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Frontline myeloma treatments: ASCT vs. CAR T
“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.
“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.
“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.
AT LLM CONGRESS 2023
Survival on the upswing in myeloma
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.
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.
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.
Debate: 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.
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.
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.
FROM SOHO 2023
FDA approves motixafortide for stem cell mobilization in myeloma
The success of autologous stem cell transplantation (ASCT) depends on adequate mobilization of stem cells during the treatment process. Collection of a sufficient number of stem cells to perform two transplantations is recommended. However, in up to 47% of patients, collecting target numbers of hematopoietic stem cells for ASCT after one apheresis session remains a challenge, BioLineRx explained in a press release today, announcing the approval.
The goal of combining motixafortide with filgrastim is to mobilize stem cells more reliably than filgrastim can alone, with fewer days of apheresis sessions and fewer doses of filgrastim.
“We believe [motixafortide] will play a critical role in addressing unmet needs and introduce a new treatment paradigm for” patients with multiple myeloma, CEO Philip Serlin said in the release.
The drug approval was based on the GENESIS trial, which randomized 122 patients to either motixafortide plus filgrastim or placebo plus filgrastim.
BioLineRx said the trial included patients considered representative of the typical multiple myeloma population undergoing ASCT, with a median age of 63 years and with about 70% of patients in both arms of the trial receiving lenalidomide-containing induction therapy.
Motixafortide plus filgrastim enabled 67.5% of patients to achieve the stem cell collection goal of 6 million or more CD34+ cells/kg within two apheresis sessions, versus 9.5% of patients receiving the placebo plus filgrastim regimen. Additionally, 92.5% of patients reached the stem cell collection goal in up to two apheresis sessions in the motixafortide arm and 21.4% in the placebo arm.
However, “the data are descriptive and were not statistically powered nor prespecified. The information should be cautiously interpreted,” the company said.
Serious adverse reactions occurred in 5.4% of patients in the motixafortide arm, including vomiting, injection-site reaction, hypersensitivity reaction, injection-site cellulitis, hypokalemia, and hypoxia. The most common adverse reactions, occurring in more than 20% of patients, were injection site reactions (pain, erythema, and pruritus), pruritus, flushing, and back pain.
Labeling for the subcutaneous injection is available online.
A version of this article first appeared on Medscape.com.
The success of autologous stem cell transplantation (ASCT) depends on adequate mobilization of stem cells during the treatment process. Collection of a sufficient number of stem cells to perform two transplantations is recommended. However, in up to 47% of patients, collecting target numbers of hematopoietic stem cells for ASCT after one apheresis session remains a challenge, BioLineRx explained in a press release today, announcing the approval.
The goal of combining motixafortide with filgrastim is to mobilize stem cells more reliably than filgrastim can alone, with fewer days of apheresis sessions and fewer doses of filgrastim.
“We believe [motixafortide] will play a critical role in addressing unmet needs and introduce a new treatment paradigm for” patients with multiple myeloma, CEO Philip Serlin said in the release.
The drug approval was based on the GENESIS trial, which randomized 122 patients to either motixafortide plus filgrastim or placebo plus filgrastim.
BioLineRx said the trial included patients considered representative of the typical multiple myeloma population undergoing ASCT, with a median age of 63 years and with about 70% of patients in both arms of the trial receiving lenalidomide-containing induction therapy.
Motixafortide plus filgrastim enabled 67.5% of patients to achieve the stem cell collection goal of 6 million or more CD34+ cells/kg within two apheresis sessions, versus 9.5% of patients receiving the placebo plus filgrastim regimen. Additionally, 92.5% of patients reached the stem cell collection goal in up to two apheresis sessions in the motixafortide arm and 21.4% in the placebo arm.
However, “the data are descriptive and were not statistically powered nor prespecified. The information should be cautiously interpreted,” the company said.
Serious adverse reactions occurred in 5.4% of patients in the motixafortide arm, including vomiting, injection-site reaction, hypersensitivity reaction, injection-site cellulitis, hypokalemia, and hypoxia. The most common adverse reactions, occurring in more than 20% of patients, were injection site reactions (pain, erythema, and pruritus), pruritus, flushing, and back pain.
Labeling for the subcutaneous injection is available online.
A version of this article first appeared on Medscape.com.
The success of autologous stem cell transplantation (ASCT) depends on adequate mobilization of stem cells during the treatment process. Collection of a sufficient number of stem cells to perform two transplantations is recommended. However, in up to 47% of patients, collecting target numbers of hematopoietic stem cells for ASCT after one apheresis session remains a challenge, BioLineRx explained in a press release today, announcing the approval.
The goal of combining motixafortide with filgrastim is to mobilize stem cells more reliably than filgrastim can alone, with fewer days of apheresis sessions and fewer doses of filgrastim.
“We believe [motixafortide] will play a critical role in addressing unmet needs and introduce a new treatment paradigm for” patients with multiple myeloma, CEO Philip Serlin said in the release.
The drug approval was based on the GENESIS trial, which randomized 122 patients to either motixafortide plus filgrastim or placebo plus filgrastim.
BioLineRx said the trial included patients considered representative of the typical multiple myeloma population undergoing ASCT, with a median age of 63 years and with about 70% of patients in both arms of the trial receiving lenalidomide-containing induction therapy.
Motixafortide plus filgrastim enabled 67.5% of patients to achieve the stem cell collection goal of 6 million or more CD34+ cells/kg within two apheresis sessions, versus 9.5% of patients receiving the placebo plus filgrastim regimen. Additionally, 92.5% of patients reached the stem cell collection goal in up to two apheresis sessions in the motixafortide arm and 21.4% in the placebo arm.
However, “the data are descriptive and were not statistically powered nor prespecified. The information should be cautiously interpreted,” the company said.
Serious adverse reactions occurred in 5.4% of patients in the motixafortide arm, including vomiting, injection-site reaction, hypersensitivity reaction, injection-site cellulitis, hypokalemia, and hypoxia. The most common adverse reactions, occurring in more than 20% of patients, were injection site reactions (pain, erythema, and pruritus), pruritus, flushing, and back pain.
Labeling for the subcutaneous injection is available online.
A version of this article first appeared on Medscape.com.
ClonoSEQ Testing for Minimal Residual Disease in Multiple Myeloma: Cleveland VA Experience And Cost Analysis
BACKGROUND
Minimal residual disease (MRD) testing in myeloma has been shown to be a strong prognostic marker for progression-free and overall survival. Limited data suggest MRD results may also be useful for therapy discontinuation decisions. The clonoSEQ Assay utilizes next generation sequencing involving a bone marrow sample, obtained at the time of diagnosis, to identify patient-specific sequence(s).
DISCUSSION
The same methodology is then applied later to assess for MRD. Although widely adopted at most US academic centers, there has been limited use of MRD across VA centers. In 2022 the Cleveland Louis Stokes VAMC partnered with Adaptive Biotechnologies to develop a process for MRD/clonoSEQ testing in myeloma pts. Hematology, Pathology, Medicine, Administration and Adaptive Biotechnologies representatives met to develop a streamlined process for ordering, sample procurement, billing and result documentation. In 5/2022 the 1st specimen was sent. EQUATE is a national cooperative group trial requiring baseline clono- SEQ testing with a positive sequence ID. Daratumumab hyaluronidase (part of standard treatment) is provided to the institution at no cost on the trial but otherwise would cost the VA $5,797.38/dose. clonoSEQ costs VA $1950/test. There have been 14 specimens sent involving 12 pts: 12 baseline marrow and 2 for MRD (posttransplant). All of the baseline specimens were found to have an identifiable sequence. Both of the MRD tracking specimens were positive. The average turnaround time for clonoSEQ results was 13.2 days (range 7 to 18 days). 4 of the 12 pts with a positive initial clonoSEQ ID qualified for the EQUATE trial but would not have been deemed eligible without the baseline clonoSEQ results. 2 of these pts have enrolled on the trial and started treatment. Costs for 14 clonoSEQ tests: $27,300. Estimated cost savings for the 2 pts enrolled onto EQUATE: $127, 542.36/pt/year= $255,084.72/year. Overall cost savings: $227,784.72.
CONCLUSIONS
An efficient process for baseline and post-treatment (MRD) clonoSEQ testing in myeloma pts was developed. Although expensive, use of this test resulted in significant overall cost savings by allowing enrollment onto a clinical trial. In addition, if studies determine that negative MRD results can guide therapeutic decisions, use of clonoSEQ testing may result in further benefits.
BACKGROUND
Minimal residual disease (MRD) testing in myeloma has been shown to be a strong prognostic marker for progression-free and overall survival. Limited data suggest MRD results may also be useful for therapy discontinuation decisions. The clonoSEQ Assay utilizes next generation sequencing involving a bone marrow sample, obtained at the time of diagnosis, to identify patient-specific sequence(s).
DISCUSSION
The same methodology is then applied later to assess for MRD. Although widely adopted at most US academic centers, there has been limited use of MRD across VA centers. In 2022 the Cleveland Louis Stokes VAMC partnered with Adaptive Biotechnologies to develop a process for MRD/clonoSEQ testing in myeloma pts. Hematology, Pathology, Medicine, Administration and Adaptive Biotechnologies representatives met to develop a streamlined process for ordering, sample procurement, billing and result documentation. In 5/2022 the 1st specimen was sent. EQUATE is a national cooperative group trial requiring baseline clono- SEQ testing with a positive sequence ID. Daratumumab hyaluronidase (part of standard treatment) is provided to the institution at no cost on the trial but otherwise would cost the VA $5,797.38/dose. clonoSEQ costs VA $1950/test. There have been 14 specimens sent involving 12 pts: 12 baseline marrow and 2 for MRD (posttransplant). All of the baseline specimens were found to have an identifiable sequence. Both of the MRD tracking specimens were positive. The average turnaround time for clonoSEQ results was 13.2 days (range 7 to 18 days). 4 of the 12 pts with a positive initial clonoSEQ ID qualified for the EQUATE trial but would not have been deemed eligible without the baseline clonoSEQ results. 2 of these pts have enrolled on the trial and started treatment. Costs for 14 clonoSEQ tests: $27,300. Estimated cost savings for the 2 pts enrolled onto EQUATE: $127, 542.36/pt/year= $255,084.72/year. Overall cost savings: $227,784.72.
CONCLUSIONS
An efficient process for baseline and post-treatment (MRD) clonoSEQ testing in myeloma pts was developed. Although expensive, use of this test resulted in significant overall cost savings by allowing enrollment onto a clinical trial. In addition, if studies determine that negative MRD results can guide therapeutic decisions, use of clonoSEQ testing may result in further benefits.
BACKGROUND
Minimal residual disease (MRD) testing in myeloma has been shown to be a strong prognostic marker for progression-free and overall survival. Limited data suggest MRD results may also be useful for therapy discontinuation decisions. The clonoSEQ Assay utilizes next generation sequencing involving a bone marrow sample, obtained at the time of diagnosis, to identify patient-specific sequence(s).
DISCUSSION
The same methodology is then applied later to assess for MRD. Although widely adopted at most US academic centers, there has been limited use of MRD across VA centers. In 2022 the Cleveland Louis Stokes VAMC partnered with Adaptive Biotechnologies to develop a process for MRD/clonoSEQ testing in myeloma pts. Hematology, Pathology, Medicine, Administration and Adaptive Biotechnologies representatives met to develop a streamlined process for ordering, sample procurement, billing and result documentation. In 5/2022 the 1st specimen was sent. EQUATE is a national cooperative group trial requiring baseline clono- SEQ testing with a positive sequence ID. Daratumumab hyaluronidase (part of standard treatment) is provided to the institution at no cost on the trial but otherwise would cost the VA $5,797.38/dose. clonoSEQ costs VA $1950/test. There have been 14 specimens sent involving 12 pts: 12 baseline marrow and 2 for MRD (posttransplant). All of the baseline specimens were found to have an identifiable sequence. Both of the MRD tracking specimens were positive. The average turnaround time for clonoSEQ results was 13.2 days (range 7 to 18 days). 4 of the 12 pts with a positive initial clonoSEQ ID qualified for the EQUATE trial but would not have been deemed eligible without the baseline clonoSEQ results. 2 of these pts have enrolled on the trial and started treatment. Costs for 14 clonoSEQ tests: $27,300. Estimated cost savings for the 2 pts enrolled onto EQUATE: $127, 542.36/pt/year= $255,084.72/year. Overall cost savings: $227,784.72.
CONCLUSIONS
An efficient process for baseline and post-treatment (MRD) clonoSEQ testing in myeloma pts was developed. Although expensive, use of this test resulted in significant overall cost savings by allowing enrollment onto a clinical trial. In addition, if studies determine that negative MRD results can guide therapeutic decisions, use of clonoSEQ testing may result in further benefits.
Comparing Outcomes and Toxicities With Standard and Reduced Dose Melphalan in Autologous Stem Cell Transplant Patients With Multiple Myeloma
BACKGROUND
Multiple myeloma, an incurable plasma cell malignancy, has an average age of diagnosis over 65 years. For transplant-eligible patients, high-dose melphalan 200 mg/m2 (MEL200), followed by autologous stem cell rescue (ASCR) is the standard in consolidation therapy. Most clinical trials evaluating MEL200 with ASCR excluded patients over 65 due to concerns for toxicity and treatment-related mortality, leading to use of reduced dose melphalan 140 mg/m2 (MEL140) in clinical practice for older patients. As this dose has limited studies surrounding its reduction, the purpose of this study was to compare outcomes and toxicities of MEL140 in patients over the age of 65 to MEL200 in patients 65 and under.
METHODS
This single-center institutional review board approved retrospective study was conducted at VA Tennessee Valley Healthcare System. All multiple myeloma patients greater than 18 years of age who received melphalan with ASCR from January 1, 2018, to December 31, 2021, were included. Patients were divided into two arms: age < 65 treated with MEL200 and age >65 treated with MEL140. The primary endpoint was oneyear progression-free survival (PFS). The secondary endpoints were one-year overall survival (OS), treatment related mortality, time to neutrophil engraftment, and toxicities including febrile neutropenia, diarrhea, mucositis, infection, and intensive care unit transfers.
RESULTS
A total of 222 patients were included, 114 patients in the MEL200 arm and 108 patients in the MEL140 arm. The primary endpoint of one-year PFS had no significant difference, with 103 (90.4%) patients in the MEL200 group compared to 99 (91.7%) patients in the MEL140 group (p=0.732). Similarly, there was no statistically significant difference in the secondary endpoint of one-year OS with 112 (98.3%) patients in the MEL200 group compared to 106 (98.2%) in the MEL140 group (p=0.956). Toxicities were similar; however, grade 3 mucositis was higher in the MEL200 arm.
CONCLUSIONS
Our study found no difference in oneyear PFS or one-year OS when comparing MEL140 to MEL200 with minimal differences in regimen-related toxicities. Although not powered to detect statistical difference, results suggests that dose reduction with MEL140 in patients >65 years does not impact one-year PFS when compared to patients <65 receiving standard MEL200.
BACKGROUND
Multiple myeloma, an incurable plasma cell malignancy, has an average age of diagnosis over 65 years. For transplant-eligible patients, high-dose melphalan 200 mg/m2 (MEL200), followed by autologous stem cell rescue (ASCR) is the standard in consolidation therapy. Most clinical trials evaluating MEL200 with ASCR excluded patients over 65 due to concerns for toxicity and treatment-related mortality, leading to use of reduced dose melphalan 140 mg/m2 (MEL140) in clinical practice for older patients. As this dose has limited studies surrounding its reduction, the purpose of this study was to compare outcomes and toxicities of MEL140 in patients over the age of 65 to MEL200 in patients 65 and under.
METHODS
This single-center institutional review board approved retrospective study was conducted at VA Tennessee Valley Healthcare System. All multiple myeloma patients greater than 18 years of age who received melphalan with ASCR from January 1, 2018, to December 31, 2021, were included. Patients were divided into two arms: age < 65 treated with MEL200 and age >65 treated with MEL140. The primary endpoint was oneyear progression-free survival (PFS). The secondary endpoints were one-year overall survival (OS), treatment related mortality, time to neutrophil engraftment, and toxicities including febrile neutropenia, diarrhea, mucositis, infection, and intensive care unit transfers.
RESULTS
A total of 222 patients were included, 114 patients in the MEL200 arm and 108 patients in the MEL140 arm. The primary endpoint of one-year PFS had no significant difference, with 103 (90.4%) patients in the MEL200 group compared to 99 (91.7%) patients in the MEL140 group (p=0.732). Similarly, there was no statistically significant difference in the secondary endpoint of one-year OS with 112 (98.3%) patients in the MEL200 group compared to 106 (98.2%) in the MEL140 group (p=0.956). Toxicities were similar; however, grade 3 mucositis was higher in the MEL200 arm.
CONCLUSIONS
Our study found no difference in oneyear PFS or one-year OS when comparing MEL140 to MEL200 with minimal differences in regimen-related toxicities. Although not powered to detect statistical difference, results suggests that dose reduction with MEL140 in patients >65 years does not impact one-year PFS when compared to patients <65 receiving standard MEL200.
BACKGROUND
Multiple myeloma, an incurable plasma cell malignancy, has an average age of diagnosis over 65 years. For transplant-eligible patients, high-dose melphalan 200 mg/m2 (MEL200), followed by autologous stem cell rescue (ASCR) is the standard in consolidation therapy. Most clinical trials evaluating MEL200 with ASCR excluded patients over 65 due to concerns for toxicity and treatment-related mortality, leading to use of reduced dose melphalan 140 mg/m2 (MEL140) in clinical practice for older patients. As this dose has limited studies surrounding its reduction, the purpose of this study was to compare outcomes and toxicities of MEL140 in patients over the age of 65 to MEL200 in patients 65 and under.
METHODS
This single-center institutional review board approved retrospective study was conducted at VA Tennessee Valley Healthcare System. All multiple myeloma patients greater than 18 years of age who received melphalan with ASCR from January 1, 2018, to December 31, 2021, were included. Patients were divided into two arms: age < 65 treated with MEL200 and age >65 treated with MEL140. The primary endpoint was oneyear progression-free survival (PFS). The secondary endpoints were one-year overall survival (OS), treatment related mortality, time to neutrophil engraftment, and toxicities including febrile neutropenia, diarrhea, mucositis, infection, and intensive care unit transfers.
RESULTS
A total of 222 patients were included, 114 patients in the MEL200 arm and 108 patients in the MEL140 arm. The primary endpoint of one-year PFS had no significant difference, with 103 (90.4%) patients in the MEL200 group compared to 99 (91.7%) patients in the MEL140 group (p=0.732). Similarly, there was no statistically significant difference in the secondary endpoint of one-year OS with 112 (98.3%) patients in the MEL200 group compared to 106 (98.2%) in the MEL140 group (p=0.956). Toxicities were similar; however, grade 3 mucositis was higher in the MEL200 arm.
CONCLUSIONS
Our study found no difference in oneyear PFS or one-year OS when comparing MEL140 to MEL200 with minimal differences in regimen-related toxicities. Although not powered to detect statistical difference, results suggests that dose reduction with MEL140 in patients >65 years does not impact one-year PFS when compared to patients <65 receiving standard MEL200.
FDA approves elranatamab for multiple myeloma
The B-cell maturation antigen (BCMA) CD3-targeted bispecific antibody (BsAb) was given Priority Review in February and had previously received Breakthrough Therapy Designation for relapsed or refractory multiple myeloma (RRMM), according to Pfizer.
FDA approval was based on favorable response and duration of response rates in the single-arm, phase 2 MagnetisMM-3 trial. The trial showed meaningful responses in heavily pretreated patients with RRMM who received elranatamab as their first BCMA-directed therapy.
The overall response rate in 97 BCMA-naive patients (cohort A) who previously received at least four lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody, was 58%, with an estimated 82% maintaining the response for 9 months or longer. Median time to first response was 1.2 months.
In 63 patients who received at least four prior lines of therapy, which also included a BCMA-directed therapy, the overall response rate was 33% after median follow-up of 10.2 months. An estimated 84% maintained a response for at least 9 months.
Elranatamab was given subcutaneously at a dose of 76 mg weekly on a 28-day cycle with a step-up priming dose regimen. The priming regimen included 12 mg and 32 mg doses on days 1 and 4, respectively, during cycle 1. Patients who received at least six cycles and showed at least a partial response for 2 or more months had a biweekly dosing interval.
Elranatamab carries a boxed warning for cytokine release syndrome (CRS) and neurologic toxicity, as well as warnings and precautions for infections, neutropenia, hepatotoxicity, and embryo–fetal toxicity. Therefore, the agent is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS).
The boxed warning is included in the full prescribing information.
A confirmatory trial to gather additional safety and efficacy data was launched in 2022. Continued FDA approval is contingent on confirmed safety and efficacy data.
A version of this article first appeared on Medscape.com.
The B-cell maturation antigen (BCMA) CD3-targeted bispecific antibody (BsAb) was given Priority Review in February and had previously received Breakthrough Therapy Designation for relapsed or refractory multiple myeloma (RRMM), according to Pfizer.
FDA approval was based on favorable response and duration of response rates in the single-arm, phase 2 MagnetisMM-3 trial. The trial showed meaningful responses in heavily pretreated patients with RRMM who received elranatamab as their first BCMA-directed therapy.
The overall response rate in 97 BCMA-naive patients (cohort A) who previously received at least four lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody, was 58%, with an estimated 82% maintaining the response for 9 months or longer. Median time to first response was 1.2 months.
In 63 patients who received at least four prior lines of therapy, which also included a BCMA-directed therapy, the overall response rate was 33% after median follow-up of 10.2 months. An estimated 84% maintained a response for at least 9 months.
Elranatamab was given subcutaneously at a dose of 76 mg weekly on a 28-day cycle with a step-up priming dose regimen. The priming regimen included 12 mg and 32 mg doses on days 1 and 4, respectively, during cycle 1. Patients who received at least six cycles and showed at least a partial response for 2 or more months had a biweekly dosing interval.
Elranatamab carries a boxed warning for cytokine release syndrome (CRS) and neurologic toxicity, as well as warnings and precautions for infections, neutropenia, hepatotoxicity, and embryo–fetal toxicity. Therefore, the agent is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS).
The boxed warning is included in the full prescribing information.
A confirmatory trial to gather additional safety and efficacy data was launched in 2022. Continued FDA approval is contingent on confirmed safety and efficacy data.
A version of this article first appeared on Medscape.com.
The B-cell maturation antigen (BCMA) CD3-targeted bispecific antibody (BsAb) was given Priority Review in February and had previously received Breakthrough Therapy Designation for relapsed or refractory multiple myeloma (RRMM), according to Pfizer.
FDA approval was based on favorable response and duration of response rates in the single-arm, phase 2 MagnetisMM-3 trial. The trial showed meaningful responses in heavily pretreated patients with RRMM who received elranatamab as their first BCMA-directed therapy.
The overall response rate in 97 BCMA-naive patients (cohort A) who previously received at least four lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody, was 58%, with an estimated 82% maintaining the response for 9 months or longer. Median time to first response was 1.2 months.
In 63 patients who received at least four prior lines of therapy, which also included a BCMA-directed therapy, the overall response rate was 33% after median follow-up of 10.2 months. An estimated 84% maintained a response for at least 9 months.
Elranatamab was given subcutaneously at a dose of 76 mg weekly on a 28-day cycle with a step-up priming dose regimen. The priming regimen included 12 mg and 32 mg doses on days 1 and 4, respectively, during cycle 1. Patients who received at least six cycles and showed at least a partial response for 2 or more months had a biweekly dosing interval.
Elranatamab carries a boxed warning for cytokine release syndrome (CRS) and neurologic toxicity, as well as warnings and precautions for infections, neutropenia, hepatotoxicity, and embryo–fetal toxicity. Therefore, the agent is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS).
The boxed warning is included in the full prescribing information.
A confirmatory trial to gather additional safety and efficacy data was launched in 2022. Continued FDA approval is contingent on confirmed safety and efficacy data.
A version of this article first appeared on Medscape.com.
FDA OKs talquetamab, a first-in-class myeloma tx
Patients must have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
The agent, which also received breakthrough and orphan drug designation, is available only through the Tecvayli-Talvey Risk Evaluation and Mitigation Strategy (REMS) because of a boxed warning for life-threatening or fatal cytokine release syndrome (CRS) and neurological toxicity, including immune effector cell–associated neurotoxicity (ICANS), the FDA announced.
Talquetamab-tgvs was evaluated in the single-arm, open-label MonumenTAL-1 study of 187 patients who had previously been treated with at least four prior systemic therapies.
The overall response rate in 100 patients who received a subcutaneous dose of 0.4 mg/kg weekly was 73% and median duration of response was 9.5 months. The overall response rate in 87 patients who received a subcutaneous dose of 0.8 mg/kg biweekly was 73.6%, with about 85% of responders maintaining their response for at least 9 months. In this group, the median duration of response was not estimable.
Patients in the 0.4 mg/kg weekly dose group were treated following two step-up doses in the first week of therapy, and those in the 0.8 mg/kg biweekly group were treated following three step-up doses, until disease progression or unacceptable toxicity.
Adverse reactions occurring in at least 20% of the 339 patients in the safety population included CRS, dysgeusia (foul, metallic taste sensation), nail disorder, musculoskeletal pain, skin disorder, rash, fatigue, decreased weight, dry mouth, pyrexia, xerosis, dysphagia, upper respiratory tract infection, and diarrhea.
Both the weekly 0.4 mg/kg and biweekly 0.8 mg/kg doses are recommended. The full dosing schedule is included in the prescribing information.
The approval follows a series of market withdrawals for other multiple myeloma drugs that initially received accelerated FDA approval. For instance, the FDA recently requested withdrawal of melphalan flufenamide (Pepaxto) after 2021 confirmatory trial results showed an increased risk of death. This agent had received accelerated approval in 2021. GlaxoSmithKline’s blood cancer drugs panobinostat (Farydak) and belantamab mafodotin-blmf (Blenrep) were also withdrawn based on confirmatory trial results.
Continued approval of talquetemab-tgvs for this indication is also contingent on verifying efficacy in confirmatory trials.
The new treatment approach represents a “welcome addition to the myeloma community,” Michael Andreini, president and chief executive officer of the Multiple Myeloma Research Foundation stated in a Janssen press release. “Although options for the treatment of multiple myeloma have expanded significantly in recent years, the disease remains incurable, and therefore, patients are in need of new treatment options.”
Health care professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.
A version of this article first appeared on Medscape.com.
Patients must have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
The agent, which also received breakthrough and orphan drug designation, is available only through the Tecvayli-Talvey Risk Evaluation and Mitigation Strategy (REMS) because of a boxed warning for life-threatening or fatal cytokine release syndrome (CRS) and neurological toxicity, including immune effector cell–associated neurotoxicity (ICANS), the FDA announced.
Talquetamab-tgvs was evaluated in the single-arm, open-label MonumenTAL-1 study of 187 patients who had previously been treated with at least four prior systemic therapies.
The overall response rate in 100 patients who received a subcutaneous dose of 0.4 mg/kg weekly was 73% and median duration of response was 9.5 months. The overall response rate in 87 patients who received a subcutaneous dose of 0.8 mg/kg biweekly was 73.6%, with about 85% of responders maintaining their response for at least 9 months. In this group, the median duration of response was not estimable.
Patients in the 0.4 mg/kg weekly dose group were treated following two step-up doses in the first week of therapy, and those in the 0.8 mg/kg biweekly group were treated following three step-up doses, until disease progression or unacceptable toxicity.
Adverse reactions occurring in at least 20% of the 339 patients in the safety population included CRS, dysgeusia (foul, metallic taste sensation), nail disorder, musculoskeletal pain, skin disorder, rash, fatigue, decreased weight, dry mouth, pyrexia, xerosis, dysphagia, upper respiratory tract infection, and diarrhea.
Both the weekly 0.4 mg/kg and biweekly 0.8 mg/kg doses are recommended. The full dosing schedule is included in the prescribing information.
The approval follows a series of market withdrawals for other multiple myeloma drugs that initially received accelerated FDA approval. For instance, the FDA recently requested withdrawal of melphalan flufenamide (Pepaxto) after 2021 confirmatory trial results showed an increased risk of death. This agent had received accelerated approval in 2021. GlaxoSmithKline’s blood cancer drugs panobinostat (Farydak) and belantamab mafodotin-blmf (Blenrep) were also withdrawn based on confirmatory trial results.
Continued approval of talquetemab-tgvs for this indication is also contingent on verifying efficacy in confirmatory trials.
The new treatment approach represents a “welcome addition to the myeloma community,” Michael Andreini, president and chief executive officer of the Multiple Myeloma Research Foundation stated in a Janssen press release. “Although options for the treatment of multiple myeloma have expanded significantly in recent years, the disease remains incurable, and therefore, patients are in need of new treatment options.”
Health care professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.
A version of this article first appeared on Medscape.com.
Patients must have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
The agent, which also received breakthrough and orphan drug designation, is available only through the Tecvayli-Talvey Risk Evaluation and Mitigation Strategy (REMS) because of a boxed warning for life-threatening or fatal cytokine release syndrome (CRS) and neurological toxicity, including immune effector cell–associated neurotoxicity (ICANS), the FDA announced.
Talquetamab-tgvs was evaluated in the single-arm, open-label MonumenTAL-1 study of 187 patients who had previously been treated with at least four prior systemic therapies.
The overall response rate in 100 patients who received a subcutaneous dose of 0.4 mg/kg weekly was 73% and median duration of response was 9.5 months. The overall response rate in 87 patients who received a subcutaneous dose of 0.8 mg/kg biweekly was 73.6%, with about 85% of responders maintaining their response for at least 9 months. In this group, the median duration of response was not estimable.
Patients in the 0.4 mg/kg weekly dose group were treated following two step-up doses in the first week of therapy, and those in the 0.8 mg/kg biweekly group were treated following three step-up doses, until disease progression or unacceptable toxicity.
Adverse reactions occurring in at least 20% of the 339 patients in the safety population included CRS, dysgeusia (foul, metallic taste sensation), nail disorder, musculoskeletal pain, skin disorder, rash, fatigue, decreased weight, dry mouth, pyrexia, xerosis, dysphagia, upper respiratory tract infection, and diarrhea.
Both the weekly 0.4 mg/kg and biweekly 0.8 mg/kg doses are recommended. The full dosing schedule is included in the prescribing information.
The approval follows a series of market withdrawals for other multiple myeloma drugs that initially received accelerated FDA approval. For instance, the FDA recently requested withdrawal of melphalan flufenamide (Pepaxto) after 2021 confirmatory trial results showed an increased risk of death. This agent had received accelerated approval in 2021. GlaxoSmithKline’s blood cancer drugs panobinostat (Farydak) and belantamab mafodotin-blmf (Blenrep) were also withdrawn based on confirmatory trial results.
Continued approval of talquetemab-tgvs for this indication is also contingent on verifying efficacy in confirmatory trials.
The new treatment approach represents a “welcome addition to the myeloma community,” Michael Andreini, president and chief executive officer of the Multiple Myeloma Research Foundation stated in a Janssen press release. “Although options for the treatment of multiple myeloma have expanded significantly in recent years, the disease remains incurable, and therefore, patients are in need of new treatment options.”
Health care professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.
A version of this article first appeared on Medscape.com.
Antibody shows promise in preventing GVHD
Early, intriguing research suggests that preventing acute graft-versus-host disease (GVHD) in the gut – a potentially life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT) – could be accomplished by the administration of a single antibody that targets the anti-DLL4 Notch signaling pathway, without compromising the stem cell transplant.
“The major surprise was that none of the anti–DLL4-treated animals developed acute gastrointestinal GVHD for the entire duration of the study. This was a remarkable finding, given that intestinal GVHD is otherwise seen in the vast majority of nonhuman primate transplant recipients that receive either no prophylaxis, or prophylaxis with agents other than anti-DLL4 antibodies,” co–senior author Ivan Maillard, MD, PhD, a professor of medicine and vice chief for research in hematology-oncology at the University of Pennsylvania, Philadelphia, said in an interview.
“The timing was critical,” the authors noted in the study, recently published in Science Translational Medicine. “Intervening before any symptoms of GvHD appear made the long-term protection possible.”
While GVHD may be mild to moderate in chronic forms, acute cases can be serious, if not fatal, and nearly all severe acute GVHD prominently involves the gastrointestinal tract, which can drive activation of pathogenic T cells and potentially lead to tissue damage following allo-HCT.
Systemic corticosteroids are standard first-line treatment for acute GVHD. However, response rates generally range only from 40% to 60%, and there are concerns of side effects. Meanwhile, second-line treatments are of inconsistent benefit.
With previous studies on mice showing benefits of targeting Notch pathway inhibition, particularly DLL4, Dr. Maillard and colleagues further investigated the effects in nonhuman primates that were allo-HCT recipients, using the anti-DLL4 antibody REGN421, which has pharmacokinetic and toxicity information available from previous studies.
The nonhuman primates were treated with one of two dosing regimens: a single dose of REGN421 3 mg/kg at baseline, post HCT, (n = 7) or three weekly doses at days 0, 7 and 14, post transplant (n = 4). Those primates were compared with 11 primates receiving allo-HCT transplants that received supportive care only.
Primates receiving three weekly doses of REGN421 showed antibody concentrations of greater than 2 mcg/mL for more than 30 days post HCT. A single dose of REGN421 was associated with protection from acute GVHD at day 0, while three weekly doses showed protection at day 0, 7, and 14, consistent with an impact of REGN421 during the early phases of T-cell activation.
Compared with animals receiving only supportive care, prophylaxis with REGN421 was associated with delayed acute GVHD onset and lengthened survival.
Of the 11 primates treated with REGN421, none developed clinical signs of gastrointestinal acute GVHD, whereas the majority of those receiving standard care or other preventive interventions did.
“Detailed analysis of acute GVHD clinical presentations in REGN421-treated animals in comparison to no treatment controls revealed near complete protection from GI-acute GvHD with REGN421,” the authors reported.
Furthermore, pathology scores in the gastrointestinal tract were lower with REGN421 treatment, compared with the no-treatment cohort, and the scores matched those of healthy nontransplanted nonhuman primates.
The primates treated with REGN421 did ultimately develop other clinical and pathologic signs of skin, hepatic or pulmonary acute GVHD, but without gastrointestinal disease.
The treatment was not associated with any adverse effects on the allo-HCT, with primates receiving either a single dose or three weekly doses of REGN421 showing rapid donor engraftment after allo-HCT, including high bone marrow, whole blood, and T-cell donor chimerism.
“Reassuringly, short-term systemic DLL4 blockade with REGN421 did not trigger unexpected side effects in our nonhuman primate model, while preserving rapid engraftment as well hematopoietic and immune reconstitution.”
The mechanism preserving the engraftment, described as a “major surprise,” specifically involved DLL4 inhibition blocking the homing of pathogenic T cells to the gut while preserving homing of regulatory T cells that dampen the immune response, Dr. Maillard explained.
“This effect turned out to be at least in part through a posttranslational effect of DLL4/Notch blockade on integrin pairing at the T-cell surface,” he explained. “This was a novel and quite unexpected mechanism of action conserved from mice to nonhuman primates.”
The results are encouraging in terms of translating to humans because of their closer similarities in various physiological factors, Dr. Maillard said.
“The nonhuman primate model of transplantation [offers] a transplantation model very close to what is being performed in humans, as well as the opportunity to study an immune system very similar to that of humans in nonhuman primates,” he said.
Dr. Maillard noted that, while trials in humans are not underway yet, “we are in active discussions about it,” and the team is indeed interested in testing REGN421 itself, with the effects likely to be as a prophylactic strategy.
There are currently no approved anti-DLL4 antibody drugs for use in humans.
“Our approach is mostly promising as a preventive treatment, rather than as a secondary treatment for GVHD, because DLL4/Notch blockade seems most active when applied early after transplantation during the time of initial seeding of the gut by T cells (in mice, we had observed the critical time window for a successful intervention to be within 48 hours of transplantation),” Dr. Maillard said.“There remain questions about which other prophylactic treatments we should ideally combine anti-DLL4 antibodies with.”
Dr. Maillard has received research funding from Regeneron and Genentech and is a member of Garuda Therapeutics’s scientific advisory board.
Early, intriguing research suggests that preventing acute graft-versus-host disease (GVHD) in the gut – a potentially life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT) – could be accomplished by the administration of a single antibody that targets the anti-DLL4 Notch signaling pathway, without compromising the stem cell transplant.
“The major surprise was that none of the anti–DLL4-treated animals developed acute gastrointestinal GVHD for the entire duration of the study. This was a remarkable finding, given that intestinal GVHD is otherwise seen in the vast majority of nonhuman primate transplant recipients that receive either no prophylaxis, or prophylaxis with agents other than anti-DLL4 antibodies,” co–senior author Ivan Maillard, MD, PhD, a professor of medicine and vice chief for research in hematology-oncology at the University of Pennsylvania, Philadelphia, said in an interview.
“The timing was critical,” the authors noted in the study, recently published in Science Translational Medicine. “Intervening before any symptoms of GvHD appear made the long-term protection possible.”
While GVHD may be mild to moderate in chronic forms, acute cases can be serious, if not fatal, and nearly all severe acute GVHD prominently involves the gastrointestinal tract, which can drive activation of pathogenic T cells and potentially lead to tissue damage following allo-HCT.
Systemic corticosteroids are standard first-line treatment for acute GVHD. However, response rates generally range only from 40% to 60%, and there are concerns of side effects. Meanwhile, second-line treatments are of inconsistent benefit.
With previous studies on mice showing benefits of targeting Notch pathway inhibition, particularly DLL4, Dr. Maillard and colleagues further investigated the effects in nonhuman primates that were allo-HCT recipients, using the anti-DLL4 antibody REGN421, which has pharmacokinetic and toxicity information available from previous studies.
The nonhuman primates were treated with one of two dosing regimens: a single dose of REGN421 3 mg/kg at baseline, post HCT, (n = 7) or three weekly doses at days 0, 7 and 14, post transplant (n = 4). Those primates were compared with 11 primates receiving allo-HCT transplants that received supportive care only.
Primates receiving three weekly doses of REGN421 showed antibody concentrations of greater than 2 mcg/mL for more than 30 days post HCT. A single dose of REGN421 was associated with protection from acute GVHD at day 0, while three weekly doses showed protection at day 0, 7, and 14, consistent with an impact of REGN421 during the early phases of T-cell activation.
Compared with animals receiving only supportive care, prophylaxis with REGN421 was associated with delayed acute GVHD onset and lengthened survival.
Of the 11 primates treated with REGN421, none developed clinical signs of gastrointestinal acute GVHD, whereas the majority of those receiving standard care or other preventive interventions did.
“Detailed analysis of acute GVHD clinical presentations in REGN421-treated animals in comparison to no treatment controls revealed near complete protection from GI-acute GvHD with REGN421,” the authors reported.
Furthermore, pathology scores in the gastrointestinal tract were lower with REGN421 treatment, compared with the no-treatment cohort, and the scores matched those of healthy nontransplanted nonhuman primates.
The primates treated with REGN421 did ultimately develop other clinical and pathologic signs of skin, hepatic or pulmonary acute GVHD, but without gastrointestinal disease.
The treatment was not associated with any adverse effects on the allo-HCT, with primates receiving either a single dose or three weekly doses of REGN421 showing rapid donor engraftment after allo-HCT, including high bone marrow, whole blood, and T-cell donor chimerism.
“Reassuringly, short-term systemic DLL4 blockade with REGN421 did not trigger unexpected side effects in our nonhuman primate model, while preserving rapid engraftment as well hematopoietic and immune reconstitution.”
The mechanism preserving the engraftment, described as a “major surprise,” specifically involved DLL4 inhibition blocking the homing of pathogenic T cells to the gut while preserving homing of regulatory T cells that dampen the immune response, Dr. Maillard explained.
“This effect turned out to be at least in part through a posttranslational effect of DLL4/Notch blockade on integrin pairing at the T-cell surface,” he explained. “This was a novel and quite unexpected mechanism of action conserved from mice to nonhuman primates.”
The results are encouraging in terms of translating to humans because of their closer similarities in various physiological factors, Dr. Maillard said.
“The nonhuman primate model of transplantation [offers] a transplantation model very close to what is being performed in humans, as well as the opportunity to study an immune system very similar to that of humans in nonhuman primates,” he said.
Dr. Maillard noted that, while trials in humans are not underway yet, “we are in active discussions about it,” and the team is indeed interested in testing REGN421 itself, with the effects likely to be as a prophylactic strategy.
There are currently no approved anti-DLL4 antibody drugs for use in humans.
“Our approach is mostly promising as a preventive treatment, rather than as a secondary treatment for GVHD, because DLL4/Notch blockade seems most active when applied early after transplantation during the time of initial seeding of the gut by T cells (in mice, we had observed the critical time window for a successful intervention to be within 48 hours of transplantation),” Dr. Maillard said.“There remain questions about which other prophylactic treatments we should ideally combine anti-DLL4 antibodies with.”
Dr. Maillard has received research funding from Regeneron and Genentech and is a member of Garuda Therapeutics’s scientific advisory board.
Early, intriguing research suggests that preventing acute graft-versus-host disease (GVHD) in the gut – a potentially life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT) – could be accomplished by the administration of a single antibody that targets the anti-DLL4 Notch signaling pathway, without compromising the stem cell transplant.
“The major surprise was that none of the anti–DLL4-treated animals developed acute gastrointestinal GVHD for the entire duration of the study. This was a remarkable finding, given that intestinal GVHD is otherwise seen in the vast majority of nonhuman primate transplant recipients that receive either no prophylaxis, or prophylaxis with agents other than anti-DLL4 antibodies,” co–senior author Ivan Maillard, MD, PhD, a professor of medicine and vice chief for research in hematology-oncology at the University of Pennsylvania, Philadelphia, said in an interview.
“The timing was critical,” the authors noted in the study, recently published in Science Translational Medicine. “Intervening before any symptoms of GvHD appear made the long-term protection possible.”
While GVHD may be mild to moderate in chronic forms, acute cases can be serious, if not fatal, and nearly all severe acute GVHD prominently involves the gastrointestinal tract, which can drive activation of pathogenic T cells and potentially lead to tissue damage following allo-HCT.
Systemic corticosteroids are standard first-line treatment for acute GVHD. However, response rates generally range only from 40% to 60%, and there are concerns of side effects. Meanwhile, second-line treatments are of inconsistent benefit.
With previous studies on mice showing benefits of targeting Notch pathway inhibition, particularly DLL4, Dr. Maillard and colleagues further investigated the effects in nonhuman primates that were allo-HCT recipients, using the anti-DLL4 antibody REGN421, which has pharmacokinetic and toxicity information available from previous studies.
The nonhuman primates were treated with one of two dosing regimens: a single dose of REGN421 3 mg/kg at baseline, post HCT, (n = 7) or three weekly doses at days 0, 7 and 14, post transplant (n = 4). Those primates were compared with 11 primates receiving allo-HCT transplants that received supportive care only.
Primates receiving three weekly doses of REGN421 showed antibody concentrations of greater than 2 mcg/mL for more than 30 days post HCT. A single dose of REGN421 was associated with protection from acute GVHD at day 0, while three weekly doses showed protection at day 0, 7, and 14, consistent with an impact of REGN421 during the early phases of T-cell activation.
Compared with animals receiving only supportive care, prophylaxis with REGN421 was associated with delayed acute GVHD onset and lengthened survival.
Of the 11 primates treated with REGN421, none developed clinical signs of gastrointestinal acute GVHD, whereas the majority of those receiving standard care or other preventive interventions did.
“Detailed analysis of acute GVHD clinical presentations in REGN421-treated animals in comparison to no treatment controls revealed near complete protection from GI-acute GvHD with REGN421,” the authors reported.
Furthermore, pathology scores in the gastrointestinal tract were lower with REGN421 treatment, compared with the no-treatment cohort, and the scores matched those of healthy nontransplanted nonhuman primates.
The primates treated with REGN421 did ultimately develop other clinical and pathologic signs of skin, hepatic or pulmonary acute GVHD, but without gastrointestinal disease.
The treatment was not associated with any adverse effects on the allo-HCT, with primates receiving either a single dose or three weekly doses of REGN421 showing rapid donor engraftment after allo-HCT, including high bone marrow, whole blood, and T-cell donor chimerism.
“Reassuringly, short-term systemic DLL4 blockade with REGN421 did not trigger unexpected side effects in our nonhuman primate model, while preserving rapid engraftment as well hematopoietic and immune reconstitution.”
The mechanism preserving the engraftment, described as a “major surprise,” specifically involved DLL4 inhibition blocking the homing of pathogenic T cells to the gut while preserving homing of regulatory T cells that dampen the immune response, Dr. Maillard explained.
“This effect turned out to be at least in part through a posttranslational effect of DLL4/Notch blockade on integrin pairing at the T-cell surface,” he explained. “This was a novel and quite unexpected mechanism of action conserved from mice to nonhuman primates.”
The results are encouraging in terms of translating to humans because of their closer similarities in various physiological factors, Dr. Maillard said.
“The nonhuman primate model of transplantation [offers] a transplantation model very close to what is being performed in humans, as well as the opportunity to study an immune system very similar to that of humans in nonhuman primates,” he said.
Dr. Maillard noted that, while trials in humans are not underway yet, “we are in active discussions about it,” and the team is indeed interested in testing REGN421 itself, with the effects likely to be as a prophylactic strategy.
There are currently no approved anti-DLL4 antibody drugs for use in humans.
“Our approach is mostly promising as a preventive treatment, rather than as a secondary treatment for GVHD, because DLL4/Notch blockade seems most active when applied early after transplantation during the time of initial seeding of the gut by T cells (in mice, we had observed the critical time window for a successful intervention to be within 48 hours of transplantation),” Dr. Maillard said.“There remain questions about which other prophylactic treatments we should ideally combine anti-DLL4 antibodies with.”
Dr. Maillard has received research funding from Regeneron and Genentech and is a member of Garuda Therapeutics’s scientific advisory board.
FROM SCIENCE TRANSLATIONAL MEDICINE
MM: Newest IKEMA results back isatuximab
Median follow up was 44 months in the new update, about 2 additional years past the earlier report.
As in the earlier analysis, adding the anti-CD38 antibody to carfilzomib and dexamethasone brought substantial benefits, including a median progression free survival (PFS) of 35.7 months versus 19.2 months with placebo, as well as a higher rates of complete response (CR, 44.1% vs. 28.5%), minimal residual disease (MRD) negativity (33.5% vs. 15.4%), and MRD negativity CR (26.3% vs. 12.2%).
Although overall survival data are not yet mature, the probability of being alive at 42 months was 66.3% with isatuximab add-on versus 54.5% with placebo.
Investigators led by Thomas G. Martin, MD, director of the University of California, San Francisco, myeloma program, noted that median PFS of nearly 3 years “is the longest PFS reported to date with a PI-based regimen in the relapsed MM [multiple myeloma] setting.” The updated results further support the combination “as a standard of care treatment for patients with relapsed MM.”
Overall, the trial adds “another effective triplet in the treatment of patients with” relapsed/refractory MM, Sergio A. Giralt, MD, head of the division of hematologic malignancies at Memorial Sloan Kettering Cancer Center, New York, said when asked for comment. The study was published May 9 in Blood Cancer Journal.
Safety similar to interim analysis
IKEMA randomized 179 patients to isatuximab add-on and 123 to placebo. Patients had relapsed/refractory MM with one to three prior treatment lines. Isatuximab was dosed at10 mg/kg IV in the open-label trial, weekly in the first cycle then biweekly.
The PFS benefit held across various subgroups, including the elderly and others with poor prognoses.
In their write-up, the investigators acknowledged isatuximab’s rival anti-CD38 antibody, daratumumab (Darzalex), which is also approved in the United States for use in combination with carfilzomib and dexamethasone for relapsed/refractory MM after one to three treatment lines.
“Although inter-trial evaluations should be interpreted with caution,” they noted that PFS in the latest analysis of daratumumab’s CANDOR trial in combination with carfilzomib and dexamethasone was shorter than in IKEMA, 28.6 months versus 15.2 months with placebo.
Like efficacy, safety in latest update of IKEMA was similar to that of the interim analysis. However, while there was no difference in the incidence of all-cause serious treatment-emergent adverse events (TEAEs) in the earlier report, the incidence was higher with isatuximab than placebo in the newest findings (70.1% vs. 59.8%).
The investigators said the difference was likely because patients in the isatuximab arm stayed on treatment longer, a median of 94 weeks versus 61.9 weeks in the placebo arm, making adverse events more likely.
The most common, nonhematologic TEAEs were infusion reactions (45.8% in the isatuximab arm vs. 3.3% in the placebo group), diarrhea (39.5% vs. 32%), hypertension (37.9% vs 35.2%), upper respiratory tract infection (37.3% vs 27%), and fatigue (31.6% vs 20.5%).
Grade 3 or higher pneumonia occurred in 18.6% patients in the isatuximab arm versus 12.3% in the placebo group. The incidence of skin cancer was 6.2% with isatuximab versus 3.3%. The incidence of treatment-emergent fatal events remained similar between study arms, 5.6% with isatuximab versus 4.9% with placebo.
The study was funded by Sanofi, maker of isatuximab. Investigators included two Sanofi employees. Others reported a range of ties to the company, including Dr. Martin, who reported research funding and sitting on a Sanofi steering committee.
Median follow up was 44 months in the new update, about 2 additional years past the earlier report.
As in the earlier analysis, adding the anti-CD38 antibody to carfilzomib and dexamethasone brought substantial benefits, including a median progression free survival (PFS) of 35.7 months versus 19.2 months with placebo, as well as a higher rates of complete response (CR, 44.1% vs. 28.5%), minimal residual disease (MRD) negativity (33.5% vs. 15.4%), and MRD negativity CR (26.3% vs. 12.2%).
Although overall survival data are not yet mature, the probability of being alive at 42 months was 66.3% with isatuximab add-on versus 54.5% with placebo.
Investigators led by Thomas G. Martin, MD, director of the University of California, San Francisco, myeloma program, noted that median PFS of nearly 3 years “is the longest PFS reported to date with a PI-based regimen in the relapsed MM [multiple myeloma] setting.” The updated results further support the combination “as a standard of care treatment for patients with relapsed MM.”
Overall, the trial adds “another effective triplet in the treatment of patients with” relapsed/refractory MM, Sergio A. Giralt, MD, head of the division of hematologic malignancies at Memorial Sloan Kettering Cancer Center, New York, said when asked for comment. The study was published May 9 in Blood Cancer Journal.
Safety similar to interim analysis
IKEMA randomized 179 patients to isatuximab add-on and 123 to placebo. Patients had relapsed/refractory MM with one to three prior treatment lines. Isatuximab was dosed at10 mg/kg IV in the open-label trial, weekly in the first cycle then biweekly.
The PFS benefit held across various subgroups, including the elderly and others with poor prognoses.
In their write-up, the investigators acknowledged isatuximab’s rival anti-CD38 antibody, daratumumab (Darzalex), which is also approved in the United States for use in combination with carfilzomib and dexamethasone for relapsed/refractory MM after one to three treatment lines.
“Although inter-trial evaluations should be interpreted with caution,” they noted that PFS in the latest analysis of daratumumab’s CANDOR trial in combination with carfilzomib and dexamethasone was shorter than in IKEMA, 28.6 months versus 15.2 months with placebo.
Like efficacy, safety in latest update of IKEMA was similar to that of the interim analysis. However, while there was no difference in the incidence of all-cause serious treatment-emergent adverse events (TEAEs) in the earlier report, the incidence was higher with isatuximab than placebo in the newest findings (70.1% vs. 59.8%).
The investigators said the difference was likely because patients in the isatuximab arm stayed on treatment longer, a median of 94 weeks versus 61.9 weeks in the placebo arm, making adverse events more likely.
The most common, nonhematologic TEAEs were infusion reactions (45.8% in the isatuximab arm vs. 3.3% in the placebo group), diarrhea (39.5% vs. 32%), hypertension (37.9% vs 35.2%), upper respiratory tract infection (37.3% vs 27%), and fatigue (31.6% vs 20.5%).
Grade 3 or higher pneumonia occurred in 18.6% patients in the isatuximab arm versus 12.3% in the placebo group. The incidence of skin cancer was 6.2% with isatuximab versus 3.3%. The incidence of treatment-emergent fatal events remained similar between study arms, 5.6% with isatuximab versus 4.9% with placebo.
The study was funded by Sanofi, maker of isatuximab. Investigators included two Sanofi employees. Others reported a range of ties to the company, including Dr. Martin, who reported research funding and sitting on a Sanofi steering committee.
Median follow up was 44 months in the new update, about 2 additional years past the earlier report.
As in the earlier analysis, adding the anti-CD38 antibody to carfilzomib and dexamethasone brought substantial benefits, including a median progression free survival (PFS) of 35.7 months versus 19.2 months with placebo, as well as a higher rates of complete response (CR, 44.1% vs. 28.5%), minimal residual disease (MRD) negativity (33.5% vs. 15.4%), and MRD negativity CR (26.3% vs. 12.2%).
Although overall survival data are not yet mature, the probability of being alive at 42 months was 66.3% with isatuximab add-on versus 54.5% with placebo.
Investigators led by Thomas G. Martin, MD, director of the University of California, San Francisco, myeloma program, noted that median PFS of nearly 3 years “is the longest PFS reported to date with a PI-based regimen in the relapsed MM [multiple myeloma] setting.” The updated results further support the combination “as a standard of care treatment for patients with relapsed MM.”
Overall, the trial adds “another effective triplet in the treatment of patients with” relapsed/refractory MM, Sergio A. Giralt, MD, head of the division of hematologic malignancies at Memorial Sloan Kettering Cancer Center, New York, said when asked for comment. The study was published May 9 in Blood Cancer Journal.
Safety similar to interim analysis
IKEMA randomized 179 patients to isatuximab add-on and 123 to placebo. Patients had relapsed/refractory MM with one to three prior treatment lines. Isatuximab was dosed at10 mg/kg IV in the open-label trial, weekly in the first cycle then biweekly.
The PFS benefit held across various subgroups, including the elderly and others with poor prognoses.
In their write-up, the investigators acknowledged isatuximab’s rival anti-CD38 antibody, daratumumab (Darzalex), which is also approved in the United States for use in combination with carfilzomib and dexamethasone for relapsed/refractory MM after one to three treatment lines.
“Although inter-trial evaluations should be interpreted with caution,” they noted that PFS in the latest analysis of daratumumab’s CANDOR trial in combination with carfilzomib and dexamethasone was shorter than in IKEMA, 28.6 months versus 15.2 months with placebo.
Like efficacy, safety in latest update of IKEMA was similar to that of the interim analysis. However, while there was no difference in the incidence of all-cause serious treatment-emergent adverse events (TEAEs) in the earlier report, the incidence was higher with isatuximab than placebo in the newest findings (70.1% vs. 59.8%).
The investigators said the difference was likely because patients in the isatuximab arm stayed on treatment longer, a median of 94 weeks versus 61.9 weeks in the placebo arm, making adverse events more likely.
The most common, nonhematologic TEAEs were infusion reactions (45.8% in the isatuximab arm vs. 3.3% in the placebo group), diarrhea (39.5% vs. 32%), hypertension (37.9% vs 35.2%), upper respiratory tract infection (37.3% vs 27%), and fatigue (31.6% vs 20.5%).
Grade 3 or higher pneumonia occurred in 18.6% patients in the isatuximab arm versus 12.3% in the placebo group. The incidence of skin cancer was 6.2% with isatuximab versus 3.3%. The incidence of treatment-emergent fatal events remained similar between study arms, 5.6% with isatuximab versus 4.9% with placebo.
The study was funded by Sanofi, maker of isatuximab. Investigators included two Sanofi employees. Others reported a range of ties to the company, including Dr. Martin, who reported research funding and sitting on a Sanofi steering committee.
FROM BLOOD CANCER JOURNAL