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Are Food Emulsifiers Associated With Increased Cancer Risk?
Food emulsifiers are among the most widespread food additives.
Ultraprocessed foods constitute a significant part of our diet, representing approximately 30% of energy intake in France.
Large epidemiologic studies have already linked diets rich in ultraprocessed products to an increased risk for cardiovascular diseases, diabetes, obesity, and mortality. Possible explanations for this association include the presence of additives, particularly emulsifiers. These additives are intended to improve the texture and shelf life of foods.
Recent experimental studies have shown that emulsifiers alter the gut microbiota and may lead to low-grade inflammation. Dysbiosis and chronic inflammation not only increase the risk for inflammatory bowel diseases but are also implicated in the etiology of several other chronic pathologies and certain extraintestinal cancers.
The NutriNet-Santé study provided extensive information on the dietary habits of > 100,000 French participants. A new analysis was conducted, examining the possible link between the presence of emulsifiers in the diet and cancer occurrence. Data from 92,000 participants (78.8% women) were utilized. They covered an average follow-up of 6.7 years, during which 2604 cancer cases were diagnosed, including 750 breast cancers, 322 prostate cancers, and 207 colorectal cancers.
In this cohort, the risk for cancer increased with a higher presence in the diet of products containing certain emulsifiers widely used in industrial food in Europe: Carrageenans (E407), mono- and diglycerides of fatty acids (E471), pectins (E440), and sodium carbonate (E500).
Notably, the highest consumption of mono- and diglycerides of fatty acids (E471) was associated with a 15% increase in the risk for all types of cancer, a 24% increase in breast cancer risk, and a 46% increase in prostate cancer risk. The highest consumption of carrageenans (E407) was associated with a 28% increase in breast cancer risk.
In an analysis by menopausal status, the risk for breast cancer before menopause was associated with high consumption of diphosphates (E450; 45% increase), pectins (E440; 55% increase), and sodium bicarbonate (E500; 48% increase). No link was found between emulsifier consumption and colorectal cancer risk. While some associations were observed for other emulsifiers, they did not persist in sensitivity analyses.
The European Food Safety Agency recently evaluated the risks of emulsifiers, however, and found no safety issues or need to limit daily consumption of several of them, notably E471.
It is certain that cancer is multifactorial, and a single factor (here, exposure to emulsifiers) will not significantly increase the risk. However, while not essential to human health, emulsifiers are widely prevalent in the global market. Therefore, if causality is established, the increased risk could translate into a significant number of preventable cancers at the population level. Confirmation of this causal link will need to be obtained through experimental and epidemiological studies.
This story was translated from JIM, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Food emulsifiers are among the most widespread food additives.
Ultraprocessed foods constitute a significant part of our diet, representing approximately 30% of energy intake in France.
Large epidemiologic studies have already linked diets rich in ultraprocessed products to an increased risk for cardiovascular diseases, diabetes, obesity, and mortality. Possible explanations for this association include the presence of additives, particularly emulsifiers. These additives are intended to improve the texture and shelf life of foods.
Recent experimental studies have shown that emulsifiers alter the gut microbiota and may lead to low-grade inflammation. Dysbiosis and chronic inflammation not only increase the risk for inflammatory bowel diseases but are also implicated in the etiology of several other chronic pathologies and certain extraintestinal cancers.
The NutriNet-Santé study provided extensive information on the dietary habits of > 100,000 French participants. A new analysis was conducted, examining the possible link between the presence of emulsifiers in the diet and cancer occurrence. Data from 92,000 participants (78.8% women) were utilized. They covered an average follow-up of 6.7 years, during which 2604 cancer cases were diagnosed, including 750 breast cancers, 322 prostate cancers, and 207 colorectal cancers.
In this cohort, the risk for cancer increased with a higher presence in the diet of products containing certain emulsifiers widely used in industrial food in Europe: Carrageenans (E407), mono- and diglycerides of fatty acids (E471), pectins (E440), and sodium carbonate (E500).
Notably, the highest consumption of mono- and diglycerides of fatty acids (E471) was associated with a 15% increase in the risk for all types of cancer, a 24% increase in breast cancer risk, and a 46% increase in prostate cancer risk. The highest consumption of carrageenans (E407) was associated with a 28% increase in breast cancer risk.
In an analysis by menopausal status, the risk for breast cancer before menopause was associated with high consumption of diphosphates (E450; 45% increase), pectins (E440; 55% increase), and sodium bicarbonate (E500; 48% increase). No link was found between emulsifier consumption and colorectal cancer risk. While some associations were observed for other emulsifiers, they did not persist in sensitivity analyses.
The European Food Safety Agency recently evaluated the risks of emulsifiers, however, and found no safety issues or need to limit daily consumption of several of them, notably E471.
It is certain that cancer is multifactorial, and a single factor (here, exposure to emulsifiers) will not significantly increase the risk. However, while not essential to human health, emulsifiers are widely prevalent in the global market. Therefore, if causality is established, the increased risk could translate into a significant number of preventable cancers at the population level. Confirmation of this causal link will need to be obtained through experimental and epidemiological studies.
This story was translated from JIM, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Food emulsifiers are among the most widespread food additives.
Ultraprocessed foods constitute a significant part of our diet, representing approximately 30% of energy intake in France.
Large epidemiologic studies have already linked diets rich in ultraprocessed products to an increased risk for cardiovascular diseases, diabetes, obesity, and mortality. Possible explanations for this association include the presence of additives, particularly emulsifiers. These additives are intended to improve the texture and shelf life of foods.
Recent experimental studies have shown that emulsifiers alter the gut microbiota and may lead to low-grade inflammation. Dysbiosis and chronic inflammation not only increase the risk for inflammatory bowel diseases but are also implicated in the etiology of several other chronic pathologies and certain extraintestinal cancers.
The NutriNet-Santé study provided extensive information on the dietary habits of > 100,000 French participants. A new analysis was conducted, examining the possible link between the presence of emulsifiers in the diet and cancer occurrence. Data from 92,000 participants (78.8% women) were utilized. They covered an average follow-up of 6.7 years, during which 2604 cancer cases were diagnosed, including 750 breast cancers, 322 prostate cancers, and 207 colorectal cancers.
In this cohort, the risk for cancer increased with a higher presence in the diet of products containing certain emulsifiers widely used in industrial food in Europe: Carrageenans (E407), mono- and diglycerides of fatty acids (E471), pectins (E440), and sodium carbonate (E500).
Notably, the highest consumption of mono- and diglycerides of fatty acids (E471) was associated with a 15% increase in the risk for all types of cancer, a 24% increase in breast cancer risk, and a 46% increase in prostate cancer risk. The highest consumption of carrageenans (E407) was associated with a 28% increase in breast cancer risk.
In an analysis by menopausal status, the risk for breast cancer before menopause was associated with high consumption of diphosphates (E450; 45% increase), pectins (E440; 55% increase), and sodium bicarbonate (E500; 48% increase). No link was found between emulsifier consumption and colorectal cancer risk. While some associations were observed for other emulsifiers, they did not persist in sensitivity analyses.
The European Food Safety Agency recently evaluated the risks of emulsifiers, however, and found no safety issues or need to limit daily consumption of several of them, notably E471.
It is certain that cancer is multifactorial, and a single factor (here, exposure to emulsifiers) will not significantly increase the risk. However, while not essential to human health, emulsifiers are widely prevalent in the global market. Therefore, if causality is established, the increased risk could translate into a significant number of preventable cancers at the population level. Confirmation of this causal link will need to be obtained through experimental and epidemiological studies.
This story was translated from JIM, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Democratic Lawmakers Press Pfizer on Chemotherapy Drug Shortages
In a statement about their February 21 action, the legislators, led by Rep. Jamie Raskin (D-Md.), the committee’s ranking minority member, described their work as a follow up to an earlier investigation into price hikes of generic drugs. While the committee members queried Pfizer over the three oncology medications only, they also sent letters to drugmakers Teva and Sandoz with respect to shortages in other drug classes.
A representative for Pfizer confirmed to MDedge Oncology that the company had received the representatives’ letter but said “we have no further details to provide at this time.”
What is the basis for concern?
All three generic chemotherapy drugs are mainstay treatments used across a broad array of cancers. Though shortages have been reported for several years, they became especially acute after December 2022, when an inspection by the US Food and Drug Administration (FDA) led to regulatory action against an Indian manufacturer, Intas, that produced up to half of the platinum-based therapies supplied globally. The National Comprehensive Cancer Care Network reported in October 2023 that more than 90% of its member centers were struggling to maintain adequate supplies of carboplatin, and 70% had trouble obtaining cisplatin, while the American Society of Clinical Oncology published clinical guidance on alternative treatment strategies.
What has the government done in response to the recent shortages?
The White House and the FDA announced in September that they were working with several manufacturers to help increase supplies of the platinum-based chemotherapies and of methotrexate, and taking measures that included relaxing rules on imports. Recent guidance under a pandemic-era federal law, the 2020 CARES Act, strengthened manufacturer reporting requirements related to drug shortages, and other measures have been proposed. While federal regulators have many tools with which to address drug shortages, they cannot legally oblige a manufacturer to increase production of a drug.
What can the lawmakers expect to achieve with their letter?
By pressuring Pfizer publicly, the lawmakers may be able to nudge the company to take measures to assure more consistent supplies of the three drugs. The lawmakers also said they hoped to glean from Pfizer more insight into the root causes of the shortages and potential remedies. They noted that, in a May 2023 letter by Pfizer to customers, the company had warned of depleted and limited supplies of the three drugs and said it was “working diligently” to increase output. However, the lawmakers wrote, “the root cause is not yet resolved and carboplatin, cisplatin, and methotrexate continue to experience residual delays.”
Why did the committee target Pfizer specifically?
Pfizer and its subsidiaries are among the major manufacturers of the three generic chemotherapy agents mentioned in the letter. The legislators noted that “pharmaceutical companies may not be motivated to produce generic drugs like carboplatin, cisplatin, and methotrexate, because they are not as lucrative as producing patented brand name drugs,” and that “as a principal supplier of carboplatin, cisplatin, and methotrexate, it is critical that Pfizer continues to increase production of these life-sustaining cancer medications, even amidst potential lower profitability.”
The committee members also made reference to news reports of price-gouging with these medications, as smaller hospitals or oncology centers are forced to turn to unscrupulous third-party suppliers.
What is being demanded of Pfizer?
Pfizer was given until March 6 to respond, in writing and in a briefing with committee staff, to a six questions. These queries concern what specific steps the company has taken to increase supplies of the three generic oncology drugs, what Pfizer is doing to help avert price-gouging, whether further oncology drug shortages are anticipated, and how the company is working with the FDA on the matter.
In a statement about their February 21 action, the legislators, led by Rep. Jamie Raskin (D-Md.), the committee’s ranking minority member, described their work as a follow up to an earlier investigation into price hikes of generic drugs. While the committee members queried Pfizer over the three oncology medications only, they also sent letters to drugmakers Teva and Sandoz with respect to shortages in other drug classes.
A representative for Pfizer confirmed to MDedge Oncology that the company had received the representatives’ letter but said “we have no further details to provide at this time.”
What is the basis for concern?
All three generic chemotherapy drugs are mainstay treatments used across a broad array of cancers. Though shortages have been reported for several years, they became especially acute after December 2022, when an inspection by the US Food and Drug Administration (FDA) led to regulatory action against an Indian manufacturer, Intas, that produced up to half of the platinum-based therapies supplied globally. The National Comprehensive Cancer Care Network reported in October 2023 that more than 90% of its member centers were struggling to maintain adequate supplies of carboplatin, and 70% had trouble obtaining cisplatin, while the American Society of Clinical Oncology published clinical guidance on alternative treatment strategies.
What has the government done in response to the recent shortages?
The White House and the FDA announced in September that they were working with several manufacturers to help increase supplies of the platinum-based chemotherapies and of methotrexate, and taking measures that included relaxing rules on imports. Recent guidance under a pandemic-era federal law, the 2020 CARES Act, strengthened manufacturer reporting requirements related to drug shortages, and other measures have been proposed. While federal regulators have many tools with which to address drug shortages, they cannot legally oblige a manufacturer to increase production of a drug.
What can the lawmakers expect to achieve with their letter?
By pressuring Pfizer publicly, the lawmakers may be able to nudge the company to take measures to assure more consistent supplies of the three drugs. The lawmakers also said they hoped to glean from Pfizer more insight into the root causes of the shortages and potential remedies. They noted that, in a May 2023 letter by Pfizer to customers, the company had warned of depleted and limited supplies of the three drugs and said it was “working diligently” to increase output. However, the lawmakers wrote, “the root cause is not yet resolved and carboplatin, cisplatin, and methotrexate continue to experience residual delays.”
Why did the committee target Pfizer specifically?
Pfizer and its subsidiaries are among the major manufacturers of the three generic chemotherapy agents mentioned in the letter. The legislators noted that “pharmaceutical companies may not be motivated to produce generic drugs like carboplatin, cisplatin, and methotrexate, because they are not as lucrative as producing patented brand name drugs,” and that “as a principal supplier of carboplatin, cisplatin, and methotrexate, it is critical that Pfizer continues to increase production of these life-sustaining cancer medications, even amidst potential lower profitability.”
The committee members also made reference to news reports of price-gouging with these medications, as smaller hospitals or oncology centers are forced to turn to unscrupulous third-party suppliers.
What is being demanded of Pfizer?
Pfizer was given until March 6 to respond, in writing and in a briefing with committee staff, to a six questions. These queries concern what specific steps the company has taken to increase supplies of the three generic oncology drugs, what Pfizer is doing to help avert price-gouging, whether further oncology drug shortages are anticipated, and how the company is working with the FDA on the matter.
In a statement about their February 21 action, the legislators, led by Rep. Jamie Raskin (D-Md.), the committee’s ranking minority member, described their work as a follow up to an earlier investigation into price hikes of generic drugs. While the committee members queried Pfizer over the three oncology medications only, they also sent letters to drugmakers Teva and Sandoz with respect to shortages in other drug classes.
A representative for Pfizer confirmed to MDedge Oncology that the company had received the representatives’ letter but said “we have no further details to provide at this time.”
What is the basis for concern?
All three generic chemotherapy drugs are mainstay treatments used across a broad array of cancers. Though shortages have been reported for several years, they became especially acute after December 2022, when an inspection by the US Food and Drug Administration (FDA) led to regulatory action against an Indian manufacturer, Intas, that produced up to half of the platinum-based therapies supplied globally. The National Comprehensive Cancer Care Network reported in October 2023 that more than 90% of its member centers were struggling to maintain adequate supplies of carboplatin, and 70% had trouble obtaining cisplatin, while the American Society of Clinical Oncology published clinical guidance on alternative treatment strategies.
What has the government done in response to the recent shortages?
The White House and the FDA announced in September that they were working with several manufacturers to help increase supplies of the platinum-based chemotherapies and of methotrexate, and taking measures that included relaxing rules on imports. Recent guidance under a pandemic-era federal law, the 2020 CARES Act, strengthened manufacturer reporting requirements related to drug shortages, and other measures have been proposed. While federal regulators have many tools with which to address drug shortages, they cannot legally oblige a manufacturer to increase production of a drug.
What can the lawmakers expect to achieve with their letter?
By pressuring Pfizer publicly, the lawmakers may be able to nudge the company to take measures to assure more consistent supplies of the three drugs. The lawmakers also said they hoped to glean from Pfizer more insight into the root causes of the shortages and potential remedies. They noted that, in a May 2023 letter by Pfizer to customers, the company had warned of depleted and limited supplies of the three drugs and said it was “working diligently” to increase output. However, the lawmakers wrote, “the root cause is not yet resolved and carboplatin, cisplatin, and methotrexate continue to experience residual delays.”
Why did the committee target Pfizer specifically?
Pfizer and its subsidiaries are among the major manufacturers of the three generic chemotherapy agents mentioned in the letter. The legislators noted that “pharmaceutical companies may not be motivated to produce generic drugs like carboplatin, cisplatin, and methotrexate, because they are not as lucrative as producing patented brand name drugs,” and that “as a principal supplier of carboplatin, cisplatin, and methotrexate, it is critical that Pfizer continues to increase production of these life-sustaining cancer medications, even amidst potential lower profitability.”
The committee members also made reference to news reports of price-gouging with these medications, as smaller hospitals or oncology centers are forced to turn to unscrupulous third-party suppliers.
What is being demanded of Pfizer?
Pfizer was given until March 6 to respond, in writing and in a briefing with committee staff, to a six questions. These queries concern what specific steps the company has taken to increase supplies of the three generic oncology drugs, what Pfizer is doing to help avert price-gouging, whether further oncology drug shortages are anticipated, and how the company is working with the FDA on the matter.
Unleashing Our Immune Response to Quash Cancer
This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”
It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.
Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.
Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.
And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.
As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.
Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.
An Ever-Expanding Armamentarium
Immune Checkpoint Inhibitors
The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.
But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.
Therapeutic Cancer Vaccines
There are many therapeutic cancer vaccines in the works, as reviewed in depth here.
Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.
An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.
Antibody-Drug Conjugates (ADC)
There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.
A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.
This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.
Oncolytic Viruses
Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.
After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.
Engineering T Cells (Chimeric Antigen Receptor [CAR-T])
As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.
As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.
Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.
Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.
Summary
Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.
Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.
Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.
Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.
Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.
A version of this article appeared on Medscape.com.
This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”
It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.
Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.
Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.
And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.
As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.
Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.
An Ever-Expanding Armamentarium
Immune Checkpoint Inhibitors
The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.
But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.
Therapeutic Cancer Vaccines
There are many therapeutic cancer vaccines in the works, as reviewed in depth here.
Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.
An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.
Antibody-Drug Conjugates (ADC)
There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.
A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.
This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.
Oncolytic Viruses
Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.
After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.
Engineering T Cells (Chimeric Antigen Receptor [CAR-T])
As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.
As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.
Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.
Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.
Summary
Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.
Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.
Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.
Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.
Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.
A version of this article appeared on Medscape.com.
This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”
It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.
Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.
Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.
And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.
As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.
Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.
An Ever-Expanding Armamentarium
Immune Checkpoint Inhibitors
The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.
But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.
Therapeutic Cancer Vaccines
There are many therapeutic cancer vaccines in the works, as reviewed in depth here.
Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.
An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.
Antibody-Drug Conjugates (ADC)
There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.
A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.
This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.
Oncolytic Viruses
Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.
After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.
Engineering T Cells (Chimeric Antigen Receptor [CAR-T])
As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.
As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.
Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.
Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.
Summary
Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.
Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.
Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.
Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.
Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.
A version of this article appeared on Medscape.com.
Belantamab Mafodotin Tops Daratumumab in Multiple Myeloma
TOPLINE:
METHODOLOGY:
- Belantamab mafodotin, a first-in-class anti-BCMA monoclonal antibody conjugate, was approved in the US in 2020 for adult patients with relapsed or refractory multiple myeloma who had received at least 4 prior therapies. However, in February 2023, the FDA withdrew this approval, following disappointing findings from a large confirmatory trial, called DREAMM-3. Although the agent is still being investigated to treat relapsed or refractory multiple myeloma, the current FDA label says the agent is only available in the US through a restricted program.
- Patients with multiple myeloma who relapse often become refractory to frontline triplet or quadruplet regimens and need effective second-line options.
- In the current phase 3 DREAMM-7 study, the researchers evaluated triplet therapy with belantamab mafodotin vs daratumumab as a second-line or later treatment option in patients with relapsed or refractory multiple myeloma.
- In this multicenter, open-label, randomized, phase 3 trial, 494 patients with relapsed/refractory multiple myeloma who previously received at least one prior line of therapy received bortezomib plus dexamethasone with either belantamab mafodotin or daratumumab.
- The primary outcome was PFS; secondary endpoints were overall survival, duration of response, and overall response rate.
TAKEAWAY:
- At a median follow-up of 28.2 months, patients who received belantamab mafodotin demonstrated significantly longer median PFS than those who received daratumumab (36.6 vs 13.4 months; hazard ratio [HR], 0.41). The improvement was evident in all prespecified groups, including patients refractory to lenalidomide (HR, 0.37) and those with a high risk for cytogenetic abnormalities (HR, 0.36).
- The early overall survival trend favored belantamab mafodotin — with 84% of patients alive at 18 months vs 73% in the daratumumab group — but overall survival follow-up is ongoing.
- The overall response rate was 83% in the belantamab mafodotin group vs 71% in the daratumumab group. Complete response rates were also higher in the belantamab mafodotin: 34.6% vs 17.1%. Median duration of response was twice as long in the belantamab mafodotin group (36 vs 18 months).
- Grade 3 or higher non-ocular adverse events in belantamab mafodotin vs daratumumab group included thrombocytopenia (55% vs 35%), infections and infestations (31% vs 20%), neutropenia (12% vs 6%), pneumonia (12% vs 4%), and anemia (8% vs 10%). Grade 3 or higher ocular adverse events were reported in 34% of patients treated with belantamab mafodotin, but ocular toxicities reversed in most patients.
IN PRACTICE:
Based on favorable PFS and manageable safety profile, belantamab mafodotin in combination with bortezomib plus dexamethasone has potential to become a new standard of care in the second line or later among patients with relapsed or refractory multiple myeloma, the author concluded.
SOURCE:
This study, led by Maria-Victoria Mateos, MD, PhD, from University Hospital of Salamanca, Salamanca, Spain, was presented at ASCO Plenary Series: February 2024 Session and published in the Journal of Clinical Oncology.
LIMITATIONS:
Open-label design was a limitation of this study. Follow-up for overall survival was ongoing.
DISCLOSURES:
This study was funded by GSK. Dr. Mateos reported receiving honoraria, consulting/personal fees outside this work.
A version of this article first appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Belantamab mafodotin, a first-in-class anti-BCMA monoclonal antibody conjugate, was approved in the US in 2020 for adult patients with relapsed or refractory multiple myeloma who had received at least 4 prior therapies. However, in February 2023, the FDA withdrew this approval, following disappointing findings from a large confirmatory trial, called DREAMM-3. Although the agent is still being investigated to treat relapsed or refractory multiple myeloma, the current FDA label says the agent is only available in the US through a restricted program.
- Patients with multiple myeloma who relapse often become refractory to frontline triplet or quadruplet regimens and need effective second-line options.
- In the current phase 3 DREAMM-7 study, the researchers evaluated triplet therapy with belantamab mafodotin vs daratumumab as a second-line or later treatment option in patients with relapsed or refractory multiple myeloma.
- In this multicenter, open-label, randomized, phase 3 trial, 494 patients with relapsed/refractory multiple myeloma who previously received at least one prior line of therapy received bortezomib plus dexamethasone with either belantamab mafodotin or daratumumab.
- The primary outcome was PFS; secondary endpoints were overall survival, duration of response, and overall response rate.
TAKEAWAY:
- At a median follow-up of 28.2 months, patients who received belantamab mafodotin demonstrated significantly longer median PFS than those who received daratumumab (36.6 vs 13.4 months; hazard ratio [HR], 0.41). The improvement was evident in all prespecified groups, including patients refractory to lenalidomide (HR, 0.37) and those with a high risk for cytogenetic abnormalities (HR, 0.36).
- The early overall survival trend favored belantamab mafodotin — with 84% of patients alive at 18 months vs 73% in the daratumumab group — but overall survival follow-up is ongoing.
- The overall response rate was 83% in the belantamab mafodotin group vs 71% in the daratumumab group. Complete response rates were also higher in the belantamab mafodotin: 34.6% vs 17.1%. Median duration of response was twice as long in the belantamab mafodotin group (36 vs 18 months).
- Grade 3 or higher non-ocular adverse events in belantamab mafodotin vs daratumumab group included thrombocytopenia (55% vs 35%), infections and infestations (31% vs 20%), neutropenia (12% vs 6%), pneumonia (12% vs 4%), and anemia (8% vs 10%). Grade 3 or higher ocular adverse events were reported in 34% of patients treated with belantamab mafodotin, but ocular toxicities reversed in most patients.
IN PRACTICE:
Based on favorable PFS and manageable safety profile, belantamab mafodotin in combination with bortezomib plus dexamethasone has potential to become a new standard of care in the second line or later among patients with relapsed or refractory multiple myeloma, the author concluded.
SOURCE:
This study, led by Maria-Victoria Mateos, MD, PhD, from University Hospital of Salamanca, Salamanca, Spain, was presented at ASCO Plenary Series: February 2024 Session and published in the Journal of Clinical Oncology.
LIMITATIONS:
Open-label design was a limitation of this study. Follow-up for overall survival was ongoing.
DISCLOSURES:
This study was funded by GSK. Dr. Mateos reported receiving honoraria, consulting/personal fees outside this work.
A version of this article first appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Belantamab mafodotin, a first-in-class anti-BCMA monoclonal antibody conjugate, was approved in the US in 2020 for adult patients with relapsed or refractory multiple myeloma who had received at least 4 prior therapies. However, in February 2023, the FDA withdrew this approval, following disappointing findings from a large confirmatory trial, called DREAMM-3. Although the agent is still being investigated to treat relapsed or refractory multiple myeloma, the current FDA label says the agent is only available in the US through a restricted program.
- Patients with multiple myeloma who relapse often become refractory to frontline triplet or quadruplet regimens and need effective second-line options.
- In the current phase 3 DREAMM-7 study, the researchers evaluated triplet therapy with belantamab mafodotin vs daratumumab as a second-line or later treatment option in patients with relapsed or refractory multiple myeloma.
- In this multicenter, open-label, randomized, phase 3 trial, 494 patients with relapsed/refractory multiple myeloma who previously received at least one prior line of therapy received bortezomib plus dexamethasone with either belantamab mafodotin or daratumumab.
- The primary outcome was PFS; secondary endpoints were overall survival, duration of response, and overall response rate.
TAKEAWAY:
- At a median follow-up of 28.2 months, patients who received belantamab mafodotin demonstrated significantly longer median PFS than those who received daratumumab (36.6 vs 13.4 months; hazard ratio [HR], 0.41). The improvement was evident in all prespecified groups, including patients refractory to lenalidomide (HR, 0.37) and those with a high risk for cytogenetic abnormalities (HR, 0.36).
- The early overall survival trend favored belantamab mafodotin — with 84% of patients alive at 18 months vs 73% in the daratumumab group — but overall survival follow-up is ongoing.
- The overall response rate was 83% in the belantamab mafodotin group vs 71% in the daratumumab group. Complete response rates were also higher in the belantamab mafodotin: 34.6% vs 17.1%. Median duration of response was twice as long in the belantamab mafodotin group (36 vs 18 months).
- Grade 3 or higher non-ocular adverse events in belantamab mafodotin vs daratumumab group included thrombocytopenia (55% vs 35%), infections and infestations (31% vs 20%), neutropenia (12% vs 6%), pneumonia (12% vs 4%), and anemia (8% vs 10%). Grade 3 or higher ocular adverse events were reported in 34% of patients treated with belantamab mafodotin, but ocular toxicities reversed in most patients.
IN PRACTICE:
Based on favorable PFS and manageable safety profile, belantamab mafodotin in combination with bortezomib plus dexamethasone has potential to become a new standard of care in the second line or later among patients with relapsed or refractory multiple myeloma, the author concluded.
SOURCE:
This study, led by Maria-Victoria Mateos, MD, PhD, from University Hospital of Salamanca, Salamanca, Spain, was presented at ASCO Plenary Series: February 2024 Session and published in the Journal of Clinical Oncology.
LIMITATIONS:
Open-label design was a limitation of this study. Follow-up for overall survival was ongoing.
DISCLOSURES:
This study was funded by GSK. Dr. Mateos reported receiving honoraria, consulting/personal fees outside this work.
A version of this article first appeared on Medscape.com.
Young Myeloma Specialist Forges Ahead, Gives Back
Ahead of the conference held in San Diego in December, Dr. Mohyuddin, a blood cancer specialist with a focus on multiple myeloma and medical education, put out a heartfelt appeal on X (formerly Twitter): “If you’re a trainee and interested in meeting me at #ASH23, please reach out … (especially if [international medical graduate]) I’d love to meet and offer support in whatever capacity I can! I can’t have a research project for each one of you, but happy to help/mentor in any other way possible,” he posted on X back in late November.
An international medical graduate himself, Dr. Mohyuddin recalls how overwhelmed he felt when he first attended an annual ASH conference as a trainee, so he aims to reassure others that they “don’t have to know everything.”
“It’s about networking and broadening horizons,” he said in an interview that took place between ASH sessions, his own research presentations, and meetings with the many trainees who took him up on the offer he made via X. “I’ve spent most of this ASH meeting trainees — it’s the most rewarding thing for me at these meetings.
“Reassurance is a lot of what we do in oncology,” he continued, drawing a connection between his affinity for helping trainees and providing compassionate care to patients. “For an oncologist, the single most important thing is having excellent communication skills and being able to express support and empathy. The ability to connect deeply with your patients during their time of need is profoundly important.
“You can compensate for lack of knowledge, because we have so many other sources of support for knowledge, but you simply cannot compensate for poor communication skills, and your patient suffers as a result,” he said.
Relationship Building
In addition to the guidance he received from mentors, Dr. Mohyuddin noted that it was the chance to build supportive, empathetic relationships that drew him to specialize in blood cancer and, in particular, to caring for patients with multiple myeloma and conducting research focused on improving the patient experience.
Dr. Mohyuddin attended medical school at the Aga Khan University in Pakistan, then completed his internal medicine residency and fellowship at the University of Kansas in Kansas City. As a chief resident there, he focused on novel approaches to education delivery and improving access to research for trainees. As a fellow, he developed clinical and research interests in multiple myeloma, which he describes as an “incredibly rewarding field” marked by “truly spectacular advances over the last two decades.”
“There are some cancers you can cure, which means you don’t get to see patients often, and there are some you can’t cure, where patients die early, and there’s not a lot of time to build a relationship,” he said. “But there are some where patients can do well even though they aren’t currently cured, and you get to form really amazing and meaningful relationships over a long period of time.
“Multiple myeloma occupies that space, and that’s why I’m drawn to it,” Dr. Mohyuddin added, noting that he doesn’t shy away from forging emotional connections with patients. “I recognize that makes me vulnerable, but I think that is essentially what your patients deserve from you — to be invested at an emotional level with them through their suffering.”
Improving value and the patient experience
“One thing, philosophically, that I research is value in multiple myeloma care: identifying areas where we are overtreating patients and where we can do less and get away with it,” he said.
Despite the major advances in multiple myeloma in recent years, which “represent a lot of what is going right with oncology,” this blood cancer still “also represents a lot of what is wrong with oncology,” he noted. As an example, he cited “the approval of low-value drugs, the sequencing of drugs, adding more and more drugs without responsibly addressing quality-of-life questions, and identifying more responsible ways to provide high-value efficacious care without bankrupting the economy.
“So my research and policy work apply to that,” he explained. “What can we do better? What sort of trials should we be doing? What populations do we enroll? Are we asking the right questions or looking at trivialities? Are we serving patients foremost?”
Sometimes, this means comparing multiple myeloma staging systems in a real-world cohort, or assessing whether a widely available, cheap, and safe drug like budesonide can help patients avoid diarrhea during chemotherapy, whether control arms in myeloma randomized trials are fair, whether drugs ever get approved in low- or middle-income countries after their approval in the United States, and whether smoldering myeloma, a multiple myeloma precursor, really requires treatment, as current guidelines suggest, or if patients would do just as well — or perhaps better — with a close surveillance protocol.
“Pharma won’t do those studies and many key opinion leaders feel the question [about whether smoldering myeloma needs to be treated] has already been answered, so we are launching a prospective study that will define the natural history of smoldering myeloma and allow for patients to stay off therapy while undergoing rigorous surveillance with imaging,” he said.
Another study Dr. Mohyuddin hopes to launch soon will look at a “start low, go slow” treatment approach for the frailest patients with newly diagnosed myeloma.
His upbringing in Pakistan, where there are “mind-boggling” differences in health care access, affordability, and outcomes when compared with the United States, provided a foundation for both his “enthusiasm for cost-effective care” and his desire to give back, he said.
Another aspect of life in Pakistan — an across-the-board sense of closeness and solidarity in families and communities that is sometimes lacking in the United States — contributed to his desire to build relationships.
“That is something I dearly miss,” he said. “I am very privileged and so thankful to be here in the US, but that is one thing I do deeply miss.”
Connecting and Making a Difference
Dr. Mohyuddin seeks connection through his relationships with patients, trainees, and his many followers on social media platforms like X, where he frequently shares his thoughts on research quality and findings, heme/onc trends, and treatment-related insight.
“How to treat myeloma after #ASH23,” he posted on X as the conference came to a close. His takeaways: Don’t treat smoldering myeloma, do quadruple therapy for transplant-eligible patients (but no cd38 maintenance therapy afterward), don’t do quads for carfilzomib in newly diagnosed frail or older patients, and don’t do a salvage autologous transplant, no matter how good the first transplant was.
Dr. Mohyuddin also works to make a difference through his research and involvement in helping to launch initiatives like Common Sense Oncology, an ambitious global effort to reform cancer clinical trials and care, and through a current project with colleagues in India and Pakistan to create a consortium for pooling data on hematologic malignancies from South Asian countries. The hope is that such a collaborative effort will lead to good prospective research relevant to the needs of participating countries, he explained.
“Those are things where I want to make a difference. Taking care of patients is number one, but more than research, the number two thing for me is teaching and hopefully inspiring trainees and others to think differently, to look at data differently,” he said, noting that despite the major advances in myeloma, the reality is that “a lot of what we offer in oncology is very marginal.”
The effect sizes of interventions are often very small, and outcomes can still be really bad, he explained, adding that “[i]t really hits you when you see a lot of death and suffering. It’s a huge wake-up call … we have so many advances, but the reality is very, very sobering.
“Critically understanding and interpreting data is something where education really fails us. I’m incredibly passionate about it. I’ve found great resources to help me interpret data better, and I want to make them more accessible and inspire others to understand better,” he said. “We need to know how to defend ourselves from the hype.”
His efforts have not gone unnoticed. Dr. Mohyuddin was the recipient of the 2023 Hematology and Medical Oncology Fellowship Faculty Teaching Award at the University of Utah, Salt Lake City, where he is currently a faculty member.
“The recognition means more than any publication or grant award,” he said. “It’s great to know that medical education is appreciated, because so often we are in a rat race of getting more papers and grants out, but teaching and inspiring people is what is really, really important to me.”
Ahead of the conference held in San Diego in December, Dr. Mohyuddin, a blood cancer specialist with a focus on multiple myeloma and medical education, put out a heartfelt appeal on X (formerly Twitter): “If you’re a trainee and interested in meeting me at #ASH23, please reach out … (especially if [international medical graduate]) I’d love to meet and offer support in whatever capacity I can! I can’t have a research project for each one of you, but happy to help/mentor in any other way possible,” he posted on X back in late November.
An international medical graduate himself, Dr. Mohyuddin recalls how overwhelmed he felt when he first attended an annual ASH conference as a trainee, so he aims to reassure others that they “don’t have to know everything.”
“It’s about networking and broadening horizons,” he said in an interview that took place between ASH sessions, his own research presentations, and meetings with the many trainees who took him up on the offer he made via X. “I’ve spent most of this ASH meeting trainees — it’s the most rewarding thing for me at these meetings.
“Reassurance is a lot of what we do in oncology,” he continued, drawing a connection between his affinity for helping trainees and providing compassionate care to patients. “For an oncologist, the single most important thing is having excellent communication skills and being able to express support and empathy. The ability to connect deeply with your patients during their time of need is profoundly important.
“You can compensate for lack of knowledge, because we have so many other sources of support for knowledge, but you simply cannot compensate for poor communication skills, and your patient suffers as a result,” he said.
Relationship Building
In addition to the guidance he received from mentors, Dr. Mohyuddin noted that it was the chance to build supportive, empathetic relationships that drew him to specialize in blood cancer and, in particular, to caring for patients with multiple myeloma and conducting research focused on improving the patient experience.
Dr. Mohyuddin attended medical school at the Aga Khan University in Pakistan, then completed his internal medicine residency and fellowship at the University of Kansas in Kansas City. As a chief resident there, he focused on novel approaches to education delivery and improving access to research for trainees. As a fellow, he developed clinical and research interests in multiple myeloma, which he describes as an “incredibly rewarding field” marked by “truly spectacular advances over the last two decades.”
“There are some cancers you can cure, which means you don’t get to see patients often, and there are some you can’t cure, where patients die early, and there’s not a lot of time to build a relationship,” he said. “But there are some where patients can do well even though they aren’t currently cured, and you get to form really amazing and meaningful relationships over a long period of time.
“Multiple myeloma occupies that space, and that’s why I’m drawn to it,” Dr. Mohyuddin added, noting that he doesn’t shy away from forging emotional connections with patients. “I recognize that makes me vulnerable, but I think that is essentially what your patients deserve from you — to be invested at an emotional level with them through their suffering.”
Improving value and the patient experience
“One thing, philosophically, that I research is value in multiple myeloma care: identifying areas where we are overtreating patients and where we can do less and get away with it,” he said.
Despite the major advances in multiple myeloma in recent years, which “represent a lot of what is going right with oncology,” this blood cancer still “also represents a lot of what is wrong with oncology,” he noted. As an example, he cited “the approval of low-value drugs, the sequencing of drugs, adding more and more drugs without responsibly addressing quality-of-life questions, and identifying more responsible ways to provide high-value efficacious care without bankrupting the economy.
“So my research and policy work apply to that,” he explained. “What can we do better? What sort of trials should we be doing? What populations do we enroll? Are we asking the right questions or looking at trivialities? Are we serving patients foremost?”
Sometimes, this means comparing multiple myeloma staging systems in a real-world cohort, or assessing whether a widely available, cheap, and safe drug like budesonide can help patients avoid diarrhea during chemotherapy, whether control arms in myeloma randomized trials are fair, whether drugs ever get approved in low- or middle-income countries after their approval in the United States, and whether smoldering myeloma, a multiple myeloma precursor, really requires treatment, as current guidelines suggest, or if patients would do just as well — or perhaps better — with a close surveillance protocol.
“Pharma won’t do those studies and many key opinion leaders feel the question [about whether smoldering myeloma needs to be treated] has already been answered, so we are launching a prospective study that will define the natural history of smoldering myeloma and allow for patients to stay off therapy while undergoing rigorous surveillance with imaging,” he said.
Another study Dr. Mohyuddin hopes to launch soon will look at a “start low, go slow” treatment approach for the frailest patients with newly diagnosed myeloma.
His upbringing in Pakistan, where there are “mind-boggling” differences in health care access, affordability, and outcomes when compared with the United States, provided a foundation for both his “enthusiasm for cost-effective care” and his desire to give back, he said.
Another aspect of life in Pakistan — an across-the-board sense of closeness and solidarity in families and communities that is sometimes lacking in the United States — contributed to his desire to build relationships.
“That is something I dearly miss,” he said. “I am very privileged and so thankful to be here in the US, but that is one thing I do deeply miss.”
Connecting and Making a Difference
Dr. Mohyuddin seeks connection through his relationships with patients, trainees, and his many followers on social media platforms like X, where he frequently shares his thoughts on research quality and findings, heme/onc trends, and treatment-related insight.
“How to treat myeloma after #ASH23,” he posted on X as the conference came to a close. His takeaways: Don’t treat smoldering myeloma, do quadruple therapy for transplant-eligible patients (but no cd38 maintenance therapy afterward), don’t do quads for carfilzomib in newly diagnosed frail or older patients, and don’t do a salvage autologous transplant, no matter how good the first transplant was.
Dr. Mohyuddin also works to make a difference through his research and involvement in helping to launch initiatives like Common Sense Oncology, an ambitious global effort to reform cancer clinical trials and care, and through a current project with colleagues in India and Pakistan to create a consortium for pooling data on hematologic malignancies from South Asian countries. The hope is that such a collaborative effort will lead to good prospective research relevant to the needs of participating countries, he explained.
“Those are things where I want to make a difference. Taking care of patients is number one, but more than research, the number two thing for me is teaching and hopefully inspiring trainees and others to think differently, to look at data differently,” he said, noting that despite the major advances in myeloma, the reality is that “a lot of what we offer in oncology is very marginal.”
The effect sizes of interventions are often very small, and outcomes can still be really bad, he explained, adding that “[i]t really hits you when you see a lot of death and suffering. It’s a huge wake-up call … we have so many advances, but the reality is very, very sobering.
“Critically understanding and interpreting data is something where education really fails us. I’m incredibly passionate about it. I’ve found great resources to help me interpret data better, and I want to make them more accessible and inspire others to understand better,” he said. “We need to know how to defend ourselves from the hype.”
His efforts have not gone unnoticed. Dr. Mohyuddin was the recipient of the 2023 Hematology and Medical Oncology Fellowship Faculty Teaching Award at the University of Utah, Salt Lake City, where he is currently a faculty member.
“The recognition means more than any publication or grant award,” he said. “It’s great to know that medical education is appreciated, because so often we are in a rat race of getting more papers and grants out, but teaching and inspiring people is what is really, really important to me.”
Ahead of the conference held in San Diego in December, Dr. Mohyuddin, a blood cancer specialist with a focus on multiple myeloma and medical education, put out a heartfelt appeal on X (formerly Twitter): “If you’re a trainee and interested in meeting me at #ASH23, please reach out … (especially if [international medical graduate]) I’d love to meet and offer support in whatever capacity I can! I can’t have a research project for each one of you, but happy to help/mentor in any other way possible,” he posted on X back in late November.
An international medical graduate himself, Dr. Mohyuddin recalls how overwhelmed he felt when he first attended an annual ASH conference as a trainee, so he aims to reassure others that they “don’t have to know everything.”
“It’s about networking and broadening horizons,” he said in an interview that took place between ASH sessions, his own research presentations, and meetings with the many trainees who took him up on the offer he made via X. “I’ve spent most of this ASH meeting trainees — it’s the most rewarding thing for me at these meetings.
“Reassurance is a lot of what we do in oncology,” he continued, drawing a connection between his affinity for helping trainees and providing compassionate care to patients. “For an oncologist, the single most important thing is having excellent communication skills and being able to express support and empathy. The ability to connect deeply with your patients during their time of need is profoundly important.
“You can compensate for lack of knowledge, because we have so many other sources of support for knowledge, but you simply cannot compensate for poor communication skills, and your patient suffers as a result,” he said.
Relationship Building
In addition to the guidance he received from mentors, Dr. Mohyuddin noted that it was the chance to build supportive, empathetic relationships that drew him to specialize in blood cancer and, in particular, to caring for patients with multiple myeloma and conducting research focused on improving the patient experience.
Dr. Mohyuddin attended medical school at the Aga Khan University in Pakistan, then completed his internal medicine residency and fellowship at the University of Kansas in Kansas City. As a chief resident there, he focused on novel approaches to education delivery and improving access to research for trainees. As a fellow, he developed clinical and research interests in multiple myeloma, which he describes as an “incredibly rewarding field” marked by “truly spectacular advances over the last two decades.”
“There are some cancers you can cure, which means you don’t get to see patients often, and there are some you can’t cure, where patients die early, and there’s not a lot of time to build a relationship,” he said. “But there are some where patients can do well even though they aren’t currently cured, and you get to form really amazing and meaningful relationships over a long period of time.
“Multiple myeloma occupies that space, and that’s why I’m drawn to it,” Dr. Mohyuddin added, noting that he doesn’t shy away from forging emotional connections with patients. “I recognize that makes me vulnerable, but I think that is essentially what your patients deserve from you — to be invested at an emotional level with them through their suffering.”
Improving value and the patient experience
“One thing, philosophically, that I research is value in multiple myeloma care: identifying areas where we are overtreating patients and where we can do less and get away with it,” he said.
Despite the major advances in multiple myeloma in recent years, which “represent a lot of what is going right with oncology,” this blood cancer still “also represents a lot of what is wrong with oncology,” he noted. As an example, he cited “the approval of low-value drugs, the sequencing of drugs, adding more and more drugs without responsibly addressing quality-of-life questions, and identifying more responsible ways to provide high-value efficacious care without bankrupting the economy.
“So my research and policy work apply to that,” he explained. “What can we do better? What sort of trials should we be doing? What populations do we enroll? Are we asking the right questions or looking at trivialities? Are we serving patients foremost?”
Sometimes, this means comparing multiple myeloma staging systems in a real-world cohort, or assessing whether a widely available, cheap, and safe drug like budesonide can help patients avoid diarrhea during chemotherapy, whether control arms in myeloma randomized trials are fair, whether drugs ever get approved in low- or middle-income countries after their approval in the United States, and whether smoldering myeloma, a multiple myeloma precursor, really requires treatment, as current guidelines suggest, or if patients would do just as well — or perhaps better — with a close surveillance protocol.
“Pharma won’t do those studies and many key opinion leaders feel the question [about whether smoldering myeloma needs to be treated] has already been answered, so we are launching a prospective study that will define the natural history of smoldering myeloma and allow for patients to stay off therapy while undergoing rigorous surveillance with imaging,” he said.
Another study Dr. Mohyuddin hopes to launch soon will look at a “start low, go slow” treatment approach for the frailest patients with newly diagnosed myeloma.
His upbringing in Pakistan, where there are “mind-boggling” differences in health care access, affordability, and outcomes when compared with the United States, provided a foundation for both his “enthusiasm for cost-effective care” and his desire to give back, he said.
Another aspect of life in Pakistan — an across-the-board sense of closeness and solidarity in families and communities that is sometimes lacking in the United States — contributed to his desire to build relationships.
“That is something I dearly miss,” he said. “I am very privileged and so thankful to be here in the US, but that is one thing I do deeply miss.”
Connecting and Making a Difference
Dr. Mohyuddin seeks connection through his relationships with patients, trainees, and his many followers on social media platforms like X, where he frequently shares his thoughts on research quality and findings, heme/onc trends, and treatment-related insight.
“How to treat myeloma after #ASH23,” he posted on X as the conference came to a close. His takeaways: Don’t treat smoldering myeloma, do quadruple therapy for transplant-eligible patients (but no cd38 maintenance therapy afterward), don’t do quads for carfilzomib in newly diagnosed frail or older patients, and don’t do a salvage autologous transplant, no matter how good the first transplant was.
Dr. Mohyuddin also works to make a difference through his research and involvement in helping to launch initiatives like Common Sense Oncology, an ambitious global effort to reform cancer clinical trials and care, and through a current project with colleagues in India and Pakistan to create a consortium for pooling data on hematologic malignancies from South Asian countries. The hope is that such a collaborative effort will lead to good prospective research relevant to the needs of participating countries, he explained.
“Those are things where I want to make a difference. Taking care of patients is number one, but more than research, the number two thing for me is teaching and hopefully inspiring trainees and others to think differently, to look at data differently,” he said, noting that despite the major advances in myeloma, the reality is that “a lot of what we offer in oncology is very marginal.”
The effect sizes of interventions are often very small, and outcomes can still be really bad, he explained, adding that “[i]t really hits you when you see a lot of death and suffering. It’s a huge wake-up call … we have so many advances, but the reality is very, very sobering.
“Critically understanding and interpreting data is something where education really fails us. I’m incredibly passionate about it. I’ve found great resources to help me interpret data better, and I want to make them more accessible and inspire others to understand better,” he said. “We need to know how to defend ourselves from the hype.”
His efforts have not gone unnoticed. Dr. Mohyuddin was the recipient of the 2023 Hematology and Medical Oncology Fellowship Faculty Teaching Award at the University of Utah, Salt Lake City, where he is currently a faculty member.
“The recognition means more than any publication or grant award,” he said. “It’s great to know that medical education is appreciated, because so often we are in a rat race of getting more papers and grants out, but teaching and inspiring people is what is really, really important to me.”
New Multiple Myeloma Staging Systems Outperform the Standard
.
The findings should encourage greater use of these newer staging systems in routine clinical practice, first author Manni Mohyuddin, MD, said during a presentation at the American Society of Hematology annual meeting.
Dr. Mohyuddin and his colleagues retrospectively compared the standard Revised International Staging System (R-ISS) with two newer systems, the Second Revision of the R-ISS (R2-ISS) and the Mayo Additive Staging System (MASS), using real-world data from nearly 500 patients with newly diagnosed multiple myeloma.
The R-ISS, the most common multiple myeloma staging system, incorporates a range of prognostic features, including high-risk genetic markers assessed using fluorescence in situ hybridization as well as levels of lactate dehydrogenase, albumin, and beta-2 microglobulin, explained Dr. Mohyuddin, assistant professor at the Huntsman Cancer Institute, University of Utah, Salt Lake City.
R2-ISS and MASS include additional factors that reflect experts’ growing understanding of multiple myeloma. Specifically, the systems also evaluate a gain of chromosome 1q, in which patients have an extra copy of chromosome 1q, as well as the additive effects of multiple high-risk cytogenetic abnormalities, both of which indicate worse prognosis in multiple myeloma, Dr. Mohyuddin said in an interview.
To compare the three staging systems, the investigators used information on newly diagnosed patients in the Flatiron Health EHR–derived deidentified database, which includes data from cancer clinics across the United States. Patients were followed from first-line treatment initiation until death, the end of the study period, or last recorded activity.
The patients from the database had a median age of 70 years, and most had not received a transplant. The most common cytogenetic abnormality was gain 1q, present in about one third of patients.
Given that the R2-ISS originated from patients in clinical trials, Dr. Mohyuddin noted the importance of assessing how the system would perform in a real-world setting.
Of the 497 patients in the analysis, the R-ISS staging system classified 24% as stage I, 63% as stage II, and 13% as stage III. Overall survival differed across these R-ISS stages, indicating the system was prognostic for survival. Median overall survival was not reached for those with stage I disease, was 62.9 months for those with stage II disease, and 37.6 months for those with stage III disease.
Because the R-ISS doesn’t consider the additive effect of multiple cytogenetic abnormalities, many patients end up in the R-ISS stage II category but ultimately may have vastly different outcomes, Dr. Mohyuddin said.
The R2-ISS includes four risk categories, which provide more granularity to the stage II classification: Stage I is low risk, stage II is low-intermediate, stage III is intermediate, and stage IV is high risk. Using this staging system, 20% of patients were stage I, 25% were stage II, 46% were stage III, and 9% were stage IV.
The R2-ISS was also prognostic for survival, which generally worsened from stage I to stage IV: Median overall survival was not reached in stage I patients, was 69.3 months for stage II, 50.0 months for stage III, and 50.6 months for stage IV patients. However, Dr. Mohyuddin noted that there was some overlap in the survival curves for stages I and II and for stages III and IV.
When applying MASS, 34% of patients were categorized as stage I, 35% as stage II, and 31% as stage III disease. This system was prognostic for survival as well, with median overall survival of 76.9 months for stage I, 61.2 months for stage II, and 45.0 months for stage III.
With R2-ISS, many of those in R-ISS stage II are moved into stage I and III. With MASS, the R-ISS stage II patients are more evenly distributed across stages I, II, and III.
In other words, “we show that both these newer staging systems basically recategorize patients into different stages,” essentially “decreasing the number of people in the large, ambiguous (R-ISS) stage II category,” said Dr. Mohyuddin.
Dr. Mohyuddin and colleagues also evaluated the staging systems in fully adjusted analyses that controlled for age, race/ethnicity, sex, practice type, and diagnosis year.
Using R2-ISS, stage I patients had a similar risk for death compared with stage II patients (hazard ratio [HR], 1.2). Compared with stage I patients, stage III and IV patients had comparable risks for death, both about 2.5-fold higher than in those with stage I disease (HR, 2.4 and 2.6, respectively).
Compared with stage I MASS patients, those with stage II had a twofold higher risk for death (HR, 2.0), and those with stage III had an almost threefold higher risk (HR, 2.7).
Although no system considers all factors associated with myeloma outcomes, R2-ISS and MASS do offer a benefit over R-ISS, Dr. Mohyuddin said.
He added that the R2-ISS and MASS are similar from a statistical standpoint, but he gave MASS a slight edge for use in clinical practice.
MASS “more cleanly demarcated [patients] into prognostic subsets,” plus it is “a little easier to remember by heart,” he explained. MASS also puts more emphasis on the presence of multiple high-risk cytogenetic abnormalities, which is a worse prognostic in this era of quadruplet therapy for multiple myeloma, he added.
Because the study largely took place in an era when triplet therapy dominated, “we would be curious to see, with longer follow-up and more use of quadruplets, how these staging systems would perform,” he said.
Despite the benefits of these newer staging systems, many factors play a role in multiple myeloma outcomes, Dr. Mohyuddin explained. Staging systems are “only a piece of the puzzle.”
Dr. Mohyuddin reported having no financial interests to disclose.
A version of this article appeared on Medscape.com.
.
The findings should encourage greater use of these newer staging systems in routine clinical practice, first author Manni Mohyuddin, MD, said during a presentation at the American Society of Hematology annual meeting.
Dr. Mohyuddin and his colleagues retrospectively compared the standard Revised International Staging System (R-ISS) with two newer systems, the Second Revision of the R-ISS (R2-ISS) and the Mayo Additive Staging System (MASS), using real-world data from nearly 500 patients with newly diagnosed multiple myeloma.
The R-ISS, the most common multiple myeloma staging system, incorporates a range of prognostic features, including high-risk genetic markers assessed using fluorescence in situ hybridization as well as levels of lactate dehydrogenase, albumin, and beta-2 microglobulin, explained Dr. Mohyuddin, assistant professor at the Huntsman Cancer Institute, University of Utah, Salt Lake City.
R2-ISS and MASS include additional factors that reflect experts’ growing understanding of multiple myeloma. Specifically, the systems also evaluate a gain of chromosome 1q, in which patients have an extra copy of chromosome 1q, as well as the additive effects of multiple high-risk cytogenetic abnormalities, both of which indicate worse prognosis in multiple myeloma, Dr. Mohyuddin said in an interview.
To compare the three staging systems, the investigators used information on newly diagnosed patients in the Flatiron Health EHR–derived deidentified database, which includes data from cancer clinics across the United States. Patients were followed from first-line treatment initiation until death, the end of the study period, or last recorded activity.
The patients from the database had a median age of 70 years, and most had not received a transplant. The most common cytogenetic abnormality was gain 1q, present in about one third of patients.
Given that the R2-ISS originated from patients in clinical trials, Dr. Mohyuddin noted the importance of assessing how the system would perform in a real-world setting.
Of the 497 patients in the analysis, the R-ISS staging system classified 24% as stage I, 63% as stage II, and 13% as stage III. Overall survival differed across these R-ISS stages, indicating the system was prognostic for survival. Median overall survival was not reached for those with stage I disease, was 62.9 months for those with stage II disease, and 37.6 months for those with stage III disease.
Because the R-ISS doesn’t consider the additive effect of multiple cytogenetic abnormalities, many patients end up in the R-ISS stage II category but ultimately may have vastly different outcomes, Dr. Mohyuddin said.
The R2-ISS includes four risk categories, which provide more granularity to the stage II classification: Stage I is low risk, stage II is low-intermediate, stage III is intermediate, and stage IV is high risk. Using this staging system, 20% of patients were stage I, 25% were stage II, 46% were stage III, and 9% were stage IV.
The R2-ISS was also prognostic for survival, which generally worsened from stage I to stage IV: Median overall survival was not reached in stage I patients, was 69.3 months for stage II, 50.0 months for stage III, and 50.6 months for stage IV patients. However, Dr. Mohyuddin noted that there was some overlap in the survival curves for stages I and II and for stages III and IV.
When applying MASS, 34% of patients were categorized as stage I, 35% as stage II, and 31% as stage III disease. This system was prognostic for survival as well, with median overall survival of 76.9 months for stage I, 61.2 months for stage II, and 45.0 months for stage III.
With R2-ISS, many of those in R-ISS stage II are moved into stage I and III. With MASS, the R-ISS stage II patients are more evenly distributed across stages I, II, and III.
In other words, “we show that both these newer staging systems basically recategorize patients into different stages,” essentially “decreasing the number of people in the large, ambiguous (R-ISS) stage II category,” said Dr. Mohyuddin.
Dr. Mohyuddin and colleagues also evaluated the staging systems in fully adjusted analyses that controlled for age, race/ethnicity, sex, practice type, and diagnosis year.
Using R2-ISS, stage I patients had a similar risk for death compared with stage II patients (hazard ratio [HR], 1.2). Compared with stage I patients, stage III and IV patients had comparable risks for death, both about 2.5-fold higher than in those with stage I disease (HR, 2.4 and 2.6, respectively).
Compared with stage I MASS patients, those with stage II had a twofold higher risk for death (HR, 2.0), and those with stage III had an almost threefold higher risk (HR, 2.7).
Although no system considers all factors associated with myeloma outcomes, R2-ISS and MASS do offer a benefit over R-ISS, Dr. Mohyuddin said.
He added that the R2-ISS and MASS are similar from a statistical standpoint, but he gave MASS a slight edge for use in clinical practice.
MASS “more cleanly demarcated [patients] into prognostic subsets,” plus it is “a little easier to remember by heart,” he explained. MASS also puts more emphasis on the presence of multiple high-risk cytogenetic abnormalities, which is a worse prognostic in this era of quadruplet therapy for multiple myeloma, he added.
Because the study largely took place in an era when triplet therapy dominated, “we would be curious to see, with longer follow-up and more use of quadruplets, how these staging systems would perform,” he said.
Despite the benefits of these newer staging systems, many factors play a role in multiple myeloma outcomes, Dr. Mohyuddin explained. Staging systems are “only a piece of the puzzle.”
Dr. Mohyuddin reported having no financial interests to disclose.
A version of this article appeared on Medscape.com.
.
The findings should encourage greater use of these newer staging systems in routine clinical practice, first author Manni Mohyuddin, MD, said during a presentation at the American Society of Hematology annual meeting.
Dr. Mohyuddin and his colleagues retrospectively compared the standard Revised International Staging System (R-ISS) with two newer systems, the Second Revision of the R-ISS (R2-ISS) and the Mayo Additive Staging System (MASS), using real-world data from nearly 500 patients with newly diagnosed multiple myeloma.
The R-ISS, the most common multiple myeloma staging system, incorporates a range of prognostic features, including high-risk genetic markers assessed using fluorescence in situ hybridization as well as levels of lactate dehydrogenase, albumin, and beta-2 microglobulin, explained Dr. Mohyuddin, assistant professor at the Huntsman Cancer Institute, University of Utah, Salt Lake City.
R2-ISS and MASS include additional factors that reflect experts’ growing understanding of multiple myeloma. Specifically, the systems also evaluate a gain of chromosome 1q, in which patients have an extra copy of chromosome 1q, as well as the additive effects of multiple high-risk cytogenetic abnormalities, both of which indicate worse prognosis in multiple myeloma, Dr. Mohyuddin said in an interview.
To compare the three staging systems, the investigators used information on newly diagnosed patients in the Flatiron Health EHR–derived deidentified database, which includes data from cancer clinics across the United States. Patients were followed from first-line treatment initiation until death, the end of the study period, or last recorded activity.
The patients from the database had a median age of 70 years, and most had not received a transplant. The most common cytogenetic abnormality was gain 1q, present in about one third of patients.
Given that the R2-ISS originated from patients in clinical trials, Dr. Mohyuddin noted the importance of assessing how the system would perform in a real-world setting.
Of the 497 patients in the analysis, the R-ISS staging system classified 24% as stage I, 63% as stage II, and 13% as stage III. Overall survival differed across these R-ISS stages, indicating the system was prognostic for survival. Median overall survival was not reached for those with stage I disease, was 62.9 months for those with stage II disease, and 37.6 months for those with stage III disease.
Because the R-ISS doesn’t consider the additive effect of multiple cytogenetic abnormalities, many patients end up in the R-ISS stage II category but ultimately may have vastly different outcomes, Dr. Mohyuddin said.
The R2-ISS includes four risk categories, which provide more granularity to the stage II classification: Stage I is low risk, stage II is low-intermediate, stage III is intermediate, and stage IV is high risk. Using this staging system, 20% of patients were stage I, 25% were stage II, 46% were stage III, and 9% were stage IV.
The R2-ISS was also prognostic for survival, which generally worsened from stage I to stage IV: Median overall survival was not reached in stage I patients, was 69.3 months for stage II, 50.0 months for stage III, and 50.6 months for stage IV patients. However, Dr. Mohyuddin noted that there was some overlap in the survival curves for stages I and II and for stages III and IV.
When applying MASS, 34% of patients were categorized as stage I, 35% as stage II, and 31% as stage III disease. This system was prognostic for survival as well, with median overall survival of 76.9 months for stage I, 61.2 months for stage II, and 45.0 months for stage III.
With R2-ISS, many of those in R-ISS stage II are moved into stage I and III. With MASS, the R-ISS stage II patients are more evenly distributed across stages I, II, and III.
In other words, “we show that both these newer staging systems basically recategorize patients into different stages,” essentially “decreasing the number of people in the large, ambiguous (R-ISS) stage II category,” said Dr. Mohyuddin.
Dr. Mohyuddin and colleagues also evaluated the staging systems in fully adjusted analyses that controlled for age, race/ethnicity, sex, practice type, and diagnosis year.
Using R2-ISS, stage I patients had a similar risk for death compared with stage II patients (hazard ratio [HR], 1.2). Compared with stage I patients, stage III and IV patients had comparable risks for death, both about 2.5-fold higher than in those with stage I disease (HR, 2.4 and 2.6, respectively).
Compared with stage I MASS patients, those with stage II had a twofold higher risk for death (HR, 2.0), and those with stage III had an almost threefold higher risk (HR, 2.7).
Although no system considers all factors associated with myeloma outcomes, R2-ISS and MASS do offer a benefit over R-ISS, Dr. Mohyuddin said.
He added that the R2-ISS and MASS are similar from a statistical standpoint, but he gave MASS a slight edge for use in clinical practice.
MASS “more cleanly demarcated [patients] into prognostic subsets,” plus it is “a little easier to remember by heart,” he explained. MASS also puts more emphasis on the presence of multiple high-risk cytogenetic abnormalities, which is a worse prognostic in this era of quadruplet therapy for multiple myeloma, he added.
Because the study largely took place in an era when triplet therapy dominated, “we would be curious to see, with longer follow-up and more use of quadruplets, how these staging systems would perform,” he said.
Despite the benefits of these newer staging systems, many factors play a role in multiple myeloma outcomes, Dr. Mohyuddin explained. Staging systems are “only a piece of the puzzle.”
Dr. Mohyuddin reported having no financial interests to disclose.
A version of this article appeared on Medscape.com.
FROM ASH 2023
In Transplant-Ineligible Myeloma, This Frontline Tx Is Better
The study found that frontline triple therapy with daratumumab plus lenalidomide and dexamethasone led to significantly longer time to next treatment or time to death compared with the triple combination that includes bortezomib instead of daratumumab.
In the absence of head-to-head randomized controlled clinical trials, this study may help clinicians make more informed decisions when choosing therapies for patients with newly diagnosed, transplant-ineligible multiple myeloma, said investigator Doris K. Hansen, MD, from the Moffitt Cancer Center & Research Institute in Tampa, Florida, who presented finding from the analysis at the annual meeting of the American Society of Hematology.
Despite the lack of head-to-head randomized trials in this setting, several indirect comparisons have suggested that the daratumumab regimen carries an efficacy edge.
For instance, an indirect comparison of patients who received the daratumumab regimen in the MAIA trial with those who received the bortezomib regimen in the SWOG S0777 trial revealed a 40% lower risk for disease progression or death among patients treated with daratumumab. Researchers also observed a benefit for the daratumumab regimen — a 32% lower risk for disease progression or death — when comparing patient outcomes in the MAIA and PEGASUS studies.
To more directly compare the efficacy of the two regimens, Dr. Hansen and colleagues combed data from Acentrus, a de-identified academic electronic medical records database, to find patients who started a frontline treatment regimen for multiple myeloma between January 2018 and May 2023. The team used several methods to balance baseline characteristics between cohorts.
After making these adjustments, the study included data on 302 patients who received frontline therapy with the daratumumab regimen and 341 who received the bortezomib regimen. Patients who underwent hematopoietic stem cell transplant before or during therapy were excluded, as were those who had prior primary solid tumors, hematologic malignancies, or amyloidosis.
During a 20.2-month median follow-up for patients on daratumumab, 98 (32%) switched to a new therapy or died. During a 21.5-month median follow-up for those on bortezomib, 175 (51%) switched treatments or died.
The median time to death was 37.8 months in the daratumumab group vs 18.7 months in the bortezomib group. Overall, patients who received the daratumumab regimen had a 42% lower risk for death or time-to-next treatment (adjusted hazard ratio [HR], 0.58; P < .001).
Dr. Hansen acknowledged several limitations of the study, including that the data used came from provider-based records and may be missing patients who saw an out-of-network clinician. The database also does not include information on ECOG performance status, patient frailty, or cytogenetic risk profiles, which may have influenced outcomes.
The outcome measure combined time-to-next treatment and time to death; however, Dr. Hansen noted, time-to-next treatment is not a direct surrogate for progression-free survival.
Overall, findings from this real-world study support the use of daratumumab plus lenalidomide and dexamethasone over bortezomib plus lenalidomide and dexamethasone in this population of transplant-ineligible patients with newly diagnosed multiple myeloma, Dr. Hansen concluded.
The study was supported by Janssen. Dr. Hansen reported consulting for Janssen and others, receiving honoraria from OncLive and Survivorship, and other disclosures.
A version of this article appeared on Medscape.com.
The study found that frontline triple therapy with daratumumab plus lenalidomide and dexamethasone led to significantly longer time to next treatment or time to death compared with the triple combination that includes bortezomib instead of daratumumab.
In the absence of head-to-head randomized controlled clinical trials, this study may help clinicians make more informed decisions when choosing therapies for patients with newly diagnosed, transplant-ineligible multiple myeloma, said investigator Doris K. Hansen, MD, from the Moffitt Cancer Center & Research Institute in Tampa, Florida, who presented finding from the analysis at the annual meeting of the American Society of Hematology.
Despite the lack of head-to-head randomized trials in this setting, several indirect comparisons have suggested that the daratumumab regimen carries an efficacy edge.
For instance, an indirect comparison of patients who received the daratumumab regimen in the MAIA trial with those who received the bortezomib regimen in the SWOG S0777 trial revealed a 40% lower risk for disease progression or death among patients treated with daratumumab. Researchers also observed a benefit for the daratumumab regimen — a 32% lower risk for disease progression or death — when comparing patient outcomes in the MAIA and PEGASUS studies.
To more directly compare the efficacy of the two regimens, Dr. Hansen and colleagues combed data from Acentrus, a de-identified academic electronic medical records database, to find patients who started a frontline treatment regimen for multiple myeloma between January 2018 and May 2023. The team used several methods to balance baseline characteristics between cohorts.
After making these adjustments, the study included data on 302 patients who received frontline therapy with the daratumumab regimen and 341 who received the bortezomib regimen. Patients who underwent hematopoietic stem cell transplant before or during therapy were excluded, as were those who had prior primary solid tumors, hematologic malignancies, or amyloidosis.
During a 20.2-month median follow-up for patients on daratumumab, 98 (32%) switched to a new therapy or died. During a 21.5-month median follow-up for those on bortezomib, 175 (51%) switched treatments or died.
The median time to death was 37.8 months in the daratumumab group vs 18.7 months in the bortezomib group. Overall, patients who received the daratumumab regimen had a 42% lower risk for death or time-to-next treatment (adjusted hazard ratio [HR], 0.58; P < .001).
Dr. Hansen acknowledged several limitations of the study, including that the data used came from provider-based records and may be missing patients who saw an out-of-network clinician. The database also does not include information on ECOG performance status, patient frailty, or cytogenetic risk profiles, which may have influenced outcomes.
The outcome measure combined time-to-next treatment and time to death; however, Dr. Hansen noted, time-to-next treatment is not a direct surrogate for progression-free survival.
Overall, findings from this real-world study support the use of daratumumab plus lenalidomide and dexamethasone over bortezomib plus lenalidomide and dexamethasone in this population of transplant-ineligible patients with newly diagnosed multiple myeloma, Dr. Hansen concluded.
The study was supported by Janssen. Dr. Hansen reported consulting for Janssen and others, receiving honoraria from OncLive and Survivorship, and other disclosures.
A version of this article appeared on Medscape.com.
The study found that frontline triple therapy with daratumumab plus lenalidomide and dexamethasone led to significantly longer time to next treatment or time to death compared with the triple combination that includes bortezomib instead of daratumumab.
In the absence of head-to-head randomized controlled clinical trials, this study may help clinicians make more informed decisions when choosing therapies for patients with newly diagnosed, transplant-ineligible multiple myeloma, said investigator Doris K. Hansen, MD, from the Moffitt Cancer Center & Research Institute in Tampa, Florida, who presented finding from the analysis at the annual meeting of the American Society of Hematology.
Despite the lack of head-to-head randomized trials in this setting, several indirect comparisons have suggested that the daratumumab regimen carries an efficacy edge.
For instance, an indirect comparison of patients who received the daratumumab regimen in the MAIA trial with those who received the bortezomib regimen in the SWOG S0777 trial revealed a 40% lower risk for disease progression or death among patients treated with daratumumab. Researchers also observed a benefit for the daratumumab regimen — a 32% lower risk for disease progression or death — when comparing patient outcomes in the MAIA and PEGASUS studies.
To more directly compare the efficacy of the two regimens, Dr. Hansen and colleagues combed data from Acentrus, a de-identified academic electronic medical records database, to find patients who started a frontline treatment regimen for multiple myeloma between January 2018 and May 2023. The team used several methods to balance baseline characteristics between cohorts.
After making these adjustments, the study included data on 302 patients who received frontline therapy with the daratumumab regimen and 341 who received the bortezomib regimen. Patients who underwent hematopoietic stem cell transplant before or during therapy were excluded, as were those who had prior primary solid tumors, hematologic malignancies, or amyloidosis.
During a 20.2-month median follow-up for patients on daratumumab, 98 (32%) switched to a new therapy or died. During a 21.5-month median follow-up for those on bortezomib, 175 (51%) switched treatments or died.
The median time to death was 37.8 months in the daratumumab group vs 18.7 months in the bortezomib group. Overall, patients who received the daratumumab regimen had a 42% lower risk for death or time-to-next treatment (adjusted hazard ratio [HR], 0.58; P < .001).
Dr. Hansen acknowledged several limitations of the study, including that the data used came from provider-based records and may be missing patients who saw an out-of-network clinician. The database also does not include information on ECOG performance status, patient frailty, or cytogenetic risk profiles, which may have influenced outcomes.
The outcome measure combined time-to-next treatment and time to death; however, Dr. Hansen noted, time-to-next treatment is not a direct surrogate for progression-free survival.
Overall, findings from this real-world study support the use of daratumumab plus lenalidomide and dexamethasone over bortezomib plus lenalidomide and dexamethasone in this population of transplant-ineligible patients with newly diagnosed multiple myeloma, Dr. Hansen concluded.
The study was supported by Janssen. Dr. Hansen reported consulting for Janssen and others, receiving honoraria from OncLive and Survivorship, and other disclosures.
A version of this article appeared on Medscape.com.
FROM ASH 2023
No Benefit to Salvage Transplant in R/R Multiple Myeloma
Patients receiving a second, salvage-autologous stem cell transplant alongside lenalidomide-dexamethasone maintenance therapy did not demonstrate improved progression-free survival (PFS) or overall survival compared with patients who continued the two-drug regimen without salvage transplant, according to research presented at the American Society of Hematology annual meeting.
The primary phase 3 analysis, published in 2021, showed no survival benefit following salvage transplant at the time of relapse, though it only followed patients for a median of 37 months.
However, because a significant fraction of patients in the transplant arm — about 29% — did not undergo the planned salvage transplant before dropping out of the study, the researchers performed further analyses that “suggested a survival benefit in patients who actually received the transplant,” first author Marc-Andrea Baertsch, MD, of the German Cancer Research Center and University Hospital Heidelberg, reported at ASH.
Now, the latest analysis, which followed patients for a median of 99 months (8.25 years), confirmed the initial 2021 findings, Dr. Baertsch explained.
“The writing on the wall is clear: Don’t repeat a transplant at the time of relapse for those who have already gotten a transplant,” said Manni Mohyuddin, MD, of the University of Utah in Salt Lake City, who was not involved in the research. Dr. Mohyuddin added, however, that this finding doesn’t apply to those who haven’t yet gotten a transplant. “Data from other trials suggests a role of transplant in this situation, depending on the unique circumstances.”
The current trial included 282 adult patients, aged 75 years or younger, with relapsed or refractory multiple myeloma. Between 2010 and 2016, patients in the intention-to-treat analysis (n = 277) were randomized to lenalidomide-dexamethasone reinduction and maintenance, along with salvage high-dose chemotherapy with melphalan and autologous stem cell transplantation (n = 139) or just continuous lenalidomide-dexamethasone until progression (n = 138).
Patients in both arms received three cycles of lenalidomide-dexamethasone up front: 25 mg of lenalidomide on days 1 through 21, and 40 mg of dexamethasone on days 1, 8, 15, and 22 in 4-week cycles. Those in the salvage transplant arm then received high-dose chemotherapy with 200 mg/m2 of melphalan followed by transplant and 10 mg of lenalidomide maintenance therapy daily, while those in the control arm continued with receiving lenalidomide-dexamethasone.
All patients had received one to three prior lines of therapy, had good performance status, and had a time-to-disease-progression of at least 12 months after frontline autologous stem cell transplant.
In the primary 2021 study, patients in the salvage transplant group did not demonstrate a survival benefit (hazard ratio [HR] for PFS, 0.87; HR for overall survival, 0.81).
In the latest analysis, no survival benefit emerged after following patients for a median of about 8 years. Patients in the salvage transplant arm had a median PFS of 20.5 months vs 19.3 months in the continuous therapy arms (HR, 0.98; 95% CI, 0.76-1.27; P = .9). Median overall survival was 67.1 months in the salvage transplant arm and 62.7 months in the continuous treatment arm (HR, 0.89; 95% CI, 0.66 - 1.20; P = .44).
Time to first progression after frontline transplant was associated with a PFS benefit but did not predict an overall survival benefit, Dr. Baertsch noted.
When evaluating outcomes from the time of salvage transplant to account for the high number of dropouts, the PFS and overall survival findings held. Patients who received salvage transplant did not experience significantly improved PFS (HR, 0.91) or overall survival (76.3 months in the salvage group vs 65.9 months in the continuous treatment arm; HR, 0.80).
The lack of PFS and overall survival benefit occurred across all myeloma subgroups, Dr. Baertsch said.
Overall, the results indicate that “ a repeat transplant at the time of relapse for patients who had already gotten a transplant previously was no better than continuing a two-drug regimen,” Dr. Mohyuddin said.
However, he noted, “a lot has changed for myeloma care” since this trial was initially conducted. “We now have better regimens available that do not involve a transplant. If a repeat transplant couldn’t beat a two-drug regimen, it surely cannot beat a three drug or four drug regimen.”
Dr. Baertsch reported no disclosures.
A version of this article first appeared on Medscape.com.
Patients receiving a second, salvage-autologous stem cell transplant alongside lenalidomide-dexamethasone maintenance therapy did not demonstrate improved progression-free survival (PFS) or overall survival compared with patients who continued the two-drug regimen without salvage transplant, according to research presented at the American Society of Hematology annual meeting.
The primary phase 3 analysis, published in 2021, showed no survival benefit following salvage transplant at the time of relapse, though it only followed patients for a median of 37 months.
However, because a significant fraction of patients in the transplant arm — about 29% — did not undergo the planned salvage transplant before dropping out of the study, the researchers performed further analyses that “suggested a survival benefit in patients who actually received the transplant,” first author Marc-Andrea Baertsch, MD, of the German Cancer Research Center and University Hospital Heidelberg, reported at ASH.
Now, the latest analysis, which followed patients for a median of 99 months (8.25 years), confirmed the initial 2021 findings, Dr. Baertsch explained.
“The writing on the wall is clear: Don’t repeat a transplant at the time of relapse for those who have already gotten a transplant,” said Manni Mohyuddin, MD, of the University of Utah in Salt Lake City, who was not involved in the research. Dr. Mohyuddin added, however, that this finding doesn’t apply to those who haven’t yet gotten a transplant. “Data from other trials suggests a role of transplant in this situation, depending on the unique circumstances.”
The current trial included 282 adult patients, aged 75 years or younger, with relapsed or refractory multiple myeloma. Between 2010 and 2016, patients in the intention-to-treat analysis (n = 277) were randomized to lenalidomide-dexamethasone reinduction and maintenance, along with salvage high-dose chemotherapy with melphalan and autologous stem cell transplantation (n = 139) or just continuous lenalidomide-dexamethasone until progression (n = 138).
Patients in both arms received three cycles of lenalidomide-dexamethasone up front: 25 mg of lenalidomide on days 1 through 21, and 40 mg of dexamethasone on days 1, 8, 15, and 22 in 4-week cycles. Those in the salvage transplant arm then received high-dose chemotherapy with 200 mg/m2 of melphalan followed by transplant and 10 mg of lenalidomide maintenance therapy daily, while those in the control arm continued with receiving lenalidomide-dexamethasone.
All patients had received one to three prior lines of therapy, had good performance status, and had a time-to-disease-progression of at least 12 months after frontline autologous stem cell transplant.
In the primary 2021 study, patients in the salvage transplant group did not demonstrate a survival benefit (hazard ratio [HR] for PFS, 0.87; HR for overall survival, 0.81).
In the latest analysis, no survival benefit emerged after following patients for a median of about 8 years. Patients in the salvage transplant arm had a median PFS of 20.5 months vs 19.3 months in the continuous therapy arms (HR, 0.98; 95% CI, 0.76-1.27; P = .9). Median overall survival was 67.1 months in the salvage transplant arm and 62.7 months in the continuous treatment arm (HR, 0.89; 95% CI, 0.66 - 1.20; P = .44).
Time to first progression after frontline transplant was associated with a PFS benefit but did not predict an overall survival benefit, Dr. Baertsch noted.
When evaluating outcomes from the time of salvage transplant to account for the high number of dropouts, the PFS and overall survival findings held. Patients who received salvage transplant did not experience significantly improved PFS (HR, 0.91) or overall survival (76.3 months in the salvage group vs 65.9 months in the continuous treatment arm; HR, 0.80).
The lack of PFS and overall survival benefit occurred across all myeloma subgroups, Dr. Baertsch said.
Overall, the results indicate that “ a repeat transplant at the time of relapse for patients who had already gotten a transplant previously was no better than continuing a two-drug regimen,” Dr. Mohyuddin said.
However, he noted, “a lot has changed for myeloma care” since this trial was initially conducted. “We now have better regimens available that do not involve a transplant. If a repeat transplant couldn’t beat a two-drug regimen, it surely cannot beat a three drug or four drug regimen.”
Dr. Baertsch reported no disclosures.
A version of this article first appeared on Medscape.com.
Patients receiving a second, salvage-autologous stem cell transplant alongside lenalidomide-dexamethasone maintenance therapy did not demonstrate improved progression-free survival (PFS) or overall survival compared with patients who continued the two-drug regimen without salvage transplant, according to research presented at the American Society of Hematology annual meeting.
The primary phase 3 analysis, published in 2021, showed no survival benefit following salvage transplant at the time of relapse, though it only followed patients for a median of 37 months.
However, because a significant fraction of patients in the transplant arm — about 29% — did not undergo the planned salvage transplant before dropping out of the study, the researchers performed further analyses that “suggested a survival benefit in patients who actually received the transplant,” first author Marc-Andrea Baertsch, MD, of the German Cancer Research Center and University Hospital Heidelberg, reported at ASH.
Now, the latest analysis, which followed patients for a median of 99 months (8.25 years), confirmed the initial 2021 findings, Dr. Baertsch explained.
“The writing on the wall is clear: Don’t repeat a transplant at the time of relapse for those who have already gotten a transplant,” said Manni Mohyuddin, MD, of the University of Utah in Salt Lake City, who was not involved in the research. Dr. Mohyuddin added, however, that this finding doesn’t apply to those who haven’t yet gotten a transplant. “Data from other trials suggests a role of transplant in this situation, depending on the unique circumstances.”
The current trial included 282 adult patients, aged 75 years or younger, with relapsed or refractory multiple myeloma. Between 2010 and 2016, patients in the intention-to-treat analysis (n = 277) were randomized to lenalidomide-dexamethasone reinduction and maintenance, along with salvage high-dose chemotherapy with melphalan and autologous stem cell transplantation (n = 139) or just continuous lenalidomide-dexamethasone until progression (n = 138).
Patients in both arms received three cycles of lenalidomide-dexamethasone up front: 25 mg of lenalidomide on days 1 through 21, and 40 mg of dexamethasone on days 1, 8, 15, and 22 in 4-week cycles. Those in the salvage transplant arm then received high-dose chemotherapy with 200 mg/m2 of melphalan followed by transplant and 10 mg of lenalidomide maintenance therapy daily, while those in the control arm continued with receiving lenalidomide-dexamethasone.
All patients had received one to three prior lines of therapy, had good performance status, and had a time-to-disease-progression of at least 12 months after frontline autologous stem cell transplant.
In the primary 2021 study, patients in the salvage transplant group did not demonstrate a survival benefit (hazard ratio [HR] for PFS, 0.87; HR for overall survival, 0.81).
In the latest analysis, no survival benefit emerged after following patients for a median of about 8 years. Patients in the salvage transplant arm had a median PFS of 20.5 months vs 19.3 months in the continuous therapy arms (HR, 0.98; 95% CI, 0.76-1.27; P = .9). Median overall survival was 67.1 months in the salvage transplant arm and 62.7 months in the continuous treatment arm (HR, 0.89; 95% CI, 0.66 - 1.20; P = .44).
Time to first progression after frontline transplant was associated with a PFS benefit but did not predict an overall survival benefit, Dr. Baertsch noted.
When evaluating outcomes from the time of salvage transplant to account for the high number of dropouts, the PFS and overall survival findings held. Patients who received salvage transplant did not experience significantly improved PFS (HR, 0.91) or overall survival (76.3 months in the salvage group vs 65.9 months in the continuous treatment arm; HR, 0.80).
The lack of PFS and overall survival benefit occurred across all myeloma subgroups, Dr. Baertsch said.
Overall, the results indicate that “ a repeat transplant at the time of relapse for patients who had already gotten a transplant previously was no better than continuing a two-drug regimen,” Dr. Mohyuddin said.
However, he noted, “a lot has changed for myeloma care” since this trial was initially conducted. “We now have better regimens available that do not involve a transplant. If a repeat transplant couldn’t beat a two-drug regimen, it surely cannot beat a three drug or four drug regimen.”
Dr. Baertsch reported no disclosures.
A version of this article first appeared on Medscape.com.
FROM ASH 2023
Distinct toxicity profiles for anti-BCMA myeloma therapies
Among 1803 patients with multiple myeloma treated with either chimeric antigen receptor (CAR) T-cell constructs or a bispecific antibody, CAR T-cell therapy was associated with a “prominent” risk for both cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, while the antibody was associated with a high risk for infection-related mortality, reported Zimu Gong, MD, PhD, from the Cancer Center at Houston Methodist Hospital.“When we are selecting or sequencing these agents, because they are approved for almost identical indications, we need to carefully consider their unique toxicity profile,” he said in an oral abstract session at the annual meeting of the American Society of Hematology (ASH) here.
Going to the FAERS
Dr. Gong and colleagues drew on the FDA Adverse Event Reporting System (FAERS) database for data on toxicities associated with three BCMA-directed therapies: CAR T-cell treatments idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti), and the bispecific antibody teclistamab (Tecvayli).
They identified a total of 1803 cases with a total of 4423 reported adverse events.
The authors calculated a reporting odds ratio (ROR) by dividing the odds of a specific event occurring with an agent by the odds of the same event occurring with all other BCMA-directed agents in the FAERS database.
They found that the highest ROR for cytokine release syndrome was with ide-cel, at 1.8, compared with 0.74 with cilta-cel, and 0.63 with teclistamab. Ide-cel was also most strongly associated with risk for both immune effector cell-associated neurotoxicity syndrome, with an ROR of 1.38, compared with 1.04 with cilta-cel and 0.69 with teclistamab, and with non-immune effector cell-associated neurotoxicity, with an ROR of 2.19 vs 0.83 and 0.4, respectively.
There were 14 reported cases of Bell’s palsy, 13 of which were associated with cilta-cel and 1 with teclistamab, and 11 cases of Parkinsonism, including 7 occurring with cilta-cel, 4 with ide-cel, and none with teclistamab.
In contrast, risk for infection was highest with teclistamab, with an ROR of 4.38 compared with 1.3 with cilta-cel and 0.12 with ide-cel. The infections most commonly reported with teclistamab included pneumonia, sepsis, COVID-19 pneumonia, pneumocystis jirovecii pneumonia, cytomegalovirus reactive and cytomegalovirus pneumonia.
The antibody was also associated with the highest risk for nonrelapse mortality, with an ROR of 1.73 compared with 1.28 with cilta-cel and 0.13 with ide-cel.
There were 309 reported deaths. The investigators calculated nonrelapse mortality by excluding disease progress from cases with death as the final reported outcome. Ide-cell had the lowest odds ratio for non-relapse mortality, at 0.53, compared with 0.99 for cilta-cel, and 1.72 for teclistamab. The most common cause of nonrelapse deaths was toxicities associated with CAR T-cell therapy, and infections, Dr. Gong said.
Dr. Gong acknowledged that one of the major limitations of the study is the nature of the FAERS database itself, which includes both mandatory reports on adverse events, medication errors, and product quality complaints submitted as required by law by manufacturers, but also voluntarily reported by healthcare professionals and consumers.
In an interview with this news organization, David Miklos, MD, PhD, chief of the blood and marrow transplantation and cellular therapy division at Stanford University, who attended the session but was not involved in the study, commented that although the study showed differences among various anti-BCMA products in terms of adverse events, the analysis is only one of several that show different values.
“The concern I have about the FAERS database is simply the lack of validation, and maybe, with no disrespect to the institution, this is kind of like review scores on Amazon.com: not validated, nobody knows who put them out there, and we don’t even know if it’s true,” he said.
He noted that whatever the system, data collection and reporting is both time- and resource-consuming, and given the potential of cellular therapies to significantly improve survival may burden clinicians with requirements for decades of follow-up and reporting.
“Self-reporting isn’t the answer either,” said Dr. Miklos. Perhaps, he suggested, there is a role for apps with “patients self-reporting” and medical practitioners validating the reports.
Dr. Gong and colleagues did not report a study funding source. Dr. Gong had no conflict of interest disclosures. Dr. Miklos has disclosed serving as a director, officer, partner, employee, advisor, consultant, or trustee for: Kite-Gilead, Novartis, Juno-Celgene-Bristol-Myers Squibb, Adaptive Biotech, Pharmacyclics, and Janssen; received research funding from: Kite-Gilead, Novartis, Juno-Celgene-Bristol-Myers Squibb, Adaptive Biotech, Pharmacyclic; patents, royalties, or other intellectual property from Pharmacyclics, and travel support from Kite-Gilead, Novartis, Juno-Celgene-Bristol-Myers Squibb, Adaptive Biotech, Pharmacyclics, and Janssen.
A version of this article first appeared on Medscape.com.
Among 1803 patients with multiple myeloma treated with either chimeric antigen receptor (CAR) T-cell constructs or a bispecific antibody, CAR T-cell therapy was associated with a “prominent” risk for both cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, while the antibody was associated with a high risk for infection-related mortality, reported Zimu Gong, MD, PhD, from the Cancer Center at Houston Methodist Hospital.“When we are selecting or sequencing these agents, because they are approved for almost identical indications, we need to carefully consider their unique toxicity profile,” he said in an oral abstract session at the annual meeting of the American Society of Hematology (ASH) here.
Going to the FAERS
Dr. Gong and colleagues drew on the FDA Adverse Event Reporting System (FAERS) database for data on toxicities associated with three BCMA-directed therapies: CAR T-cell treatments idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti), and the bispecific antibody teclistamab (Tecvayli).
They identified a total of 1803 cases with a total of 4423 reported adverse events.
The authors calculated a reporting odds ratio (ROR) by dividing the odds of a specific event occurring with an agent by the odds of the same event occurring with all other BCMA-directed agents in the FAERS database.
They found that the highest ROR for cytokine release syndrome was with ide-cel, at 1.8, compared with 0.74 with cilta-cel, and 0.63 with teclistamab. Ide-cel was also most strongly associated with risk for both immune effector cell-associated neurotoxicity syndrome, with an ROR of 1.38, compared with 1.04 with cilta-cel and 0.69 with teclistamab, and with non-immune effector cell-associated neurotoxicity, with an ROR of 2.19 vs 0.83 and 0.4, respectively.
There were 14 reported cases of Bell’s palsy, 13 of which were associated with cilta-cel and 1 with teclistamab, and 11 cases of Parkinsonism, including 7 occurring with cilta-cel, 4 with ide-cel, and none with teclistamab.
In contrast, risk for infection was highest with teclistamab, with an ROR of 4.38 compared with 1.3 with cilta-cel and 0.12 with ide-cel. The infections most commonly reported with teclistamab included pneumonia, sepsis, COVID-19 pneumonia, pneumocystis jirovecii pneumonia, cytomegalovirus reactive and cytomegalovirus pneumonia.
The antibody was also associated with the highest risk for nonrelapse mortality, with an ROR of 1.73 compared with 1.28 with cilta-cel and 0.13 with ide-cel.
There were 309 reported deaths. The investigators calculated nonrelapse mortality by excluding disease progress from cases with death as the final reported outcome. Ide-cell had the lowest odds ratio for non-relapse mortality, at 0.53, compared with 0.99 for cilta-cel, and 1.72 for teclistamab. The most common cause of nonrelapse deaths was toxicities associated with CAR T-cell therapy, and infections, Dr. Gong said.
Dr. Gong acknowledged that one of the major limitations of the study is the nature of the FAERS database itself, which includes both mandatory reports on adverse events, medication errors, and product quality complaints submitted as required by law by manufacturers, but also voluntarily reported by healthcare professionals and consumers.
In an interview with this news organization, David Miklos, MD, PhD, chief of the blood and marrow transplantation and cellular therapy division at Stanford University, who attended the session but was not involved in the study, commented that although the study showed differences among various anti-BCMA products in terms of adverse events, the analysis is only one of several that show different values.
“The concern I have about the FAERS database is simply the lack of validation, and maybe, with no disrespect to the institution, this is kind of like review scores on Amazon.com: not validated, nobody knows who put them out there, and we don’t even know if it’s true,” he said.
He noted that whatever the system, data collection and reporting is both time- and resource-consuming, and given the potential of cellular therapies to significantly improve survival may burden clinicians with requirements for decades of follow-up and reporting.
“Self-reporting isn’t the answer either,” said Dr. Miklos. Perhaps, he suggested, there is a role for apps with “patients self-reporting” and medical practitioners validating the reports.
Dr. Gong and colleagues did not report a study funding source. Dr. Gong had no conflict of interest disclosures. Dr. Miklos has disclosed serving as a director, officer, partner, employee, advisor, consultant, or trustee for: Kite-Gilead, Novartis, Juno-Celgene-Bristol-Myers Squibb, Adaptive Biotech, Pharmacyclics, and Janssen; received research funding from: Kite-Gilead, Novartis, Juno-Celgene-Bristol-Myers Squibb, Adaptive Biotech, Pharmacyclic; patents, royalties, or other intellectual property from Pharmacyclics, and travel support from Kite-Gilead, Novartis, Juno-Celgene-Bristol-Myers Squibb, Adaptive Biotech, Pharmacyclics, and Janssen.
A version of this article first appeared on Medscape.com.
Among 1803 patients with multiple myeloma treated with either chimeric antigen receptor (CAR) T-cell constructs or a bispecific antibody, CAR T-cell therapy was associated with a “prominent” risk for both cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, while the antibody was associated with a high risk for infection-related mortality, reported Zimu Gong, MD, PhD, from the Cancer Center at Houston Methodist Hospital.“When we are selecting or sequencing these agents, because they are approved for almost identical indications, we need to carefully consider their unique toxicity profile,” he said in an oral abstract session at the annual meeting of the American Society of Hematology (ASH) here.
Going to the FAERS
Dr. Gong and colleagues drew on the FDA Adverse Event Reporting System (FAERS) database for data on toxicities associated with three BCMA-directed therapies: CAR T-cell treatments idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti), and the bispecific antibody teclistamab (Tecvayli).
They identified a total of 1803 cases with a total of 4423 reported adverse events.
The authors calculated a reporting odds ratio (ROR) by dividing the odds of a specific event occurring with an agent by the odds of the same event occurring with all other BCMA-directed agents in the FAERS database.
They found that the highest ROR for cytokine release syndrome was with ide-cel, at 1.8, compared with 0.74 with cilta-cel, and 0.63 with teclistamab. Ide-cel was also most strongly associated with risk for both immune effector cell-associated neurotoxicity syndrome, with an ROR of 1.38, compared with 1.04 with cilta-cel and 0.69 with teclistamab, and with non-immune effector cell-associated neurotoxicity, with an ROR of 2.19 vs 0.83 and 0.4, respectively.
There were 14 reported cases of Bell’s palsy, 13 of which were associated with cilta-cel and 1 with teclistamab, and 11 cases of Parkinsonism, including 7 occurring with cilta-cel, 4 with ide-cel, and none with teclistamab.
In contrast, risk for infection was highest with teclistamab, with an ROR of 4.38 compared with 1.3 with cilta-cel and 0.12 with ide-cel. The infections most commonly reported with teclistamab included pneumonia, sepsis, COVID-19 pneumonia, pneumocystis jirovecii pneumonia, cytomegalovirus reactive and cytomegalovirus pneumonia.
The antibody was also associated with the highest risk for nonrelapse mortality, with an ROR of 1.73 compared with 1.28 with cilta-cel and 0.13 with ide-cel.
There were 309 reported deaths. The investigators calculated nonrelapse mortality by excluding disease progress from cases with death as the final reported outcome. Ide-cell had the lowest odds ratio for non-relapse mortality, at 0.53, compared with 0.99 for cilta-cel, and 1.72 for teclistamab. The most common cause of nonrelapse deaths was toxicities associated with CAR T-cell therapy, and infections, Dr. Gong said.
Dr. Gong acknowledged that one of the major limitations of the study is the nature of the FAERS database itself, which includes both mandatory reports on adverse events, medication errors, and product quality complaints submitted as required by law by manufacturers, but also voluntarily reported by healthcare professionals and consumers.
In an interview with this news organization, David Miklos, MD, PhD, chief of the blood and marrow transplantation and cellular therapy division at Stanford University, who attended the session but was not involved in the study, commented that although the study showed differences among various anti-BCMA products in terms of adverse events, the analysis is only one of several that show different values.
“The concern I have about the FAERS database is simply the lack of validation, and maybe, with no disrespect to the institution, this is kind of like review scores on Amazon.com: not validated, nobody knows who put them out there, and we don’t even know if it’s true,” he said.
He noted that whatever the system, data collection and reporting is both time- and resource-consuming, and given the potential of cellular therapies to significantly improve survival may burden clinicians with requirements for decades of follow-up and reporting.
“Self-reporting isn’t the answer either,” said Dr. Miklos. Perhaps, he suggested, there is a role for apps with “patients self-reporting” and medical practitioners validating the reports.
Dr. Gong and colleagues did not report a study funding source. Dr. Gong had no conflict of interest disclosures. Dr. Miklos has disclosed serving as a director, officer, partner, employee, advisor, consultant, or trustee for: Kite-Gilead, Novartis, Juno-Celgene-Bristol-Myers Squibb, Adaptive Biotech, Pharmacyclics, and Janssen; received research funding from: Kite-Gilead, Novartis, Juno-Celgene-Bristol-Myers Squibb, Adaptive Biotech, Pharmacyclic; patents, royalties, or other intellectual property from Pharmacyclics, and travel support from Kite-Gilead, Novartis, Juno-Celgene-Bristol-Myers Squibb, Adaptive Biotech, Pharmacyclics, and Janssen.
A version of this article first appeared on Medscape.com.
FROM ASH 2023
Myeloma: Isatuximab Four-Drug Regimen Boosts MRD Negativity
“This [research] builds on our experience that four-drug combinations with a monoclonal antibody, proteasome inhibitor, immunomodulatory drug and steroids are superior to three-drug combinations,” Joseph Mikhael, MD, chief medical officer of the International Myeloma Foundation, said in an interview on the study.
“It also demonstrates the value of CD38 antibodies, and specifically isatuximab, in the frontline setting,” said Dr. Mikhael, professor at the Translational Genomics Research Institute (TGen), City of Hope Cancer Center in Goodyear, Ariz.
The findings were presented at the annual meeting of the American Society of Hematology.
The current standard of care for transplant-eligible, newly diagnosed MM consists of the quadruple combination of a CD38 monoclonal antibody, an immunomodulatory drug, a proteasome inhibitor, and a glucocorticoid, followed by high-dose melphalan and autologous stem-cell transplantation (ASCT).
Isatuximab already has approval in combination with the regimen of carfilzomib and dexamethasone (KRd) in the treatment of relapsed or refractory MM patients who have received prior lines of therapy.
To investigate the efficacy and safety of addition of isatuximab in the setting of transplant-eligible, newly diagnosed MM patients, first author Francesca Gay, MD, PhD, of the Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy, and colleagues conducted the multisite, phase-3 Iskia trial, enrolling 302 transplant-eligible newly diagnosed MM patients.
The patients were randomized to groups of 151 each to treatment either with IsaKRd or KRd alone. The treatment regimen for KRd included four cycles in induction including weekly carfilzomib at 56 mg on day 1, 8 and 15, lenalidomide 25 mg at day 1-21, and dexamethasone at 40 mg weekly, and the IsaKRd group included four 28-day cycles of isatuximab 10 mg/kg IV days 1, 8, 15, and 22 in cycle 1, followed by 10 mg/kg days 1, 15 in cycles 2-4.
The induction was followed by stem cell mobilization and collection and high dose chemotherapy, followed by four cycles of full-dose consolidation at the same doses and schedule as induction, followed by a light consolidation phase of 12 28-day cycles of reduced dose KRd.
Patients had a median age of 61 and 60 in the isatuximab versus KRd group, respectively, and characteristics were similar between the two arms.
With the current follow-up of a mean of 21 months, the primary endpoint was met, with the intention-to-treat analysis showing a rate of post-consolidation MRD negativity, as assessed with a next-generation sequencing (NGS) cut-off of 10-5, of 77% with isatuximab versus 67% with KRd alone (OR 1.67; P = .049).
With an NGS cut-off of 10-6, the respective rates were 67% vs. 48% (OR 2.29; P < .001).
“This difference in MRD negativity in the depth of response was seen despite the responses analyzed according to the conventional criteria being comparable in the two arms, with more than 90% of patients achieving at least a very good partial response and more than 70% achieving at least a complete response,” Dr. Gay noted.
For the key secondary endpoint of MRD negativity over time, the rates were also significantly higher with IsaKRd vs. KRd at post-induction (10-5 cut-off, 45% vs. 26%, OR 2.34; P < .001; 10-6 cut-off, 27% vs. 14%, OR 2.36, P = .004).
IsaKRd also had greater MRD negativity post-ASCT (10-5 cutoff 64% vs. 49%; P = .006; 10-6 cutoff, 52% vs. 27%, P < .001) and post-consolidation (10-5 cutoff, 77% vs. 67%; P = .049 and 10-6 cutoff, 67% vs. 48%, P < .001).
The increase in the MRD negativity in the IsaKRd group was observed in all subgroups of patients analyzed at the 10-5 and 10-6 cut-offs.
The improved post-consolidation rate of MRD negativity with IsaKRd was also observed among patients based on all levels of cytogenetic risk, which was not the case in the KRd alone arm, which showed a reduction in MRD negativity among very high-risk patients, Dr. Gay observed.
The study’s other key secondary endpoint of progression-free survival will be presented in the future, when longer-term outcomes are available.
As of the current follow-up, 17% of patients in the IsaKRd group had discontinued the study treatment versus 10% with KRd, with the leading cause of adverse events for 6% and 5%, respectively.
At least one hematologic adverse event occurred in 55% of patients treated with IsaKRd and 44% in the KRd alone group, with the most prominent grade 3-4 adverse events occurring more commonly with IsaKRd being neutropenia (36% vs. 22%) and thrombocytopenia (15% vs. 17%).
Non-hematologic grade 3-4 adverse events occurred in 41% of patients in the IsaKRd group versus 37% in KRd only, which included infections (15% vs. 11%), and gastrointestinal (7% vs. 5%), vascular (5% vs. 10%) and cardiac events (<1% vs. 3%).
Discontinuation for toxicity occurred in similar rates in both groups (6% in IsaKRd vs. 5% in KRd); with four treatment-related deaths occurring with IsaKRd (two COVID, one pneumonia, one pulmonary embolism) and one with KRd (septic shock).
“Treatment was tolerable with a toxicity profile that was similar to that in previous reports,” Dr. Gay said.
“In the context of these highly effective regimens that produce a high rate of response, the 10-6 MRD cutoff might be more informative than other result categories,” she added.
Longer follow-up will provide more insights in survival endpoints, and “the trial can potentially offer the opportunity to explore correlations between depth of MRD negativity and survival endpoints,” Dr. Gay noted.
Further commenting on the study, Irene Ghobrial, MD, of Medical Oncology, with the Dana-Farber Cancer Institute, Boston, said the results are encouraging.
“We’re seeing two phase three trials now showing us that indeed a CD38 antibody in addition to our triplet standards of care are making a huge difference in MRD response,” she said in an interview.
“So, I think the main message here is that the four-drug regimen is the way to go from now on in multiple myeloma.”
The study received funding from Sanofi and Amgen. Dr. Gay disclosed relationships with AbbVie; Bristol Myers Squibb/Celgene; Sanofi; Roche; GlaxoSmithKline; Pfizer; Oncopeptides; Takeda; Janssen; and Amgen. Dr. Mikhael reported ties with Amgen, BMS, Janssen, Sanofi and Takeda.
“This [research] builds on our experience that four-drug combinations with a monoclonal antibody, proteasome inhibitor, immunomodulatory drug and steroids are superior to three-drug combinations,” Joseph Mikhael, MD, chief medical officer of the International Myeloma Foundation, said in an interview on the study.
“It also demonstrates the value of CD38 antibodies, and specifically isatuximab, in the frontline setting,” said Dr. Mikhael, professor at the Translational Genomics Research Institute (TGen), City of Hope Cancer Center in Goodyear, Ariz.
The findings were presented at the annual meeting of the American Society of Hematology.
The current standard of care for transplant-eligible, newly diagnosed MM consists of the quadruple combination of a CD38 monoclonal antibody, an immunomodulatory drug, a proteasome inhibitor, and a glucocorticoid, followed by high-dose melphalan and autologous stem-cell transplantation (ASCT).
Isatuximab already has approval in combination with the regimen of carfilzomib and dexamethasone (KRd) in the treatment of relapsed or refractory MM patients who have received prior lines of therapy.
To investigate the efficacy and safety of addition of isatuximab in the setting of transplant-eligible, newly diagnosed MM patients, first author Francesca Gay, MD, PhD, of the Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy, and colleagues conducted the multisite, phase-3 Iskia trial, enrolling 302 transplant-eligible newly diagnosed MM patients.
The patients were randomized to groups of 151 each to treatment either with IsaKRd or KRd alone. The treatment regimen for KRd included four cycles in induction including weekly carfilzomib at 56 mg on day 1, 8 and 15, lenalidomide 25 mg at day 1-21, and dexamethasone at 40 mg weekly, and the IsaKRd group included four 28-day cycles of isatuximab 10 mg/kg IV days 1, 8, 15, and 22 in cycle 1, followed by 10 mg/kg days 1, 15 in cycles 2-4.
The induction was followed by stem cell mobilization and collection and high dose chemotherapy, followed by four cycles of full-dose consolidation at the same doses and schedule as induction, followed by a light consolidation phase of 12 28-day cycles of reduced dose KRd.
Patients had a median age of 61 and 60 in the isatuximab versus KRd group, respectively, and characteristics were similar between the two arms.
With the current follow-up of a mean of 21 months, the primary endpoint was met, with the intention-to-treat analysis showing a rate of post-consolidation MRD negativity, as assessed with a next-generation sequencing (NGS) cut-off of 10-5, of 77% with isatuximab versus 67% with KRd alone (OR 1.67; P = .049).
With an NGS cut-off of 10-6, the respective rates were 67% vs. 48% (OR 2.29; P < .001).
“This difference in MRD negativity in the depth of response was seen despite the responses analyzed according to the conventional criteria being comparable in the two arms, with more than 90% of patients achieving at least a very good partial response and more than 70% achieving at least a complete response,” Dr. Gay noted.
For the key secondary endpoint of MRD negativity over time, the rates were also significantly higher with IsaKRd vs. KRd at post-induction (10-5 cut-off, 45% vs. 26%, OR 2.34; P < .001; 10-6 cut-off, 27% vs. 14%, OR 2.36, P = .004).
IsaKRd also had greater MRD negativity post-ASCT (10-5 cutoff 64% vs. 49%; P = .006; 10-6 cutoff, 52% vs. 27%, P < .001) and post-consolidation (10-5 cutoff, 77% vs. 67%; P = .049 and 10-6 cutoff, 67% vs. 48%, P < .001).
The increase in the MRD negativity in the IsaKRd group was observed in all subgroups of patients analyzed at the 10-5 and 10-6 cut-offs.
The improved post-consolidation rate of MRD negativity with IsaKRd was also observed among patients based on all levels of cytogenetic risk, which was not the case in the KRd alone arm, which showed a reduction in MRD negativity among very high-risk patients, Dr. Gay observed.
The study’s other key secondary endpoint of progression-free survival will be presented in the future, when longer-term outcomes are available.
As of the current follow-up, 17% of patients in the IsaKRd group had discontinued the study treatment versus 10% with KRd, with the leading cause of adverse events for 6% and 5%, respectively.
At least one hematologic adverse event occurred in 55% of patients treated with IsaKRd and 44% in the KRd alone group, with the most prominent grade 3-4 adverse events occurring more commonly with IsaKRd being neutropenia (36% vs. 22%) and thrombocytopenia (15% vs. 17%).
Non-hematologic grade 3-4 adverse events occurred in 41% of patients in the IsaKRd group versus 37% in KRd only, which included infections (15% vs. 11%), and gastrointestinal (7% vs. 5%), vascular (5% vs. 10%) and cardiac events (<1% vs. 3%).
Discontinuation for toxicity occurred in similar rates in both groups (6% in IsaKRd vs. 5% in KRd); with four treatment-related deaths occurring with IsaKRd (two COVID, one pneumonia, one pulmonary embolism) and one with KRd (septic shock).
“Treatment was tolerable with a toxicity profile that was similar to that in previous reports,” Dr. Gay said.
“In the context of these highly effective regimens that produce a high rate of response, the 10-6 MRD cutoff might be more informative than other result categories,” she added.
Longer follow-up will provide more insights in survival endpoints, and “the trial can potentially offer the opportunity to explore correlations between depth of MRD negativity and survival endpoints,” Dr. Gay noted.
Further commenting on the study, Irene Ghobrial, MD, of Medical Oncology, with the Dana-Farber Cancer Institute, Boston, said the results are encouraging.
“We’re seeing two phase three trials now showing us that indeed a CD38 antibody in addition to our triplet standards of care are making a huge difference in MRD response,” she said in an interview.
“So, I think the main message here is that the four-drug regimen is the way to go from now on in multiple myeloma.”
The study received funding from Sanofi and Amgen. Dr. Gay disclosed relationships with AbbVie; Bristol Myers Squibb/Celgene; Sanofi; Roche; GlaxoSmithKline; Pfizer; Oncopeptides; Takeda; Janssen; and Amgen. Dr. Mikhael reported ties with Amgen, BMS, Janssen, Sanofi and Takeda.
“This [research] builds on our experience that four-drug combinations with a monoclonal antibody, proteasome inhibitor, immunomodulatory drug and steroids are superior to three-drug combinations,” Joseph Mikhael, MD, chief medical officer of the International Myeloma Foundation, said in an interview on the study.
“It also demonstrates the value of CD38 antibodies, and specifically isatuximab, in the frontline setting,” said Dr. Mikhael, professor at the Translational Genomics Research Institute (TGen), City of Hope Cancer Center in Goodyear, Ariz.
The findings were presented at the annual meeting of the American Society of Hematology.
The current standard of care for transplant-eligible, newly diagnosed MM consists of the quadruple combination of a CD38 monoclonal antibody, an immunomodulatory drug, a proteasome inhibitor, and a glucocorticoid, followed by high-dose melphalan and autologous stem-cell transplantation (ASCT).
Isatuximab already has approval in combination with the regimen of carfilzomib and dexamethasone (KRd) in the treatment of relapsed or refractory MM patients who have received prior lines of therapy.
To investigate the efficacy and safety of addition of isatuximab in the setting of transplant-eligible, newly diagnosed MM patients, first author Francesca Gay, MD, PhD, of the Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy, and colleagues conducted the multisite, phase-3 Iskia trial, enrolling 302 transplant-eligible newly diagnosed MM patients.
The patients were randomized to groups of 151 each to treatment either with IsaKRd or KRd alone. The treatment regimen for KRd included four cycles in induction including weekly carfilzomib at 56 mg on day 1, 8 and 15, lenalidomide 25 mg at day 1-21, and dexamethasone at 40 mg weekly, and the IsaKRd group included four 28-day cycles of isatuximab 10 mg/kg IV days 1, 8, 15, and 22 in cycle 1, followed by 10 mg/kg days 1, 15 in cycles 2-4.
The induction was followed by stem cell mobilization and collection and high dose chemotherapy, followed by four cycles of full-dose consolidation at the same doses and schedule as induction, followed by a light consolidation phase of 12 28-day cycles of reduced dose KRd.
Patients had a median age of 61 and 60 in the isatuximab versus KRd group, respectively, and characteristics were similar between the two arms.
With the current follow-up of a mean of 21 months, the primary endpoint was met, with the intention-to-treat analysis showing a rate of post-consolidation MRD negativity, as assessed with a next-generation sequencing (NGS) cut-off of 10-5, of 77% with isatuximab versus 67% with KRd alone (OR 1.67; P = .049).
With an NGS cut-off of 10-6, the respective rates were 67% vs. 48% (OR 2.29; P < .001).
“This difference in MRD negativity in the depth of response was seen despite the responses analyzed according to the conventional criteria being comparable in the two arms, with more than 90% of patients achieving at least a very good partial response and more than 70% achieving at least a complete response,” Dr. Gay noted.
For the key secondary endpoint of MRD negativity over time, the rates were also significantly higher with IsaKRd vs. KRd at post-induction (10-5 cut-off, 45% vs. 26%, OR 2.34; P < .001; 10-6 cut-off, 27% vs. 14%, OR 2.36, P = .004).
IsaKRd also had greater MRD negativity post-ASCT (10-5 cutoff 64% vs. 49%; P = .006; 10-6 cutoff, 52% vs. 27%, P < .001) and post-consolidation (10-5 cutoff, 77% vs. 67%; P = .049 and 10-6 cutoff, 67% vs. 48%, P < .001).
The increase in the MRD negativity in the IsaKRd group was observed in all subgroups of patients analyzed at the 10-5 and 10-6 cut-offs.
The improved post-consolidation rate of MRD negativity with IsaKRd was also observed among patients based on all levels of cytogenetic risk, which was not the case in the KRd alone arm, which showed a reduction in MRD negativity among very high-risk patients, Dr. Gay observed.
The study’s other key secondary endpoint of progression-free survival will be presented in the future, when longer-term outcomes are available.
As of the current follow-up, 17% of patients in the IsaKRd group had discontinued the study treatment versus 10% with KRd, with the leading cause of adverse events for 6% and 5%, respectively.
At least one hematologic adverse event occurred in 55% of patients treated with IsaKRd and 44% in the KRd alone group, with the most prominent grade 3-4 adverse events occurring more commonly with IsaKRd being neutropenia (36% vs. 22%) and thrombocytopenia (15% vs. 17%).
Non-hematologic grade 3-4 adverse events occurred in 41% of patients in the IsaKRd group versus 37% in KRd only, which included infections (15% vs. 11%), and gastrointestinal (7% vs. 5%), vascular (5% vs. 10%) and cardiac events (<1% vs. 3%).
Discontinuation for toxicity occurred in similar rates in both groups (6% in IsaKRd vs. 5% in KRd); with four treatment-related deaths occurring with IsaKRd (two COVID, one pneumonia, one pulmonary embolism) and one with KRd (septic shock).
“Treatment was tolerable with a toxicity profile that was similar to that in previous reports,” Dr. Gay said.
“In the context of these highly effective regimens that produce a high rate of response, the 10-6 MRD cutoff might be more informative than other result categories,” she added.
Longer follow-up will provide more insights in survival endpoints, and “the trial can potentially offer the opportunity to explore correlations between depth of MRD negativity and survival endpoints,” Dr. Gay noted.
Further commenting on the study, Irene Ghobrial, MD, of Medical Oncology, with the Dana-Farber Cancer Institute, Boston, said the results are encouraging.
“We’re seeing two phase three trials now showing us that indeed a CD38 antibody in addition to our triplet standards of care are making a huge difference in MRD response,” she said in an interview.
“So, I think the main message here is that the four-drug regimen is the way to go from now on in multiple myeloma.”
The study received funding from Sanofi and Amgen. Dr. Gay disclosed relationships with AbbVie; Bristol Myers Squibb/Celgene; Sanofi; Roche; GlaxoSmithKline; Pfizer; Oncopeptides; Takeda; Janssen; and Amgen. Dr. Mikhael reported ties with Amgen, BMS, Janssen, Sanofi and Takeda.
FROM ASH 2023