so much data coming from genome-wide association studies,” Dr. Yao explained.

It has “advantages” over other methods, including observational studies. One of its strengths is that it is “not impacted by reverse causality,” because genetic risk does not change over time.

However, he said, it is “quite straightforward to think that the genetics do not change, but at the same time, the environment we live in throughout our life course changes,” and the impact of genetic variants may be “washed out.”

How genetics influences cancer risk may therefore change over time, and it is a “dynamic process,” Dr. Yao commented.

In addition, this approach has its own limitations, he said, because it depends on how much of the variation in a given measure can be attributed to genetic factors.
 

New conclusions

In their study, Dr. Fang and colleagues reviewed 204 meta-analyses of 2,179 individual estimates from 507 cohort or case-control studies. They found “strong evidence” that supports the association between obesity and 11 cancers.

These are esophageal adenocarcinoma, multiple myeloma, and cancers of the gastric cardia, colon, rectum, biliary tract system, pancreas, breast, endometrium, ovary, and kidney.

They note, however, that the associations “may be causal for some malignancies” but that the co-occurrence of obesity with various cancer risk factors means that others may be “susceptible to potential confounding bias.”

To overcome some of these limitations, the team looked to Mendelian randomization studies that examined the association between genetic variants linked to body mass index (BMI), indicating lifetime risk of high BMI, and cancer risk for a range of cancer types.

These Mendelian randomization studies were then compared with the results of large-scale conventional observational studies, as well as with evidence in reports from the International Agency for Research on Cancer and the World Cancer Research Fund–American Institute of Cancer Research, which also include experimental studies.

The researchers say that, overall, the Mendelian randomization studies “further establish the causality of obesity” with six cancer types: colorectal, endometrial, ovarian, kidney, and pancreatic cancer, and esophageal adenocarcinoma.

In addition, these studies further establish the inverse relationship of early-life obesity with breast cancer.

However, the approach could not confirm a positive association between obesity and gallbladder and gastric cardia cancer, as well as multiple myeloma.

“This could be due to low power,” the team suggests, “and larger studies are required.”

With respect to lung cancer, the Mendelian randomization identified a positive association with obesity that supports the inverse association identified in observational studies, that is, that obesity may reduce the risk for lung cancer.

The researchers suggest this may reflect reverse causality related to the loss of lean body mass before diagnosis, as well as confounding by smoking.

For prostate cancer, the evidence was “conflicting” and “implies a complicated role of obesity,” Dr. Zhang and colleagues comment.

The link between obesity and lower prostate-specific antigen levels, they suggest, may result in a detection bias by masking the presence of prostate cancer, or it “could be biological” in origin, owing to reduced androgen levels.

For six cancer types for which a causal relationship with obesity could be established, the effect estimates from the Mendelian randomization studies were stronger than those seen in conventional studies, with the magnitude of risk ranging from 1.14-fold for early-life obesity and breast cancer to 1.37-fold for adult obesity and esophageal adenocarcinoma.

In another editorial accompanying the new study, Graham A. Colditz, MD, DrPH, from Washington University School of Medicine, St. Louis, underlined that childhood and adolescent obesity and their contribution to cancer risk need further attention.

“To reap the reward from past research, we must act to implement effective strategies to reduce childhood and adolescent adiposity, reduce excess weight gain in adult years, and maintain a healthy weight,” he writes.

“This will require us to change the way we live, but COVID-19 has shown we can make changes to how we live and work. Let us keep the changes we have already made, or take on new ones, that will cut our collective cancer toll,” he implores.

No funding for the study was described. Dr. Colditz is supported by the Breast Cancer Research Foundation. No other relevant financial relationships were described.

A version of this article first appeared on Medscape.com.

When the Food and Drug Administration approved abatacept in December 2021 as prophylaxis for acute graft-versus-host disease (aGVHD) in adults and children 2 years and older who are undergoing hematopoietic stem cell transplantation (HSCT), the announcement was notable for couple of key reasons.

Firstly, abatacept – initially approved in 2005 as a treatment for rheumatoid arthritis – was being repurposed for a different indication. Secondly, the new use for abatacept held promise for patients who are receiving HSCT and have trouble finding available, matched unrelated donors, a problem that disproportionately affects people of color.

Abatacept was approved based on results from the ABA2 trial, which evaluated 142 adults and children with hematologic malignancies who received a four-dose regimen of abatacept in addition to standard of care – a calcineurin inhibitor (CNI) plus methotrexate (MTX) – prior to undergoing an 8/8 HLA-matched, unrelated donor (URD) HSCT, or standard of care alone.

Another arm of the trial examined 43 recipients of a 7/8 HLA-mismatched URD HSCT who received abatacept plus standard of care, compared with a prespecified registry cohort group provided by the Center for International Blood and Marrow Transplant Research, who received CNI and MTX.

Results published in the Journal of Clinical Oncology showed the proportion of patients in the 8/8 group with severe aGVHD in the abatacept group 100 days after HSCT was not significantly lower, compared with the standard of care group (6.8% vs. 14.8%; P = .13), but there was a significant improvement in severe aGVHD–free survival (SGFS) 180 days after HSCT in the abatacept group, compared with the group that received standard of care (93.2% vs. 80%; P = .05).

Among patients in the 7/8 group, there was a significant difference in the proportion of patients with severe aGVHD favoring the abatacept group (2.3% vs. 30.2%; P < .001), and significantly improved SGFS, compared with the CIBMTR registry cohort (97.7% vs. 58.7%; P < .001)

A post hoc analysis of ABA2 published as a research letter in Blood Advances assessed abatacept using real-world data from CIBMTR. Researchers compared the 8/8 group that received standard of care with the 7/8 group that received abatacept plus standard of care and found no significant differences between relapse-free survival and overall survival for patients in the 8/8 group (adjusted hazard ratio, 0.60; 95% confidence interval, 0.28-1.28; P = .19) and 7/8 group (aHR, 0.77; 95% CI, 0.34-1.71; P = .51).

The results suggest “abatacept may eliminate that risk of a mismatched transplant in the setting of that analysis and that small cohort that was assessed there, which is good news for patients that may not have a fully matched donor on the registry,” said Stephen Spellman, vice president at Be The Match Research (operated by the National Marrow Donor Program), and senior scientific director of CIBMTR. The findings from ABA2 “were even more impressive than necessarily expected, especially in the 7/8 arm. This is a truly substantial reduction in acute GVHD risk in that patient population,” he said in an interview.
 

Could abatacept fuel greater use of mismatched, unrelated donors?

One downside of using an HLA-mismatched donor is the potential risk of developing aGVHD, Doris M. Ponce, MD, a hematologic oncologist with Memorial Sloan Kettering Cancer Center in New York, who was not involved with the research, said in an interview.

Potential risk factors for aGVHD include “having a female multiparous donor, HLA-mismatched donor, unrelated donor, donor and recipient age (>40 years), [peripheral blood stem cell] stem cell graft, recipient [cytomegalovirus] serostatus (recipient/donor), myeloablative conditioning, [total body irradiation]–based conditioning, [and] gut microbiome dysbiosis,” Dr. Ponce explained.

Abatacept’s approval may have particular relevance for people of color. “It’s been understood for a long time that the likelihood of finding an 8/8 well-matched, volunteer unrelated donor varies by race or ethnicity,” Steven Devine, MD, a board-certified oncologist who is chief medical officer of Be The Match and associate scientific director at CIBMTR, said in an interview.

Mr. Spellman noted that, of the more than 35 million donors on worldwide registries accessible through the National Marrow Donor Program’s Be The Match Registry, “the match rates differ quite substantially by race and ethnicity.” Approximately 29% of African Americans find a full match on the registry, compared with 81% of Whites, 49% of Hispanics, and 47% Asian/Pacific Islanders.

“Being able to utilize a 7/8 match in a safe, effective manner using abatacept, which abatacept has been approved for, does increase those match rates quite substantially,” he explained. Among African Americans, this means the match rate increases to 84%, among Hispanics and Asian/Pacific Islanders to approximately 90%, and among Whites to about 98%.

That kind of improvement in the match rate is “the equivalent of adding more than more than 10 million ethnically diverse donors to the registry in 1 day,” Dr. Devine said. “The availability of abatacept could really level the playing field for patients in need of a lifesaving transplant.”
 

Further study of abatacept

With abatacept, “I think the results are really encouraging, and I think that further studies [are needed] to better define how the drug would work and whether it can later prevent chronic graft versus host disease,” Dr. Devine said. He said the ABA3 trial has been designed around this question, with the hypothesis that extending abatacept to an eight-dose regimen may help with chronic GVHD.

Although the FDA’s approval of abatacept was recent, Mr. Spellman said, Be The Match has seen early indications that mismatched donors in the registry are being used, which may point to an increased utilization of abatacept. “Through October to December of 2021, there was a pretty substantial increase in the use of mismatched, unrelated donors in that time frame.”

Dr. Devine noted that he is seeing a lot of interest in using abatacept. “I think people are still learning how best to incorporate it into their standard of care right now.”

Meanwhile, Memorial Sloan Kettering Cancer Center is already planning to use abatacept, Dr. Ponce noted. “We have abatacept in our formulary for adult and children, and are planning on using it for patients receiving an unmodified graft from a [matched unrelated donor] or 1-allele [mismatched unrelated donor] using CNI and MTX-based GVHD prophylaxis.”

Dr. Devine and Mr. Spellman are employees of Be The Match and CIBMTR, which provided the registry control group for the ABA2 trial. Dr. Devine also reported that he has been a scientific advisory board member for Bristol-Myers Squibb. Dr. Ponce reports no relevant conflicts of interest.

When the Food and Drug Administration approved abatacept in December 2021 as prophylaxis for acute graft-versus-host disease (aGVHD) in adults and children 2 years and older who are undergoing hematopoietic stem cell transplantation (HSCT), the announcement was notable for couple of key reasons.

Firstly, abatacept – initially approved in 2005 as a treatment for rheumatoid arthritis – was being repurposed for a different indication. Secondly, the new use for abatacept held promise for patients who are receiving HSCT and have trouble finding available, matched unrelated donors, a problem that disproportionately affects people of color.

Abatacept was approved based on results from the ABA2 trial, which evaluated 142 adults and children with hematologic malignancies who received a four-dose regimen of abatacept in addition to standard of care – a calcineurin inhibitor (CNI) plus methotrexate (MTX) – prior to undergoing an 8/8 HLA-matched, unrelated donor (URD) HSCT, or standard of care alone.

Another arm of the trial examined 43 recipients of a 7/8 HLA-mismatched URD HSCT who received abatacept plus standard of care, compared with a prespecified registry cohort group provided by the Center for International Blood and Marrow Transplant Research, who received CNI and MTX.

Results published in the Journal of Clinical Oncology showed the proportion of patients in the 8/8 group with severe aGVHD in the abatacept group 100 days after HSCT was not significantly lower, compared with the standard of care group (6.8% vs. 14.8%; P = .13), but there was a significant improvement in severe aGVHD–free survival (SGFS) 180 days after HSCT in the abatacept group, compared with the group that received standard of care (93.2% vs. 80%; P = .05).

Among patients in the 7/8 group, there was a significant difference in the proportion of patients with severe aGVHD favoring the abatacept group (2.3% vs. 30.2%; P < .001), and significantly improved SGFS, compared with the CIBMTR registry cohort (97.7% vs. 58.7%; P < .001)

A post hoc analysis of ABA2 published as a research letter in Blood Advances assessed abatacept using real-world data from CIBMTR. Researchers compared the 8/8 group that received standard of care with the 7/8 group that received abatacept plus standard of care and found no significant differences between relapse-free survival and overall survival for patients in the 8/8 group (adjusted hazard ratio, 0.60; 95% confidence interval, 0.28-1.28; P = .19) and 7/8 group (aHR, 0.77; 95% CI, 0.34-1.71; P = .51).

The results suggest “abatacept may eliminate that risk of a mismatched transplant in the setting of that analysis and that small cohort that was assessed there, which is good news for patients that may not have a fully matched donor on the registry,” said Stephen Spellman, vice president at Be The Match Research (operated by the National Marrow Donor Program), and senior scientific director of CIBMTR. The findings from ABA2 “were even more impressive than necessarily expected, especially in the 7/8 arm. This is a truly substantial reduction in acute GVHD risk in that patient population,” he said in an interview.
 

Could abatacept fuel greater use of mismatched, unrelated donors?

One downside of using an HLA-mismatched donor is the potential risk of developing aGVHD, Doris M. Ponce, MD, a hematologic oncologist with Memorial Sloan Kettering Cancer Center in New York, who was not involved with the research, said in an interview.

Potential risk factors for aGVHD include “having a female multiparous donor, HLA-mismatched donor, unrelated donor, donor and recipient age (>40 years), [peripheral blood stem cell] stem cell graft, recipient [cytomegalovirus] serostatus (recipient/donor), myeloablative conditioning, [total body irradiation]–based conditioning, [and] gut microbiome dysbiosis,” Dr. Ponce explained.

Abatacept’s approval may have particular relevance for people of color. “It’s been understood for a long time that the likelihood of finding an 8/8 well-matched, volunteer unrelated donor varies by race or ethnicity,” Steven Devine, MD, a board-certified oncologist who is chief medical officer of Be The Match and associate scientific director at CIBMTR, said in an interview.

Mr. Spellman noted that, of the more than 35 million donors on worldwide registries accessible through the National Marrow Donor Program’s Be The Match Registry, “the match rates differ quite substantially by race and ethnicity.” Approximately 29% of African Americans find a full match on the registry, compared with 81% of Whites, 49% of Hispanics, and 47% Asian/Pacific Islanders.

“Being able to utilize a 7/8 match in a safe, effective manner using abatacept, which abatacept has been approved for, does increase those match rates quite substantially,” he explained. Among African Americans, this means the match rate increases to 84%, among Hispanics and Asian/Pacific Islanders to approximately 90%, and among Whites to about 98%.

That kind of improvement in the match rate is “the equivalent of adding more than more than 10 million ethnically diverse donors to the registry in 1 day,” Dr. Devine said. “The availability of abatacept could really level the playing field for patients in need of a lifesaving transplant.”
 

Further study of abatacept

With abatacept, “I think the results are really encouraging, and I think that further studies [are needed] to better define how the drug would work and whether it can later prevent chronic graft versus host disease,” Dr. Devine said. He said the ABA3 trial has been designed around this question, with the hypothesis that extending abatacept to an eight-dose regimen may help with chronic GVHD.

Although the FDA’s approval of abatacept was recent, Mr. Spellman said, Be The Match has seen early indications that mismatched donors in the registry are being used, which may point to an increased utilization of abatacept. “Through October to December of 2021, there was a pretty substantial increase in the use of mismatched, unrelated donors in that time frame.”

Dr. Devine noted that he is seeing a lot of interest in using abatacept. “I think people are still learning how best to incorporate it into their standard of care right now.”

Meanwhile, Memorial Sloan Kettering Cancer Center is already planning to use abatacept, Dr. Ponce noted. “We have abatacept in our formulary for adult and children, and are planning on using it for patients receiving an unmodified graft from a [matched unrelated donor] or 1-allele [mismatched unrelated donor] using CNI and MTX-based GVHD prophylaxis.”

Dr. Devine and Mr. Spellman are employees of Be The Match and CIBMTR, which provided the registry control group for the ABA2 trial. Dr. Devine also reported that he has been a scientific advisory board member for Bristol-Myers Squibb. Dr. Ponce reports no relevant conflicts of interest.

When the Food and Drug Administration approved abatacept in December 2021 as prophylaxis for acute graft-versus-host disease (aGVHD) in adults and children 2 years and older who are undergoing hematopoietic stem cell transplantation (HSCT), the announcement was notable for couple of key reasons.

Firstly, abatacept – initially approved in 2005 as a treatment for rheumatoid arthritis – was being repurposed for a different indication. Secondly, the new use for abatacept held promise for patients who are receiving HSCT and have trouble finding available, matched unrelated donors, a problem that disproportionately affects people of color.

Abatacept was approved based on results from the ABA2 trial, which evaluated 142 adults and children with hematologic malignancies who received a four-dose regimen of abatacept in addition to standard of care – a calcineurin inhibitor (CNI) plus methotrexate (MTX) – prior to undergoing an 8/8 HLA-matched, unrelated donor (URD) HSCT, or standard of care alone.

Another arm of the trial examined 43 recipients of a 7/8 HLA-mismatched URD HSCT who received abatacept plus standard of care, compared with a prespecified registry cohort group provided by the Center for International Blood and Marrow Transplant Research, who received CNI and MTX.

Results published in the Journal of Clinical Oncology showed the proportion of patients in the 8/8 group with severe aGVHD in the abatacept group 100 days after HSCT was not significantly lower, compared with the standard of care group (6.8% vs. 14.8%; P = .13), but there was a significant improvement in severe aGVHD–free survival (SGFS) 180 days after HSCT in the abatacept group, compared with the group that received standard of care (93.2% vs. 80%; P = .05).

Among patients in the 7/8 group, there was a significant difference in the proportion of patients with severe aGVHD favoring the abatacept group (2.3% vs. 30.2%; P < .001), and significantly improved SGFS, compared with the CIBMTR registry cohort (97.7% vs. 58.7%; P < .001)

A post hoc analysis of ABA2 published as a research letter in Blood Advances assessed abatacept using real-world data from CIBMTR. Researchers compared the 8/8 group that received standard of care with the 7/8 group that received abatacept plus standard of care and found no significant differences between relapse-free survival and overall survival for patients in the 8/8 group (adjusted hazard ratio, 0.60; 95% confidence interval, 0.28-1.28; P = .19) and 7/8 group (aHR, 0.77; 95% CI, 0.34-1.71; P = .51).

The results suggest “abatacept may eliminate that risk of a mismatched transplant in the setting of that analysis and that small cohort that was assessed there, which is good news for patients that may not have a fully matched donor on the registry,” said Stephen Spellman, vice president at Be The Match Research (operated by the National Marrow Donor Program), and senior scientific director of CIBMTR. The findings from ABA2 “were even more impressive than necessarily expected, especially in the 7/8 arm. This is a truly substantial reduction in acute GVHD risk in that patient population,” he said in an interview.
 

Could abatacept fuel greater use of mismatched, unrelated donors?

One downside of using an HLA-mismatched donor is the potential risk of developing aGVHD, Doris M. Ponce, MD, a hematologic oncologist with Memorial Sloan Kettering Cancer Center in New York, who was not involved with the research, said in an interview.

Potential risk factors for aGVHD include “having a female multiparous donor, HLA-mismatched donor, unrelated donor, donor and recipient age (>40 years), [peripheral blood stem cell] stem cell graft, recipient [cytomegalovirus] serostatus (recipient/donor), myeloablative conditioning, [total body irradiation]–based conditioning, [and] gut microbiome dysbiosis,” Dr. Ponce explained.

Abatacept’s approval may have particular relevance for people of color. “It’s been understood for a long time that the likelihood of finding an 8/8 well-matched, volunteer unrelated donor varies by race or ethnicity,” Steven Devine, MD, a board-certified oncologist who is chief medical officer of Be The Match and associate scientific director at CIBMTR, said in an interview.

Mr. Spellman noted that, of the more than 35 million donors on worldwide registries accessible through the National Marrow Donor Program’s Be The Match Registry, “the match rates differ quite substantially by race and ethnicity.” Approximately 29% of African Americans find a full match on the registry, compared with 81% of Whites, 49% of Hispanics, and 47% Asian/Pacific Islanders.

“Being able to utilize a 7/8 match in a safe, effective manner using abatacept, which abatacept has been approved for, does increase those match rates quite substantially,” he explained. Among African Americans, this means the match rate increases to 84%, among Hispanics and Asian/Pacific Islanders to approximately 90%, and among Whites to about 98%.

That kind of improvement in the match rate is “the equivalent of adding more than more than 10 million ethnically diverse donors to the registry in 1 day,” Dr. Devine said. “The availability of abatacept could really level the playing field for patients in need of a lifesaving transplant.”
 

Further study of abatacept

With abatacept, “I think the results are really encouraging, and I think that further studies [are needed] to better define how the drug would work and whether it can later prevent chronic graft versus host disease,” Dr. Devine said. He said the ABA3 trial has been designed around this question, with the hypothesis that extending abatacept to an eight-dose regimen may help with chronic GVHD.

Although the FDA’s approval of abatacept was recent, Mr. Spellman said, Be The Match has seen early indications that mismatched donors in the registry are being used, which may point to an increased utilization of abatacept. “Through October to December of 2021, there was a pretty substantial increase in the use of mismatched, unrelated donors in that time frame.”

Dr. Devine noted that he is seeing a lot of interest in using abatacept. “I think people are still learning how best to incorporate it into their standard of care right now.”

Meanwhile, Memorial Sloan Kettering Cancer Center is already planning to use abatacept, Dr. Ponce noted. “We have abatacept in our formulary for adult and children, and are planning on using it for patients receiving an unmodified graft from a [matched unrelated donor] or 1-allele [mismatched unrelated donor] using CNI and MTX-based GVHD prophylaxis.”

Dr. Devine and Mr. Spellman are employees of Be The Match and CIBMTR, which provided the registry control group for the ABA2 trial. Dr. Devine also reported that he has been a scientific advisory board member for Bristol-Myers Squibb. Dr. Ponce reports no relevant conflicts of interest.