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Cardiovascular complications most common with carfilzomib in relapsed myeloma
Cardiovascular (CV) adverse events were common in patients receiving proteasome inhibitor therapy for relapsed multiple myeloma, especially with carfilzomib-based therapy, according to results from the PROTECT study.
While prior studies have shown an increased risk for CV toxicities with proteasome inhibitor therapy, detailed descriptions of the events and risk factors have been lacking. “Furthermore, there is no validated protocol to help determine which patients are at highest risk of CV toxicity during therapy, nor is there management guidance for patients who experience a [CV adverse event],” wrote Robert F. Cornell, MD, of Vanderbilt University, Nashville, Tenn., and colleagues in the Journal of Clinical Oncology.
The PROTECT (Prospective Observation of Cardiac Safety with Proteasome Inhibitor) study was conducted at Vanderbilt University Medical Center and the University of Pennsylvania Abramson Cancer Center, Philadelphia, between September 2015 and March 2018.
Researchers followed 95 patients with relapsed multiple myeloma who were treated with either bortezomib or carfilzomib for a total duration of 18 months. A total of 65 patients received a carfilzomib-based therapy and 30 patients received a bortezomib-based therapy.
Study patients received a CV assessment at baseline and at the beginning of each treatment cycle for the initial six cycles of proteasome inhibitor therapy. Subsequently, patients were monitored for the development of CV adverse events. CV assessments included ECG, echocardiography, and measurement of other cardiac biomarkers, such as NTproBNP and troponin I or T.
CV toxicities were reported among 5 patients (16.7%) of patients treated with bortezomib and 33 patients (50.7%) treated with carfilzomib (P = .005).
In total, there were 64 CV adverse events reported, most of which were grade 2 or 3, and 56 of which occurred while on carfilzomib-based therapy. For carfilzomib, the most common complications were heart failure (23 cases), followed by grade 3 or 4 hypertension (13 cases). Cardiac chest pain, atrial fibrillation, and acute coronary syndrome were reported in fewer cases.
The researchers also found that elevated natriuretic peptides that occurred before starting carfilzomib therapy or within the first 3 weeks of carfilzomib therapy were associated with a substantially higher risk of CV adverse events.
Patients who have multiple CV risk factors, and especially patients with a history of CV complications and elevated baseline natriuretic peptides, should be referred for a comprehensive cardiac evaluation, the researchers advised. “Such patients are at highest risk of CV [adverse events] with carfilzomib-based therapy, and optimization of CV therapy seems to improve overall care, allow continuation of potentially lifesaving cancer treatment, and affect severity or development of CV [adverse events],” they wrote.
A key limitation of the study was the lack of standardized treatment regimens. As a result, there was a broad dosing range for carfilzomib, in comparison to bortezomib.
Some authors reported financial relationships with carfilzomib maker Amgen and bortezomib maker Takeda, as well as with other companies.
SOURCE: Cornell RF et al. J Clin Oncol. 2019 Jun 12. doi: 10.1200/JCO.19.00231.
Cardiovascular (CV) adverse events were common in patients receiving proteasome inhibitor therapy for relapsed multiple myeloma, especially with carfilzomib-based therapy, according to results from the PROTECT study.
While prior studies have shown an increased risk for CV toxicities with proteasome inhibitor therapy, detailed descriptions of the events and risk factors have been lacking. “Furthermore, there is no validated protocol to help determine which patients are at highest risk of CV toxicity during therapy, nor is there management guidance for patients who experience a [CV adverse event],” wrote Robert F. Cornell, MD, of Vanderbilt University, Nashville, Tenn., and colleagues in the Journal of Clinical Oncology.
The PROTECT (Prospective Observation of Cardiac Safety with Proteasome Inhibitor) study was conducted at Vanderbilt University Medical Center and the University of Pennsylvania Abramson Cancer Center, Philadelphia, between September 2015 and March 2018.
Researchers followed 95 patients with relapsed multiple myeloma who were treated with either bortezomib or carfilzomib for a total duration of 18 months. A total of 65 patients received a carfilzomib-based therapy and 30 patients received a bortezomib-based therapy.
Study patients received a CV assessment at baseline and at the beginning of each treatment cycle for the initial six cycles of proteasome inhibitor therapy. Subsequently, patients were monitored for the development of CV adverse events. CV assessments included ECG, echocardiography, and measurement of other cardiac biomarkers, such as NTproBNP and troponin I or T.
CV toxicities were reported among 5 patients (16.7%) of patients treated with bortezomib and 33 patients (50.7%) treated with carfilzomib (P = .005).
In total, there were 64 CV adverse events reported, most of which were grade 2 or 3, and 56 of which occurred while on carfilzomib-based therapy. For carfilzomib, the most common complications were heart failure (23 cases), followed by grade 3 or 4 hypertension (13 cases). Cardiac chest pain, atrial fibrillation, and acute coronary syndrome were reported in fewer cases.
The researchers also found that elevated natriuretic peptides that occurred before starting carfilzomib therapy or within the first 3 weeks of carfilzomib therapy were associated with a substantially higher risk of CV adverse events.
Patients who have multiple CV risk factors, and especially patients with a history of CV complications and elevated baseline natriuretic peptides, should be referred for a comprehensive cardiac evaluation, the researchers advised. “Such patients are at highest risk of CV [adverse events] with carfilzomib-based therapy, and optimization of CV therapy seems to improve overall care, allow continuation of potentially lifesaving cancer treatment, and affect severity or development of CV [adverse events],” they wrote.
A key limitation of the study was the lack of standardized treatment regimens. As a result, there was a broad dosing range for carfilzomib, in comparison to bortezomib.
Some authors reported financial relationships with carfilzomib maker Amgen and bortezomib maker Takeda, as well as with other companies.
SOURCE: Cornell RF et al. J Clin Oncol. 2019 Jun 12. doi: 10.1200/JCO.19.00231.
Cardiovascular (CV) adverse events were common in patients receiving proteasome inhibitor therapy for relapsed multiple myeloma, especially with carfilzomib-based therapy, according to results from the PROTECT study.
While prior studies have shown an increased risk for CV toxicities with proteasome inhibitor therapy, detailed descriptions of the events and risk factors have been lacking. “Furthermore, there is no validated protocol to help determine which patients are at highest risk of CV toxicity during therapy, nor is there management guidance for patients who experience a [CV adverse event],” wrote Robert F. Cornell, MD, of Vanderbilt University, Nashville, Tenn., and colleagues in the Journal of Clinical Oncology.
The PROTECT (Prospective Observation of Cardiac Safety with Proteasome Inhibitor) study was conducted at Vanderbilt University Medical Center and the University of Pennsylvania Abramson Cancer Center, Philadelphia, between September 2015 and March 2018.
Researchers followed 95 patients with relapsed multiple myeloma who were treated with either bortezomib or carfilzomib for a total duration of 18 months. A total of 65 patients received a carfilzomib-based therapy and 30 patients received a bortezomib-based therapy.
Study patients received a CV assessment at baseline and at the beginning of each treatment cycle for the initial six cycles of proteasome inhibitor therapy. Subsequently, patients were monitored for the development of CV adverse events. CV assessments included ECG, echocardiography, and measurement of other cardiac biomarkers, such as NTproBNP and troponin I or T.
CV toxicities were reported among 5 patients (16.7%) of patients treated with bortezomib and 33 patients (50.7%) treated with carfilzomib (P = .005).
In total, there were 64 CV adverse events reported, most of which were grade 2 or 3, and 56 of which occurred while on carfilzomib-based therapy. For carfilzomib, the most common complications were heart failure (23 cases), followed by grade 3 or 4 hypertension (13 cases). Cardiac chest pain, atrial fibrillation, and acute coronary syndrome were reported in fewer cases.
The researchers also found that elevated natriuretic peptides that occurred before starting carfilzomib therapy or within the first 3 weeks of carfilzomib therapy were associated with a substantially higher risk of CV adverse events.
Patients who have multiple CV risk factors, and especially patients with a history of CV complications and elevated baseline natriuretic peptides, should be referred for a comprehensive cardiac evaluation, the researchers advised. “Such patients are at highest risk of CV [adverse events] with carfilzomib-based therapy, and optimization of CV therapy seems to improve overall care, allow continuation of potentially lifesaving cancer treatment, and affect severity or development of CV [adverse events],” they wrote.
A key limitation of the study was the lack of standardized treatment regimens. As a result, there was a broad dosing range for carfilzomib, in comparison to bortezomib.
Some authors reported financial relationships with carfilzomib maker Amgen and bortezomib maker Takeda, as well as with other companies.
SOURCE: Cornell RF et al. J Clin Oncol. 2019 Jun 12. doi: 10.1200/JCO.19.00231.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
TP53 double hit predicts aggressive myeloma
Relapsed multiple myeloma becomes increasingly aggressive and difficult to treat with each additional TP53 alteration, according to investigators.
Findings from the study help illuminate the mechanics of myeloma disease progression and demonstrate the value of clonal competition assays, reported lead author Umair Munawar of the University Hospital Würzburg (Germany) and colleagues.
“The implications of mono-allelic TP53 lesions for the clinical outcome remain controversial, but clonal selection and evolution is a common feature of myeloma progression, and patients with TP53 wild-type or mono-allelic inactivation may present a double hit on relapse,” the investigators wrote in Blood. “Here, we addressed the hypothesis that sequential acquisition of TP53 hits lead to a gain of proliferative fitness of [multiple myeloma] cancer cells, inducing the expansion and domination of the affected clones within the patient’s bone marrow.”
The investigators used sleeping beauty and CRISPR/Cas9 techniques to create double- and single-hit multiple myeloma cell lines that were stably transfected with fluorescent proteins. By observing coculture pairings of wild-type, single-hit, and double-hit cells, the investigators found a hierarchy of proliferation that depended on the number of TP53 alterations. For instance, when double-hit cells were cocultured with wild-type cells in a 1:3 ratio, it took 21 days for the double-hit cells to reach 50% of the total culture population. Similarly, single-hit cells outcompeted wild-type cells after 38 days, while double-hit cells took 35 days to overcome the single-hit population.
Further testing showed that comparatively smaller initial populations of TP53-aberrant cells required longer to outcompete larger wild-type populations, which could explain why deeper responses in the clinic are often followed by longer periods without disease progression, the investigators suggested.
A comparison of transcriptomes between wild-type cells and TP53 mutants revealed differences in about 900 genes, including 14 signaling pathways. Specifically, downregulation impacted antigen processing and presentation, chemokine signaling, and oxidative phosphorylation.
“These differences on the transcriptomic level well reflect the biology of ultra–high risk disease,” the investigators wrote, referring to increased glucose uptake on PET, resistance to immunotherapies, and extramedullary disease.
“[This study] underscores the power of clonal competition assays to decipher the effect of genomic lesions in tumors to better understand their impact on progression and disease relapse in [multiple myeloma],” the investigators concluded.
The study was funded by Deutsche Forschungsgemeinschaft, the CDW Stiftung, and the IZKF Würzburg. The investigators reported additional support from the CRIS foundation, the German Cancer Aid, and the University of Würzburg.
SOURCE: Munawar U et al. Blood. 2019 Jul 24. doi: 10.1182/blood.2019000080.
Relapsed multiple myeloma becomes increasingly aggressive and difficult to treat with each additional TP53 alteration, according to investigators.
Findings from the study help illuminate the mechanics of myeloma disease progression and demonstrate the value of clonal competition assays, reported lead author Umair Munawar of the University Hospital Würzburg (Germany) and colleagues.
“The implications of mono-allelic TP53 lesions for the clinical outcome remain controversial, but clonal selection and evolution is a common feature of myeloma progression, and patients with TP53 wild-type or mono-allelic inactivation may present a double hit on relapse,” the investigators wrote in Blood. “Here, we addressed the hypothesis that sequential acquisition of TP53 hits lead to a gain of proliferative fitness of [multiple myeloma] cancer cells, inducing the expansion and domination of the affected clones within the patient’s bone marrow.”
The investigators used sleeping beauty and CRISPR/Cas9 techniques to create double- and single-hit multiple myeloma cell lines that were stably transfected with fluorescent proteins. By observing coculture pairings of wild-type, single-hit, and double-hit cells, the investigators found a hierarchy of proliferation that depended on the number of TP53 alterations. For instance, when double-hit cells were cocultured with wild-type cells in a 1:3 ratio, it took 21 days for the double-hit cells to reach 50% of the total culture population. Similarly, single-hit cells outcompeted wild-type cells after 38 days, while double-hit cells took 35 days to overcome the single-hit population.
Further testing showed that comparatively smaller initial populations of TP53-aberrant cells required longer to outcompete larger wild-type populations, which could explain why deeper responses in the clinic are often followed by longer periods without disease progression, the investigators suggested.
A comparison of transcriptomes between wild-type cells and TP53 mutants revealed differences in about 900 genes, including 14 signaling pathways. Specifically, downregulation impacted antigen processing and presentation, chemokine signaling, and oxidative phosphorylation.
“These differences on the transcriptomic level well reflect the biology of ultra–high risk disease,” the investigators wrote, referring to increased glucose uptake on PET, resistance to immunotherapies, and extramedullary disease.
“[This study] underscores the power of clonal competition assays to decipher the effect of genomic lesions in tumors to better understand their impact on progression and disease relapse in [multiple myeloma],” the investigators concluded.
The study was funded by Deutsche Forschungsgemeinschaft, the CDW Stiftung, and the IZKF Würzburg. The investigators reported additional support from the CRIS foundation, the German Cancer Aid, and the University of Würzburg.
SOURCE: Munawar U et al. Blood. 2019 Jul 24. doi: 10.1182/blood.2019000080.
Relapsed multiple myeloma becomes increasingly aggressive and difficult to treat with each additional TP53 alteration, according to investigators.
Findings from the study help illuminate the mechanics of myeloma disease progression and demonstrate the value of clonal competition assays, reported lead author Umair Munawar of the University Hospital Würzburg (Germany) and colleagues.
“The implications of mono-allelic TP53 lesions for the clinical outcome remain controversial, but clonal selection and evolution is a common feature of myeloma progression, and patients with TP53 wild-type or mono-allelic inactivation may present a double hit on relapse,” the investigators wrote in Blood. “Here, we addressed the hypothesis that sequential acquisition of TP53 hits lead to a gain of proliferative fitness of [multiple myeloma] cancer cells, inducing the expansion and domination of the affected clones within the patient’s bone marrow.”
The investigators used sleeping beauty and CRISPR/Cas9 techniques to create double- and single-hit multiple myeloma cell lines that were stably transfected with fluorescent proteins. By observing coculture pairings of wild-type, single-hit, and double-hit cells, the investigators found a hierarchy of proliferation that depended on the number of TP53 alterations. For instance, when double-hit cells were cocultured with wild-type cells in a 1:3 ratio, it took 21 days for the double-hit cells to reach 50% of the total culture population. Similarly, single-hit cells outcompeted wild-type cells after 38 days, while double-hit cells took 35 days to overcome the single-hit population.
Further testing showed that comparatively smaller initial populations of TP53-aberrant cells required longer to outcompete larger wild-type populations, which could explain why deeper responses in the clinic are often followed by longer periods without disease progression, the investigators suggested.
A comparison of transcriptomes between wild-type cells and TP53 mutants revealed differences in about 900 genes, including 14 signaling pathways. Specifically, downregulation impacted antigen processing and presentation, chemokine signaling, and oxidative phosphorylation.
“These differences on the transcriptomic level well reflect the biology of ultra–high risk disease,” the investigators wrote, referring to increased glucose uptake on PET, resistance to immunotherapies, and extramedullary disease.
“[This study] underscores the power of clonal competition assays to decipher the effect of genomic lesions in tumors to better understand their impact on progression and disease relapse in [multiple myeloma],” the investigators concluded.
The study was funded by Deutsche Forschungsgemeinschaft, the CDW Stiftung, and the IZKF Würzburg. The investigators reported additional support from the CRIS foundation, the German Cancer Aid, and the University of Würzburg.
SOURCE: Munawar U et al. Blood. 2019 Jul 24. doi: 10.1182/blood.2019000080.
FROM BLOOD
Potential improvements in convenience, tolerability of hematologic treatment
In this edition of “How I will treat my next patient,” I highlight two recent presentations regarding potential improvements in the convenience and tolerability of treatment for two hematologic malignancies: multiple myeloma and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
SC-Dara in myeloma
At the 2019 annual meeting of the American Society of Clinical Oncology, Maria-Victoria Mateos, MD, PhD, and colleagues, reported the results of COLUMBA, a phase 3 evaluation in 522 patients with multiple myeloma who were randomized to subcutaneous daratumumab (SC-Dara) or standard intravenous infusions of daratumumab (IV-Dara). A previous phase 1b study (Blood. 2017;130:838) had suggested comparable efficacy from the more convenient SC regime. Whereas conventional infusions of IV-Dara (16 mg/kg) take several hours, the SC formulation (1,800 mg–flat dose) is delivered in minutes. In COLUMBA, patients were randomized between SC- and IV-Dara weekly (cycles 1-2), then every 2 weeks (cycles 3-6), then every 4 weeks until disease progression.
Among the IV-Dara patients, the median duration of the first infusion was 421 minutes in cycle 1, 255 minutes in cycle 2, and 205 minutes in subsequent cycles – compatible with standard practice in the United States. As reported, at a median follow-up of 7.46 months, the efficacy (overall response rate, complete response rate, stringent-complete response rate, very good-partial response rate, progression-free survival, and 6-month overall survival) and safety profile were non-inferior for SC-Dara. SC-Dara patients also reported higher satisfaction with therapy.
What this means in practice
It is always a good idea to await publication of the manuscript because there may be study details and statistical nuances that make SC-Dara appear better than it will prove to be. For example, patient characteristics were slightly different between the two arms. Peer review of the final manuscript could be important in placing these results in context.
However, for treatments that demand frequent office visits over many months, reducing treatment burden for patients has value. Based on COLUMBA, it appears likely that SC-Dara will be a major convenience for patients, without obvious drawbacks in efficacy or toxicity. Meanwhile, flat dosing will be a time-saver for physicians, nursing, and pharmacy staff. If the price of the SC formulation is not exorbitant, I would expect a “win-win” that will support converting from IV- to SC-Dara as standard practice.
Acalabrutinib in CLL/SLL
Preclinical studies have shown acalabrutinib (Acala) to be more selective for Bruton’s tyrosine kinase (BTK) than the first-in-class agent ibrutinib, with less off-target kinase inhibition. As reported at the 2019 annual congress of the European Hematology Association by Paolo Ghia, MD, PhD, and colleagues in the phase 3 ASCEND trial, 310 patients with previously treated CLL were randomized between oral Acala twice daily and treatment of physician’s choice (TPC) – either idelalisib plus rituximab (maximum of seven infusions) or bendamustine plus rituximab (maximum of six cycles).
Progression-free survival was the primary endpoint. At a median of 16.1 months, progression-free survival had not been reached for Acala, in comparison with 16.5 months for TPC. Significant benefit of Acala was observed in all prognostic subsets.
Although there was no difference in overall survival at a median follow-up of about 16 months, 85% of Acala patients had a response lasting at least 12 months, compared with 60% of TPC patients. Adverse events of any grade occurred in 94% of patients treated with Acala, with 45% being grade 3-4 toxicities and six treatment-related deaths.
What this means in practice
The vast majority of CLL/SLL patients will relapse after primary therapy and will require further treatment, so the progression-free survival improvement associated with Acala in ASCEND is eye-catching. However, there are important considerations that demand closer scrutiny.
With oral agents administered until progression or unacceptable toxicity, low-grade toxicities can influence patient adherence, quality of life, and potentially the need for dose reduction or treatment interruptions. Regimens of finite duration and easy adherence monitoring may be, on balance, preferred by patients and providers – especially if the oral agent can be given in later-line with comparable overall survival.
With ibrutinib (Blood. 2017;129:2612-5), Paul M. Barr, MD, and colleagues demonstrated that higher dose intensity was associated with improved progression-free survival and that holds were associated with worsened progression-free survival. Acala’s promise of high efficacy and lower off-target toxicity will be solidified if the large (more than 500 patients) phase 3 ACE-CL-006 study (Acala vs. ibrutinib) demonstrates its relative benefit from efficacy, toxicity, and adherence perspectives, in comparison with a standard therapy that similarly demands adherence until disease progression or unacceptable toxicity.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I will treat my next patient,” I highlight two recent presentations regarding potential improvements in the convenience and tolerability of treatment for two hematologic malignancies: multiple myeloma and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
SC-Dara in myeloma
At the 2019 annual meeting of the American Society of Clinical Oncology, Maria-Victoria Mateos, MD, PhD, and colleagues, reported the results of COLUMBA, a phase 3 evaluation in 522 patients with multiple myeloma who were randomized to subcutaneous daratumumab (SC-Dara) or standard intravenous infusions of daratumumab (IV-Dara). A previous phase 1b study (Blood. 2017;130:838) had suggested comparable efficacy from the more convenient SC regime. Whereas conventional infusions of IV-Dara (16 mg/kg) take several hours, the SC formulation (1,800 mg–flat dose) is delivered in minutes. In COLUMBA, patients were randomized between SC- and IV-Dara weekly (cycles 1-2), then every 2 weeks (cycles 3-6), then every 4 weeks until disease progression.
Among the IV-Dara patients, the median duration of the first infusion was 421 minutes in cycle 1, 255 minutes in cycle 2, and 205 minutes in subsequent cycles – compatible with standard practice in the United States. As reported, at a median follow-up of 7.46 months, the efficacy (overall response rate, complete response rate, stringent-complete response rate, very good-partial response rate, progression-free survival, and 6-month overall survival) and safety profile were non-inferior for SC-Dara. SC-Dara patients also reported higher satisfaction with therapy.
What this means in practice
It is always a good idea to await publication of the manuscript because there may be study details and statistical nuances that make SC-Dara appear better than it will prove to be. For example, patient characteristics were slightly different between the two arms. Peer review of the final manuscript could be important in placing these results in context.
However, for treatments that demand frequent office visits over many months, reducing treatment burden for patients has value. Based on COLUMBA, it appears likely that SC-Dara will be a major convenience for patients, without obvious drawbacks in efficacy or toxicity. Meanwhile, flat dosing will be a time-saver for physicians, nursing, and pharmacy staff. If the price of the SC formulation is not exorbitant, I would expect a “win-win” that will support converting from IV- to SC-Dara as standard practice.
Acalabrutinib in CLL/SLL
Preclinical studies have shown acalabrutinib (Acala) to be more selective for Bruton’s tyrosine kinase (BTK) than the first-in-class agent ibrutinib, with less off-target kinase inhibition. As reported at the 2019 annual congress of the European Hematology Association by Paolo Ghia, MD, PhD, and colleagues in the phase 3 ASCEND trial, 310 patients with previously treated CLL were randomized between oral Acala twice daily and treatment of physician’s choice (TPC) – either idelalisib plus rituximab (maximum of seven infusions) or bendamustine plus rituximab (maximum of six cycles).
Progression-free survival was the primary endpoint. At a median of 16.1 months, progression-free survival had not been reached for Acala, in comparison with 16.5 months for TPC. Significant benefit of Acala was observed in all prognostic subsets.
Although there was no difference in overall survival at a median follow-up of about 16 months, 85% of Acala patients had a response lasting at least 12 months, compared with 60% of TPC patients. Adverse events of any grade occurred in 94% of patients treated with Acala, with 45% being grade 3-4 toxicities and six treatment-related deaths.
What this means in practice
The vast majority of CLL/SLL patients will relapse after primary therapy and will require further treatment, so the progression-free survival improvement associated with Acala in ASCEND is eye-catching. However, there are important considerations that demand closer scrutiny.
With oral agents administered until progression or unacceptable toxicity, low-grade toxicities can influence patient adherence, quality of life, and potentially the need for dose reduction or treatment interruptions. Regimens of finite duration and easy adherence monitoring may be, on balance, preferred by patients and providers – especially if the oral agent can be given in later-line with comparable overall survival.
With ibrutinib (Blood. 2017;129:2612-5), Paul M. Barr, MD, and colleagues demonstrated that higher dose intensity was associated with improved progression-free survival and that holds were associated with worsened progression-free survival. Acala’s promise of high efficacy and lower off-target toxicity will be solidified if the large (more than 500 patients) phase 3 ACE-CL-006 study (Acala vs. ibrutinib) demonstrates its relative benefit from efficacy, toxicity, and adherence perspectives, in comparison with a standard therapy that similarly demands adherence until disease progression or unacceptable toxicity.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I will treat my next patient,” I highlight two recent presentations regarding potential improvements in the convenience and tolerability of treatment for two hematologic malignancies: multiple myeloma and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
SC-Dara in myeloma
At the 2019 annual meeting of the American Society of Clinical Oncology, Maria-Victoria Mateos, MD, PhD, and colleagues, reported the results of COLUMBA, a phase 3 evaluation in 522 patients with multiple myeloma who were randomized to subcutaneous daratumumab (SC-Dara) or standard intravenous infusions of daratumumab (IV-Dara). A previous phase 1b study (Blood. 2017;130:838) had suggested comparable efficacy from the more convenient SC regime. Whereas conventional infusions of IV-Dara (16 mg/kg) take several hours, the SC formulation (1,800 mg–flat dose) is delivered in minutes. In COLUMBA, patients were randomized between SC- and IV-Dara weekly (cycles 1-2), then every 2 weeks (cycles 3-6), then every 4 weeks until disease progression.
Among the IV-Dara patients, the median duration of the first infusion was 421 minutes in cycle 1, 255 minutes in cycle 2, and 205 minutes in subsequent cycles – compatible with standard practice in the United States. As reported, at a median follow-up of 7.46 months, the efficacy (overall response rate, complete response rate, stringent-complete response rate, very good-partial response rate, progression-free survival, and 6-month overall survival) and safety profile were non-inferior for SC-Dara. SC-Dara patients also reported higher satisfaction with therapy.
What this means in practice
It is always a good idea to await publication of the manuscript because there may be study details and statistical nuances that make SC-Dara appear better than it will prove to be. For example, patient characteristics were slightly different between the two arms. Peer review of the final manuscript could be important in placing these results in context.
However, for treatments that demand frequent office visits over many months, reducing treatment burden for patients has value. Based on COLUMBA, it appears likely that SC-Dara will be a major convenience for patients, without obvious drawbacks in efficacy or toxicity. Meanwhile, flat dosing will be a time-saver for physicians, nursing, and pharmacy staff. If the price of the SC formulation is not exorbitant, I would expect a “win-win” that will support converting from IV- to SC-Dara as standard practice.
Acalabrutinib in CLL/SLL
Preclinical studies have shown acalabrutinib (Acala) to be more selective for Bruton’s tyrosine kinase (BTK) than the first-in-class agent ibrutinib, with less off-target kinase inhibition. As reported at the 2019 annual congress of the European Hematology Association by Paolo Ghia, MD, PhD, and colleagues in the phase 3 ASCEND trial, 310 patients with previously treated CLL were randomized between oral Acala twice daily and treatment of physician’s choice (TPC) – either idelalisib plus rituximab (maximum of seven infusions) or bendamustine plus rituximab (maximum of six cycles).
Progression-free survival was the primary endpoint. At a median of 16.1 months, progression-free survival had not been reached for Acala, in comparison with 16.5 months for TPC. Significant benefit of Acala was observed in all prognostic subsets.
Although there was no difference in overall survival at a median follow-up of about 16 months, 85% of Acala patients had a response lasting at least 12 months, compared with 60% of TPC patients. Adverse events of any grade occurred in 94% of patients treated with Acala, with 45% being grade 3-4 toxicities and six treatment-related deaths.
What this means in practice
The vast majority of CLL/SLL patients will relapse after primary therapy and will require further treatment, so the progression-free survival improvement associated with Acala in ASCEND is eye-catching. However, there are important considerations that demand closer scrutiny.
With oral agents administered until progression or unacceptable toxicity, low-grade toxicities can influence patient adherence, quality of life, and potentially the need for dose reduction or treatment interruptions. Regimens of finite duration and easy adherence monitoring may be, on balance, preferred by patients and providers – especially if the oral agent can be given in later-line with comparable overall survival.
With ibrutinib (Blood. 2017;129:2612-5), Paul M. Barr, MD, and colleagues demonstrated that higher dose intensity was associated with improved progression-free survival and that holds were associated with worsened progression-free survival. Acala’s promise of high efficacy and lower off-target toxicity will be solidified if the large (more than 500 patients) phase 3 ACE-CL-006 study (Acala vs. ibrutinib) demonstrates its relative benefit from efficacy, toxicity, and adherence perspectives, in comparison with a standard therapy that similarly demands adherence until disease progression or unacceptable toxicity.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
SC daratumumab deemed feasible for every multiple myeloma patient
CHICAGO – Subcutaneous (SC) daratumumab is noninferior to intravenous (IV) daratumumab for patients with relapsed or refractory multiple myeloma (MM), according findings from a phase 3 trial.
In the COLUMBA trial, SC daratumumab proved noninferior to IV daratumumab with regard to overall response rate and maximum trough concentration (Ctrough).
The safety profiles of the two formulations were similar, although patients who received SC daratumumab had a lower rate of infusion-related reactions. SC daratumumab also had a lower treatment burden.
“The COLUMBA study shows that [SC daratumumab] can be used in every myeloma patient [as a] single agent or, maybe in the future, in combination with the different backbones,” said Maria-Victoria Mateos, MD, PhD, of University Hospital of Salamanca (Spain).
Dr. Mateos presented results from the COLUMBA trial at the annual meeting of the American Society of Clinical Oncology.
Dr. Mateos cited a previous phase 1b study that had suggested that SC daratumumab might produce similar results as IV daratumumab (Blood. 2017;130:838) while providing a more convenient delivery method. She pointed out that infusions of IV daratumumab can last hours, while the SC formulation can be delivered in minutes.
The aim of the phase 3 COLUMBA study was to compare the IV and SC formulations head-to-head. The trial enrolled 522 patients with relapsed/refractory multiple myeloma. They were randomized to receive daratumumab SC (n = 263) or IV (n = 259).
The median patient age was 68 years (range, 33-92 years) in the IV arm and 65 years (range, 42-84 years) in the SC arm. Patients had received a median of four prior lines of therapy (range, 1-15 in the IV arm and 2-12 in the SC arm). Most patients were refractory to their last line of therapy – 85% in the IV arm and 80% in the SC arm – and most patients had standard-risk cytogenetics – 83% and 74%, respectively.
Treatment
Patients received SC daratumumab at 1,800 mg and IV daratumumab at 16 mg/kg. Both were given weekly for cycles 1-2, every 2 weeks for cycles 3-6, and every 4 weeks thereafter until disease progression.
The median duration of the first infusion was 421 minutes in the IV arm and 5 minutes in the SC arm. The median duration of the second infusion was 255 minutes and 5 minutes, respectively, and the median duration of subsequent infusions was 205 minutes and 5 minutes, respectively.
At a median follow-up of 7.46 months, 57% of patients in each arm had discontinued the study treatment. The most common reasons for discontinuation were progression – 44% of the IV arm and 43% of the SC arm – and adverse events (AEs) – 8% and 7%, respectively.
Safety
Dr. Mateos said the safety profiles of IV and SC daratumumab were comparable. However, infusion-related reactions were significantly less likely in the SC arm, occurring in 12.7% of those patients and 34.5% of patients in the IV arm (P less than .0001).
Grade 3 or higher treatment-emergent AEs occurred in 49% of patients in the IV arm and 46% of those in the SC arm. Rates of grade 5 AEs were 7% and 5%, respectively. The most common grade 3/4 AEs (in the IV and SC arms, respectively) were anemia (14% and 13%), thrombocytopenia (14% for both), neutropenia (8% and 13%), lymphopenia (6% and 5%), and hypertension (6% and 3%).
Efficacy
One of the study’s primary endpoints was overall response rate, which was 37.1% in the IV arm and 41.1% in the SC arm (relative risk, 1.11; 95% CI, 0.89-1.37; P less than .0001). This met the criteria for noninferiority, and overall response rates were comparable across all patient subgroups, Dr. Mateos noted.
The rates of complete response or stringent complete response were also comparable at 2.7% in the IV arm and 1.9% in the SC arm. Rates of very good partial response were 17.0% and 19.0%, respectively.
The study’s other primary endpoint was maximum Ctrough predose on day 1 of cycle 3. The ratio of maximum Ctrough for daratumumab SC over IV was 107.93% (90% CI, 95.74%-121.67%), which met the noninferiority criterion.
Survival outcomes were also similar between the IV and SC arms. The median progression-free survival was 6.1 months and 5.6 months, respectively (P = .9258). The rate of overall survival at 6 months was 83.0% and 87.5%, respectively (P = .6032).
Considering these results together, Dr. Mateos and colleagues concluded that SC daratumumab is noninferior to IV daratumumab.
“[SC daratumumab] has a reduced treatment burden due to a considerably shorter administration duration, and patients treated with [SC daratumumab] reported higher satisfaction with therapy,” Dr. Mateos said.
The results support the use of flat-dose 1,800-mg SC daratumumab, which is comparable with the IV formulation, she said.
The COLUMBA trial was sponsored by Janssen Research & Development. Dr. Mateos reported relationships with Amgen, Celgene, Janssen-Cilag, and Takeda.
SOURCE: Mateos MV et al. ASCO 2019, Abstract 8005.
CHICAGO – Subcutaneous (SC) daratumumab is noninferior to intravenous (IV) daratumumab for patients with relapsed or refractory multiple myeloma (MM), according findings from a phase 3 trial.
In the COLUMBA trial, SC daratumumab proved noninferior to IV daratumumab with regard to overall response rate and maximum trough concentration (Ctrough).
The safety profiles of the two formulations were similar, although patients who received SC daratumumab had a lower rate of infusion-related reactions. SC daratumumab also had a lower treatment burden.
“The COLUMBA study shows that [SC daratumumab] can be used in every myeloma patient [as a] single agent or, maybe in the future, in combination with the different backbones,” said Maria-Victoria Mateos, MD, PhD, of University Hospital of Salamanca (Spain).
Dr. Mateos presented results from the COLUMBA trial at the annual meeting of the American Society of Clinical Oncology.
Dr. Mateos cited a previous phase 1b study that had suggested that SC daratumumab might produce similar results as IV daratumumab (Blood. 2017;130:838) while providing a more convenient delivery method. She pointed out that infusions of IV daratumumab can last hours, while the SC formulation can be delivered in minutes.
The aim of the phase 3 COLUMBA study was to compare the IV and SC formulations head-to-head. The trial enrolled 522 patients with relapsed/refractory multiple myeloma. They were randomized to receive daratumumab SC (n = 263) or IV (n = 259).
The median patient age was 68 years (range, 33-92 years) in the IV arm and 65 years (range, 42-84 years) in the SC arm. Patients had received a median of four prior lines of therapy (range, 1-15 in the IV arm and 2-12 in the SC arm). Most patients were refractory to their last line of therapy – 85% in the IV arm and 80% in the SC arm – and most patients had standard-risk cytogenetics – 83% and 74%, respectively.
Treatment
Patients received SC daratumumab at 1,800 mg and IV daratumumab at 16 mg/kg. Both were given weekly for cycles 1-2, every 2 weeks for cycles 3-6, and every 4 weeks thereafter until disease progression.
The median duration of the first infusion was 421 minutes in the IV arm and 5 minutes in the SC arm. The median duration of the second infusion was 255 minutes and 5 minutes, respectively, and the median duration of subsequent infusions was 205 minutes and 5 minutes, respectively.
At a median follow-up of 7.46 months, 57% of patients in each arm had discontinued the study treatment. The most common reasons for discontinuation were progression – 44% of the IV arm and 43% of the SC arm – and adverse events (AEs) – 8% and 7%, respectively.
Safety
Dr. Mateos said the safety profiles of IV and SC daratumumab were comparable. However, infusion-related reactions were significantly less likely in the SC arm, occurring in 12.7% of those patients and 34.5% of patients in the IV arm (P less than .0001).
Grade 3 or higher treatment-emergent AEs occurred in 49% of patients in the IV arm and 46% of those in the SC arm. Rates of grade 5 AEs were 7% and 5%, respectively. The most common grade 3/4 AEs (in the IV and SC arms, respectively) were anemia (14% and 13%), thrombocytopenia (14% for both), neutropenia (8% and 13%), lymphopenia (6% and 5%), and hypertension (6% and 3%).
Efficacy
One of the study’s primary endpoints was overall response rate, which was 37.1% in the IV arm and 41.1% in the SC arm (relative risk, 1.11; 95% CI, 0.89-1.37; P less than .0001). This met the criteria for noninferiority, and overall response rates were comparable across all patient subgroups, Dr. Mateos noted.
The rates of complete response or stringent complete response were also comparable at 2.7% in the IV arm and 1.9% in the SC arm. Rates of very good partial response were 17.0% and 19.0%, respectively.
The study’s other primary endpoint was maximum Ctrough predose on day 1 of cycle 3. The ratio of maximum Ctrough for daratumumab SC over IV was 107.93% (90% CI, 95.74%-121.67%), which met the noninferiority criterion.
Survival outcomes were also similar between the IV and SC arms. The median progression-free survival was 6.1 months and 5.6 months, respectively (P = .9258). The rate of overall survival at 6 months was 83.0% and 87.5%, respectively (P = .6032).
Considering these results together, Dr. Mateos and colleagues concluded that SC daratumumab is noninferior to IV daratumumab.
“[SC daratumumab] has a reduced treatment burden due to a considerably shorter administration duration, and patients treated with [SC daratumumab] reported higher satisfaction with therapy,” Dr. Mateos said.
The results support the use of flat-dose 1,800-mg SC daratumumab, which is comparable with the IV formulation, she said.
The COLUMBA trial was sponsored by Janssen Research & Development. Dr. Mateos reported relationships with Amgen, Celgene, Janssen-Cilag, and Takeda.
SOURCE: Mateos MV et al. ASCO 2019, Abstract 8005.
CHICAGO – Subcutaneous (SC) daratumumab is noninferior to intravenous (IV) daratumumab for patients with relapsed or refractory multiple myeloma (MM), according findings from a phase 3 trial.
In the COLUMBA trial, SC daratumumab proved noninferior to IV daratumumab with regard to overall response rate and maximum trough concentration (Ctrough).
The safety profiles of the two formulations were similar, although patients who received SC daratumumab had a lower rate of infusion-related reactions. SC daratumumab also had a lower treatment burden.
“The COLUMBA study shows that [SC daratumumab] can be used in every myeloma patient [as a] single agent or, maybe in the future, in combination with the different backbones,” said Maria-Victoria Mateos, MD, PhD, of University Hospital of Salamanca (Spain).
Dr. Mateos presented results from the COLUMBA trial at the annual meeting of the American Society of Clinical Oncology.
Dr. Mateos cited a previous phase 1b study that had suggested that SC daratumumab might produce similar results as IV daratumumab (Blood. 2017;130:838) while providing a more convenient delivery method. She pointed out that infusions of IV daratumumab can last hours, while the SC formulation can be delivered in minutes.
The aim of the phase 3 COLUMBA study was to compare the IV and SC formulations head-to-head. The trial enrolled 522 patients with relapsed/refractory multiple myeloma. They were randomized to receive daratumumab SC (n = 263) or IV (n = 259).
The median patient age was 68 years (range, 33-92 years) in the IV arm and 65 years (range, 42-84 years) in the SC arm. Patients had received a median of four prior lines of therapy (range, 1-15 in the IV arm and 2-12 in the SC arm). Most patients were refractory to their last line of therapy – 85% in the IV arm and 80% in the SC arm – and most patients had standard-risk cytogenetics – 83% and 74%, respectively.
Treatment
Patients received SC daratumumab at 1,800 mg and IV daratumumab at 16 mg/kg. Both were given weekly for cycles 1-2, every 2 weeks for cycles 3-6, and every 4 weeks thereafter until disease progression.
The median duration of the first infusion was 421 minutes in the IV arm and 5 minutes in the SC arm. The median duration of the second infusion was 255 minutes and 5 minutes, respectively, and the median duration of subsequent infusions was 205 minutes and 5 minutes, respectively.
At a median follow-up of 7.46 months, 57% of patients in each arm had discontinued the study treatment. The most common reasons for discontinuation were progression – 44% of the IV arm and 43% of the SC arm – and adverse events (AEs) – 8% and 7%, respectively.
Safety
Dr. Mateos said the safety profiles of IV and SC daratumumab were comparable. However, infusion-related reactions were significantly less likely in the SC arm, occurring in 12.7% of those patients and 34.5% of patients in the IV arm (P less than .0001).
Grade 3 or higher treatment-emergent AEs occurred in 49% of patients in the IV arm and 46% of those in the SC arm. Rates of grade 5 AEs were 7% and 5%, respectively. The most common grade 3/4 AEs (in the IV and SC arms, respectively) were anemia (14% and 13%), thrombocytopenia (14% for both), neutropenia (8% and 13%), lymphopenia (6% and 5%), and hypertension (6% and 3%).
Efficacy
One of the study’s primary endpoints was overall response rate, which was 37.1% in the IV arm and 41.1% in the SC arm (relative risk, 1.11; 95% CI, 0.89-1.37; P less than .0001). This met the criteria for noninferiority, and overall response rates were comparable across all patient subgroups, Dr. Mateos noted.
The rates of complete response or stringent complete response were also comparable at 2.7% in the IV arm and 1.9% in the SC arm. Rates of very good partial response were 17.0% and 19.0%, respectively.
The study’s other primary endpoint was maximum Ctrough predose on day 1 of cycle 3. The ratio of maximum Ctrough for daratumumab SC over IV was 107.93% (90% CI, 95.74%-121.67%), which met the noninferiority criterion.
Survival outcomes were also similar between the IV and SC arms. The median progression-free survival was 6.1 months and 5.6 months, respectively (P = .9258). The rate of overall survival at 6 months was 83.0% and 87.5%, respectively (P = .6032).
Considering these results together, Dr. Mateos and colleagues concluded that SC daratumumab is noninferior to IV daratumumab.
“[SC daratumumab] has a reduced treatment burden due to a considerably shorter administration duration, and patients treated with [SC daratumumab] reported higher satisfaction with therapy,” Dr. Mateos said.
The results support the use of flat-dose 1,800-mg SC daratumumab, which is comparable with the IV formulation, she said.
The COLUMBA trial was sponsored by Janssen Research & Development. Dr. Mateos reported relationships with Amgen, Celgene, Janssen-Cilag, and Takeda.
SOURCE: Mateos MV et al. ASCO 2019, Abstract 8005.
REPORTING FROM ASCO 2019
Recombinant vaccine cut herpes zoster rate in immunocompromised patients
Two doses of recombinant zoster vaccine significantly reduced incidence of herpes zoster in adults who had undergone autologous hematopoietic stem cell transplantation (HSCT), results of a randomized, placebo-controlled trial indicate.
The incidence of herpes zoster was 30 per 1,000 person-years for patients who received the adjuvanted recombinant zoster vaccine (Shingrix) versus 94 per 1,000 person-years for those who received placebo, according to study results.
Recombinant zoster vaccine induced humoral and cellular responses that were strong and occurring at a rate higher than what was seen in the placebo group, said senior author Keith M. Sullivan, MD, of Duke University Medical Center, Durham, N.C., and coauthors, who reported findings on behalf of the Zoster Efficacy Study in Patients Undergoing HSCT (ZOE-HSCT) Study Group.
“The vaccinations were generally well tolerated, and most symptoms were mild and transient and did not substantially deter participants from receiving their second dose,” Dr. Sullivan and colleagues wrote in JAMA.
The risk of herpes zoster is increased for 2-3 years after autologous HSCT because of diminished T-cell immunity, according to the authors.
“Antiviral prophylaxis is commonly administered to patients after HSCT to prevent such complications, but the efficacy depends on adherence to treatment,” they said.
While vaccines could provide long-term protection, immunocompromised individuals receiving live attenuated vaccine would be at increased risk of varicella caused by spread of the vaccine strain, they added.
There have been a few encouraging recent studies of non-live vaccines in this setting, including one large phase 3 trial of a heat-inactivated varicella-zoster virus vaccine that showed patients undergoing autologous HSCT had a 63.8% estimated efficacy in preventing herpes zoster, investigators from that study said in The Lancet (2018 May 26;391[10135]:2116-27).
A phase 1/2a study of the adjuvanted recombinant zoster vaccine in patients undergoing HSCT demonstrated strong humoral and cell-mediated immunity responses, which provided the rationale for studying the vaccine further in the randomized ZOE-HSCT study, according to Dr. Sullivan and coauthors.
Their study included a total of 1,846 adults who had undergone autologous HSCT. They were randomized to receive two doses of the recombinant zoster vaccine, the first at 50-70 days after the procedure and the second 1-2 months later.
Herpes zoster cases were seen in 49 and 136 individuals in the vaccine and placebo groups, respectively, which resulted in overall incidences of 30 and 94 per 1,000 person-years.
The incidence rate ratio of a first episode of herpes zoster was 0.36 for individuals receiving at least one dose, which authors said was equivalent to a vaccine efficacy of 63.7%.
That efficacy rate is “very similar” to the estimated efficacy reported for the heat-inactivated varicella-zoster virus vaccine reported in The Lancet, said Dr. Sullivan and coauthors.
However, the heat-inactivated vaccine achieved that level of protection with a four-dose schedule, including one dose given prior to autologous HSCT.
“An advantage of the short 2-dose posttransplantation schedule is that more patients might complete the vaccination program,” they said in a discussion of the results, noting that 94.7% of the recombinant zoster vaccine recipients completed two doses, compared with 81.9% of recipients who received the heat-inactivated herpes zoster vaccine in the previous report.
The study was funded and sponsored by GlaxoSmithKline Biologicals SA. Dr. Sullivan reported disclosures related to GlaxoSmithKline (GSK), Kiadis Pharmaceutical, Roche Genentech, and the National Institute of Allergy and Infectious Diseases. Coauthors provided disclosures related to GSK, AbbVie, Roche, Gilead, Janssen, Pharmacyclics, Morphosys, Helsinn, Celgene, and others.
SOURCE: Bastidas A et al. JAMA. 2019 July 9. doi: 10.1001/jama.2019.9053.
Two doses of recombinant zoster vaccine significantly reduced incidence of herpes zoster in adults who had undergone autologous hematopoietic stem cell transplantation (HSCT), results of a randomized, placebo-controlled trial indicate.
The incidence of herpes zoster was 30 per 1,000 person-years for patients who received the adjuvanted recombinant zoster vaccine (Shingrix) versus 94 per 1,000 person-years for those who received placebo, according to study results.
Recombinant zoster vaccine induced humoral and cellular responses that were strong and occurring at a rate higher than what was seen in the placebo group, said senior author Keith M. Sullivan, MD, of Duke University Medical Center, Durham, N.C., and coauthors, who reported findings on behalf of the Zoster Efficacy Study in Patients Undergoing HSCT (ZOE-HSCT) Study Group.
“The vaccinations were generally well tolerated, and most symptoms were mild and transient and did not substantially deter participants from receiving their second dose,” Dr. Sullivan and colleagues wrote in JAMA.
The risk of herpes zoster is increased for 2-3 years after autologous HSCT because of diminished T-cell immunity, according to the authors.
“Antiviral prophylaxis is commonly administered to patients after HSCT to prevent such complications, but the efficacy depends on adherence to treatment,” they said.
While vaccines could provide long-term protection, immunocompromised individuals receiving live attenuated vaccine would be at increased risk of varicella caused by spread of the vaccine strain, they added.
There have been a few encouraging recent studies of non-live vaccines in this setting, including one large phase 3 trial of a heat-inactivated varicella-zoster virus vaccine that showed patients undergoing autologous HSCT had a 63.8% estimated efficacy in preventing herpes zoster, investigators from that study said in The Lancet (2018 May 26;391[10135]:2116-27).
A phase 1/2a study of the adjuvanted recombinant zoster vaccine in patients undergoing HSCT demonstrated strong humoral and cell-mediated immunity responses, which provided the rationale for studying the vaccine further in the randomized ZOE-HSCT study, according to Dr. Sullivan and coauthors.
Their study included a total of 1,846 adults who had undergone autologous HSCT. They were randomized to receive two doses of the recombinant zoster vaccine, the first at 50-70 days after the procedure and the second 1-2 months later.
Herpes zoster cases were seen in 49 and 136 individuals in the vaccine and placebo groups, respectively, which resulted in overall incidences of 30 and 94 per 1,000 person-years.
The incidence rate ratio of a first episode of herpes zoster was 0.36 for individuals receiving at least one dose, which authors said was equivalent to a vaccine efficacy of 63.7%.
That efficacy rate is “very similar” to the estimated efficacy reported for the heat-inactivated varicella-zoster virus vaccine reported in The Lancet, said Dr. Sullivan and coauthors.
However, the heat-inactivated vaccine achieved that level of protection with a four-dose schedule, including one dose given prior to autologous HSCT.
“An advantage of the short 2-dose posttransplantation schedule is that more patients might complete the vaccination program,” they said in a discussion of the results, noting that 94.7% of the recombinant zoster vaccine recipients completed two doses, compared with 81.9% of recipients who received the heat-inactivated herpes zoster vaccine in the previous report.
The study was funded and sponsored by GlaxoSmithKline Biologicals SA. Dr. Sullivan reported disclosures related to GlaxoSmithKline (GSK), Kiadis Pharmaceutical, Roche Genentech, and the National Institute of Allergy and Infectious Diseases. Coauthors provided disclosures related to GSK, AbbVie, Roche, Gilead, Janssen, Pharmacyclics, Morphosys, Helsinn, Celgene, and others.
SOURCE: Bastidas A et al. JAMA. 2019 July 9. doi: 10.1001/jama.2019.9053.
Two doses of recombinant zoster vaccine significantly reduced incidence of herpes zoster in adults who had undergone autologous hematopoietic stem cell transplantation (HSCT), results of a randomized, placebo-controlled trial indicate.
The incidence of herpes zoster was 30 per 1,000 person-years for patients who received the adjuvanted recombinant zoster vaccine (Shingrix) versus 94 per 1,000 person-years for those who received placebo, according to study results.
Recombinant zoster vaccine induced humoral and cellular responses that were strong and occurring at a rate higher than what was seen in the placebo group, said senior author Keith M. Sullivan, MD, of Duke University Medical Center, Durham, N.C., and coauthors, who reported findings on behalf of the Zoster Efficacy Study in Patients Undergoing HSCT (ZOE-HSCT) Study Group.
“The vaccinations were generally well tolerated, and most symptoms were mild and transient and did not substantially deter participants from receiving their second dose,” Dr. Sullivan and colleagues wrote in JAMA.
The risk of herpes zoster is increased for 2-3 years after autologous HSCT because of diminished T-cell immunity, according to the authors.
“Antiviral prophylaxis is commonly administered to patients after HSCT to prevent such complications, but the efficacy depends on adherence to treatment,” they said.
While vaccines could provide long-term protection, immunocompromised individuals receiving live attenuated vaccine would be at increased risk of varicella caused by spread of the vaccine strain, they added.
There have been a few encouraging recent studies of non-live vaccines in this setting, including one large phase 3 trial of a heat-inactivated varicella-zoster virus vaccine that showed patients undergoing autologous HSCT had a 63.8% estimated efficacy in preventing herpes zoster, investigators from that study said in The Lancet (2018 May 26;391[10135]:2116-27).
A phase 1/2a study of the adjuvanted recombinant zoster vaccine in patients undergoing HSCT demonstrated strong humoral and cell-mediated immunity responses, which provided the rationale for studying the vaccine further in the randomized ZOE-HSCT study, according to Dr. Sullivan and coauthors.
Their study included a total of 1,846 adults who had undergone autologous HSCT. They were randomized to receive two doses of the recombinant zoster vaccine, the first at 50-70 days after the procedure and the second 1-2 months later.
Herpes zoster cases were seen in 49 and 136 individuals in the vaccine and placebo groups, respectively, which resulted in overall incidences of 30 and 94 per 1,000 person-years.
The incidence rate ratio of a first episode of herpes zoster was 0.36 for individuals receiving at least one dose, which authors said was equivalent to a vaccine efficacy of 63.7%.
That efficacy rate is “very similar” to the estimated efficacy reported for the heat-inactivated varicella-zoster virus vaccine reported in The Lancet, said Dr. Sullivan and coauthors.
However, the heat-inactivated vaccine achieved that level of protection with a four-dose schedule, including one dose given prior to autologous HSCT.
“An advantage of the short 2-dose posttransplantation schedule is that more patients might complete the vaccination program,” they said in a discussion of the results, noting that 94.7% of the recombinant zoster vaccine recipients completed two doses, compared with 81.9% of recipients who received the heat-inactivated herpes zoster vaccine in the previous report.
The study was funded and sponsored by GlaxoSmithKline Biologicals SA. Dr. Sullivan reported disclosures related to GlaxoSmithKline (GSK), Kiadis Pharmaceutical, Roche Genentech, and the National Institute of Allergy and Infectious Diseases. Coauthors provided disclosures related to GSK, AbbVie, Roche, Gilead, Janssen, Pharmacyclics, Morphosys, Helsinn, Celgene, and others.
SOURCE: Bastidas A et al. JAMA. 2019 July 9. doi: 10.1001/jama.2019.9053.
FROM JAMA
Key clinical point: Two doses of recombinant zoster vaccine significantly reduced incidence of herpes zoster versus placebo in adults who had undergone autologous hematopoietic stem cell transplantation (HSCT).
Major finding: Herpes zoster cases were seen in 49 and 136 individuals in the vaccine and placebo groups, respectively, resulting in overall incidences of 30 and 94 per 1,000 person-years.
Study details: A randomized clinical trial (ZOE-HSCT) including 1,846 adults who had undergone autologous HSCT.
Disclosures: The study was funded and sponsored by GlaxoSmithKline Biologicals SA. Study authors reported disclosures related to GlaxoSmithKline, Kiadis Pharmaceutical, Roche Genentech, AbbVie, Roche, Gilead, Janssen, Pharmacyclics, Morphosys, Helsinn, Celgene, and others.
Source: Bastidas A et al. JAMA. 2019 July 9. doi: 10.1001/jama.2019.9053.
FDA approves Xpovio for relapsed/refractory multiple myeloma
The oral therapy was approved for patients who have received at least four prior therapies and whose disease is resistant to several other forms of treatment, including at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody, according to the FDA.
The approval provides a “treatment option for patients with multiple myeloma with no (other) available therapy,” said Richard Pazdur, MD, director of the FDA Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA Center for Drug Evaluation and Research.
The approval was based on a study that included 83 patients with RRMM who had an overall response rate of 25.3% to Xpovio in combination with dexamethasone.
“The median time to first response was 4 weeks, with a range of 1-10 weeks. The median duration of response was 3.8 months. The efficacy evaluation was supported by additional information from an ongoing, randomized trial in patients with multiple myeloma,” according to the statement.
Common side effects seen in patients taking Xpovio in combination with dexamethasone include leukopenia, neutropenia, thrombocytopenia, and anemia. Patients also reported vomiting, nausea, fatigue, diarrhea, fever, decreased appetite and weight, constipation, upper respiratory tract infections, and hyponatremia.
Patients taking Xpovio should be monitored for low blood counts, platelets, and sodium levels, and should avoid other medications that may cause dizziness or confusion. Patients’ hydration status, blood counts, and other medications should be optimized to avoid dizziness or confusion. Females of reproductive age and males with a female partner of reproductive potential must use effective contraception during treatment with Xpovio. Women who are pregnant or breastfeeding should not take Xpovio.
Xpovio must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.
Xpovio in combination with dexamethasone was granted accelerated approval, and further clinical trials are required to verify and describe the drug’s clinical benefit.
The FDA granted the approval of Xpovio to Karyopharm Therapeutics.
The oral therapy was approved for patients who have received at least four prior therapies and whose disease is resistant to several other forms of treatment, including at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody, according to the FDA.
The approval provides a “treatment option for patients with multiple myeloma with no (other) available therapy,” said Richard Pazdur, MD, director of the FDA Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA Center for Drug Evaluation and Research.
The approval was based on a study that included 83 patients with RRMM who had an overall response rate of 25.3% to Xpovio in combination with dexamethasone.
“The median time to first response was 4 weeks, with a range of 1-10 weeks. The median duration of response was 3.8 months. The efficacy evaluation was supported by additional information from an ongoing, randomized trial in patients with multiple myeloma,” according to the statement.
Common side effects seen in patients taking Xpovio in combination with dexamethasone include leukopenia, neutropenia, thrombocytopenia, and anemia. Patients also reported vomiting, nausea, fatigue, diarrhea, fever, decreased appetite and weight, constipation, upper respiratory tract infections, and hyponatremia.
Patients taking Xpovio should be monitored for low blood counts, platelets, and sodium levels, and should avoid other medications that may cause dizziness or confusion. Patients’ hydration status, blood counts, and other medications should be optimized to avoid dizziness or confusion. Females of reproductive age and males with a female partner of reproductive potential must use effective contraception during treatment with Xpovio. Women who are pregnant or breastfeeding should not take Xpovio.
Xpovio must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.
Xpovio in combination with dexamethasone was granted accelerated approval, and further clinical trials are required to verify and describe the drug’s clinical benefit.
The FDA granted the approval of Xpovio to Karyopharm Therapeutics.
The oral therapy was approved for patients who have received at least four prior therapies and whose disease is resistant to several other forms of treatment, including at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody, according to the FDA.
The approval provides a “treatment option for patients with multiple myeloma with no (other) available therapy,” said Richard Pazdur, MD, director of the FDA Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA Center for Drug Evaluation and Research.
The approval was based on a study that included 83 patients with RRMM who had an overall response rate of 25.3% to Xpovio in combination with dexamethasone.
“The median time to first response was 4 weeks, with a range of 1-10 weeks. The median duration of response was 3.8 months. The efficacy evaluation was supported by additional information from an ongoing, randomized trial in patients with multiple myeloma,” according to the statement.
Common side effects seen in patients taking Xpovio in combination with dexamethasone include leukopenia, neutropenia, thrombocytopenia, and anemia. Patients also reported vomiting, nausea, fatigue, diarrhea, fever, decreased appetite and weight, constipation, upper respiratory tract infections, and hyponatremia.
Patients taking Xpovio should be monitored for low blood counts, platelets, and sodium levels, and should avoid other medications that may cause dizziness or confusion. Patients’ hydration status, blood counts, and other medications should be optimized to avoid dizziness or confusion. Females of reproductive age and males with a female partner of reproductive potential must use effective contraception during treatment with Xpovio. Women who are pregnant or breastfeeding should not take Xpovio.
Xpovio must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.
Xpovio in combination with dexamethasone was granted accelerated approval, and further clinical trials are required to verify and describe the drug’s clinical benefit.
The FDA granted the approval of Xpovio to Karyopharm Therapeutics.
Daratumumab wins new indication for newly diagnosed myeloma patients
Janssen’s daratumumab (Darzalex) has picked up a sixth adult multiple myeloma indication, this time in combination with lenalidomide (Revlimid) and dexamethasone in newly diagnosed patients ineligible for autologous stem cell transplants.
The phase 3 MAIA trial found that 97 of 368 patients (26.4%) treated with the combination – dubbed DRd – progressed or died at a median follow-up of 28 months, versus 143 of 269 (38.8%) treated with lenalidomide and dexamethasone alone (Rd). An estimated 55.6% of patients on lenalidomide and dexamethasone, versus 70.6% with the daratumumab add-on, were alive without progression at 30 months (N Engl J Med. 2019 May 30;380[22]:2104-15).
Previously approved indications for daratumumab include relapsed or refractory disease after at least one other therapy; and combination treatment with bortezomib, melphalan, and prednisone, also in newly diagnosed patients who are ineligible for transplant.
The most common grade 3 and 4 adverse events reported in the MAIA trial were neutropenia (50.0% for the DRd group versus 35.3% for the Rd group), anemia (11.8% vs. 19.7%), lymphopenia (15.1% vs. 10.7%), and pneumonia (13.7% vs. 7.9%).
Janssen’s daratumumab (Darzalex) has picked up a sixth adult multiple myeloma indication, this time in combination with lenalidomide (Revlimid) and dexamethasone in newly diagnosed patients ineligible for autologous stem cell transplants.
The phase 3 MAIA trial found that 97 of 368 patients (26.4%) treated with the combination – dubbed DRd – progressed or died at a median follow-up of 28 months, versus 143 of 269 (38.8%) treated with lenalidomide and dexamethasone alone (Rd). An estimated 55.6% of patients on lenalidomide and dexamethasone, versus 70.6% with the daratumumab add-on, were alive without progression at 30 months (N Engl J Med. 2019 May 30;380[22]:2104-15).
Previously approved indications for daratumumab include relapsed or refractory disease after at least one other therapy; and combination treatment with bortezomib, melphalan, and prednisone, also in newly diagnosed patients who are ineligible for transplant.
The most common grade 3 and 4 adverse events reported in the MAIA trial were neutropenia (50.0% for the DRd group versus 35.3% for the Rd group), anemia (11.8% vs. 19.7%), lymphopenia (15.1% vs. 10.7%), and pneumonia (13.7% vs. 7.9%).
Janssen’s daratumumab (Darzalex) has picked up a sixth adult multiple myeloma indication, this time in combination with lenalidomide (Revlimid) and dexamethasone in newly diagnosed patients ineligible for autologous stem cell transplants.
The phase 3 MAIA trial found that 97 of 368 patients (26.4%) treated with the combination – dubbed DRd – progressed or died at a median follow-up of 28 months, versus 143 of 269 (38.8%) treated with lenalidomide and dexamethasone alone (Rd). An estimated 55.6% of patients on lenalidomide and dexamethasone, versus 70.6% with the daratumumab add-on, were alive without progression at 30 months (N Engl J Med. 2019 May 30;380[22]:2104-15).
Previously approved indications for daratumumab include relapsed or refractory disease after at least one other therapy; and combination treatment with bortezomib, melphalan, and prednisone, also in newly diagnosed patients who are ineligible for transplant.
The most common grade 3 and 4 adverse events reported in the MAIA trial were neutropenia (50.0% for the DRd group versus 35.3% for the Rd group), anemia (11.8% vs. 19.7%), lymphopenia (15.1% vs. 10.7%), and pneumonia (13.7% vs. 7.9%).
Triplet offers longest PFS yet seen in relapsed/refractory myeloma
CHICAGO – Adding isatuximab, an anti-CD38 monoclonal antibody, to pomalidomide and dexamethasone can prolong progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma, a phase 3 trial suggests.
The median PFS was 11.53 months among patients who received isatuximab (isa) plus pomalidomide and dexamethasone (Pd), compared with 6.47 months in patients who received Pd alone (P = .001).
“[W]e now have the first randomized, phase 3 study demonstrating a significant prolonged PFS benefit of CD38 targeting combined with pomalidomide and dexamethasone in relapsed/refractory myeloma,” said Paul Richardson, MD, of the Dana-Farber Cancer Institute in Boston.
“The PFS was the longest observed in this population to date ..., and ... this PFS benefit was consistent among subgroups.”
Dr. Richardson presented these results from the ICARIA-MM trial at the annual meeting of the American Society of Clinical Oncology.
Researchers enrolled 307 patients with relapsed/refractory multiple myeloma. The patients had a median age of 67 years (range, 36-86 years) and a median time from diagnosis of 4.23 years (range, 0.5-20.5 years).
The patients had received a median of three prior therapies (range, 2-11 for the isa-Pd arm and 2-10 for the Pd arm). All patients had previously received a proteasome inhibitor and an immunomodulatory agent.
The patients received isatuximab at 10 mg/kg on days 1, 8, 15, and 22 in cycle 1, then on days 1 and 15 for subsequent cycles. Pomalidomide and dexamethasone were given at standard doses in both treatment arms.
At a median follow-up of 11.6 months, 42.2% of patients were still receiving isa-Pd, and 22.9% of patients were still on Pd alone. The most common reason for stopping either treatment was disease progression (42.9% in the isa-Pd arm and 57.5% in the Pd arm).
Efficacy
The overall response rate was 60.4% in the isa-Pd arm and 35.3% in the Pd arm (P less than .0001). The rates of complete response/stringent complete response were 4.5% and 2.0%, respectively. The rates of minimal residual disease negativity were 5.2% and 0%, respectively.
The median time to next treatment was 9.1 months in the Pd arm and was not reached in the isa-Pd arm (hazard ratio, 0.538).
The median PFS was 11.53 months in the isa-Pd arm and 6.47 months in the Pd arm (HR, 0.596; P = .001). There was a PFS benefit with isa-Pd across subgroups, including in patients with renal dysfunction, those with high-risk cytogenetics, and patients who were refractory to lenalidomide.
The median overall survival was not reached in either treatment arm. The overall survival rate was 72% in the isa-Pd arm and 63% in the Pd arm (HR, 0.687).
Safety
There were more grade 3 or higher treatment-emergent adverse events (TEAEs) with isa-Pd. However, as Dr. Richardson noted, adding isa to Pd did not increase the rates of TEAEs leading to treatment discontinuation or death.
The incidence of grade 3 or higher TEAEs was 86.8% in the isa-Pd arm and 70.5% in the Pd arm. The rate of serious TEAEs was 61.8% and 53.7%, respectively.
TEAEs leading to treatment discontinuation occurred in 7.2% of patients in the isa-Pd arm and 12.8% in the Pd arm. TEAEs leading to death occurred in 7.9% and 9.4%, respectively.
Grade 3 TEAEs (in the isa-Pd and Pd arms, respectively) included upper respiratory tract infection (3.3% and 0.7%), diarrhea (2.0% and 0.7%), bronchitis (3.3% and 0.7%), pneumonia (15.1% and 13.4%), fatigue (3.9% and 0%), back pain (2.0% and 1.3%), asthenia (3.3% and 2.7%), and dyspnea (3.9% and 1.3%).
The only grade 4 TEAE was pneumonia (1.3% in both arms).
Based on the safety and efficacy results, Dr. Richardson concluded that isa-Pd “is an important new treatment option for our patients with relapsed/refractory myeloma.”
This study was funded by Sanofi. Dr. Richardson reported financial relationships with Celgene, Janssen, and Takeda. His coinvestigators reported relationships with a range of companies.
SOURCE: Richardson P et al. ASCO 2019, Abstract 8004.
CHICAGO – Adding isatuximab, an anti-CD38 monoclonal antibody, to pomalidomide and dexamethasone can prolong progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma, a phase 3 trial suggests.
The median PFS was 11.53 months among patients who received isatuximab (isa) plus pomalidomide and dexamethasone (Pd), compared with 6.47 months in patients who received Pd alone (P = .001).
“[W]e now have the first randomized, phase 3 study demonstrating a significant prolonged PFS benefit of CD38 targeting combined with pomalidomide and dexamethasone in relapsed/refractory myeloma,” said Paul Richardson, MD, of the Dana-Farber Cancer Institute in Boston.
“The PFS was the longest observed in this population to date ..., and ... this PFS benefit was consistent among subgroups.”
Dr. Richardson presented these results from the ICARIA-MM trial at the annual meeting of the American Society of Clinical Oncology.
Researchers enrolled 307 patients with relapsed/refractory multiple myeloma. The patients had a median age of 67 years (range, 36-86 years) and a median time from diagnosis of 4.23 years (range, 0.5-20.5 years).
The patients had received a median of three prior therapies (range, 2-11 for the isa-Pd arm and 2-10 for the Pd arm). All patients had previously received a proteasome inhibitor and an immunomodulatory agent.
The patients received isatuximab at 10 mg/kg on days 1, 8, 15, and 22 in cycle 1, then on days 1 and 15 for subsequent cycles. Pomalidomide and dexamethasone were given at standard doses in both treatment arms.
At a median follow-up of 11.6 months, 42.2% of patients were still receiving isa-Pd, and 22.9% of patients were still on Pd alone. The most common reason for stopping either treatment was disease progression (42.9% in the isa-Pd arm and 57.5% in the Pd arm).
Efficacy
The overall response rate was 60.4% in the isa-Pd arm and 35.3% in the Pd arm (P less than .0001). The rates of complete response/stringent complete response were 4.5% and 2.0%, respectively. The rates of minimal residual disease negativity were 5.2% and 0%, respectively.
The median time to next treatment was 9.1 months in the Pd arm and was not reached in the isa-Pd arm (hazard ratio, 0.538).
The median PFS was 11.53 months in the isa-Pd arm and 6.47 months in the Pd arm (HR, 0.596; P = .001). There was a PFS benefit with isa-Pd across subgroups, including in patients with renal dysfunction, those with high-risk cytogenetics, and patients who were refractory to lenalidomide.
The median overall survival was not reached in either treatment arm. The overall survival rate was 72% in the isa-Pd arm and 63% in the Pd arm (HR, 0.687).
Safety
There were more grade 3 or higher treatment-emergent adverse events (TEAEs) with isa-Pd. However, as Dr. Richardson noted, adding isa to Pd did not increase the rates of TEAEs leading to treatment discontinuation or death.
The incidence of grade 3 or higher TEAEs was 86.8% in the isa-Pd arm and 70.5% in the Pd arm. The rate of serious TEAEs was 61.8% and 53.7%, respectively.
TEAEs leading to treatment discontinuation occurred in 7.2% of patients in the isa-Pd arm and 12.8% in the Pd arm. TEAEs leading to death occurred in 7.9% and 9.4%, respectively.
Grade 3 TEAEs (in the isa-Pd and Pd arms, respectively) included upper respiratory tract infection (3.3% and 0.7%), diarrhea (2.0% and 0.7%), bronchitis (3.3% and 0.7%), pneumonia (15.1% and 13.4%), fatigue (3.9% and 0%), back pain (2.0% and 1.3%), asthenia (3.3% and 2.7%), and dyspnea (3.9% and 1.3%).
The only grade 4 TEAE was pneumonia (1.3% in both arms).
Based on the safety and efficacy results, Dr. Richardson concluded that isa-Pd “is an important new treatment option for our patients with relapsed/refractory myeloma.”
This study was funded by Sanofi. Dr. Richardson reported financial relationships with Celgene, Janssen, and Takeda. His coinvestigators reported relationships with a range of companies.
SOURCE: Richardson P et al. ASCO 2019, Abstract 8004.
CHICAGO – Adding isatuximab, an anti-CD38 monoclonal antibody, to pomalidomide and dexamethasone can prolong progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma, a phase 3 trial suggests.
The median PFS was 11.53 months among patients who received isatuximab (isa) plus pomalidomide and dexamethasone (Pd), compared with 6.47 months in patients who received Pd alone (P = .001).
“[W]e now have the first randomized, phase 3 study demonstrating a significant prolonged PFS benefit of CD38 targeting combined with pomalidomide and dexamethasone in relapsed/refractory myeloma,” said Paul Richardson, MD, of the Dana-Farber Cancer Institute in Boston.
“The PFS was the longest observed in this population to date ..., and ... this PFS benefit was consistent among subgroups.”
Dr. Richardson presented these results from the ICARIA-MM trial at the annual meeting of the American Society of Clinical Oncology.
Researchers enrolled 307 patients with relapsed/refractory multiple myeloma. The patients had a median age of 67 years (range, 36-86 years) and a median time from diagnosis of 4.23 years (range, 0.5-20.5 years).
The patients had received a median of three prior therapies (range, 2-11 for the isa-Pd arm and 2-10 for the Pd arm). All patients had previously received a proteasome inhibitor and an immunomodulatory agent.
The patients received isatuximab at 10 mg/kg on days 1, 8, 15, and 22 in cycle 1, then on days 1 and 15 for subsequent cycles. Pomalidomide and dexamethasone were given at standard doses in both treatment arms.
At a median follow-up of 11.6 months, 42.2% of patients were still receiving isa-Pd, and 22.9% of patients were still on Pd alone. The most common reason for stopping either treatment was disease progression (42.9% in the isa-Pd arm and 57.5% in the Pd arm).
Efficacy
The overall response rate was 60.4% in the isa-Pd arm and 35.3% in the Pd arm (P less than .0001). The rates of complete response/stringent complete response were 4.5% and 2.0%, respectively. The rates of minimal residual disease negativity were 5.2% and 0%, respectively.
The median time to next treatment was 9.1 months in the Pd arm and was not reached in the isa-Pd arm (hazard ratio, 0.538).
The median PFS was 11.53 months in the isa-Pd arm and 6.47 months in the Pd arm (HR, 0.596; P = .001). There was a PFS benefit with isa-Pd across subgroups, including in patients with renal dysfunction, those with high-risk cytogenetics, and patients who were refractory to lenalidomide.
The median overall survival was not reached in either treatment arm. The overall survival rate was 72% in the isa-Pd arm and 63% in the Pd arm (HR, 0.687).
Safety
There were more grade 3 or higher treatment-emergent adverse events (TEAEs) with isa-Pd. However, as Dr. Richardson noted, adding isa to Pd did not increase the rates of TEAEs leading to treatment discontinuation or death.
The incidence of grade 3 or higher TEAEs was 86.8% in the isa-Pd arm and 70.5% in the Pd arm. The rate of serious TEAEs was 61.8% and 53.7%, respectively.
TEAEs leading to treatment discontinuation occurred in 7.2% of patients in the isa-Pd arm and 12.8% in the Pd arm. TEAEs leading to death occurred in 7.9% and 9.4%, respectively.
Grade 3 TEAEs (in the isa-Pd and Pd arms, respectively) included upper respiratory tract infection (3.3% and 0.7%), diarrhea (2.0% and 0.7%), bronchitis (3.3% and 0.7%), pneumonia (15.1% and 13.4%), fatigue (3.9% and 0%), back pain (2.0% and 1.3%), asthenia (3.3% and 2.7%), and dyspnea (3.9% and 1.3%).
The only grade 4 TEAE was pneumonia (1.3% in both arms).
Based on the safety and efficacy results, Dr. Richardson concluded that isa-Pd “is an important new treatment option for our patients with relapsed/refractory myeloma.”
This study was funded by Sanofi. Dr. Richardson reported financial relationships with Celgene, Janssen, and Takeda. His coinvestigators reported relationships with a range of companies.
SOURCE: Richardson P et al. ASCO 2019, Abstract 8004.
REPORTING FROM ASCO 2019
Four-drug combo bests triplet in newly diagnosed myeloma
CHICAGO – Daratumumab plus bortezomib, thalidomide, and dexamethasone (D-VTd) provided a “robust clinical benefit” over bortezomib, thalidomide, and dexamethasone alone (VTd) in a phase 3 trial of patients with newly diagnosed multiple myeloma, according to the trial’s principal investigator.
D-VTd produced significantly higher rates of stringent complete response (sCR) and progression-free survival (PFS) than did VTd, said Philippe Moreau, MD, of the University Hospital of Nantes (France).
Dr. Moreau presented these results, from the CASSIOPEIA trial, at the annual meeting of the American Society of Clinical Oncology. The findings were simultaneously published in the Lancet (2019 Jun 3. doi: 10.1016/S0140-6736[19]31240-1).
CASSIOPEIA enrolled 1,085 patients with newly diagnosed multiple myeloma who were eligible for high-dose chemotherapy and hematopoietic stem cell transplant (HSCT). This is a two-part trial, and Dr. Moreau presented final results from part 1.
In part 1, patients were randomized to induction with D-VTd or VTd, followed by autologous HSCT and consolidation with D-VTd or VTd. In part 2, which is ongoing, patients who achieve a partial response or better are randomized to observation or maintenance with daratumumab for up to 2 years.
Baseline characteristics were well balanced between the D-VTd and VTd arms. The median age was 59 years (range, 22-65) and 58 years (range, 26-65), respectively. Most patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and most had an International Staging System stage of I or II.
The median follow-up was 18.8 months. Most patients completed induction – 85% in the D-VTd arm and 81% in the VTd arm – and went on to HSCT – 90% and 89%, respectively. The most common reasons for treatment discontinuation in both arms were adverse events and progression.
Response and survival
The primary endpoint for part 1 was the rate of sCR at 100 days after HSCT. The sCR rate was significantly higher in the D-VTd arm than it was in the VTd arm – 29% and 20%, respectively (odds ratio, 1.60; P less than .0010).
The overall response rate was significantly higher in the D-VTd arm than in the VTd arm – 93% and 90%, respectively (P less than .0001) – as was the rate of minimal residual disease (MRD) negativity – 64% and 44%, respectively (P less than .0001).
Dr. Moreau noted that sCR and MRD negativity rates were superior with D-VTd across all subgroups except among patients with high-risk cytogenetics and International Staging System stage III disease.
“Dara-VTd resulted in a robust clinical benefit with a higher rate of response, including stringent CR, including MRD negativity,” Dr. Moreau said. “And this translated into a better progression-free survival, with a 53% reduction in the risk of progression or death.”
The 18-month PFS was 93% in the D-VTd arm and 85% in the VTd arm (hazard ratio, 0.47; P less than .0001). D-VTd reduced the risk of progression or death across all subgroups.
The median overall survival (OS) was not reached in either treatment arm. The 18-month OS rate was 98% in the D-VTd arm and 95% in the VTd arm. The 24-month OS rate was 97% and 93%, respectively.
“These results are the best ever reported in the setting of stem cell transplantation,” Dr. Moreau said.
Safety
The most common grade 3/4 treatment-emergent adverse events (in the D-VTd and VTd arms, respectively) were neutropenia (28% and 15%), lymphopenia (17% and 10%), stomatitis (13% and 16%), and thrombocytopenia (11% and 7%).
The rate of infusion-related reactions was 35% in the D-VTd arm and 0% in the VTd arm. The rate of infections was 66% and 57%, respectively. The most common serious infection was pneumonia, which occurred in 4% and 2% of patients, respectively. The rate of second primary malignancies was 2% in both arms.
Based on the safety and efficacy results, Dr. Moreau concluded that D-VTd “should be considered a valid treatment option” for newly diagnosed multiple myeloma patients who are eligible for HSCT.
Dr. Moreau reported relationships with Amgen, Celgene, Janssen-Cilag, Novartis, and Takeda. The study is sponsored by the French Intergroupe Francophone du Myelome in collaboration with the Dutch-Belgian Cooperative Trial Group for Hematology Oncology and Janssen Research & Development.
SOURCE: Moreau P et al. ASCO 2019, Abstract 8003.
CHICAGO – Daratumumab plus bortezomib, thalidomide, and dexamethasone (D-VTd) provided a “robust clinical benefit” over bortezomib, thalidomide, and dexamethasone alone (VTd) in a phase 3 trial of patients with newly diagnosed multiple myeloma, according to the trial’s principal investigator.
D-VTd produced significantly higher rates of stringent complete response (sCR) and progression-free survival (PFS) than did VTd, said Philippe Moreau, MD, of the University Hospital of Nantes (France).
Dr. Moreau presented these results, from the CASSIOPEIA trial, at the annual meeting of the American Society of Clinical Oncology. The findings were simultaneously published in the Lancet (2019 Jun 3. doi: 10.1016/S0140-6736[19]31240-1).
CASSIOPEIA enrolled 1,085 patients with newly diagnosed multiple myeloma who were eligible for high-dose chemotherapy and hematopoietic stem cell transplant (HSCT). This is a two-part trial, and Dr. Moreau presented final results from part 1.
In part 1, patients were randomized to induction with D-VTd or VTd, followed by autologous HSCT and consolidation with D-VTd or VTd. In part 2, which is ongoing, patients who achieve a partial response or better are randomized to observation or maintenance with daratumumab for up to 2 years.
Baseline characteristics were well balanced between the D-VTd and VTd arms. The median age was 59 years (range, 22-65) and 58 years (range, 26-65), respectively. Most patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and most had an International Staging System stage of I or II.
The median follow-up was 18.8 months. Most patients completed induction – 85% in the D-VTd arm and 81% in the VTd arm – and went on to HSCT – 90% and 89%, respectively. The most common reasons for treatment discontinuation in both arms were adverse events and progression.
Response and survival
The primary endpoint for part 1 was the rate of sCR at 100 days after HSCT. The sCR rate was significantly higher in the D-VTd arm than it was in the VTd arm – 29% and 20%, respectively (odds ratio, 1.60; P less than .0010).
The overall response rate was significantly higher in the D-VTd arm than in the VTd arm – 93% and 90%, respectively (P less than .0001) – as was the rate of minimal residual disease (MRD) negativity – 64% and 44%, respectively (P less than .0001).
Dr. Moreau noted that sCR and MRD negativity rates were superior with D-VTd across all subgroups except among patients with high-risk cytogenetics and International Staging System stage III disease.
“Dara-VTd resulted in a robust clinical benefit with a higher rate of response, including stringent CR, including MRD negativity,” Dr. Moreau said. “And this translated into a better progression-free survival, with a 53% reduction in the risk of progression or death.”
The 18-month PFS was 93% in the D-VTd arm and 85% in the VTd arm (hazard ratio, 0.47; P less than .0001). D-VTd reduced the risk of progression or death across all subgroups.
The median overall survival (OS) was not reached in either treatment arm. The 18-month OS rate was 98% in the D-VTd arm and 95% in the VTd arm. The 24-month OS rate was 97% and 93%, respectively.
“These results are the best ever reported in the setting of stem cell transplantation,” Dr. Moreau said.
Safety
The most common grade 3/4 treatment-emergent adverse events (in the D-VTd and VTd arms, respectively) were neutropenia (28% and 15%), lymphopenia (17% and 10%), stomatitis (13% and 16%), and thrombocytopenia (11% and 7%).
The rate of infusion-related reactions was 35% in the D-VTd arm and 0% in the VTd arm. The rate of infections was 66% and 57%, respectively. The most common serious infection was pneumonia, which occurred in 4% and 2% of patients, respectively. The rate of second primary malignancies was 2% in both arms.
Based on the safety and efficacy results, Dr. Moreau concluded that D-VTd “should be considered a valid treatment option” for newly diagnosed multiple myeloma patients who are eligible for HSCT.
Dr. Moreau reported relationships with Amgen, Celgene, Janssen-Cilag, Novartis, and Takeda. The study is sponsored by the French Intergroupe Francophone du Myelome in collaboration with the Dutch-Belgian Cooperative Trial Group for Hematology Oncology and Janssen Research & Development.
SOURCE: Moreau P et al. ASCO 2019, Abstract 8003.
CHICAGO – Daratumumab plus bortezomib, thalidomide, and dexamethasone (D-VTd) provided a “robust clinical benefit” over bortezomib, thalidomide, and dexamethasone alone (VTd) in a phase 3 trial of patients with newly diagnosed multiple myeloma, according to the trial’s principal investigator.
D-VTd produced significantly higher rates of stringent complete response (sCR) and progression-free survival (PFS) than did VTd, said Philippe Moreau, MD, of the University Hospital of Nantes (France).
Dr. Moreau presented these results, from the CASSIOPEIA trial, at the annual meeting of the American Society of Clinical Oncology. The findings were simultaneously published in the Lancet (2019 Jun 3. doi: 10.1016/S0140-6736[19]31240-1).
CASSIOPEIA enrolled 1,085 patients with newly diagnosed multiple myeloma who were eligible for high-dose chemotherapy and hematopoietic stem cell transplant (HSCT). This is a two-part trial, and Dr. Moreau presented final results from part 1.
In part 1, patients were randomized to induction with D-VTd or VTd, followed by autologous HSCT and consolidation with D-VTd or VTd. In part 2, which is ongoing, patients who achieve a partial response or better are randomized to observation or maintenance with daratumumab for up to 2 years.
Baseline characteristics were well balanced between the D-VTd and VTd arms. The median age was 59 years (range, 22-65) and 58 years (range, 26-65), respectively. Most patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and most had an International Staging System stage of I or II.
The median follow-up was 18.8 months. Most patients completed induction – 85% in the D-VTd arm and 81% in the VTd arm – and went on to HSCT – 90% and 89%, respectively. The most common reasons for treatment discontinuation in both arms were adverse events and progression.
Response and survival
The primary endpoint for part 1 was the rate of sCR at 100 days after HSCT. The sCR rate was significantly higher in the D-VTd arm than it was in the VTd arm – 29% and 20%, respectively (odds ratio, 1.60; P less than .0010).
The overall response rate was significantly higher in the D-VTd arm than in the VTd arm – 93% and 90%, respectively (P less than .0001) – as was the rate of minimal residual disease (MRD) negativity – 64% and 44%, respectively (P less than .0001).
Dr. Moreau noted that sCR and MRD negativity rates were superior with D-VTd across all subgroups except among patients with high-risk cytogenetics and International Staging System stage III disease.
“Dara-VTd resulted in a robust clinical benefit with a higher rate of response, including stringent CR, including MRD negativity,” Dr. Moreau said. “And this translated into a better progression-free survival, with a 53% reduction in the risk of progression or death.”
The 18-month PFS was 93% in the D-VTd arm and 85% in the VTd arm (hazard ratio, 0.47; P less than .0001). D-VTd reduced the risk of progression or death across all subgroups.
The median overall survival (OS) was not reached in either treatment arm. The 18-month OS rate was 98% in the D-VTd arm and 95% in the VTd arm. The 24-month OS rate was 97% and 93%, respectively.
“These results are the best ever reported in the setting of stem cell transplantation,” Dr. Moreau said.
Safety
The most common grade 3/4 treatment-emergent adverse events (in the D-VTd and VTd arms, respectively) were neutropenia (28% and 15%), lymphopenia (17% and 10%), stomatitis (13% and 16%), and thrombocytopenia (11% and 7%).
The rate of infusion-related reactions was 35% in the D-VTd arm and 0% in the VTd arm. The rate of infections was 66% and 57%, respectively. The most common serious infection was pneumonia, which occurred in 4% and 2% of patients, respectively. The rate of second primary malignancies was 2% in both arms.
Based on the safety and efficacy results, Dr. Moreau concluded that D-VTd “should be considered a valid treatment option” for newly diagnosed multiple myeloma patients who are eligible for HSCT.
Dr. Moreau reported relationships with Amgen, Celgene, Janssen-Cilag, Novartis, and Takeda. The study is sponsored by the French Intergroupe Francophone du Myelome in collaboration with the Dutch-Belgian Cooperative Trial Group for Hematology Oncology and Janssen Research & Development.
SOURCE: Moreau P et al. ASCO 2019, Abstract 8003.
REPORTING FROM ASCO 2019
Daratumumab regimen shows benefit in transplant-ineligible myeloma
For patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT), adding daratumumab to lenalidomide and dexamethasone provides better outcomes than standard therapy alone, based on an interim analysis from the phase 3 MAIA trial.
A greater proportion of patients in the daratumumab group had complete responses and were alive without disease progression after a median follow-up of 28 months, reported lead author Thierry Facon, MD, of the University of Lille (France) and colleagues, who also noted that daratumumab was associated with higher rates of grade 3 or 4 pneumonia, neutropenia, and lymphopenia.
“For patients who are ineligible for stem-cell transplantation, multiagent regimens, including alkylating agents, glucocorticoids, immunomodulatory drugs, proteasome inhibitors, and new agents, are the standard of care,” the investigators wrote in the New England Journal of Medicine.
The findings from MAIA add clarity to the efficacy and safety of daratumumab in this setting, building on previous phase 3 myeloma trials in the same area, such as ALCYONE, CASTOR, and POLLUX, the investigators noted.
MAIA was an open-label, international trial involving 737 patients with newly diagnosed multiple myeloma who were ineligible for ASCT. Patients were randomized in a 1:1 ratio to receive either daratumumab, lenalidomide, and dexamethasone (daratumumab group; n = 368) or lenalidomide and dexamethasone alone (control group; n = 369).
On a 28-day cycle, all patients received oral lenalidomide 25 mg on days 1-21 and oral dexamethasone 40 mg on days 1, 8, 15, and 22. Patients in the daratumumab group received intravenous daratumumab dosed at 16 mg/kg once a week for cycles 1 and 2, every 2 weeks for cycles 3-6, and then every 4 weeks thereafter. Treatment was continued until unacceptable toxic effects or disease progression occurred.
The primary end point was progression-free survival (PFS). Various secondary end points were also evaluated, including time to progression, complete responses, overall survival, and others.
Among the 737 randomized patients, 729 ultimately underwent treatment. The median patient age was 73 years.
Generally, efficacy measures favored adding daratumumab. After a median follow-up of 28.0 months, disease progression or death had occurred in 26.4% of patients in the daratumumab group, compared with 38.8% in the control group.
The median PFS was not reached in the daratumumab group, compared with 31.9 months in the control group. There was a 44% lower risk of disease progression or death among patients who received daratumumab, compared with the control group (hazard ratio, 0.56, P less than .001).
This PFS trend was consistent across most subgroups, including those for sex, age, and race, with the exception of patients with baseline hepatic impairment.
Additional efficacy measures added weight to the apparent benefit of adding daratumumab. For instance, more patients in the daratumumab group achieved a complete response or better (47.6% vs. 24.9%) and were negative for minimum residual disease (24.2% vs. 7.3%).
In terms of safety, more patients in the daratumumab group than the control group developed grade 3 or higher neutropenia (50% vs. 35.3%), lymphopenia (15.1% vs. 10.7%), infections (32.1% vs. 23.3%) or pneumonia (13.7% vs. 7.9%).
In contrast, grade 3 or 4 anemia was less common in the daratumumab group than the control group (11.8% vs. 19.7%). Overall, the rate of serious adverse events was similar for both groups (approximately 63%), as was the rate of adverse events resulting in death (approximately 6%-7%).
“In this trial involving patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation, the addition of daratumumab to lenalidomide and dexamethasone resulted in significantly longer progression-free survival, a higher response rate, an increased depth of response, and a longer duration of response than lenalidomide and dexamethasone alone,” the investigators concluded.
The study was funded by Janssen Research and Development. The investigators reported relationships with Janssen, Celgene, Takeda, Sanofi, and other companies.
SOURCE: Facon T et al. N Engl J Med. 2019;380:2104-15.
The findings from the phase 3 MAIA trial highlight the “superior efficacy” of adding daratumumab to lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma who are ineligible for stem cell transplantation, Jacob Laubach, MD, commented in an accompanying editorial.
Dr. Laubach noted several important clinical implications of the study findings, including that the use of CD38-targeting monoclonal antibody therapy was associated with a significant improvement in the number of patients who had a complete response to therapy and who were negative for minimal residual disease.
However, with daratumumab as a component of induction and maintenance therapy for patients with multiple myeloma who are ineligible for transplantation, it is important to consider the feasibility of retreatment with CD38-targeting therapy in patients who become resistant to daratumumab-containing regimens.
Jacob Laubach, MD, is at the Dana-Farber Cancer Institute in Boston. He reported having no financial disclosures. He made his remarks in an editorial in the New England Journal of Medicine (2019;380:2172-3).
The findings from the phase 3 MAIA trial highlight the “superior efficacy” of adding daratumumab to lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma who are ineligible for stem cell transplantation, Jacob Laubach, MD, commented in an accompanying editorial.
Dr. Laubach noted several important clinical implications of the study findings, including that the use of CD38-targeting monoclonal antibody therapy was associated with a significant improvement in the number of patients who had a complete response to therapy and who were negative for minimal residual disease.
However, with daratumumab as a component of induction and maintenance therapy for patients with multiple myeloma who are ineligible for transplantation, it is important to consider the feasibility of retreatment with CD38-targeting therapy in patients who become resistant to daratumumab-containing regimens.
Jacob Laubach, MD, is at the Dana-Farber Cancer Institute in Boston. He reported having no financial disclosures. He made his remarks in an editorial in the New England Journal of Medicine (2019;380:2172-3).
The findings from the phase 3 MAIA trial highlight the “superior efficacy” of adding daratumumab to lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma who are ineligible for stem cell transplantation, Jacob Laubach, MD, commented in an accompanying editorial.
Dr. Laubach noted several important clinical implications of the study findings, including that the use of CD38-targeting monoclonal antibody therapy was associated with a significant improvement in the number of patients who had a complete response to therapy and who were negative for minimal residual disease.
However, with daratumumab as a component of induction and maintenance therapy for patients with multiple myeloma who are ineligible for transplantation, it is important to consider the feasibility of retreatment with CD38-targeting therapy in patients who become resistant to daratumumab-containing regimens.
Jacob Laubach, MD, is at the Dana-Farber Cancer Institute in Boston. He reported having no financial disclosures. He made his remarks in an editorial in the New England Journal of Medicine (2019;380:2172-3).
For patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT), adding daratumumab to lenalidomide and dexamethasone provides better outcomes than standard therapy alone, based on an interim analysis from the phase 3 MAIA trial.
A greater proportion of patients in the daratumumab group had complete responses and were alive without disease progression after a median follow-up of 28 months, reported lead author Thierry Facon, MD, of the University of Lille (France) and colleagues, who also noted that daratumumab was associated with higher rates of grade 3 or 4 pneumonia, neutropenia, and lymphopenia.
“For patients who are ineligible for stem-cell transplantation, multiagent regimens, including alkylating agents, glucocorticoids, immunomodulatory drugs, proteasome inhibitors, and new agents, are the standard of care,” the investigators wrote in the New England Journal of Medicine.
The findings from MAIA add clarity to the efficacy and safety of daratumumab in this setting, building on previous phase 3 myeloma trials in the same area, such as ALCYONE, CASTOR, and POLLUX, the investigators noted.
MAIA was an open-label, international trial involving 737 patients with newly diagnosed multiple myeloma who were ineligible for ASCT. Patients were randomized in a 1:1 ratio to receive either daratumumab, lenalidomide, and dexamethasone (daratumumab group; n = 368) or lenalidomide and dexamethasone alone (control group; n = 369).
On a 28-day cycle, all patients received oral lenalidomide 25 mg on days 1-21 and oral dexamethasone 40 mg on days 1, 8, 15, and 22. Patients in the daratumumab group received intravenous daratumumab dosed at 16 mg/kg once a week for cycles 1 and 2, every 2 weeks for cycles 3-6, and then every 4 weeks thereafter. Treatment was continued until unacceptable toxic effects or disease progression occurred.
The primary end point was progression-free survival (PFS). Various secondary end points were also evaluated, including time to progression, complete responses, overall survival, and others.
Among the 737 randomized patients, 729 ultimately underwent treatment. The median patient age was 73 years.
Generally, efficacy measures favored adding daratumumab. After a median follow-up of 28.0 months, disease progression or death had occurred in 26.4% of patients in the daratumumab group, compared with 38.8% in the control group.
The median PFS was not reached in the daratumumab group, compared with 31.9 months in the control group. There was a 44% lower risk of disease progression or death among patients who received daratumumab, compared with the control group (hazard ratio, 0.56, P less than .001).
This PFS trend was consistent across most subgroups, including those for sex, age, and race, with the exception of patients with baseline hepatic impairment.
Additional efficacy measures added weight to the apparent benefit of adding daratumumab. For instance, more patients in the daratumumab group achieved a complete response or better (47.6% vs. 24.9%) and were negative for minimum residual disease (24.2% vs. 7.3%).
In terms of safety, more patients in the daratumumab group than the control group developed grade 3 or higher neutropenia (50% vs. 35.3%), lymphopenia (15.1% vs. 10.7%), infections (32.1% vs. 23.3%) or pneumonia (13.7% vs. 7.9%).
In contrast, grade 3 or 4 anemia was less common in the daratumumab group than the control group (11.8% vs. 19.7%). Overall, the rate of serious adverse events was similar for both groups (approximately 63%), as was the rate of adverse events resulting in death (approximately 6%-7%).
“In this trial involving patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation, the addition of daratumumab to lenalidomide and dexamethasone resulted in significantly longer progression-free survival, a higher response rate, an increased depth of response, and a longer duration of response than lenalidomide and dexamethasone alone,” the investigators concluded.
The study was funded by Janssen Research and Development. The investigators reported relationships with Janssen, Celgene, Takeda, Sanofi, and other companies.
SOURCE: Facon T et al. N Engl J Med. 2019;380:2104-15.
For patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT), adding daratumumab to lenalidomide and dexamethasone provides better outcomes than standard therapy alone, based on an interim analysis from the phase 3 MAIA trial.
A greater proportion of patients in the daratumumab group had complete responses and were alive without disease progression after a median follow-up of 28 months, reported lead author Thierry Facon, MD, of the University of Lille (France) and colleagues, who also noted that daratumumab was associated with higher rates of grade 3 or 4 pneumonia, neutropenia, and lymphopenia.
“For patients who are ineligible for stem-cell transplantation, multiagent regimens, including alkylating agents, glucocorticoids, immunomodulatory drugs, proteasome inhibitors, and new agents, are the standard of care,” the investigators wrote in the New England Journal of Medicine.
The findings from MAIA add clarity to the efficacy and safety of daratumumab in this setting, building on previous phase 3 myeloma trials in the same area, such as ALCYONE, CASTOR, and POLLUX, the investigators noted.
MAIA was an open-label, international trial involving 737 patients with newly diagnosed multiple myeloma who were ineligible for ASCT. Patients were randomized in a 1:1 ratio to receive either daratumumab, lenalidomide, and dexamethasone (daratumumab group; n = 368) or lenalidomide and dexamethasone alone (control group; n = 369).
On a 28-day cycle, all patients received oral lenalidomide 25 mg on days 1-21 and oral dexamethasone 40 mg on days 1, 8, 15, and 22. Patients in the daratumumab group received intravenous daratumumab dosed at 16 mg/kg once a week for cycles 1 and 2, every 2 weeks for cycles 3-6, and then every 4 weeks thereafter. Treatment was continued until unacceptable toxic effects or disease progression occurred.
The primary end point was progression-free survival (PFS). Various secondary end points were also evaluated, including time to progression, complete responses, overall survival, and others.
Among the 737 randomized patients, 729 ultimately underwent treatment. The median patient age was 73 years.
Generally, efficacy measures favored adding daratumumab. After a median follow-up of 28.0 months, disease progression or death had occurred in 26.4% of patients in the daratumumab group, compared with 38.8% in the control group.
The median PFS was not reached in the daratumumab group, compared with 31.9 months in the control group. There was a 44% lower risk of disease progression or death among patients who received daratumumab, compared with the control group (hazard ratio, 0.56, P less than .001).
This PFS trend was consistent across most subgroups, including those for sex, age, and race, with the exception of patients with baseline hepatic impairment.
Additional efficacy measures added weight to the apparent benefit of adding daratumumab. For instance, more patients in the daratumumab group achieved a complete response or better (47.6% vs. 24.9%) and were negative for minimum residual disease (24.2% vs. 7.3%).
In terms of safety, more patients in the daratumumab group than the control group developed grade 3 or higher neutropenia (50% vs. 35.3%), lymphopenia (15.1% vs. 10.7%), infections (32.1% vs. 23.3%) or pneumonia (13.7% vs. 7.9%).
In contrast, grade 3 or 4 anemia was less common in the daratumumab group than the control group (11.8% vs. 19.7%). Overall, the rate of serious adverse events was similar for both groups (approximately 63%), as was the rate of adverse events resulting in death (approximately 6%-7%).
“In this trial involving patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation, the addition of daratumumab to lenalidomide and dexamethasone resulted in significantly longer progression-free survival, a higher response rate, an increased depth of response, and a longer duration of response than lenalidomide and dexamethasone alone,” the investigators concluded.
The study was funded by Janssen Research and Development. The investigators reported relationships with Janssen, Celgene, Takeda, Sanofi, and other companies.
SOURCE: Facon T et al. N Engl J Med. 2019;380:2104-15.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: For patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation, adding daratumumab to lenalidomide and dexamethasone standard therapy provides better outcomes than standard therapy alone.
Major finding: After 28-month follow-up, 26.4% of patients in the daratumumab group had disease progression or died, compared with 38.8% in the control group.
Study details: A randomized, open-label, phase 3 trial involving 737 patients with newly diagnosed multiple myeloma.
Disclosures: The study was funded by Janssen Research and Development. The investigators reported relationships with Janssen, Celgene, Takeda, Sanofi, and other companies.
Source: Facon T et al. N Engl J Med. 2019;380:2104-15.