Multiple Myeloma

SAN DIEGO — Immunotherapies directed against the B-cell maturation antigen (BCMA) have significantly improved outcomes for patients with relapsed or refractory multiple myeloma, but their addition to the therapeutic arsenal comes at a high cost in terms of systemic and neurologic side effects which vary from one agent to the next, a new analysis of data from the FDA shows.

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.

SAN DIEGO — Immunotherapies directed against the B-cell maturation antigen (BCMA) have significantly improved outcomes for patients with relapsed or refractory multiple myeloma, but their addition to the therapeutic arsenal comes at a high cost in terms of systemic and neurologic side effects which vary from one agent to the next, a new analysis of data from the FDA shows.

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.

SAN DIEGO — Immunotherapies directed against the B-cell maturation antigen (BCMA) have significantly improved outcomes for patients with relapsed or refractory multiple myeloma, but their addition to the therapeutic arsenal comes at a high cost in terms of systemic and neurologic side effects which vary from one agent to the next, a new analysis of data from the FDA shows.

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.

The quadruplet combination of the anti-CD38 monoclonal antibody isatuximab with a backbone regimen of carfilzomib, lenalidomide and dexamethasone (IsaKRd) showed significant improvement in outcomes of measurable residual disease (MRD) in the treatment of newly diagnosed patients with multiple myeloma (MM).

“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.

The quadruplet combination of the anti-CD38 monoclonal antibody isatuximab with a backbone regimen of carfilzomib, lenalidomide and dexamethasone (IsaKRd) showed significant improvement in outcomes of measurable residual disease (MRD) in the treatment of newly diagnosed patients with multiple myeloma (MM).

“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.

The quadruplet combination of the anti-CD38 monoclonal antibody isatuximab with a backbone regimen of carfilzomib, lenalidomide and dexamethasone (IsaKRd) showed significant improvement in outcomes of measurable residual disease (MRD) in the treatment of newly diagnosed patients with multiple myeloma (MM).

“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.

SAN DIEGO — In the real world, outcomes for patients with multiple myeloma who received standard regimens were dramatically worse than those reported in clinical trials, a new study found. 

The analysis, which included nearly 4,000 patients with multiple myeloma, revealed that patients in a real-world setting demonstrated worse progression-free and overall survival on six of seven standard treatments compared with patients evaluated in randomized controlled trials.

Lead author Alissa Visram, MD, MPH, who spoke about the study at the annual meeting of the American Society of Hematology, said the findings will likely change the way she speaks to patients about their potential outcomes. 

“I’ll probably present both numbers [from real-life and clinical-trial data] and give them a sense of the best-case scenario,” Dr. Visram said during an ASH media briefing. But she said she will also caution her patients that the real-world numbers reflect how people on these drugs actually fare. 

The effectiveness of multiple myeloma drugs remains unclear outside the clinical trial setting, explained Dr. Visram, of the Division of Hematology at the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. Outcomes from randomized controlled trials form the basis of drug approvals but many patients in the real world do not meet the “stringent” trial inclusion criteria. 

Dr. Visram and colleagues launched the current study to better understand the potential differences between real-world and clinical trial outcomes. In the analysis, the researchers compared real-world outcomes among patients receiving seven standard multiple myeloma regimens covered by Ontario’s public health plan with patient outcomes reported in phase 3 randomized controlled trials. 

The retrospective study included 3951 patients with newly diagnosed and refractory multiple myeloma treated from 2007 to 2020 in Ontario. Regimens for newly diagnosed transplant ineligible patients included lenalidomide plus dexamethasone and triple therapy with bortezomib, lenalidomide, and dexamethasone. Regimens for patients with relapsed disease included pomalidomide plus dexamethasone or carfilzomib plus dexamethasone as well as triple combinations including carfilzomib, lenalidomide, and dexamethasone.

Overall, Dr. Visram and colleagues found that patients in the real-world setting demonstrated worse overall survival for six of the seven regimens evaluated (pooled hazard ratio [HR], 1.75; P = .010). 

The real-world patients also had worse progression-free survival for six of the seven regimens (pooled HR, 1.44; P = .034). 

For these regimens, progression-free survival was at least 3-18 months longer in the clinical trial cohort, while median overall survival was at least 19 months longer compared with real-world patients, Dr. Visram explained. 

The only regimen with comparable outcomes in the clinical trial and real-world settings was pomalidomide and dexamethasone, she said. One reason could be that patients receiving pomalidomide plus dexamethasone in the clinical trial setting had similar or more advanced disease than those in the real-world setting.

The study also found that adverse effects were similar between the clinical and real-world groups. 

The next step, Dr. Visram said, would be to explore what’s driving the differences in outcomes. 

Are patients in the real-world setting older or frailer? Do they have more advanced disease? Are providers using these regimens differently? 

Mikkael A. Sekeres, MD, MS, explained that the difference likely comes down to the health of the patient. 

Patients in these types of clinical trials “are just these pristine specimens of human beings except for the cancer that’s being treated,” Dr. Sekeres, of the Sylvester Comprehensive Cancer Center at the University of Miami, Florida, said in an earlier ASH press briefing.

Cynthia E. Dunbar, MD, noted that patients in clinical trials have other advantages as well.

“Patients who are able to enroll in clinical trials are more likely to be able to show up at the treatment center at the right time and for every dose, have transportation, and afford drugs to prevent side effects,” said Dr. Dunbar, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute and secretary of ASH. These patients also “might stay on the drug for longer, or they have nurses who are always encouraging them on how to make it through a toxicity.”

Dr. Dunbar said hematologists and patients should consider randomized controlled trials to be “the best possible outcome, and perhaps adjust their thinking if an individual patient is older, sicker, or less able to follow a regimen exactly.” 

No study funding was reported. Dr. Visram reported consulting and honoraria relationships with Apotex, Janssen, and Sanofi. Other study authors reported multiple relationships with industry. Disclosures for Dr. Dunbar and Dr. Sekeres were unavailable. 

A version of this article appeared on Medscape.com.

SAN DIEGO — In the real world, outcomes for patients with multiple myeloma who received standard regimens were dramatically worse than those reported in clinical trials, a new study found. 

The analysis, which included nearly 4,000 patients with multiple myeloma, revealed that patients in a real-world setting demonstrated worse progression-free and overall survival on six of seven standard treatments compared with patients evaluated in randomized controlled trials.

Lead author Alissa Visram, MD, MPH, who spoke about the study at the annual meeting of the American Society of Hematology, said the findings will likely change the way she speaks to patients about their potential outcomes. 

“I’ll probably present both numbers [from real-life and clinical-trial data] and give them a sense of the best-case scenario,” Dr. Visram said during an ASH media briefing. But she said she will also caution her patients that the real-world numbers reflect how people on these drugs actually fare. 

The effectiveness of multiple myeloma drugs remains unclear outside the clinical trial setting, explained Dr. Visram, of the Division of Hematology at the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. Outcomes from randomized controlled trials form the basis of drug approvals but many patients in the real world do not meet the “stringent” trial inclusion criteria. 

Dr. Visram and colleagues launched the current study to better understand the potential differences between real-world and clinical trial outcomes. In the analysis, the researchers compared real-world outcomes among patients receiving seven standard multiple myeloma regimens covered by Ontario’s public health plan with patient outcomes reported in phase 3 randomized controlled trials. 

The retrospective study included 3951 patients with newly diagnosed and refractory multiple myeloma treated from 2007 to 2020 in Ontario. Regimens for newly diagnosed transplant ineligible patients included lenalidomide plus dexamethasone and triple therapy with bortezomib, lenalidomide, and dexamethasone. Regimens for patients with relapsed disease included pomalidomide plus dexamethasone or carfilzomib plus dexamethasone as well as triple combinations including carfilzomib, lenalidomide, and dexamethasone.

Overall, Dr. Visram and colleagues found that patients in the real-world setting demonstrated worse overall survival for six of the seven regimens evaluated (pooled hazard ratio [HR], 1.75; P = .010). 

The real-world patients also had worse progression-free survival for six of the seven regimens (pooled HR, 1.44; P = .034). 

For these regimens, progression-free survival was at least 3-18 months longer in the clinical trial cohort, while median overall survival was at least 19 months longer compared with real-world patients, Dr. Visram explained. 

The only regimen with comparable outcomes in the clinical trial and real-world settings was pomalidomide and dexamethasone, she said. One reason could be that patients receiving pomalidomide plus dexamethasone in the clinical trial setting had similar or more advanced disease than those in the real-world setting.

The study also found that adverse effects were similar between the clinical and real-world groups. 

The next step, Dr. Visram said, would be to explore what’s driving the differences in outcomes. 

Are patients in the real-world setting older or frailer? Do they have more advanced disease? Are providers using these regimens differently? 

Mikkael A. Sekeres, MD, MS, explained that the difference likely comes down to the health of the patient. 

Patients in these types of clinical trials “are just these pristine specimens of human beings except for the cancer that’s being treated,” Dr. Sekeres, of the Sylvester Comprehensive Cancer Center at the University of Miami, Florida, said in an earlier ASH press briefing.

Cynthia E. Dunbar, MD, noted that patients in clinical trials have other advantages as well.

“Patients who are able to enroll in clinical trials are more likely to be able to show up at the treatment center at the right time and for every dose, have transportation, and afford drugs to prevent side effects,” said Dr. Dunbar, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute and secretary of ASH. These patients also “might stay on the drug for longer, or they have nurses who are always encouraging them on how to make it through a toxicity.”

Dr. Dunbar said hematologists and patients should consider randomized controlled trials to be “the best possible outcome, and perhaps adjust their thinking if an individual patient is older, sicker, or less able to follow a regimen exactly.” 

No study funding was reported. Dr. Visram reported consulting and honoraria relationships with Apotex, Janssen, and Sanofi. Other study authors reported multiple relationships with industry. Disclosures for Dr. Dunbar and Dr. Sekeres were unavailable. 

A version of this article appeared on Medscape.com.

SAN DIEGO — In the real world, outcomes for patients with multiple myeloma who received standard regimens were dramatically worse than those reported in clinical trials, a new study found. 

The analysis, which included nearly 4,000 patients with multiple myeloma, revealed that patients in a real-world setting demonstrated worse progression-free and overall survival on six of seven standard treatments compared with patients evaluated in randomized controlled trials.

Lead author Alissa Visram, MD, MPH, who spoke about the study at the annual meeting of the American Society of Hematology, said the findings will likely change the way she speaks to patients about their potential outcomes. 

“I’ll probably present both numbers [from real-life and clinical-trial data] and give them a sense of the best-case scenario,” Dr. Visram said during an ASH media briefing. But she said she will also caution her patients that the real-world numbers reflect how people on these drugs actually fare. 

The effectiveness of multiple myeloma drugs remains unclear outside the clinical trial setting, explained Dr. Visram, of the Division of Hematology at the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. Outcomes from randomized controlled trials form the basis of drug approvals but many patients in the real world do not meet the “stringent” trial inclusion criteria. 

Dr. Visram and colleagues launched the current study to better understand the potential differences between real-world and clinical trial outcomes. In the analysis, the researchers compared real-world outcomes among patients receiving seven standard multiple myeloma regimens covered by Ontario’s public health plan with patient outcomes reported in phase 3 randomized controlled trials. 

The retrospective study included 3951 patients with newly diagnosed and refractory multiple myeloma treated from 2007 to 2020 in Ontario. Regimens for newly diagnosed transplant ineligible patients included lenalidomide plus dexamethasone and triple therapy with bortezomib, lenalidomide, and dexamethasone. Regimens for patients with relapsed disease included pomalidomide plus dexamethasone or carfilzomib plus dexamethasone as well as triple combinations including carfilzomib, lenalidomide, and dexamethasone.

Overall, Dr. Visram and colleagues found that patients in the real-world setting demonstrated worse overall survival for six of the seven regimens evaluated (pooled hazard ratio [HR], 1.75; P = .010). 

The real-world patients also had worse progression-free survival for six of the seven regimens (pooled HR, 1.44; P = .034). 

For these regimens, progression-free survival was at least 3-18 months longer in the clinical trial cohort, while median overall survival was at least 19 months longer compared with real-world patients, Dr. Visram explained. 

The only regimen with comparable outcomes in the clinical trial and real-world settings was pomalidomide and dexamethasone, she said. One reason could be that patients receiving pomalidomide plus dexamethasone in the clinical trial setting had similar or more advanced disease than those in the real-world setting.

The study also found that adverse effects were similar between the clinical and real-world groups. 

The next step, Dr. Visram said, would be to explore what’s driving the differences in outcomes. 

Are patients in the real-world setting older or frailer? Do they have more advanced disease? Are providers using these regimens differently? 

Mikkael A. Sekeres, MD, MS, explained that the difference likely comes down to the health of the patient. 

Patients in these types of clinical trials “are just these pristine specimens of human beings except for the cancer that’s being treated,” Dr. Sekeres, of the Sylvester Comprehensive Cancer Center at the University of Miami, Florida, said in an earlier ASH press briefing.

Cynthia E. Dunbar, MD, noted that patients in clinical trials have other advantages as well.

“Patients who are able to enroll in clinical trials are more likely to be able to show up at the treatment center at the right time and for every dose, have transportation, and afford drugs to prevent side effects,” said Dr. Dunbar, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute and secretary of ASH. These patients also “might stay on the drug for longer, or they have nurses who are always encouraging them on how to make it through a toxicity.”

Dr. Dunbar said hematologists and patients should consider randomized controlled trials to be “the best possible outcome, and perhaps adjust their thinking if an individual patient is older, sicker, or less able to follow a regimen exactly.” 

No study funding was reported. Dr. Visram reported consulting and honoraria relationships with Apotex, Janssen, and Sanofi. Other study authors reported multiple relationships with industry. Disclosures for Dr. Dunbar and Dr. Sekeres were unavailable. 

A version of this article appeared on Medscape.com.

Health equity, sickle cell disease (SCD), and the thoughtful use of artificial intelligence (AI) and social media are among the key themes to be presented at the Dec. 9-12 annual meeting of the American Society of Hematology (ASH) in San Diego, association leaders told reporters in a media preview session.

Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute and secretary of ASH, added that insight into actual patient experiences also will be a major theme at ASH 2023.

“There is a huge growth in research on outcomes and focusing on using real-world data and how important that is,” Dr. Dunbar said. “Academic research and hematology is really focusing on patient-reported outcomes and how care is delivered in a real-world setting – actually looking at what matters to patients. Are they alive in a certain number of years? And how are they feeling?”

As an example, Dr. Dunbar pointed to an abstract that examined clinical databases in Canada and found that real-world outcomes in multiple myeloma treatments were much worse than those in the original clinical trials for the therapies. Patients reached relapse 44% faster and their overall survival was 75% worse.

In the media briefing, ASH chair of communications Mikkael A. Sekeres, MD, MS, of the Sylvester Comprehensive Cancer Center at the University of Miami, noted that patients in these types of clinical trials “are just these pristine specimens of human beings except for the cancer that’s being treated.”

Dr. Dunbar agreed, noting that “patients who are able to enroll in clinical trials are more likely to be able to show up at the treatment center at the right time and for every dose, have transportation, and afford drugs to prevent side effects. They might stay on the drug for longer, or they have nurses who are always encouraging them of how to make it through a toxicity.”

Hematologists and patients should consider randomized controlled trials to be “the best possible outcome, and perhaps adjust their thinking if an individual patient is older, sicker, or less able to follow a regimen exactly,” she said.

Another highlighted study linked worse outcomes in African-Americans with pediatric acute myeloid leukemia to genetic traits that are more common in that population. The traits “likely explain at least in part the worst outcomes in Black patients in prior studies and on some regimens,” Dr. Dunbar said.

She added that the findings emphasize how testing for genetic variants and biomarkers that impact outcomes should be performed “instead of assuming that a certain dose should be given simply based on perceived or reported race or ethnicity.”

ASH President Robert A. Brodsky, MD, of Johns Hopkins University School of Medicine, Baltimore, highlighted an abstract that reported on the use of AI as a clinical decision support tool to differentiate two easily confused conditions — prefibrotic primary myelofibrosis and essential thrombocythemia.

AI “is a tool that’s going to help pathologists make more accurate and faster diagnoses,” he said. He also spotlighted an abstract about the use of “social media listening” to understand the experiences of patients with SCD and their caregivers. “There can be a lot of misuse and waste of time with social media, but they used this in a way to try and gain insight as to what’s really important to the patients and the caregiver.”

Also, in regard to SCD, Dr. Dunbar pointed to a study that reports on outcomes in patients who received lovotibeglogene autotemcel (lovo-cel) gene therapy for up to 60 months. Both this treatment and a CRISPR-based therapy called exa-cel  “appear to result in comparable very impressive efficacy in terms of pain crises and organ dysfunction,” she said. “The hurdle is going to be figuring out how to deliver what will be very expensive and complicated therapies — but likely curative — therapies to patients.”

Another study to be presented at ASH — coauthored by Dr. Brodsky — shows promising results from reduced-intensity haploidentical bone marrow transplantation in adults with severe SCD. Results were similar to those seen with bone marrow from matched siblings, Dr. Sekeres said.

He added that more clarity is needed about new treatment options for SCD, perhaps through a “randomized trial where patients upfront get a haploidentical bone marrow transplant or fully matched bone marrow transplant. Then other patients are randomized to some of these other, newer technology therapies, and we follow them over time. We’re looking not only for overall survival but complications of the therapy itself and how many patients relapse from the treatment.”

Health equity, sickle cell disease (SCD), and the thoughtful use of artificial intelligence (AI) and social media are among the key themes to be presented at the Dec. 9-12 annual meeting of the American Society of Hematology (ASH) in San Diego, association leaders told reporters in a media preview session.

Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute and secretary of ASH, added that insight into actual patient experiences also will be a major theme at ASH 2023.

“There is a huge growth in research on outcomes and focusing on using real-world data and how important that is,” Dr. Dunbar said. “Academic research and hematology is really focusing on patient-reported outcomes and how care is delivered in a real-world setting – actually looking at what matters to patients. Are they alive in a certain number of years? And how are they feeling?”

As an example, Dr. Dunbar pointed to an abstract that examined clinical databases in Canada and found that real-world outcomes in multiple myeloma treatments were much worse than those in the original clinical trials for the therapies. Patients reached relapse 44% faster and their overall survival was 75% worse.

In the media briefing, ASH chair of communications Mikkael A. Sekeres, MD, MS, of the Sylvester Comprehensive Cancer Center at the University of Miami, noted that patients in these types of clinical trials “are just these pristine specimens of human beings except for the cancer that’s being treated.”

Dr. Dunbar agreed, noting that “patients who are able to enroll in clinical trials are more likely to be able to show up at the treatment center at the right time and for every dose, have transportation, and afford drugs to prevent side effects. They might stay on the drug for longer, or they have nurses who are always encouraging them of how to make it through a toxicity.”

Hematologists and patients should consider randomized controlled trials to be “the best possible outcome, and perhaps adjust their thinking if an individual patient is older, sicker, or less able to follow a regimen exactly,” she said.

Another highlighted study linked worse outcomes in African-Americans with pediatric acute myeloid leukemia to genetic traits that are more common in that population. The traits “likely explain at least in part the worst outcomes in Black patients in prior studies and on some regimens,” Dr. Dunbar said.

She added that the findings emphasize how testing for genetic variants and biomarkers that impact outcomes should be performed “instead of assuming that a certain dose should be given simply based on perceived or reported race or ethnicity.”

ASH President Robert A. Brodsky, MD, of Johns Hopkins University School of Medicine, Baltimore, highlighted an abstract that reported on the use of AI as a clinical decision support tool to differentiate two easily confused conditions — prefibrotic primary myelofibrosis and essential thrombocythemia.

AI “is a tool that’s going to help pathologists make more accurate and faster diagnoses,” he said. He also spotlighted an abstract about the use of “social media listening” to understand the experiences of patients with SCD and their caregivers. “There can be a lot of misuse and waste of time with social media, but they used this in a way to try and gain insight as to what’s really important to the patients and the caregiver.”

Also, in regard to SCD, Dr. Dunbar pointed to a study that reports on outcomes in patients who received lovotibeglogene autotemcel (lovo-cel) gene therapy for up to 60 months. Both this treatment and a CRISPR-based therapy called exa-cel  “appear to result in comparable very impressive efficacy in terms of pain crises and organ dysfunction,” she said. “The hurdle is going to be figuring out how to deliver what will be very expensive and complicated therapies — but likely curative — therapies to patients.”

Another study to be presented at ASH — coauthored by Dr. Brodsky — shows promising results from reduced-intensity haploidentical bone marrow transplantation in adults with severe SCD. Results were similar to those seen with bone marrow from matched siblings, Dr. Sekeres said.

He added that more clarity is needed about new treatment options for SCD, perhaps through a “randomized trial where patients upfront get a haploidentical bone marrow transplant or fully matched bone marrow transplant. Then other patients are randomized to some of these other, newer technology therapies, and we follow them over time. We’re looking not only for overall survival but complications of the therapy itself and how many patients relapse from the treatment.”

Health equity, sickle cell disease (SCD), and the thoughtful use of artificial intelligence (AI) and social media are among the key themes to be presented at the Dec. 9-12 annual meeting of the American Society of Hematology (ASH) in San Diego, association leaders told reporters in a media preview session.

Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute and secretary of ASH, added that insight into actual patient experiences also will be a major theme at ASH 2023.

“There is a huge growth in research on outcomes and focusing on using real-world data and how important that is,” Dr. Dunbar said. “Academic research and hematology is really focusing on patient-reported outcomes and how care is delivered in a real-world setting – actually looking at what matters to patients. Are they alive in a certain number of years? And how are they feeling?”

As an example, Dr. Dunbar pointed to an abstract that examined clinical databases in Canada and found that real-world outcomes in multiple myeloma treatments were much worse than those in the original clinical trials for the therapies. Patients reached relapse 44% faster and their overall survival was 75% worse.

In the media briefing, ASH chair of communications Mikkael A. Sekeres, MD, MS, of the Sylvester Comprehensive Cancer Center at the University of Miami, noted that patients in these types of clinical trials “are just these pristine specimens of human beings except for the cancer that’s being treated.”

Dr. Dunbar agreed, noting that “patients who are able to enroll in clinical trials are more likely to be able to show up at the treatment center at the right time and for every dose, have transportation, and afford drugs to prevent side effects. They might stay on the drug for longer, or they have nurses who are always encouraging them of how to make it through a toxicity.”

Hematologists and patients should consider randomized controlled trials to be “the best possible outcome, and perhaps adjust their thinking if an individual patient is older, sicker, or less able to follow a regimen exactly,” she said.

Another highlighted study linked worse outcomes in African-Americans with pediatric acute myeloid leukemia to genetic traits that are more common in that population. The traits “likely explain at least in part the worst outcomes in Black patients in prior studies and on some regimens,” Dr. Dunbar said.

She added that the findings emphasize how testing for genetic variants and biomarkers that impact outcomes should be performed “instead of assuming that a certain dose should be given simply based on perceived or reported race or ethnicity.”

ASH President Robert A. Brodsky, MD, of Johns Hopkins University School of Medicine, Baltimore, highlighted an abstract that reported on the use of AI as a clinical decision support tool to differentiate two easily confused conditions — prefibrotic primary myelofibrosis and essential thrombocythemia.

AI “is a tool that’s going to help pathologists make more accurate and faster diagnoses,” he said. He also spotlighted an abstract about the use of “social media listening” to understand the experiences of patients with SCD and their caregivers. “There can be a lot of misuse and waste of time with social media, but they used this in a way to try and gain insight as to what’s really important to the patients and the caregiver.”

Also, in regard to SCD, Dr. Dunbar pointed to a study that reports on outcomes in patients who received lovotibeglogene autotemcel (lovo-cel) gene therapy for up to 60 months. Both this treatment and a CRISPR-based therapy called exa-cel  “appear to result in comparable very impressive efficacy in terms of pain crises and organ dysfunction,” she said. “The hurdle is going to be figuring out how to deliver what will be very expensive and complicated therapies — but likely curative — therapies to patients.”

Another study to be presented at ASH — coauthored by Dr. Brodsky — shows promising results from reduced-intensity haploidentical bone marrow transplantation in adults with severe SCD. Results were similar to those seen with bone marrow from matched siblings, Dr. Sekeres said.

He added that more clarity is needed about new treatment options for SCD, perhaps through a “randomized trial where patients upfront get a haploidentical bone marrow transplant or fully matched bone marrow transplant. Then other patients are randomized to some of these other, newer technology therapies, and we follow them over time. We’re looking not only for overall survival but complications of the therapy itself and how many patients relapse from the treatment.”

“Maintenance therapy is big business,” warned Benjamin Derman, MD, assistant professor of medicine at the University of Chicago. He was commenting on the financial implications of new data suggesting that physicians may need to rethink maintenance with lenalidomide (Revlimid and generics) for multiple myeloma (MM).

For more than 10 years, ongoing treatment with lenalidomide following autologous hematopoietic stem cell transplantation (ASCT) has been the unchallenged gold standard.

The new findings were from the MASTER study, published in The Lancet Haematology, along with an invited commentary by Dr. Derman. In MASTER, patients who showed no evidence of disease after transplantation and two phases of consolidation therapy had the opportunity to avoid lenalidomide maintenance.

In the lenalidomide-free group, just 9% of patients without high-risk chromosome abnormalities or just one HRCA progressed within 2 years. About 47% of patients with two or more HRCAs progressed within 2 years.

The MASTER authors concluded that modern regimens of induction plus ASCT/consolidation might be good enough for many patients. Avoiding maintenance therapy “lead to most patients with newly diagnosed multiple myeloma reaching an MRD [minimal residual disease]-free, treatment-free state with a low risk of disease progression.” They also cautioned that the approach was “not optimal” for high-risk patients.

“We have been indoctrinated into continuous therapy,” said lead author Luciano Costa, MD, professor of medicine at the University of Alabama at Birmingham. “This was a reasonable approach at the time when [induction and consolidation] therapy was not as effective.”

Lenalidomide for post-ASCT maintenance became a guideline standard following a pivotal study published in the New England Journal of Medicine in 2012. The study showed that lenalidomide maintenance after transplantation almost doubled the time to progression (P < .001) and improved survival (P = .03).

Shaji Kumar, MD, is chair of the National Comprehensive Cancer Network Multiple Myeloma Guidelines and professor of medicine at the Mayo Clinic in Rochester, Minn.

Dr. Kumar said that the MASTER results alone are not sufficient to change current guidelines because the study was a single-arm, uncontrolled, phase 2 trial. However, there are “multiple reasons why we would like to stop treatment at some point in time,” Dr. Kumar said.

“Quality of life, the financial cost, and the toxicity are three main reasons why we would like to discontinue the maintenance or give maintenance only for the amount of time that a patient needs it,” Dr. Kumar added. “So then the question comes up, how do we identify the people who need long term treatment versus the people who don’t?”

“Response” in MM is conventionally classified by criteria laid down by the International Myeloma Working Group. However, the MASTER trial made use of a different measure: MRD negativity, in which myeloma cells can no longer be detected in bone-marrow aspirate at a level of 1 in 100,000 (10^–5) or, in some studies, 1 in 1 million (10^–6).

MRD is a rare bird in oncology: A surrogate endpoint that provides answers faster than progression-free survival or overall survival but is a reliable guide to both. In 2020 a team headed by Nikhil Munshi, MD, professor of medicine at Harvard Medical School, Boston, published a large meta-analysis showing that a negative MRD in a patient with MM was significantly prognostic for both progression-free survival (hazard ratio, 0.33; P < .001) and overall survival (HR, 0.45; P < .001).

In an interview from 2022, Dr. Munshi explained that patients with MRD negativity are not necessarily “cured”: “Simply, physiologically, it means that if a patient has one [myeloma] cell in a million, that cell is going to take a much longer time to grow up to be myeloma.”

In MASTER, which was based at five U.S. academic medical centers, 81% of participants (96/118) achieved MRD negativity at the 10^–5 cutoff. Eighty-four people (71%) had two consecutive MRD-negative results and did not go on to lenalidomide maintenance. Instead, they were monitored with lab tests every 8 weeks for the first 24 weeks and every 16 weeks thereafter and assessed for any changes in MRD after 6 months and 18 months.

The median age in MASTER was 61 years, 43% were women, and 20% were non-Hispanic Black. About 20% of participants had two or more HRCAs, 37% had one HRCA, and 43% had no HRCAs. All participants had four 28-day cycles of induction with Dara-KRd (daratumumab, carfilzomib, lenalidomide, and dexamethasone). This was followed by ASCT and up to two phases of consolidation with Dara-KRd.

MASTER is not the only study to show that MRD-guided discontinuation of lenalidomide seems feasible in some patients. In November 2023, Spanish researchers published a study in Blood testing a combination of lenalidomide, dexamethasone, and ixazomib. The trial allowed MRD-negative patients to stop therapy after 2 years. Progression was 17.2% over the following 4 years in the group that dropped maintenance, which included high-risk patients. The authors concluded that their results “support the safety of maintenance therapy discontinuation in patients with negative MRD at 2 years.”

These two trials are conspicuous by their rarity.

Said Dr. Derman: “We haven’t done a great job until recently of designing trials that look into discontinuation.”

Both Dr. Derman and Dr. Costa raised the elephant in the room: industry funding.

“Maintenance therapy is big business,” said Dr. Derman. He added that he had experienced problems in the past obtaining industry funding for research that involved stopping therapy.

Dr. Costa, coauthor of the MASTER trial, agreed in part: “Most pharmaceutical companies do not embark on trials like this because they’re primarily doing registration trials.” MASTER garnered some industry funding, however, and Dr. Costa found that encouraging.

How much money is at stake? In other words, what are the financial savings if patients with zero to one HRCAs who are MRD negative start to take treatment holidays from lenalidomide maintenance?

In the United States in 2019 approximately 6,410 patients received ASCT. The MASTER publication stated that “around 85%” of newly diagnosed MM patients have zero to one HRCAs and that 73% of these patients were able to stop therapy in the trial. This suggests that, each year, approximately 4,000 new patients might be eligible to avoid lenalidomide after ASCT.

The price tag of lenalidomide is approximately $20,000 per month in the United States, according to Dr. Derman. A cohort of 4,000 patients avoiding lenalidomide each year represents lost revenue of $80 million per month or almost $1 billion per year. And this does not take into account patients already on lenalidomide from previous years – or sales outside the United States. The MM multiple research pipeline reflects a lack of enthusiasm for paring down maintenance.

There are currently 229 interventional clinical studies in MM taking place nationwide. Of these, just three trials are testing what happens when patients stop therapy in the post-ASCT setting and none of the three is sponsored by industry (NCT04108624, NCT05091372, and NCT04071457). (All data from clinicaltrials.gov; search covered phase 2, 3, or 4 studies still accruing data; descriptions hand-checked; search terms: maintenance/consolidation/post-ASCT.)

Dr. Derman said that it is “incumbent on investigators” to carry out the studies to identify who is eligible to stop therapy because industry is “probably always going to err on the side of treating more.”

Sergio Giralt, MD, head of the adult bone marrow transplant service at Memorial Sloan Kettering Cancer Center, New York, was an author of the key 2012 study that enshrined lenalidomide maintenance in the guidelines. Dr. Giralt expressed concerns about the single-arm design of MASTER and said he would like to see a randomized study where some patients continued treatment and others stopped.

Dr. Giralt cautioned: “If you’re MRD negative, the chances of having to deal with your disease in the next 5 years is one in five.” Physicians could certainly “have a conversation” with patients who are MRD negative about stopping therapy, but this would need to be weighed against the need for bone-marrow biopsies every 3-6 months to check progress. (In MASTER, MRD was checked at 6 and 18 months.)

Dr. Kumar believes that “we need to pursue the concept of decreasing the duration of treatment.” However, newer immunotherapies may be the answer: “Who knows? That may be the future, that we will do more of this hit-and-run approach rather than trying to keep them persistently on something.”

Dr. Derman said: “I personally think that the data is already there ... [MASTER] shows that perhaps this notion of indefinite maintenance therapy is one that really has to go by the wayside ... patients should have the option to consider with their physician [the chance to] potentially discontinue treatment.”

For 15 years, relentless lenalidomide maintenance has “quite rightly been the strongest pillar of therapy”, said Dr. Costa. “But for patients, this is not something that they easily embrace – it’s not ideal that you are going to have to take therapy for the rest of your life.”

Dr. Costa concluded: “I don’t think we had a single patient who was reluctant to stop therapy.”

Dr. Munshi reported relationships with Adaptive, Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Karyopharm, Legend, Millennium, Novartis, Pfizer, and he is the scientific founder of Oncopep and DCT. Dr. Derman disclosed ties with Janssen, Cota, and BMS. Dr. Costa reported ties with Amgen, Cota, Janssen, BMS, AbbVie, Ionis, Genentech, Sanofi, Karyopharm, AstraZeneca, Adaptive Biotechnologies, Takeda, and Pfizer. Dr. Kumar declared relationships with AbbVie, Amgen, BMS, GlaxoSmithKline, Karyopharm, Regeneron, Roche, Sanofi, Takeda, and BeiGene. Dr. Giralt reported ties with Amgen, CSL Behring, Caladrius, Celgene, Ceramedix, ExpertConnect, GlaxoSmithKline, Janssen, Karyopharm, Kite Pharmaceuticals, Magnolia Innovation, Novartis, Omeros, Pfizer, Physicians’ Education Resource, Sanofi, TRM Oncology, and Xcenda.

“Maintenance therapy is big business,” warned Benjamin Derman, MD, assistant professor of medicine at the University of Chicago. He was commenting on the financial implications of new data suggesting that physicians may need to rethink maintenance with lenalidomide (Revlimid and generics) for multiple myeloma (MM).

For more than 10 years, ongoing treatment with lenalidomide following autologous hematopoietic stem cell transplantation (ASCT) has been the unchallenged gold standard.

The new findings were from the MASTER study, published in The Lancet Haematology, along with an invited commentary by Dr. Derman. In MASTER, patients who showed no evidence of disease after transplantation and two phases of consolidation therapy had the opportunity to avoid lenalidomide maintenance.

In the lenalidomide-free group, just 9% of patients without high-risk chromosome abnormalities or just one HRCA progressed within 2 years. About 47% of patients with two or more HRCAs progressed within 2 years.

The MASTER authors concluded that modern regimens of induction plus ASCT/consolidation might be good enough for many patients. Avoiding maintenance therapy “lead to most patients with newly diagnosed multiple myeloma reaching an MRD [minimal residual disease]-free, treatment-free state with a low risk of disease progression.” They also cautioned that the approach was “not optimal” for high-risk patients.

“We have been indoctrinated into continuous therapy,” said lead author Luciano Costa, MD, professor of medicine at the University of Alabama at Birmingham. “This was a reasonable approach at the time when [induction and consolidation] therapy was not as effective.”

Lenalidomide for post-ASCT maintenance became a guideline standard following a pivotal study published in the New England Journal of Medicine in 2012. The study showed that lenalidomide maintenance after transplantation almost doubled the time to progression (P < .001) and improved survival (P = .03).

Shaji Kumar, MD, is chair of the National Comprehensive Cancer Network Multiple Myeloma Guidelines and professor of medicine at the Mayo Clinic in Rochester, Minn.

Dr. Kumar said that the MASTER results alone are not sufficient to change current guidelines because the study was a single-arm, uncontrolled, phase 2 trial. However, there are “multiple reasons why we would like to stop treatment at some point in time,” Dr. Kumar said.

“Quality of life, the financial cost, and the toxicity are three main reasons why we would like to discontinue the maintenance or give maintenance only for the amount of time that a patient needs it,” Dr. Kumar added. “So then the question comes up, how do we identify the people who need long term treatment versus the people who don’t?”

“Response” in MM is conventionally classified by criteria laid down by the International Myeloma Working Group. However, the MASTER trial made use of a different measure: MRD negativity, in which myeloma cells can no longer be detected in bone-marrow aspirate at a level of 1 in 100,000 (10^–5) or, in some studies, 1 in 1 million (10^–6).

MRD is a rare bird in oncology: A surrogate endpoint that provides answers faster than progression-free survival or overall survival but is a reliable guide to both. In 2020 a team headed by Nikhil Munshi, MD, professor of medicine at Harvard Medical School, Boston, published a large meta-analysis showing that a negative MRD in a patient with MM was significantly prognostic for both progression-free survival (hazard ratio, 0.33; P < .001) and overall survival (HR, 0.45; P < .001).

In an interview from 2022, Dr. Munshi explained that patients with MRD negativity are not necessarily “cured”: “Simply, physiologically, it means that if a patient has one [myeloma] cell in a million, that cell is going to take a much longer time to grow up to be myeloma.”

In MASTER, which was based at five U.S. academic medical centers, 81% of participants (96/118) achieved MRD negativity at the 10^–5 cutoff. Eighty-four people (71%) had two consecutive MRD-negative results and did not go on to lenalidomide maintenance. Instead, they were monitored with lab tests every 8 weeks for the first 24 weeks and every 16 weeks thereafter and assessed for any changes in MRD after 6 months and 18 months.

The median age in MASTER was 61 years, 43% were women, and 20% were non-Hispanic Black. About 20% of participants had two or more HRCAs, 37% had one HRCA, and 43% had no HRCAs. All participants had four 28-day cycles of induction with Dara-KRd (daratumumab, carfilzomib, lenalidomide, and dexamethasone). This was followed by ASCT and up to two phases of consolidation with Dara-KRd.

MASTER is not the only study to show that MRD-guided discontinuation of lenalidomide seems feasible in some patients. In November 2023, Spanish researchers published a study in Blood testing a combination of lenalidomide, dexamethasone, and ixazomib. The trial allowed MRD-negative patients to stop therapy after 2 years. Progression was 17.2% over the following 4 years in the group that dropped maintenance, which included high-risk patients. The authors concluded that their results “support the safety of maintenance therapy discontinuation in patients with negative MRD at 2 years.”

These two trials are conspicuous by their rarity.

Said Dr. Derman: “We haven’t done a great job until recently of designing trials that look into discontinuation.”

Both Dr. Derman and Dr. Costa raised the elephant in the room: industry funding.

“Maintenance therapy is big business,” said Dr. Derman. He added that he had experienced problems in the past obtaining industry funding for research that involved stopping therapy.

Dr. Costa, coauthor of the MASTER trial, agreed in part: “Most pharmaceutical companies do not embark on trials like this because they’re primarily doing registration trials.” MASTER garnered some industry funding, however, and Dr. Costa found that encouraging.

How much money is at stake? In other words, what are the financial savings if patients with zero to one HRCAs who are MRD negative start to take treatment holidays from lenalidomide maintenance?

In the United States in 2019 approximately 6,410 patients received ASCT. The MASTER publication stated that “around 85%” of newly diagnosed MM patients have zero to one HRCAs and that 73% of these patients were able to stop therapy in the trial. This suggests that, each year, approximately 4,000 new patients might be eligible to avoid lenalidomide after ASCT.

The price tag of lenalidomide is approximately $20,000 per month in the United States, according to Dr. Derman. A cohort of 4,000 patients avoiding lenalidomide each year represents lost revenue of $80 million per month or almost $1 billion per year. And this does not take into account patients already on lenalidomide from previous years – or sales outside the United States. The MM multiple research pipeline reflects a lack of enthusiasm for paring down maintenance.

There are currently 229 interventional clinical studies in MM taking place nationwide. Of these, just three trials are testing what happens when patients stop therapy in the post-ASCT setting and none of the three is sponsored by industry (NCT04108624, NCT05091372, and NCT04071457). (All data from clinicaltrials.gov; search covered phase 2, 3, or 4 studies still accruing data; descriptions hand-checked; search terms: maintenance/consolidation/post-ASCT.)

Dr. Derman said that it is “incumbent on investigators” to carry out the studies to identify who is eligible to stop therapy because industry is “probably always going to err on the side of treating more.”

Sergio Giralt, MD, head of the adult bone marrow transplant service at Memorial Sloan Kettering Cancer Center, New York, was an author of the key 2012 study that enshrined lenalidomide maintenance in the guidelines. Dr. Giralt expressed concerns about the single-arm design of MASTER and said he would like to see a randomized study where some patients continued treatment and others stopped.

Dr. Giralt cautioned: “If you’re MRD negative, the chances of having to deal with your disease in the next 5 years is one in five.” Physicians could certainly “have a conversation” with patients who are MRD negative about stopping therapy, but this would need to be weighed against the need for bone-marrow biopsies every 3-6 months to check progress. (In MASTER, MRD was checked at 6 and 18 months.)

Dr. Kumar believes that “we need to pursue the concept of decreasing the duration of treatment.” However, newer immunotherapies may be the answer: “Who knows? That may be the future, that we will do more of this hit-and-run approach rather than trying to keep them persistently on something.”

Dr. Derman said: “I personally think that the data is already there ... [MASTER] shows that perhaps this notion of indefinite maintenance therapy is one that really has to go by the wayside ... patients should have the option to consider with their physician [the chance to] potentially discontinue treatment.”

For 15 years, relentless lenalidomide maintenance has “quite rightly been the strongest pillar of therapy”, said Dr. Costa. “But for patients, this is not something that they easily embrace – it’s not ideal that you are going to have to take therapy for the rest of your life.”

Dr. Costa concluded: “I don’t think we had a single patient who was reluctant to stop therapy.”

Dr. Munshi reported relationships with Adaptive, Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Karyopharm, Legend, Millennium, Novartis, Pfizer, and he is the scientific founder of Oncopep and DCT. Dr. Derman disclosed ties with Janssen, Cota, and BMS. Dr. Costa reported ties with Amgen, Cota, Janssen, BMS, AbbVie, Ionis, Genentech, Sanofi, Karyopharm, AstraZeneca, Adaptive Biotechnologies, Takeda, and Pfizer. Dr. Kumar declared relationships with AbbVie, Amgen, BMS, GlaxoSmithKline, Karyopharm, Regeneron, Roche, Sanofi, Takeda, and BeiGene. Dr. Giralt reported ties with Amgen, CSL Behring, Caladrius, Celgene, Ceramedix, ExpertConnect, GlaxoSmithKline, Janssen, Karyopharm, Kite Pharmaceuticals, Magnolia Innovation, Novartis, Omeros, Pfizer, Physicians’ Education Resource, Sanofi, TRM Oncology, and Xcenda.

“Maintenance therapy is big business,” warned Benjamin Derman, MD, assistant professor of medicine at the University of Chicago. He was commenting on the financial implications of new data suggesting that physicians may need to rethink maintenance with lenalidomide (Revlimid and generics) for multiple myeloma (MM).

For more than 10 years, ongoing treatment with lenalidomide following autologous hematopoietic stem cell transplantation (ASCT) has been the unchallenged gold standard.

The new findings were from the MASTER study, published in The Lancet Haematology, along with an invited commentary by Dr. Derman. In MASTER, patients who showed no evidence of disease after transplantation and two phases of consolidation therapy had the opportunity to avoid lenalidomide maintenance.

In the lenalidomide-free group, just 9% of patients without high-risk chromosome abnormalities or just one HRCA progressed within 2 years. About 47% of patients with two or more HRCAs progressed within 2 years.

The MASTER authors concluded that modern regimens of induction plus ASCT/consolidation might be good enough for many patients. Avoiding maintenance therapy “lead to most patients with newly diagnosed multiple myeloma reaching an MRD [minimal residual disease]-free, treatment-free state with a low risk of disease progression.” They also cautioned that the approach was “not optimal” for high-risk patients.

“We have been indoctrinated into continuous therapy,” said lead author Luciano Costa, MD, professor of medicine at the University of Alabama at Birmingham. “This was a reasonable approach at the time when [induction and consolidation] therapy was not as effective.”

Lenalidomide for post-ASCT maintenance became a guideline standard following a pivotal study published in the New England Journal of Medicine in 2012. The study showed that lenalidomide maintenance after transplantation almost doubled the time to progression (P < .001) and improved survival (P = .03).

Shaji Kumar, MD, is chair of the National Comprehensive Cancer Network Multiple Myeloma Guidelines and professor of medicine at the Mayo Clinic in Rochester, Minn.

Dr. Kumar said that the MASTER results alone are not sufficient to change current guidelines because the study was a single-arm, uncontrolled, phase 2 trial. However, there are “multiple reasons why we would like to stop treatment at some point in time,” Dr. Kumar said.

“Quality of life, the financial cost, and the toxicity are three main reasons why we would like to discontinue the maintenance or give maintenance only for the amount of time that a patient needs it,” Dr. Kumar added. “So then the question comes up, how do we identify the people who need long term treatment versus the people who don’t?”

“Response” in MM is conventionally classified by criteria laid down by the International Myeloma Working Group. However, the MASTER trial made use of a different measure: MRD negativity, in which myeloma cells can no longer be detected in bone-marrow aspirate at a level of 1 in 100,000 (10^–5) or, in some studies, 1 in 1 million (10^–6).

MRD is a rare bird in oncology: A surrogate endpoint that provides answers faster than progression-free survival or overall survival but is a reliable guide to both. In 2020 a team headed by Nikhil Munshi, MD, professor of medicine at Harvard Medical School, Boston, published a large meta-analysis showing that a negative MRD in a patient with MM was significantly prognostic for both progression-free survival (hazard ratio, 0.33; P < .001) and overall survival (HR, 0.45; P < .001).

In an interview from 2022, Dr. Munshi explained that patients with MRD negativity are not necessarily “cured”: “Simply, physiologically, it means that if a patient has one [myeloma] cell in a million, that cell is going to take a much longer time to grow up to be myeloma.”

In MASTER, which was based at five U.S. academic medical centers, 81% of participants (96/118) achieved MRD negativity at the 10^–5 cutoff. Eighty-four people (71%) had two consecutive MRD-negative results and did not go on to lenalidomide maintenance. Instead, they were monitored with lab tests every 8 weeks for the first 24 weeks and every 16 weeks thereafter and assessed for any changes in MRD after 6 months and 18 months.

The median age in MASTER was 61 years, 43% were women, and 20% were non-Hispanic Black. About 20% of participants had two or more HRCAs, 37% had one HRCA, and 43% had no HRCAs. All participants had four 28-day cycles of induction with Dara-KRd (daratumumab, carfilzomib, lenalidomide, and dexamethasone). This was followed by ASCT and up to two phases of consolidation with Dara-KRd.

MASTER is not the only study to show that MRD-guided discontinuation of lenalidomide seems feasible in some patients. In November 2023, Spanish researchers published a study in Blood testing a combination of lenalidomide, dexamethasone, and ixazomib. The trial allowed MRD-negative patients to stop therapy after 2 years. Progression was 17.2% over the following 4 years in the group that dropped maintenance, which included high-risk patients. The authors concluded that their results “support the safety of maintenance therapy discontinuation in patients with negative MRD at 2 years.”

These two trials are conspicuous by their rarity.

Said Dr. Derman: “We haven’t done a great job until recently of designing trials that look into discontinuation.”

Both Dr. Derman and Dr. Costa raised the elephant in the room: industry funding.

“Maintenance therapy is big business,” said Dr. Derman. He added that he had experienced problems in the past obtaining industry funding for research that involved stopping therapy.

Dr. Costa, coauthor of the MASTER trial, agreed in part: “Most pharmaceutical companies do not embark on trials like this because they’re primarily doing registration trials.” MASTER garnered some industry funding, however, and Dr. Costa found that encouraging.

How much money is at stake? In other words, what are the financial savings if patients with zero to one HRCAs who are MRD negative start to take treatment holidays from lenalidomide maintenance?

In the United States in 2019 approximately 6,410 patients received ASCT. The MASTER publication stated that “around 85%” of newly diagnosed MM patients have zero to one HRCAs and that 73% of these patients were able to stop therapy in the trial. This suggests that, each year, approximately 4,000 new patients might be eligible to avoid lenalidomide after ASCT.

The price tag of lenalidomide is approximately $20,000 per month in the United States, according to Dr. Derman. A cohort of 4,000 patients avoiding lenalidomide each year represents lost revenue of $80 million per month or almost $1 billion per year. And this does not take into account patients already on lenalidomide from previous years – or sales outside the United States. The MM multiple research pipeline reflects a lack of enthusiasm for paring down maintenance.

There are currently 229 interventional clinical studies in MM taking place nationwide. Of these, just three trials are testing what happens when patients stop therapy in the post-ASCT setting and none of the three is sponsored by industry (NCT04108624, NCT05091372, and NCT04071457). (All data from clinicaltrials.gov; search covered phase 2, 3, or 4 studies still accruing data; descriptions hand-checked; search terms: maintenance/consolidation/post-ASCT.)

Dr. Derman said that it is “incumbent on investigators” to carry out the studies to identify who is eligible to stop therapy because industry is “probably always going to err on the side of treating more.”

Sergio Giralt, MD, head of the adult bone marrow transplant service at Memorial Sloan Kettering Cancer Center, New York, was an author of the key 2012 study that enshrined lenalidomide maintenance in the guidelines. Dr. Giralt expressed concerns about the single-arm design of MASTER and said he would like to see a randomized study where some patients continued treatment and others stopped.

Dr. Giralt cautioned: “If you’re MRD negative, the chances of having to deal with your disease in the next 5 years is one in five.” Physicians could certainly “have a conversation” with patients who are MRD negative about stopping therapy, but this would need to be weighed against the need for bone-marrow biopsies every 3-6 months to check progress. (In MASTER, MRD was checked at 6 and 18 months.)

Dr. Kumar believes that “we need to pursue the concept of decreasing the duration of treatment.” However, newer immunotherapies may be the answer: “Who knows? That may be the future, that we will do more of this hit-and-run approach rather than trying to keep them persistently on something.”

Dr. Derman said: “I personally think that the data is already there ... [MASTER] shows that perhaps this notion of indefinite maintenance therapy is one that really has to go by the wayside ... patients should have the option to consider with their physician [the chance to] potentially discontinue treatment.”

For 15 years, relentless lenalidomide maintenance has “quite rightly been the strongest pillar of therapy”, said Dr. Costa. “But for patients, this is not something that they easily embrace – it’s not ideal that you are going to have to take therapy for the rest of your life.”

Dr. Costa concluded: “I don’t think we had a single patient who was reluctant to stop therapy.”

Dr. Munshi reported relationships with Adaptive, Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Karyopharm, Legend, Millennium, Novartis, Pfizer, and he is the scientific founder of Oncopep and DCT. Dr. Derman disclosed ties with Janssen, Cota, and BMS. Dr. Costa reported ties with Amgen, Cota, Janssen, BMS, AbbVie, Ionis, Genentech, Sanofi, Karyopharm, AstraZeneca, Adaptive Biotechnologies, Takeda, and Pfizer. Dr. Kumar declared relationships with AbbVie, Amgen, BMS, GlaxoSmithKline, Karyopharm, Regeneron, Roche, Sanofi, Takeda, and BeiGene. Dr. Giralt reported ties with Amgen, CSL Behring, Caladrius, Celgene, Ceramedix, ExpertConnect, GlaxoSmithKline, Janssen, Karyopharm, Kite Pharmaceuticals, Magnolia Innovation, Novartis, Omeros, Pfizer, Physicians’ Education Resource, Sanofi, TRM Oncology, and Xcenda.

The Food and Drug Administration approved a new colony-stimulating factor, efbemalenograstim alfa (Ryzneuta, Evive Biotech), to decrease the incidence of infection, as manifested by febrile neutropenia, in adults with nonmyeloid malignancies receiving myelosuppressive anticancer drugs.

Efbemalenograstim joins other agents already on the U.S. market, including pegfilgrastim (Neulasta), that aim to reduce the incidence of chemotherapy-induced febrile neutropenia.

The approval of efbemalenograstim was based on two randomized trials. The first included 122 women with either metastatic or nonmetastatic breast cancer who were receiving doxorubicin and docetaxel. These patients were randomly assigned to receive either one subcutaneous injection of efbemalenograstim or placebo on the second day of their first chemotherapy cycle. All patients received efbemalenograstim on the second day of cycles two through four.

The mean duration of grade 4 neutropenia in the first cycle was 1.4 days with efbemalenograstim versus 4.3 days with placebo. Only 4.8% of patients who received efbemalenograstim experienced chemotherapy-induced febrile neutropenia, compared with 25.6% who received the placebo.

The new agent went up against pegfilgrastim in the second trial, which included 393 women who received docetaxel and cyclophosphamide as treatment for nonmetastatic breast cancer. These patients were randomly assigned to receive either a single subcutaneous injection of efbemalenograstim or pegfilgrastim on the second day of each cycle.

During the first cycle, patients in both arms of the trial experienced a mean of 0.2 days of grade 4 neutropenia.

The most common side effects associated with efbemalenograstim were nausea, anemia, and thrombocytopenia. Similar to pegfilgrastim’s label, efbemalenograstim’s label warns of possible splenic rupture, respiratory distress syndrome, sickle cell crisis, and other serious adverse events.

The FDA recommends a dose of 20 mg subcutaneous once per chemotherapy cycle.

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

The Food and Drug Administration approved a new colony-stimulating factor, efbemalenograstim alfa (Ryzneuta, Evive Biotech), to decrease the incidence of infection, as manifested by febrile neutropenia, in adults with nonmyeloid malignancies receiving myelosuppressive anticancer drugs.

Efbemalenograstim joins other agents already on the U.S. market, including pegfilgrastim (Neulasta), that aim to reduce the incidence of chemotherapy-induced febrile neutropenia.

The approval of efbemalenograstim was based on two randomized trials. The first included 122 women with either metastatic or nonmetastatic breast cancer who were receiving doxorubicin and docetaxel. These patients were randomly assigned to receive either one subcutaneous injection of efbemalenograstim or placebo on the second day of their first chemotherapy cycle. All patients received efbemalenograstim on the second day of cycles two through four.

The mean duration of grade 4 neutropenia in the first cycle was 1.4 days with efbemalenograstim versus 4.3 days with placebo. Only 4.8% of patients who received efbemalenograstim experienced chemotherapy-induced febrile neutropenia, compared with 25.6% who received the placebo.

The new agent went up against pegfilgrastim in the second trial, which included 393 women who received docetaxel and cyclophosphamide as treatment for nonmetastatic breast cancer. These patients were randomly assigned to receive either a single subcutaneous injection of efbemalenograstim or pegfilgrastim on the second day of each cycle.

During the first cycle, patients in both arms of the trial experienced a mean of 0.2 days of grade 4 neutropenia.

The most common side effects associated with efbemalenograstim were nausea, anemia, and thrombocytopenia. Similar to pegfilgrastim’s label, efbemalenograstim’s label warns of possible splenic rupture, respiratory distress syndrome, sickle cell crisis, and other serious adverse events.

The FDA recommends a dose of 20 mg subcutaneous once per chemotherapy cycle.

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

The Food and Drug Administration approved a new colony-stimulating factor, efbemalenograstim alfa (Ryzneuta, Evive Biotech), to decrease the incidence of infection, as manifested by febrile neutropenia, in adults with nonmyeloid malignancies receiving myelosuppressive anticancer drugs.

Efbemalenograstim joins other agents already on the U.S. market, including pegfilgrastim (Neulasta), that aim to reduce the incidence of chemotherapy-induced febrile neutropenia.

The approval of efbemalenograstim was based on two randomized trials. The first included 122 women with either metastatic or nonmetastatic breast cancer who were receiving doxorubicin and docetaxel. These patients were randomly assigned to receive either one subcutaneous injection of efbemalenograstim or placebo on the second day of their first chemotherapy cycle. All patients received efbemalenograstim on the second day of cycles two through four.

The mean duration of grade 4 neutropenia in the first cycle was 1.4 days with efbemalenograstim versus 4.3 days with placebo. Only 4.8% of patients who received efbemalenograstim experienced chemotherapy-induced febrile neutropenia, compared with 25.6% who received the placebo.

The new agent went up against pegfilgrastim in the second trial, which included 393 women who received docetaxel and cyclophosphamide as treatment for nonmetastatic breast cancer. These patients were randomly assigned to receive either a single subcutaneous injection of efbemalenograstim or pegfilgrastim on the second day of each cycle.

During the first cycle, patients in both arms of the trial experienced a mean of 0.2 days of grade 4 neutropenia.

The most common side effects associated with efbemalenograstim were nausea, anemia, and thrombocytopenia. Similar to pegfilgrastim’s label, efbemalenograstim’s label warns of possible splenic rupture, respiratory distress syndrome, sickle cell crisis, and other serious adverse events.

The FDA recommends a dose of 20 mg subcutaneous once per chemotherapy cycle.

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

U.S. government advisers expressed discomfort with Acrotech Biopharma’s 2030 target completion date for a study meant to prove the clinical benefits of two lymphoma drugs that the company has been selling for years.

At a Nov. 16 meeting, the Oncologic Drugs Advisory Committee of the Food and Drug Administration reviewed the reasons for delays in confirmatory trials for pralatrexate (Folotyn) and belinostat (Beleodaq), both now owned by East Windsor, N.J.–based Acrotech. The FDA granted accelerated approval for pralatrexate in 2009 and belinostat in 2014.

“The consensus of the advisory committee is that we have significant concerns about the very prolonged delay and getting these confirmatory studies underway,” said Andy Chen, MD, PhD, of Oregon Health & Science University, Portland, who served as acting ODAC chair for the meeting.

Corporate ownership changes were among the reasons Acrotech cited for the long delays in producing the confirmatory research on pralatrexate and belinostat. Allos Therapeutics won the FDA approval of pralatrexate in 2009. In 2012, Spectrum Pharmaceuticals acquired Acrotech. Spectrum won approval of belinostat in 2014. Acrotech acquired Spectrum in 2019.

The FDA didn’t ask ODAC to take votes on any questions at the meeting. Instead, the FDA sought its expert feedback about how to address the prolonged delays with pralatrexate and belinostat research and, in general, how to promote more timely completion of confirmatory trials for drugs cleared by accelerated approval.

Pralatrexate and belinostat are both used to treat relapsed or refractory peripheral T-cell lymphoma, a rare and aggressive disease affecting about 10,000-15,000 people annually in the United States.

Through the accelerated approval process, the FDA seeks to speed medicines to people with fatal and serious conditions based on promising signs in clinical testing.

The initial pralatrexate and belinostat were based on phase 2, single-arm, monotherapy studies, with about 109 evaluable patients in the key pralatrexate study and 120 evaluable patients in the belinostat study. As is common, these phase 2 tests used measurements of cancer progression, known as the overall response rate.

The FDA then expects companies to show through more extensive testing that medicines cleared with accelerated approvals can deliver significant benefits, such as extending lives. When there are delays in confirmatory trials, patients can be exposed to medicines, often with significant side effects, that are unlikely to benefit them.

For example, the FDA granted an accelerated approval in 2011 for romidepsin for this use for peripheral T-cell lymphoma, the same condition for which pralatrexate and belinostat are used. But in 2021, Bristol-Myers Squibb withdrew the approval for that use of romidepsin when a confirmatory trial failed to meet the primary efficacy endpoint of progression free survival.

At the meeting, Richard Pazdur, MD, who leads oncology medicine at the FDA, urged Acrotech to shorten the time needed to determine whether its medicines deliver significant benefits to patients and thus merit full approval, or whether they too may fall short.

“We’re really in a situation where patients are caught in the middle here,” Dr. Pazdur said. “I feel very bad for that situation and very bad for the patients that they don’t have this information.”
 

‘Dangerous precedent’

The FDA in recent years has stepped up its efforts to get companies to complete their required studies on drugs cleared by accelerated approvals. The FDA has granted a total of 187 accelerated approvals for cancer drugs. Many of these cover new uses of established drugs and others serve to allow the introduction of new medicines.

For more than half of these cases, 96 of 187, the FDA already has learned that it made the right call in allowing early access to medicines. Companies have presented study results that confirmed the benefit of drugs and thus been able to convert accelerated approvals to traditional approvals.

But 27 of the 187 oncology accelerated approvals have been withdrawn. In these cases, subsequent research failed to establish the expected benefits of these cancer drugs.

And in 95 cases, the FDA and companies are still waiting for the results of studies to confirm the expected benefit of drugs granted accelerated approvals. The FDA classifies these as ongoing accelerated approvals. About 85% of these ongoing approvals were granted in the past 5 years, in contrast to 14 years for pralatrexate and 9 for belinostat.

“It sets a dangerous precedent for the other sponsors and drug companies to have such outliers from the same company,” said ODAC member Toni K. Choueiri, MD, of Harvard Medical School and the Dana-Farber Cancer Institute, both in Boston.

The current agreement between the FDA and Acrotech focuses on a phase 3 trial, SPI-BEL-301 as the confirmatory study. Acrotech’s plan is to start with dose optimization studies in part 1 of the trial, with part 2 meant to see if its medicines provide a significant benefit as measured by progression-free survival.

The plan is to compare treatments. One group of patients would get belinostat plus a common cancer regimen known as CHOP, another group would get pralatrexate plus the COP cancer regimen, which is CHOP without doxorubicin, and a third group would get CHOP.

Acrotech’s current time line is for part 1, which began in October, to finish by December 2025. Then the part 2 timeline would run from 2026 to 2030, with interim progression-free survival possible by 2028.

ODAC member Ashley Rosko, MD, a hematologist from Ohio State University, Columbus, asked Acrotech what steps it will take to try to speed recruitment for the study.

“We are going to implement many strategies,” including what’s called digital amplification, replied Ashish Anvekar, president of Acrotech. This will help identify patients and channel them toward participating clinical sites.

Alexander A. Vinks, PhD, PharmD, who served as a temporary member of ODAC for the Nov. 16 meeting, said many clinicians will not be excited about enrolling patients in this kind of large, traditionally designed study.

Dr. Vinks, who is professor emeritus at Cincinnati Children’s Hospital Medical Center and University of Cincinnati, now works with consultant group NDA, a firm that advises companies on developing drugs.

Dr. Vinks advised Acrotech should try “to pin down what is most likely a smaller study that could be simpler, but still give robust, informative data.”

U.S. government advisers expressed discomfort with Acrotech Biopharma’s 2030 target completion date for a study meant to prove the clinical benefits of two lymphoma drugs that the company has been selling for years.

At a Nov. 16 meeting, the Oncologic Drugs Advisory Committee of the Food and Drug Administration reviewed the reasons for delays in confirmatory trials for pralatrexate (Folotyn) and belinostat (Beleodaq), both now owned by East Windsor, N.J.–based Acrotech. The FDA granted accelerated approval for pralatrexate in 2009 and belinostat in 2014.

“The consensus of the advisory committee is that we have significant concerns about the very prolonged delay and getting these confirmatory studies underway,” said Andy Chen, MD, PhD, of Oregon Health & Science University, Portland, who served as acting ODAC chair for the meeting.

Corporate ownership changes were among the reasons Acrotech cited for the long delays in producing the confirmatory research on pralatrexate and belinostat. Allos Therapeutics won the FDA approval of pralatrexate in 2009. In 2012, Spectrum Pharmaceuticals acquired Acrotech. Spectrum won approval of belinostat in 2014. Acrotech acquired Spectrum in 2019.

The FDA didn’t ask ODAC to take votes on any questions at the meeting. Instead, the FDA sought its expert feedback about how to address the prolonged delays with pralatrexate and belinostat research and, in general, how to promote more timely completion of confirmatory trials for drugs cleared by accelerated approval.

Pralatrexate and belinostat are both used to treat relapsed or refractory peripheral T-cell lymphoma, a rare and aggressive disease affecting about 10,000-15,000 people annually in the United States.

Through the accelerated approval process, the FDA seeks to speed medicines to people with fatal and serious conditions based on promising signs in clinical testing.

The initial pralatrexate and belinostat were based on phase 2, single-arm, monotherapy studies, with about 109 evaluable patients in the key pralatrexate study and 120 evaluable patients in the belinostat study. As is common, these phase 2 tests used measurements of cancer progression, known as the overall response rate.

The FDA then expects companies to show through more extensive testing that medicines cleared with accelerated approvals can deliver significant benefits, such as extending lives. When there are delays in confirmatory trials, patients can be exposed to medicines, often with significant side effects, that are unlikely to benefit them.

For example, the FDA granted an accelerated approval in 2011 for romidepsin for this use for peripheral T-cell lymphoma, the same condition for which pralatrexate and belinostat are used. But in 2021, Bristol-Myers Squibb withdrew the approval for that use of romidepsin when a confirmatory trial failed to meet the primary efficacy endpoint of progression free survival.

At the meeting, Richard Pazdur, MD, who leads oncology medicine at the FDA, urged Acrotech to shorten the time needed to determine whether its medicines deliver significant benefits to patients and thus merit full approval, or whether they too may fall short.

“We’re really in a situation where patients are caught in the middle here,” Dr. Pazdur said. “I feel very bad for that situation and very bad for the patients that they don’t have this information.”
 

‘Dangerous precedent’

The FDA in recent years has stepped up its efforts to get companies to complete their required studies on drugs cleared by accelerated approvals. The FDA has granted a total of 187 accelerated approvals for cancer drugs. Many of these cover new uses of established drugs and others serve to allow the introduction of new medicines.

For more than half of these cases, 96 of 187, the FDA already has learned that it made the right call in allowing early access to medicines. Companies have presented study results that confirmed the benefit of drugs and thus been able to convert accelerated approvals to traditional approvals.

But 27 of the 187 oncology accelerated approvals have been withdrawn. In these cases, subsequent research failed to establish the expected benefits of these cancer drugs.

And in 95 cases, the FDA and companies are still waiting for the results of studies to confirm the expected benefit of drugs granted accelerated approvals. The FDA classifies these as ongoing accelerated approvals. About 85% of these ongoing approvals were granted in the past 5 years, in contrast to 14 years for pralatrexate and 9 for belinostat.

“It sets a dangerous precedent for the other sponsors and drug companies to have such outliers from the same company,” said ODAC member Toni K. Choueiri, MD, of Harvard Medical School and the Dana-Farber Cancer Institute, both in Boston.

The current agreement between the FDA and Acrotech focuses on a phase 3 trial, SPI-BEL-301 as the confirmatory study. Acrotech’s plan is to start with dose optimization studies in part 1 of the trial, with part 2 meant to see if its medicines provide a significant benefit as measured by progression-free survival.

The plan is to compare treatments. One group of patients would get belinostat plus a common cancer regimen known as CHOP, another group would get pralatrexate plus the COP cancer regimen, which is CHOP without doxorubicin, and a third group would get CHOP.

Acrotech’s current time line is for part 1, which began in October, to finish by December 2025. Then the part 2 timeline would run from 2026 to 2030, with interim progression-free survival possible by 2028.

ODAC member Ashley Rosko, MD, a hematologist from Ohio State University, Columbus, asked Acrotech what steps it will take to try to speed recruitment for the study.

“We are going to implement many strategies,” including what’s called digital amplification, replied Ashish Anvekar, president of Acrotech. This will help identify patients and channel them toward participating clinical sites.

Alexander A. Vinks, PhD, PharmD, who served as a temporary member of ODAC for the Nov. 16 meeting, said many clinicians will not be excited about enrolling patients in this kind of large, traditionally designed study.

Dr. Vinks, who is professor emeritus at Cincinnati Children’s Hospital Medical Center and University of Cincinnati, now works with consultant group NDA, a firm that advises companies on developing drugs.

Dr. Vinks advised Acrotech should try “to pin down what is most likely a smaller study that could be simpler, but still give robust, informative data.”

U.S. government advisers expressed discomfort with Acrotech Biopharma’s 2030 target completion date for a study meant to prove the clinical benefits of two lymphoma drugs that the company has been selling for years.

At a Nov. 16 meeting, the Oncologic Drugs Advisory Committee of the Food and Drug Administration reviewed the reasons for delays in confirmatory trials for pralatrexate (Folotyn) and belinostat (Beleodaq), both now owned by East Windsor, N.J.–based Acrotech. The FDA granted accelerated approval for pralatrexate in 2009 and belinostat in 2014.

“The consensus of the advisory committee is that we have significant concerns about the very prolonged delay and getting these confirmatory studies underway,” said Andy Chen, MD, PhD, of Oregon Health & Science University, Portland, who served as acting ODAC chair for the meeting.

Corporate ownership changes were among the reasons Acrotech cited for the long delays in producing the confirmatory research on pralatrexate and belinostat. Allos Therapeutics won the FDA approval of pralatrexate in 2009. In 2012, Spectrum Pharmaceuticals acquired Acrotech. Spectrum won approval of belinostat in 2014. Acrotech acquired Spectrum in 2019.

The FDA didn’t ask ODAC to take votes on any questions at the meeting. Instead, the FDA sought its expert feedback about how to address the prolonged delays with pralatrexate and belinostat research and, in general, how to promote more timely completion of confirmatory trials for drugs cleared by accelerated approval.

Pralatrexate and belinostat are both used to treat relapsed or refractory peripheral T-cell lymphoma, a rare and aggressive disease affecting about 10,000-15,000 people annually in the United States.

Through the accelerated approval process, the FDA seeks to speed medicines to people with fatal and serious conditions based on promising signs in clinical testing.

The initial pralatrexate and belinostat were based on phase 2, single-arm, monotherapy studies, with about 109 evaluable patients in the key pralatrexate study and 120 evaluable patients in the belinostat study. As is common, these phase 2 tests used measurements of cancer progression, known as the overall response rate.

The FDA then expects companies to show through more extensive testing that medicines cleared with accelerated approvals can deliver significant benefits, such as extending lives. When there are delays in confirmatory trials, patients can be exposed to medicines, often with significant side effects, that are unlikely to benefit them.

For example, the FDA granted an accelerated approval in 2011 for romidepsin for this use for peripheral T-cell lymphoma, the same condition for which pralatrexate and belinostat are used. But in 2021, Bristol-Myers Squibb withdrew the approval for that use of romidepsin when a confirmatory trial failed to meet the primary efficacy endpoint of progression free survival.

At the meeting, Richard Pazdur, MD, who leads oncology medicine at the FDA, urged Acrotech to shorten the time needed to determine whether its medicines deliver significant benefits to patients and thus merit full approval, or whether they too may fall short.

“We’re really in a situation where patients are caught in the middle here,” Dr. Pazdur said. “I feel very bad for that situation and very bad for the patients that they don’t have this information.”
 

‘Dangerous precedent’

The FDA in recent years has stepped up its efforts to get companies to complete their required studies on drugs cleared by accelerated approvals. The FDA has granted a total of 187 accelerated approvals for cancer drugs. Many of these cover new uses of established drugs and others serve to allow the introduction of new medicines.

For more than half of these cases, 96 of 187, the FDA already has learned that it made the right call in allowing early access to medicines. Companies have presented study results that confirmed the benefit of drugs and thus been able to convert accelerated approvals to traditional approvals.

But 27 of the 187 oncology accelerated approvals have been withdrawn. In these cases, subsequent research failed to establish the expected benefits of these cancer drugs.

And in 95 cases, the FDA and companies are still waiting for the results of studies to confirm the expected benefit of drugs granted accelerated approvals. The FDA classifies these as ongoing accelerated approvals. About 85% of these ongoing approvals were granted in the past 5 years, in contrast to 14 years for pralatrexate and 9 for belinostat.

“It sets a dangerous precedent for the other sponsors and drug companies to have such outliers from the same company,” said ODAC member Toni K. Choueiri, MD, of Harvard Medical School and the Dana-Farber Cancer Institute, both in Boston.

The current agreement between the FDA and Acrotech focuses on a phase 3 trial, SPI-BEL-301 as the confirmatory study. Acrotech’s plan is to start with dose optimization studies in part 1 of the trial, with part 2 meant to see if its medicines provide a significant benefit as measured by progression-free survival.

The plan is to compare treatments. One group of patients would get belinostat plus a common cancer regimen known as CHOP, another group would get pralatrexate plus the COP cancer regimen, which is CHOP without doxorubicin, and a third group would get CHOP.

Acrotech’s current time line is for part 1, which began in October, to finish by December 2025. Then the part 2 timeline would run from 2026 to 2030, with interim progression-free survival possible by 2028.

ODAC member Ashley Rosko, MD, a hematologist from Ohio State University, Columbus, asked Acrotech what steps it will take to try to speed recruitment for the study.

“We are going to implement many strategies,” including what’s called digital amplification, replied Ashish Anvekar, president of Acrotech. This will help identify patients and channel them toward participating clinical sites.

Alexander A. Vinks, PhD, PharmD, who served as a temporary member of ODAC for the Nov. 16 meeting, said many clinicians will not be excited about enrolling patients in this kind of large, traditionally designed study.

Dr. Vinks, who is professor emeritus at Cincinnati Children’s Hospital Medical Center and University of Cincinnati, now works with consultant group NDA, a firm that advises companies on developing drugs.

Dr. Vinks advised Acrotech should try “to pin down what is most likely a smaller study that could be simpler, but still give robust, informative data.”

NEW YORK – In the last 25 years, major advances in treating multiple myeloma (MM) have doubled survival rates, yet the still incurable disease often requires lifelong maintenance therapy. Since CAR T-cell therapy has emerged as a viable strategy to prolong survival and deepen response in relapsed or refractory (RR) patients, the question arises: Should CAR T replace autologous stem cell transplant (ASCT) in earlier lines of treatment?

courtesy MSKCC

“In an otherwise healthy treatment-naive patient with multiple myeloma, to ensure the best chances of overall survival, I would always recommend standard of care consolidation therapy of chemotherapy + ASCT,” said Sergio Giralt, MD, of New York’s Memorial Sloan Kettering Cancer Center, debating the merits of ASCT versus CAR T as consolidation therapy at the Lymphoma, Leukemia & Myeloma (LLM) Congress 2023 in New York.

Final results from the phase II GRIFFIN trial highlight the benchmarks that CAR T-cell therapy would need to reach to achieve equivalence with ASCT. At a 4-year follow-up, newly diagnosed MM patients who received daratumumab, lenalidomide, bortezomib, and dexamethasone (D-RVd) followed by ASCT + D-RVd consolidation, and daratumumab maintenance, had a progression-free survival (PFS) rate of 87.3%, 92.7% overall survival (OS) rate, and 50% achieved minimal residual disease negativity.

Dr. Adriana Rossi, MD, assistant professor of medicine, Icahn School of Medicine at Mount Sinai, New York, cited a convergence of evidence suggesting that CAR T could achieve impressive results as a consolidation therapy in fit patients with MM, including: CARTITUDE 1 and CARTITUDE 4, which studied CAR T in RR MM patients. However, due to the fact that no head-to-head study of CAR T vs. ASCT as consolidation therapy in otherwise healthy MM patients exists, “There is not enough long-term data to support the equivalence CAR T with ASCT,” Dr. Giralt concluded.

Dr. Rossi further advocated for considering CAR T as a consolidation treatment because of the risks of secondary malignancies associated with ACST maintenance regimens.

Dr. Giralt rebutted this argument by citing data about averse events (AE) in studies of CAR-T therapies in RR MM patients like KarMMa-2, in which grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 94.6%, 45.9%, and 37.8% of patients respectively. Furthermore, 2 of 37 patients in KarMMA died (1 pneumonia, 1 pseudomonal sepsis), while rates of death from AEs related to ASCT occur in less than 1% of patients, according to Dr. Giralt.

Beyond a dearth of evidence thus far about the long term PFS, OS, and safety profile superiority of CAR-T therapies, compared with ASCT in treatment-naive MM patients, Dr. Giralt also noted the facts that CAR T-cell therapies are expensive and require manufacturing infrastructure also demonstrate that they cannot be easily adopted everywhere, even as a third-line therapy.

“In many places like Morocco, where I practice, we do not have access to CAR-T therapies,” said Sadia Zafad, MD, of the Clinique Al Madina Hematology and Oncology Center in Casablanca, Morocco. Dr. Zafad attended the debate.

A lack of access to CAR T is also a problem in the United States, where wait times for the therapy can stretch up to 6 months, getting insurance approval is challenging, and many patients simply don’t live near a center where CAR T-cell therapy is available. Citing all these factors, Dr. Giralt concluded: “Even if CAR T can be shown to have the same results as transplant, it is much more resource-intensive than transplant, and insurers are going to start saying there’s no necessary benefit. We have yet to use value as a primary end point, but as cancer care gets more and more expensive, that’s going to come up more, for CAR T and other novel therapies.”

Dr. Giralt reported relationships with Actinuum, Amgen, BMS, Celgene, Crisper, J&J, Jazz, Kite, Miltenyi, Novartis, Sanofi, and Takeda. Dr. Rossi disclosed ties with Adaptive, BMS, Celgene, JNJ, Sanofi & Genzyme. Dr. Zafad reported no disclosures.

NEW YORK – In the last 25 years, major advances in treating multiple myeloma (MM) have doubled survival rates, yet the still incurable disease often requires lifelong maintenance therapy. Since CAR T-cell therapy has emerged as a viable strategy to prolong survival and deepen response in relapsed or refractory (RR) patients, the question arises: Should CAR T replace autologous stem cell transplant (ASCT) in earlier lines of treatment?

courtesy MSKCC

“In an otherwise healthy treatment-naive patient with multiple myeloma, to ensure the best chances of overall survival, I would always recommend standard of care consolidation therapy of chemotherapy + ASCT,” said Sergio Giralt, MD, of New York’s Memorial Sloan Kettering Cancer Center, debating the merits of ASCT versus CAR T as consolidation therapy at the Lymphoma, Leukemia & Myeloma (LLM) Congress 2023 in New York.

Final results from the phase II GRIFFIN trial highlight the benchmarks that CAR T-cell therapy would need to reach to achieve equivalence with ASCT. At a 4-year follow-up, newly diagnosed MM patients who received daratumumab, lenalidomide, bortezomib, and dexamethasone (D-RVd) followed by ASCT + D-RVd consolidation, and daratumumab maintenance, had a progression-free survival (PFS) rate of 87.3%, 92.7% overall survival (OS) rate, and 50% achieved minimal residual disease negativity.

Dr. Adriana Rossi, MD, assistant professor of medicine, Icahn School of Medicine at Mount Sinai, New York, cited a convergence of evidence suggesting that CAR T could achieve impressive results as a consolidation therapy in fit patients with MM, including: CARTITUDE 1 and CARTITUDE 4, which studied CAR T in RR MM patients. However, due to the fact that no head-to-head study of CAR T vs. ASCT as consolidation therapy in otherwise healthy MM patients exists, “There is not enough long-term data to support the equivalence CAR T with ASCT,” Dr. Giralt concluded.

Dr. Rossi further advocated for considering CAR T as a consolidation treatment because of the risks of secondary malignancies associated with ACST maintenance regimens.

Dr. Giralt rebutted this argument by citing data about averse events (AE) in studies of CAR-T therapies in RR MM patients like KarMMa-2, in which grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 94.6%, 45.9%, and 37.8% of patients respectively. Furthermore, 2 of 37 patients in KarMMA died (1 pneumonia, 1 pseudomonal sepsis), while rates of death from AEs related to ASCT occur in less than 1% of patients, according to Dr. Giralt.

Beyond a dearth of evidence thus far about the long term PFS, OS, and safety profile superiority of CAR-T therapies, compared with ASCT in treatment-naive MM patients, Dr. Giralt also noted the facts that CAR T-cell therapies are expensive and require manufacturing infrastructure also demonstrate that they cannot be easily adopted everywhere, even as a third-line therapy.

“In many places like Morocco, where I practice, we do not have access to CAR-T therapies,” said Sadia Zafad, MD, of the Clinique Al Madina Hematology and Oncology Center in Casablanca, Morocco. Dr. Zafad attended the debate.

A lack of access to CAR T is also a problem in the United States, where wait times for the therapy can stretch up to 6 months, getting insurance approval is challenging, and many patients simply don’t live near a center where CAR T-cell therapy is available. Citing all these factors, Dr. Giralt concluded: “Even if CAR T can be shown to have the same results as transplant, it is much more resource-intensive than transplant, and insurers are going to start saying there’s no necessary benefit. We have yet to use value as a primary end point, but as cancer care gets more and more expensive, that’s going to come up more, for CAR T and other novel therapies.”

Dr. Giralt reported relationships with Actinuum, Amgen, BMS, Celgene, Crisper, J&J, Jazz, Kite, Miltenyi, Novartis, Sanofi, and Takeda. Dr. Rossi disclosed ties with Adaptive, BMS, Celgene, JNJ, Sanofi & Genzyme. Dr. Zafad reported no disclosures.

NEW YORK – In the last 25 years, major advances in treating multiple myeloma (MM) have doubled survival rates, yet the still incurable disease often requires lifelong maintenance therapy. Since CAR T-cell therapy has emerged as a viable strategy to prolong survival and deepen response in relapsed or refractory (RR) patients, the question arises: Should CAR T replace autologous stem cell transplant (ASCT) in earlier lines of treatment?

courtesy MSKCC

“In an otherwise healthy treatment-naive patient with multiple myeloma, to ensure the best chances of overall survival, I would always recommend standard of care consolidation therapy of chemotherapy + ASCT,” said Sergio Giralt, MD, of New York’s Memorial Sloan Kettering Cancer Center, debating the merits of ASCT versus CAR T as consolidation therapy at the Lymphoma, Leukemia & Myeloma (LLM) Congress 2023 in New York.

Final results from the phase II GRIFFIN trial highlight the benchmarks that CAR T-cell therapy would need to reach to achieve equivalence with ASCT. At a 4-year follow-up, newly diagnosed MM patients who received daratumumab, lenalidomide, bortezomib, and dexamethasone (D-RVd) followed by ASCT + D-RVd consolidation, and daratumumab maintenance, had a progression-free survival (PFS) rate of 87.3%, 92.7% overall survival (OS) rate, and 50% achieved minimal residual disease negativity.

Dr. Adriana Rossi, MD, assistant professor of medicine, Icahn School of Medicine at Mount Sinai, New York, cited a convergence of evidence suggesting that CAR T could achieve impressive results as a consolidation therapy in fit patients with MM, including: CARTITUDE 1 and CARTITUDE 4, which studied CAR T in RR MM patients. However, due to the fact that no head-to-head study of CAR T vs. ASCT as consolidation therapy in otherwise healthy MM patients exists, “There is not enough long-term data to support the equivalence CAR T with ASCT,” Dr. Giralt concluded.

Dr. Rossi further advocated for considering CAR T as a consolidation treatment because of the risks of secondary malignancies associated with ACST maintenance regimens.

Dr. Giralt rebutted this argument by citing data about averse events (AE) in studies of CAR-T therapies in RR MM patients like KarMMa-2, in which grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 94.6%, 45.9%, and 37.8% of patients respectively. Furthermore, 2 of 37 patients in KarMMA died (1 pneumonia, 1 pseudomonal sepsis), while rates of death from AEs related to ASCT occur in less than 1% of patients, according to Dr. Giralt.

Beyond a dearth of evidence thus far about the long term PFS, OS, and safety profile superiority of CAR-T therapies, compared with ASCT in treatment-naive MM patients, Dr. Giralt also noted the facts that CAR T-cell therapies are expensive and require manufacturing infrastructure also demonstrate that they cannot be easily adopted everywhere, even as a third-line therapy.

“In many places like Morocco, where I practice, we do not have access to CAR-T therapies,” said Sadia Zafad, MD, of the Clinique Al Madina Hematology and Oncology Center in Casablanca, Morocco. Dr. Zafad attended the debate.

A lack of access to CAR T is also a problem in the United States, where wait times for the therapy can stretch up to 6 months, getting insurance approval is challenging, and many patients simply don’t live near a center where CAR T-cell therapy is available. Citing all these factors, Dr. Giralt concluded: “Even if CAR T can be shown to have the same results as transplant, it is much more resource-intensive than transplant, and insurers are going to start saying there’s no necessary benefit. We have yet to use value as a primary end point, but as cancer care gets more and more expensive, that’s going to come up more, for CAR T and other novel therapies.”

Dr. Giralt reported relationships with Actinuum, Amgen, BMS, Celgene, Crisper, J&J, Jazz, Kite, Miltenyi, Novartis, Sanofi, and Takeda. Dr. Rossi disclosed ties with Adaptive, BMS, Celgene, JNJ, Sanofi & Genzyme. Dr. Zafad reported no disclosures.

When hematologist James R. Berenson, MD, began practicing medicine in the 1980s, his 45-year-old cousin Stanley broke his ribs while hugging his son in a swimming pool. The cousin was a well-respected orthopedic surgeon in Los Angeles, but his specialty could do nothing for him. Stanley had the bone-ravaging disease known as multiple myeloma (MM).

Back then, the treatments for MM were chemotherapy and steroids. Stem-cell transplants were on the horizon, as was a most unexpected therapy: the infamous drug thalidomide.

But in the wake of the rib facture, the health of Stanley Katz, MD, worsened and he died after 25 weeks, Dr. Berenson recalled in an interview. At that time, Dr. Katz’s horrifically shortened lifespan following diagnosis was not unusual.

About 4 decades later, hematologists like Dr. Berenson are heralding a new era in MM, a sharp reversal of the previous eras of grim prognoses.

In a new study, Dr. Berenson tracked 161 patients with MM treated at his West Hollywood, Calif., private clinic from 2006 to 2023 and found that their median survival was 136.2 months – more than 11 years. “The OS reported in this study ... is the longest reported to date in an unselected, newly diagnosed MM population,” the study authors write.

Dr. Berenson’s patients are unique: They’re largely White, and they didn’t undergo stem-cell transplants. But other recent studies also suggest that lifespans of more than 10 years are increasingly possible after MM diagnosis. Former TV news anchor Tom Brokaw, for one, has reached that point.

In fact, a pair of other hematologists say the overall survival in Dr. Berenson’s report is hardly out of the question. And, they say, patients diagnosed today could potentially live even longer, because treatments continue to improve.

“With data that’s 10 years old, we expect the median overall survival to be 10 years,” hematologist Sagar Lonial, MD, who’s been tracking survival data in MM, said in an interview. “When patients ask about my outlook, I say it’s a constantly evolving field. Things are changing fast enough that I use 10 years as a floor.”

Dr. Lonial is chair of the department of hematology and medical oncology and chief medical officer at Emory University, Atlanta, Winship Cancer Institute.

Hematologist Rafael Fonseca, MD, chief innovation officer at Mayo Clinic–Arizona, put it this way in an interview: Dr. Berenson’s results “are probably in sync with what we would anticipate with similar cohorts of patients. The reality is that we’ve seen a huge improvement in the life expectancy of patients who were diagnosed with multiple myeloma. It’s not unusual to see patients in the clinic now that are 15 or 20 years out from their diagnosis.”

According to Yale Medicine, MM accounts for 10% of blood cancers and 1%-2% of all cancers and is more common in men vs. women and Blacks vs. Whites. It’s most frequently diagnosed between the ages of 65 and 74, according to the National Cancer Institute, and the median age at diagnosis is 69.

Among the most famous American people currently battling MM are newsman Mr. Brokaw, the former NBC News anchor, and Republican Congressman Steve Scalise, majority leader of the U.S. House of Representatives and a candidate for House speaker.

Mr. Brokaw was diagnosed in 2013 while in his early 70s and has talked about his intense struggle with the disease: the infections, operations, infusions, and daily regimens of 24 pills.

“I didn’t want to be Tom Brokaw, cancer victim,” he said in 2018 at the annual meeting of the American Society of Hematology. But he opened up about his illness, and became “the multiple myeloma poster boy.”

Rep. Scalise, who’s in his late 50s, is undergoing chemotherapy. He survived being gravely wounded in an assassination attempt in 2017.

Dr. Berenson’s new study, published in Targeted Oncology, tracked 161 patients (89 women, 72 men; median age, 65.4; 125 White, 3 Black, 10 Hispanic, 15 Asian, and 8 multi-ethnic).

All started frontline treatment at Dr. Berenson’s clinic and were included if they could read consent forms and gave permission for blood draws. None underwent stem-cell transplants as part of initial therapy. Another 1,036 patients had been treated elsewhere and were not included in the study.

Over a median of 42.7 months (range, 1.9-195.1), the 1-, 3-, and 5-year survival rates were 97.5%, 85.3%, and 76.2%, respectively.

The study claims “these results are considerably better than those reported from patients enrolled in clinical trials and those from countries with national registries.”

In the interview, Dr. Berenson said the study is unique because it’s not limited like many studies to younger, healthier patients. Nor does it include those treated at other facilities, he said.

The study is unusual in other ways. Dr. Berenson said his drug regimens aren’t necessarily standard, and he doesn’t treat patients with stem-cell transplants. “I stopped transplanting in about 2000 because clearly it was not improving the length of life,” he said.

Dr. Berenson said colleagues can learn from his insistence on sensitively treating the quality of life of patients, his embrace of clinical trials with novel combinations, and his close monitoring of myeloma proteins to gauge whether patients need to rapidly switch therapies.

He noted that his drug regimens are typically off-label and vary by patient. “We’re not using as high doses of drugs like Velcade [bortezomib] or Revlimid [lenalidomide] as my colleagues. We’re not necessarily giving as many doses. Also, we’re not adding as many drugs in many cases as they are. We’re taking it slower.”

The National Comprehensive Cancer Network recommends bortezomib and lenalidomide as standard induction treatments in patients with MM who are candidates for stem-cell transplantation, a procedure it considers the “preferred approach in transplant-eligible patients.”

There are limitations to Dr. Berenson’s new study. The patients aren’t representative of people with MM as a whole: His cohort is overwhelmingly White (78%) and just 2% Black, while an estimated one-fifth of patients with MM in the United States are Black and have poorer outcomes.

Dr. Berenson also acknowledged that his patients are most likely a wealthier group, although he said it’s not feasible to ask them about income. The study provides no information about socioeconomics.

Dr. Lonial said survival of 10-11 years is fairly typical in MM, with standard-risk patients reaching 14 years.

He highlighted a 2021 Canadian study that tracked 3,030 patients with newly diagnosed MM from 2007 to 2018 (average age, 64; 58.6% men). Those who received an upfront autologous stem-cell transplant had a median overall survival of 122.0 months (95% confidence interval, 115.0-135.0 months) vs. 54.3 months (95% CI, 50.8-58.8 months) for those who didn’t get the transplants. Not surprisingly, survival dipped with each subsequent treatment regimen.

Dr. Lonial is coauthor of a 2020 study that tracked 1,000 consecutive patients (mean age, 61; 35.2% Black) with newly diagnosed myeloma who were treated with RVD (lenalidomide, bortezomib, and dexamethasone) induction therapy from 2007 to 2016. The median overall survival was 126.6 months (95% CI, 113.3-139.8 months).

Dr. Fonseca noted that the news about MM survival rates is not entirely positive. Patients with high-risk disease often die early on in their disease course, he said.

Research suggests even the youngest patients with MM may die within years of diagnosis. A 2021 French study tracked 214 patients in the 18-40 age group for 15 years (2000-2015). At 5 years, “relative survival compared with same age- and sex-matched individuals was 83.5%,” and estimated overall survival was 14.5 years.

Still, a “very, very fertile environment for the development of drugs” has made a huge difference, Dr. Fonseca said. “We’ve had about 19 FDA approvals in the last 15 or 20 years.”

He urged colleagues to keep in mind that survival drops as patients decline in a line of therapy and need to switch to another one. “It might make intuitive sense to say ‘I’m gonna save something for later. I want to keep my powder dry.’ But put your best foot forward. Always go with your best treatments first.”

This approach can play out in a decision, say, to start with a four-drug initial regimen instead of a weaker two-drug regimen, he said. “Be mindful of managing toxicities, but hit harder.”

As he noted, side effects were worse with older generations of drugs. In regard to cost, multidrug treatments can cost hundreds of thousands of dollars. Dr. Fonseca said insurance tends to cover drugs that are approved by guidelines.

Dr. Fonseca discloses relationships with AbbVie, Adaptive Biotechnologies, Amgen, AstraZeneca, Bayer, Binding Site, BMS (Celgene), Millennium Takeda, Janssen, Juno, Kite, Merck, Pfizer, Pharmacyclics, Regeneron, Sanofi, Adaptive Biotechnologies, Caris Life Sciences, Oncotracker, Antegene, and AZBio, and a patent in MM. Dr. Berenson discloses ties with Janssen, Amgen, Sanofi, BMS, Karyopharm, and Incyte. Dr. Lonial reports ties with TG Therapeutics, Celgene, BMS, Janssen, Novartis, GlaxoSmithKline, AbbVie, Takeda, Merck, Sanofi, Pfizer, Regeneron, and Novartis.
 

When hematologist James R. Berenson, MD, began practicing medicine in the 1980s, his 45-year-old cousin Stanley broke his ribs while hugging his son in a swimming pool. The cousin was a well-respected orthopedic surgeon in Los Angeles, but his specialty could do nothing for him. Stanley had the bone-ravaging disease known as multiple myeloma (MM).

Back then, the treatments for MM were chemotherapy and steroids. Stem-cell transplants were on the horizon, as was a most unexpected therapy: the infamous drug thalidomide.

But in the wake of the rib facture, the health of Stanley Katz, MD, worsened and he died after 25 weeks, Dr. Berenson recalled in an interview. At that time, Dr. Katz’s horrifically shortened lifespan following diagnosis was not unusual.

About 4 decades later, hematologists like Dr. Berenson are heralding a new era in MM, a sharp reversal of the previous eras of grim prognoses.

In a new study, Dr. Berenson tracked 161 patients with MM treated at his West Hollywood, Calif., private clinic from 2006 to 2023 and found that their median survival was 136.2 months – more than 11 years. “The OS reported in this study ... is the longest reported to date in an unselected, newly diagnosed MM population,” the study authors write.

Dr. Berenson’s patients are unique: They’re largely White, and they didn’t undergo stem-cell transplants. But other recent studies also suggest that lifespans of more than 10 years are increasingly possible after MM diagnosis. Former TV news anchor Tom Brokaw, for one, has reached that point.

In fact, a pair of other hematologists say the overall survival in Dr. Berenson’s report is hardly out of the question. And, they say, patients diagnosed today could potentially live even longer, because treatments continue to improve.

“With data that’s 10 years old, we expect the median overall survival to be 10 years,” hematologist Sagar Lonial, MD, who’s been tracking survival data in MM, said in an interview. “When patients ask about my outlook, I say it’s a constantly evolving field. Things are changing fast enough that I use 10 years as a floor.”

Dr. Lonial is chair of the department of hematology and medical oncology and chief medical officer at Emory University, Atlanta, Winship Cancer Institute.

Hematologist Rafael Fonseca, MD, chief innovation officer at Mayo Clinic–Arizona, put it this way in an interview: Dr. Berenson’s results “are probably in sync with what we would anticipate with similar cohorts of patients. The reality is that we’ve seen a huge improvement in the life expectancy of patients who were diagnosed with multiple myeloma. It’s not unusual to see patients in the clinic now that are 15 or 20 years out from their diagnosis.”

According to Yale Medicine, MM accounts for 10% of blood cancers and 1%-2% of all cancers and is more common in men vs. women and Blacks vs. Whites. It’s most frequently diagnosed between the ages of 65 and 74, according to the National Cancer Institute, and the median age at diagnosis is 69.

Among the most famous American people currently battling MM are newsman Mr. Brokaw, the former NBC News anchor, and Republican Congressman Steve Scalise, majority leader of the U.S. House of Representatives and a candidate for House speaker.

Mr. Brokaw was diagnosed in 2013 while in his early 70s and has talked about his intense struggle with the disease: the infections, operations, infusions, and daily regimens of 24 pills.

“I didn’t want to be Tom Brokaw, cancer victim,” he said in 2018 at the annual meeting of the American Society of Hematology. But he opened up about his illness, and became “the multiple myeloma poster boy.”

Rep. Scalise, who’s in his late 50s, is undergoing chemotherapy. He survived being gravely wounded in an assassination attempt in 2017.

Dr. Berenson’s new study, published in Targeted Oncology, tracked 161 patients (89 women, 72 men; median age, 65.4; 125 White, 3 Black, 10 Hispanic, 15 Asian, and 8 multi-ethnic).

All started frontline treatment at Dr. Berenson’s clinic and were included if they could read consent forms and gave permission for blood draws. None underwent stem-cell transplants as part of initial therapy. Another 1,036 patients had been treated elsewhere and were not included in the study.

Over a median of 42.7 months (range, 1.9-195.1), the 1-, 3-, and 5-year survival rates were 97.5%, 85.3%, and 76.2%, respectively.

The study claims “these results are considerably better than those reported from patients enrolled in clinical trials and those from countries with national registries.”

In the interview, Dr. Berenson said the study is unique because it’s not limited like many studies to younger, healthier patients. Nor does it include those treated at other facilities, he said.

The study is unusual in other ways. Dr. Berenson said his drug regimens aren’t necessarily standard, and he doesn’t treat patients with stem-cell transplants. “I stopped transplanting in about 2000 because clearly it was not improving the length of life,” he said.

Dr. Berenson said colleagues can learn from his insistence on sensitively treating the quality of life of patients, his embrace of clinical trials with novel combinations, and his close monitoring of myeloma proteins to gauge whether patients need to rapidly switch therapies.

He noted that his drug regimens are typically off-label and vary by patient. “We’re not using as high doses of drugs like Velcade [bortezomib] or Revlimid [lenalidomide] as my colleagues. We’re not necessarily giving as many doses. Also, we’re not adding as many drugs in many cases as they are. We’re taking it slower.”

The National Comprehensive Cancer Network recommends bortezomib and lenalidomide as standard induction treatments in patients with MM who are candidates for stem-cell transplantation, a procedure it considers the “preferred approach in transplant-eligible patients.”

There are limitations to Dr. Berenson’s new study. The patients aren’t representative of people with MM as a whole: His cohort is overwhelmingly White (78%) and just 2% Black, while an estimated one-fifth of patients with MM in the United States are Black and have poorer outcomes.

Dr. Berenson also acknowledged that his patients are most likely a wealthier group, although he said it’s not feasible to ask them about income. The study provides no information about socioeconomics.

Dr. Lonial said survival of 10-11 years is fairly typical in MM, with standard-risk patients reaching 14 years.

He highlighted a 2021 Canadian study that tracked 3,030 patients with newly diagnosed MM from 2007 to 2018 (average age, 64; 58.6% men). Those who received an upfront autologous stem-cell transplant had a median overall survival of 122.0 months (95% confidence interval, 115.0-135.0 months) vs. 54.3 months (95% CI, 50.8-58.8 months) for those who didn’t get the transplants. Not surprisingly, survival dipped with each subsequent treatment regimen.

Dr. Lonial is coauthor of a 2020 study that tracked 1,000 consecutive patients (mean age, 61; 35.2% Black) with newly diagnosed myeloma who were treated with RVD (lenalidomide, bortezomib, and dexamethasone) induction therapy from 2007 to 2016. The median overall survival was 126.6 months (95% CI, 113.3-139.8 months).

Dr. Fonseca noted that the news about MM survival rates is not entirely positive. Patients with high-risk disease often die early on in their disease course, he said.

Research suggests even the youngest patients with MM may die within years of diagnosis. A 2021 French study tracked 214 patients in the 18-40 age group for 15 years (2000-2015). At 5 years, “relative survival compared with same age- and sex-matched individuals was 83.5%,” and estimated overall survival was 14.5 years.

Still, a “very, very fertile environment for the development of drugs” has made a huge difference, Dr. Fonseca said. “We’ve had about 19 FDA approvals in the last 15 or 20 years.”

He urged colleagues to keep in mind that survival drops as patients decline in a line of therapy and need to switch to another one. “It might make intuitive sense to say ‘I’m gonna save something for later. I want to keep my powder dry.’ But put your best foot forward. Always go with your best treatments first.”

This approach can play out in a decision, say, to start with a four-drug initial regimen instead of a weaker two-drug regimen, he said. “Be mindful of managing toxicities, but hit harder.”

As he noted, side effects were worse with older generations of drugs. In regard to cost, multidrug treatments can cost hundreds of thousands of dollars. Dr. Fonseca said insurance tends to cover drugs that are approved by guidelines.

Dr. Fonseca discloses relationships with AbbVie, Adaptive Biotechnologies, Amgen, AstraZeneca, Bayer, Binding Site, BMS (Celgene), Millennium Takeda, Janssen, Juno, Kite, Merck, Pfizer, Pharmacyclics, Regeneron, Sanofi, Adaptive Biotechnologies, Caris Life Sciences, Oncotracker, Antegene, and AZBio, and a patent in MM. Dr. Berenson discloses ties with Janssen, Amgen, Sanofi, BMS, Karyopharm, and Incyte. Dr. Lonial reports ties with TG Therapeutics, Celgene, BMS, Janssen, Novartis, GlaxoSmithKline, AbbVie, Takeda, Merck, Sanofi, Pfizer, Regeneron, and Novartis.
 

When hematologist James R. Berenson, MD, began practicing medicine in the 1980s, his 45-year-old cousin Stanley broke his ribs while hugging his son in a swimming pool. The cousin was a well-respected orthopedic surgeon in Los Angeles, but his specialty could do nothing for him. Stanley had the bone-ravaging disease known as multiple myeloma (MM).

Back then, the treatments for MM were chemotherapy and steroids. Stem-cell transplants were on the horizon, as was a most unexpected therapy: the infamous drug thalidomide.

But in the wake of the rib facture, the health of Stanley Katz, MD, worsened and he died after 25 weeks, Dr. Berenson recalled in an interview. At that time, Dr. Katz’s horrifically shortened lifespan following diagnosis was not unusual.

About 4 decades later, hematologists like Dr. Berenson are heralding a new era in MM, a sharp reversal of the previous eras of grim prognoses.

In a new study, Dr. Berenson tracked 161 patients with MM treated at his West Hollywood, Calif., private clinic from 2006 to 2023 and found that their median survival was 136.2 months – more than 11 years. “The OS reported in this study ... is the longest reported to date in an unselected, newly diagnosed MM population,” the study authors write.

Dr. Berenson’s patients are unique: They’re largely White, and they didn’t undergo stem-cell transplants. But other recent studies also suggest that lifespans of more than 10 years are increasingly possible after MM diagnosis. Former TV news anchor Tom Brokaw, for one, has reached that point.

In fact, a pair of other hematologists say the overall survival in Dr. Berenson’s report is hardly out of the question. And, they say, patients diagnosed today could potentially live even longer, because treatments continue to improve.

“With data that’s 10 years old, we expect the median overall survival to be 10 years,” hematologist Sagar Lonial, MD, who’s been tracking survival data in MM, said in an interview. “When patients ask about my outlook, I say it’s a constantly evolving field. Things are changing fast enough that I use 10 years as a floor.”

Dr. Lonial is chair of the department of hematology and medical oncology and chief medical officer at Emory University, Atlanta, Winship Cancer Institute.

Hematologist Rafael Fonseca, MD, chief innovation officer at Mayo Clinic–Arizona, put it this way in an interview: Dr. Berenson’s results “are probably in sync with what we would anticipate with similar cohorts of patients. The reality is that we’ve seen a huge improvement in the life expectancy of patients who were diagnosed with multiple myeloma. It’s not unusual to see patients in the clinic now that are 15 or 20 years out from their diagnosis.”

According to Yale Medicine, MM accounts for 10% of blood cancers and 1%-2% of all cancers and is more common in men vs. women and Blacks vs. Whites. It’s most frequently diagnosed between the ages of 65 and 74, according to the National Cancer Institute, and the median age at diagnosis is 69.

Among the most famous American people currently battling MM are newsman Mr. Brokaw, the former NBC News anchor, and Republican Congressman Steve Scalise, majority leader of the U.S. House of Representatives and a candidate for House speaker.

Mr. Brokaw was diagnosed in 2013 while in his early 70s and has talked about his intense struggle with the disease: the infections, operations, infusions, and daily regimens of 24 pills.

“I didn’t want to be Tom Brokaw, cancer victim,” he said in 2018 at the annual meeting of the American Society of Hematology. But he opened up about his illness, and became “the multiple myeloma poster boy.”

Rep. Scalise, who’s in his late 50s, is undergoing chemotherapy. He survived being gravely wounded in an assassination attempt in 2017.

Dr. Berenson’s new study, published in Targeted Oncology, tracked 161 patients (89 women, 72 men; median age, 65.4; 125 White, 3 Black, 10 Hispanic, 15 Asian, and 8 multi-ethnic).

All started frontline treatment at Dr. Berenson’s clinic and were included if they could read consent forms and gave permission for blood draws. None underwent stem-cell transplants as part of initial therapy. Another 1,036 patients had been treated elsewhere and were not included in the study.

Over a median of 42.7 months (range, 1.9-195.1), the 1-, 3-, and 5-year survival rates were 97.5%, 85.3%, and 76.2%, respectively.

The study claims “these results are considerably better than those reported from patients enrolled in clinical trials and those from countries with national registries.”

In the interview, Dr. Berenson said the study is unique because it’s not limited like many studies to younger, healthier patients. Nor does it include those treated at other facilities, he said.

The study is unusual in other ways. Dr. Berenson said his drug regimens aren’t necessarily standard, and he doesn’t treat patients with stem-cell transplants. “I stopped transplanting in about 2000 because clearly it was not improving the length of life,” he said.

Dr. Berenson said colleagues can learn from his insistence on sensitively treating the quality of life of patients, his embrace of clinical trials with novel combinations, and his close monitoring of myeloma proteins to gauge whether patients need to rapidly switch therapies.

He noted that his drug regimens are typically off-label and vary by patient. “We’re not using as high doses of drugs like Velcade [bortezomib] or Revlimid [lenalidomide] as my colleagues. We’re not necessarily giving as many doses. Also, we’re not adding as many drugs in many cases as they are. We’re taking it slower.”

The National Comprehensive Cancer Network recommends bortezomib and lenalidomide as standard induction treatments in patients with MM who are candidates for stem-cell transplantation, a procedure it considers the “preferred approach in transplant-eligible patients.”

There are limitations to Dr. Berenson’s new study. The patients aren’t representative of people with MM as a whole: His cohort is overwhelmingly White (78%) and just 2% Black, while an estimated one-fifth of patients with MM in the United States are Black and have poorer outcomes.

Dr. Berenson also acknowledged that his patients are most likely a wealthier group, although he said it’s not feasible to ask them about income. The study provides no information about socioeconomics.

Dr. Lonial said survival of 10-11 years is fairly typical in MM, with standard-risk patients reaching 14 years.

He highlighted a 2021 Canadian study that tracked 3,030 patients with newly diagnosed MM from 2007 to 2018 (average age, 64; 58.6% men). Those who received an upfront autologous stem-cell transplant had a median overall survival of 122.0 months (95% confidence interval, 115.0-135.0 months) vs. 54.3 months (95% CI, 50.8-58.8 months) for those who didn’t get the transplants. Not surprisingly, survival dipped with each subsequent treatment regimen.

Dr. Lonial is coauthor of a 2020 study that tracked 1,000 consecutive patients (mean age, 61; 35.2% Black) with newly diagnosed myeloma who were treated with RVD (lenalidomide, bortezomib, and dexamethasone) induction therapy from 2007 to 2016. The median overall survival was 126.6 months (95% CI, 113.3-139.8 months).

Dr. Fonseca noted that the news about MM survival rates is not entirely positive. Patients with high-risk disease often die early on in their disease course, he said.

Research suggests even the youngest patients with MM may die within years of diagnosis. A 2021 French study tracked 214 patients in the 18-40 age group for 15 years (2000-2015). At 5 years, “relative survival compared with same age- and sex-matched individuals was 83.5%,” and estimated overall survival was 14.5 years.

Still, a “very, very fertile environment for the development of drugs” has made a huge difference, Dr. Fonseca said. “We’ve had about 19 FDA approvals in the last 15 or 20 years.”

He urged colleagues to keep in mind that survival drops as patients decline in a line of therapy and need to switch to another one. “It might make intuitive sense to say ‘I’m gonna save something for later. I want to keep my powder dry.’ But put your best foot forward. Always go with your best treatments first.”

This approach can play out in a decision, say, to start with a four-drug initial regimen instead of a weaker two-drug regimen, he said. “Be mindful of managing toxicities, but hit harder.”

As he noted, side effects were worse with older generations of drugs. In regard to cost, multidrug treatments can cost hundreds of thousands of dollars. Dr. Fonseca said insurance tends to cover drugs that are approved by guidelines.

Dr. Fonseca discloses relationships with AbbVie, Adaptive Biotechnologies, Amgen, AstraZeneca, Bayer, Binding Site, BMS (Celgene), Millennium Takeda, Janssen, Juno, Kite, Merck, Pfizer, Pharmacyclics, Regeneron, Sanofi, Adaptive Biotechnologies, Caris Life Sciences, Oncotracker, Antegene, and AZBio, and a patent in MM. Dr. Berenson discloses ties with Janssen, Amgen, Sanofi, BMS, Karyopharm, and Incyte. Dr. Lonial reports ties with TG Therapeutics, Celgene, BMS, Janssen, Novartis, GlaxoSmithKline, AbbVie, Takeda, Merck, Sanofi, Pfizer, Regeneron, and Novartis.
 

A debate in Houston at the annual meeting of the Society of Hematologic Oncology tackled a vexing issue in hematology: Should smoldering myeloma be treated?

Hematologist Sagar Lonial, MD, a multiple myeloma specialist and researcher at Emory University, Atlanta, argued for treatment. Hematologist Angela Dispenzieri, MD, also a myeloma researcher and specialist at the Mayo Clinic in Rochester, Minn., took the opposing side, arguing for watchful waiting.

The two experts based their arguments largely on the same two studies, the only randomized trials to tackle the issue to date. While Dr. Dispenzieri focused on their shortcomings, Dr. Lonial focused on their strengths.

In a poll after the debate, about a third of audience members agreed that watchful waiting is the way to go, but about two-thirds favored a personalized approach to smoldering myeloma treatment based on patient risk.

“I’m taking this as a win,” Dr. Lonial said.

Different interpretations of two trials

The first of the two trials recruited from 2007 to 2010 and was conducted in Spain and Portugal. Fifty-seven high-risk patients were randomized to lenalidomide plus dexamethasone (Len-Dex) for up to 2 years; 62 others were randomized to observation.

At 3 years, 70% of observed patients had progressed to multiple myeloma versus only 20% in the Len-Dex group; 82% of Len-Dex patients were alive at data cut-off in 2015 versus 64% of observation patients.

The second, more recent trial, which was led by Dr. Lonial, randomized 92 intermediate or high-risk smoldering myeloma patients to lenalidomide alone for a median of 2 years and 90 others to observation. Three-year progression-free survival (PFS) was 91% in the treatment arm versus 66% with observation. Overall survival data have not yet been reported.

Dr. Dispenzieri acknowledged that the results from Spain and Portugal are impressive. “Treating with Len-Dex gives you a far superior freedom from progression. ... Overall survival was better too.” Results for Len-Dex were “fantastic,” she said.

However, the trial was done before myeloma-defining event criteria existed, so it’s very likely that the treatment arm in the Spanish study included actual myeloma cases, she said.

About 46% of treated patients in Dr. Lonial’s study met the current definition for high risk for progression based on the 2-20-20 rule, which Dr. Dispenzieri helped develop. Although there was an improvement in PFS in the high-risk group, there was no significant improvement for intermediate- and low-risk subjects. Also, more than 80% of observed patients hadn’t progressed by 2 years, and overall survival data are missing.

Meanwhile, treated patients in both trials had more adverse events, including secondary malignancies, and there’s the possibility that early treatment may make patients resistant to treatment later on when they progress to multiple myeloma, although that didn’t seem to happen in the Spanish trial.

“Of course, we want to prevent morbidity, of course we would love to cure the disease,” but “should we treat high-risk smoldering myeloma patients based on overall survival data from a trial of” just 119 “patients that may have been contaminated with actual myeloma” cases? Is it ethical to treat low- and intermediate-risk patients who have only a 50% chance of developing myeloma after 10 years?”

Her answer to both questions was “no and no. ... There’s just a lot of work to be done” to better understand the condition and when and how to intervene. In the meantime, “don’t treat smoldering melanoma patients” outside of a trial, she said.

“First, do no harm,” Dr. Dispenzieri cautioned in her final slide.

Dr. Lonial said he agreed with many of Dr. Dispenzieri’s points, but disagreed with her conclusion not to treat.

“Everybody can always be critical of randomized trials, but at the end of the day, we now have two randomized phase 3 trials comparing early intervention with no intervention demonstrating a significant delay in developing myeloma. I think it’s time to end the ‘we need more data; we need more trials.’ It’s time for us to take a stand.”

He argued for 2 years of lenalidomide for patients who meet the 2-20-20 high-risk definition, based on the median time people were treated in his trial.

He said he discusses the option “with every smoldering patient [who] walks in to see me” if they aren’t eligible for a trial.

Dr. Lonial mentioned his team is currently pulling together longer-term survival data for their trial.

A debate in Houston at the annual meeting of the Society of Hematologic Oncology tackled a vexing issue in hematology: Should smoldering myeloma be treated?

Hematologist Sagar Lonial, MD, a multiple myeloma specialist and researcher at Emory University, Atlanta, argued for treatment. Hematologist Angela Dispenzieri, MD, also a myeloma researcher and specialist at the Mayo Clinic in Rochester, Minn., took the opposing side, arguing for watchful waiting.

The two experts based their arguments largely on the same two studies, the only randomized trials to tackle the issue to date. While Dr. Dispenzieri focused on their shortcomings, Dr. Lonial focused on their strengths.

In a poll after the debate, about a third of audience members agreed that watchful waiting is the way to go, but about two-thirds favored a personalized approach to smoldering myeloma treatment based on patient risk.

“I’m taking this as a win,” Dr. Lonial said.

Different interpretations of two trials

The first of the two trials recruited from 2007 to 2010 and was conducted in Spain and Portugal. Fifty-seven high-risk patients were randomized to lenalidomide plus dexamethasone (Len-Dex) for up to 2 years; 62 others were randomized to observation.

At 3 years, 70% of observed patients had progressed to multiple myeloma versus only 20% in the Len-Dex group; 82% of Len-Dex patients were alive at data cut-off in 2015 versus 64% of observation patients.

The second, more recent trial, which was led by Dr. Lonial, randomized 92 intermediate or high-risk smoldering myeloma patients to lenalidomide alone for a median of 2 years and 90 others to observation. Three-year progression-free survival (PFS) was 91% in the treatment arm versus 66% with observation. Overall survival data have not yet been reported.

Dr. Dispenzieri acknowledged that the results from Spain and Portugal are impressive. “Treating with Len-Dex gives you a far superior freedom from progression. ... Overall survival was better too.” Results for Len-Dex were “fantastic,” she said.

However, the trial was done before myeloma-defining event criteria existed, so it’s very likely that the treatment arm in the Spanish study included actual myeloma cases, she said.

About 46% of treated patients in Dr. Lonial’s study met the current definition for high risk for progression based on the 2-20-20 rule, which Dr. Dispenzieri helped develop. Although there was an improvement in PFS in the high-risk group, there was no significant improvement for intermediate- and low-risk subjects. Also, more than 80% of observed patients hadn’t progressed by 2 years, and overall survival data are missing.

Meanwhile, treated patients in both trials had more adverse events, including secondary malignancies, and there’s the possibility that early treatment may make patients resistant to treatment later on when they progress to multiple myeloma, although that didn’t seem to happen in the Spanish trial.

“Of course, we want to prevent morbidity, of course we would love to cure the disease,” but “should we treat high-risk smoldering myeloma patients based on overall survival data from a trial of” just 119 “patients that may have been contaminated with actual myeloma” cases? Is it ethical to treat low- and intermediate-risk patients who have only a 50% chance of developing myeloma after 10 years?”

Her answer to both questions was “no and no. ... There’s just a lot of work to be done” to better understand the condition and when and how to intervene. In the meantime, “don’t treat smoldering melanoma patients” outside of a trial, she said.

“First, do no harm,” Dr. Dispenzieri cautioned in her final slide.

Dr. Lonial said he agreed with many of Dr. Dispenzieri’s points, but disagreed with her conclusion not to treat.

“Everybody can always be critical of randomized trials, but at the end of the day, we now have two randomized phase 3 trials comparing early intervention with no intervention demonstrating a significant delay in developing myeloma. I think it’s time to end the ‘we need more data; we need more trials.’ It’s time for us to take a stand.”

He argued for 2 years of lenalidomide for patients who meet the 2-20-20 high-risk definition, based on the median time people were treated in his trial.

He said he discusses the option “with every smoldering patient [who] walks in to see me” if they aren’t eligible for a trial.

Dr. Lonial mentioned his team is currently pulling together longer-term survival data for their trial.

A debate in Houston at the annual meeting of the Society of Hematologic Oncology tackled a vexing issue in hematology: Should smoldering myeloma be treated?

Hematologist Sagar Lonial, MD, a multiple myeloma specialist and researcher at Emory University, Atlanta, argued for treatment. Hematologist Angela Dispenzieri, MD, also a myeloma researcher and specialist at the Mayo Clinic in Rochester, Minn., took the opposing side, arguing for watchful waiting.

The two experts based their arguments largely on the same two studies, the only randomized trials to tackle the issue to date. While Dr. Dispenzieri focused on their shortcomings, Dr. Lonial focused on their strengths.

In a poll after the debate, about a third of audience members agreed that watchful waiting is the way to go, but about two-thirds favored a personalized approach to smoldering myeloma treatment based on patient risk.

“I’m taking this as a win,” Dr. Lonial said.

Different interpretations of two trials

The first of the two trials recruited from 2007 to 2010 and was conducted in Spain and Portugal. Fifty-seven high-risk patients were randomized to lenalidomide plus dexamethasone (Len-Dex) for up to 2 years; 62 others were randomized to observation.

At 3 years, 70% of observed patients had progressed to multiple myeloma versus only 20% in the Len-Dex group; 82% of Len-Dex patients were alive at data cut-off in 2015 versus 64% of observation patients.

The second, more recent trial, which was led by Dr. Lonial, randomized 92 intermediate or high-risk smoldering myeloma patients to lenalidomide alone for a median of 2 years and 90 others to observation. Three-year progression-free survival (PFS) was 91% in the treatment arm versus 66% with observation. Overall survival data have not yet been reported.

Dr. Dispenzieri acknowledged that the results from Spain and Portugal are impressive. “Treating with Len-Dex gives you a far superior freedom from progression. ... Overall survival was better too.” Results for Len-Dex were “fantastic,” she said.

However, the trial was done before myeloma-defining event criteria existed, so it’s very likely that the treatment arm in the Spanish study included actual myeloma cases, she said.

About 46% of treated patients in Dr. Lonial’s study met the current definition for high risk for progression based on the 2-20-20 rule, which Dr. Dispenzieri helped develop. Although there was an improvement in PFS in the high-risk group, there was no significant improvement for intermediate- and low-risk subjects. Also, more than 80% of observed patients hadn’t progressed by 2 years, and overall survival data are missing.

Meanwhile, treated patients in both trials had more adverse events, including secondary malignancies, and there’s the possibility that early treatment may make patients resistant to treatment later on when they progress to multiple myeloma, although that didn’t seem to happen in the Spanish trial.

“Of course, we want to prevent morbidity, of course we would love to cure the disease,” but “should we treat high-risk smoldering myeloma patients based on overall survival data from a trial of” just 119 “patients that may have been contaminated with actual myeloma” cases? Is it ethical to treat low- and intermediate-risk patients who have only a 50% chance of developing myeloma after 10 years?”

Her answer to both questions was “no and no. ... There’s just a lot of work to be done” to better understand the condition and when and how to intervene. In the meantime, “don’t treat smoldering melanoma patients” outside of a trial, she said.

“First, do no harm,” Dr. Dispenzieri cautioned in her final slide.

Dr. Lonial said he agreed with many of Dr. Dispenzieri’s points, but disagreed with her conclusion not to treat.

“Everybody can always be critical of randomized trials, but at the end of the day, we now have two randomized phase 3 trials comparing early intervention with no intervention demonstrating a significant delay in developing myeloma. I think it’s time to end the ‘we need more data; we need more trials.’ It’s time for us to take a stand.”

He argued for 2 years of lenalidomide for patients who meet the 2-20-20 high-risk definition, based on the median time people were treated in his trial.

He said he discusses the option “with every smoldering patient [who] walks in to see me” if they aren’t eligible for a trial.

Dr. Lonial mentioned his team is currently pulling together longer-term survival data for their trial.