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In Transplant-Ineligible Myeloma, This Frontline Tx Is Better
The study found that frontline triple therapy with daratumumab plus lenalidomide and dexamethasone led to significantly longer time to next treatment or time to death compared with the triple combination that includes bortezomib instead of daratumumab.
In the absence of head-to-head randomized controlled clinical trials, this study may help clinicians make more informed decisions when choosing therapies for patients with newly diagnosed, transplant-ineligible multiple myeloma, said investigator Doris K. Hansen, MD, from the Moffitt Cancer Center & Research Institute in Tampa, Florida, who presented finding from the analysis at the annual meeting of the American Society of Hematology.
Despite the lack of head-to-head randomized trials in this setting, several indirect comparisons have suggested that the daratumumab regimen carries an efficacy edge.
For instance, an indirect comparison of patients who received the daratumumab regimen in the MAIA trial with those who received the bortezomib regimen in the SWOG S0777 trial revealed a 40% lower risk for disease progression or death among patients treated with daratumumab. Researchers also observed a benefit for the daratumumab regimen — a 32% lower risk for disease progression or death — when comparing patient outcomes in the MAIA and PEGASUS studies.
To more directly compare the efficacy of the two regimens, Dr. Hansen and colleagues combed data from Acentrus, a de-identified academic electronic medical records database, to find patients who started a frontline treatment regimen for multiple myeloma between January 2018 and May 2023. The team used several methods to balance baseline characteristics between cohorts.
After making these adjustments, the study included data on 302 patients who received frontline therapy with the daratumumab regimen and 341 who received the bortezomib regimen. Patients who underwent hematopoietic stem cell transplant before or during therapy were excluded, as were those who had prior primary solid tumors, hematologic malignancies, or amyloidosis.
During a 20.2-month median follow-up for patients on daratumumab, 98 (32%) switched to a new therapy or died. During a 21.5-month median follow-up for those on bortezomib, 175 (51%) switched treatments or died.
The median time to death was 37.8 months in the daratumumab group vs 18.7 months in the bortezomib group. Overall, patients who received the daratumumab regimen had a 42% lower risk for death or time-to-next treatment (adjusted hazard ratio [HR], 0.58; P < .001).
Dr. Hansen acknowledged several limitations of the study, including that the data used came from provider-based records and may be missing patients who saw an out-of-network clinician. The database also does not include information on ECOG performance status, patient frailty, or cytogenetic risk profiles, which may have influenced outcomes.
The outcome measure combined time-to-next treatment and time to death; however, Dr. Hansen noted, time-to-next treatment is not a direct surrogate for progression-free survival.
Overall, findings from this real-world study support the use of daratumumab plus lenalidomide and dexamethasone over bortezomib plus lenalidomide and dexamethasone in this population of transplant-ineligible patients with newly diagnosed multiple myeloma, Dr. Hansen concluded.
The study was supported by Janssen. Dr. Hansen reported consulting for Janssen and others, receiving honoraria from OncLive and Survivorship, and other disclosures.
A version of this article appeared on Medscape.com.
The study found that frontline triple therapy with daratumumab plus lenalidomide and dexamethasone led to significantly longer time to next treatment or time to death compared with the triple combination that includes bortezomib instead of daratumumab.
In the absence of head-to-head randomized controlled clinical trials, this study may help clinicians make more informed decisions when choosing therapies for patients with newly diagnosed, transplant-ineligible multiple myeloma, said investigator Doris K. Hansen, MD, from the Moffitt Cancer Center & Research Institute in Tampa, Florida, who presented finding from the analysis at the annual meeting of the American Society of Hematology.
Despite the lack of head-to-head randomized trials in this setting, several indirect comparisons have suggested that the daratumumab regimen carries an efficacy edge.
For instance, an indirect comparison of patients who received the daratumumab regimen in the MAIA trial with those who received the bortezomib regimen in the SWOG S0777 trial revealed a 40% lower risk for disease progression or death among patients treated with daratumumab. Researchers also observed a benefit for the daratumumab regimen — a 32% lower risk for disease progression or death — when comparing patient outcomes in the MAIA and PEGASUS studies.
To more directly compare the efficacy of the two regimens, Dr. Hansen and colleagues combed data from Acentrus, a de-identified academic electronic medical records database, to find patients who started a frontline treatment regimen for multiple myeloma between January 2018 and May 2023. The team used several methods to balance baseline characteristics between cohorts.
After making these adjustments, the study included data on 302 patients who received frontline therapy with the daratumumab regimen and 341 who received the bortezomib regimen. Patients who underwent hematopoietic stem cell transplant before or during therapy were excluded, as were those who had prior primary solid tumors, hematologic malignancies, or amyloidosis.
During a 20.2-month median follow-up for patients on daratumumab, 98 (32%) switched to a new therapy or died. During a 21.5-month median follow-up for those on bortezomib, 175 (51%) switched treatments or died.
The median time to death was 37.8 months in the daratumumab group vs 18.7 months in the bortezomib group. Overall, patients who received the daratumumab regimen had a 42% lower risk for death or time-to-next treatment (adjusted hazard ratio [HR], 0.58; P < .001).
Dr. Hansen acknowledged several limitations of the study, including that the data used came from provider-based records and may be missing patients who saw an out-of-network clinician. The database also does not include information on ECOG performance status, patient frailty, or cytogenetic risk profiles, which may have influenced outcomes.
The outcome measure combined time-to-next treatment and time to death; however, Dr. Hansen noted, time-to-next treatment is not a direct surrogate for progression-free survival.
Overall, findings from this real-world study support the use of daratumumab plus lenalidomide and dexamethasone over bortezomib plus lenalidomide and dexamethasone in this population of transplant-ineligible patients with newly diagnosed multiple myeloma, Dr. Hansen concluded.
The study was supported by Janssen. Dr. Hansen reported consulting for Janssen and others, receiving honoraria from OncLive and Survivorship, and other disclosures.
A version of this article appeared on Medscape.com.
The study found that frontline triple therapy with daratumumab plus lenalidomide and dexamethasone led to significantly longer time to next treatment or time to death compared with the triple combination that includes bortezomib instead of daratumumab.
In the absence of head-to-head randomized controlled clinical trials, this study may help clinicians make more informed decisions when choosing therapies for patients with newly diagnosed, transplant-ineligible multiple myeloma, said investigator Doris K. Hansen, MD, from the Moffitt Cancer Center & Research Institute in Tampa, Florida, who presented finding from the analysis at the annual meeting of the American Society of Hematology.
Despite the lack of head-to-head randomized trials in this setting, several indirect comparisons have suggested that the daratumumab regimen carries an efficacy edge.
For instance, an indirect comparison of patients who received the daratumumab regimen in the MAIA trial with those who received the bortezomib regimen in the SWOG S0777 trial revealed a 40% lower risk for disease progression or death among patients treated with daratumumab. Researchers also observed a benefit for the daratumumab regimen — a 32% lower risk for disease progression or death — when comparing patient outcomes in the MAIA and PEGASUS studies.
To more directly compare the efficacy of the two regimens, Dr. Hansen and colleagues combed data from Acentrus, a de-identified academic electronic medical records database, to find patients who started a frontline treatment regimen for multiple myeloma between January 2018 and May 2023. The team used several methods to balance baseline characteristics between cohorts.
After making these adjustments, the study included data on 302 patients who received frontline therapy with the daratumumab regimen and 341 who received the bortezomib regimen. Patients who underwent hematopoietic stem cell transplant before or during therapy were excluded, as were those who had prior primary solid tumors, hematologic malignancies, or amyloidosis.
During a 20.2-month median follow-up for patients on daratumumab, 98 (32%) switched to a new therapy or died. During a 21.5-month median follow-up for those on bortezomib, 175 (51%) switched treatments or died.
The median time to death was 37.8 months in the daratumumab group vs 18.7 months in the bortezomib group. Overall, patients who received the daratumumab regimen had a 42% lower risk for death or time-to-next treatment (adjusted hazard ratio [HR], 0.58; P < .001).
Dr. Hansen acknowledged several limitations of the study, including that the data used came from provider-based records and may be missing patients who saw an out-of-network clinician. The database also does not include information on ECOG performance status, patient frailty, or cytogenetic risk profiles, which may have influenced outcomes.
The outcome measure combined time-to-next treatment and time to death; however, Dr. Hansen noted, time-to-next treatment is not a direct surrogate for progression-free survival.
Overall, findings from this real-world study support the use of daratumumab plus lenalidomide and dexamethasone over bortezomib plus lenalidomide and dexamethasone in this population of transplant-ineligible patients with newly diagnosed multiple myeloma, Dr. Hansen concluded.
The study was supported by Janssen. Dr. Hansen reported consulting for Janssen and others, receiving honoraria from OncLive and Survivorship, and other disclosures.
A version of this article appeared on Medscape.com.
FROM ASH 2023
GVHD raises vitiligo risk in transplant recipients
published online in JAMA Dermatology December 13.
In the cohort study, the greatest risk occurred with hematopoietic stem cell transplants (HSCTs) and in cases involving GVHD. Kidney and liver transplants carried slight increases in risk.
“The findings suggest that early detection and management of vitiligo lesions can be improved by estimating the likelihood of its development in transplant recipients and implementing a multidisciplinary approach for monitoring,” wrote the authors, from the departments of dermatology and biostatistics, at the Catholic University of Korea, Seoul.
Using claims data from South Korea’s National Health Insurance Service database, the investigators compared vitiligo incidence among 23,829 patients who had undergone solid organ transplantation (SOT) or HSCT between 2010 and 2017 versus that of 119,145 age- and sex-matched controls. At a mean observation time of 4.79 years in the transplant group (and 5.12 years for controls), the adjusted hazard ratio (AHR) for vitiligo among patients who had undergone any transplant was 1.73. AHRs for HSCT, liver transplants, and kidney transplants were 12.69, 1.63, and 1.50, respectively.
Patients who had undergone allogeneic HSCT (AHR, 14.43) or autologous transplants (AHR, 5.71), as well as those with and without GVHD (24.09 and 8.21, respectively) had significantly higher vitiligo risk than the control group.
Among those with GVHD, HSCT recipients (AHR, 16.42) and those with allogeneic grafts (AHR, 16.81) had a higher vitiligo risk than that of control patients.
In a subgroup that included 10,355 transplant recipients who underwent posttransplant health checkups, investigators found the highest vitiligo risk — AHR, 25.09 versus controls — among HSCT recipients with comorbid GVHD. However, patients who underwent SOT, autologous HSCT, or HSCT without GVHD showed no increased vitiligo risk in this analysis. “The results of health checkup data analysis may differ from the initial analysis due to additional adjustments for lifestyle factors and inclusion of only patients who underwent a health checkup,” the authors wrote.
Asked to comment on the results, George Han, MD, PhD, who was not involved with the study, told this news organization, “this is an interesting paper where the primary difference from previous studies is the new association between GVHD in hematopoietic stem cell transplant recipients and vitiligo.” Prior research had shown higher rates of vitiligo in HSCT recipients without making the GVHD distinction. Dr. Han is associate professor of dermatology in the Hofstra/Northwell Department of Dermatology, Hyde Park, New York.
Although GVHD may not be top-of-mind for dermatologists in daily practice, he said, the study enhances their understanding of vitiligo risk in HSCT recipients. “In some ways,” Dr. Han added, “the association makes sense, as the activated T cells from the graft attacking the skin in the HSCT recipient follow many of the mechanisms of vitiligo, including upregulating interferon gamma and the CXCR3/CXCL10 axis.”
Presently, he said, dermatologists worry more about solid organ recipients than about HSCT recipients because the long-term immunosuppression required by SOT increases the risk of squamous cell carcinoma (SCC). “However, the risk of skin cancers also seems to be elevated in HSCT recipients, and in this case the basal cell carcinoma (BCC):SCC ratio is not necessarily reversed as we see in solid organ transplant recipients. So the mechanisms are a bit less clear. Interestingly, acute and chronic GVHD have both been associated with increased risks of BCC and SCC/BCC, respectively.”
Overall, Dr. Han said, any transplant recipient should undergo yearly skin checks not only for skin cancers, but also for other skin conditions such as vitiligo. “It would be nice to see this codified into official guidelines, which can vary considerably but are overall more consistent in solid organ transplant recipients than in HSCT recipients. No such guidelines seem to be available for HSCTs.”
The study was funded by the Basic Research in Science & Engineering program through the National Research Foundation of Korea, which is funded by the country’s Ministry of Education. The study authors had no disclosures. Dr. Han reports no relevant financial interests.
published online in JAMA Dermatology December 13.
In the cohort study, the greatest risk occurred with hematopoietic stem cell transplants (HSCTs) and in cases involving GVHD. Kidney and liver transplants carried slight increases in risk.
“The findings suggest that early detection and management of vitiligo lesions can be improved by estimating the likelihood of its development in transplant recipients and implementing a multidisciplinary approach for monitoring,” wrote the authors, from the departments of dermatology and biostatistics, at the Catholic University of Korea, Seoul.
Using claims data from South Korea’s National Health Insurance Service database, the investigators compared vitiligo incidence among 23,829 patients who had undergone solid organ transplantation (SOT) or HSCT between 2010 and 2017 versus that of 119,145 age- and sex-matched controls. At a mean observation time of 4.79 years in the transplant group (and 5.12 years for controls), the adjusted hazard ratio (AHR) for vitiligo among patients who had undergone any transplant was 1.73. AHRs for HSCT, liver transplants, and kidney transplants were 12.69, 1.63, and 1.50, respectively.
Patients who had undergone allogeneic HSCT (AHR, 14.43) or autologous transplants (AHR, 5.71), as well as those with and without GVHD (24.09 and 8.21, respectively) had significantly higher vitiligo risk than the control group.
Among those with GVHD, HSCT recipients (AHR, 16.42) and those with allogeneic grafts (AHR, 16.81) had a higher vitiligo risk than that of control patients.
In a subgroup that included 10,355 transplant recipients who underwent posttransplant health checkups, investigators found the highest vitiligo risk — AHR, 25.09 versus controls — among HSCT recipients with comorbid GVHD. However, patients who underwent SOT, autologous HSCT, or HSCT without GVHD showed no increased vitiligo risk in this analysis. “The results of health checkup data analysis may differ from the initial analysis due to additional adjustments for lifestyle factors and inclusion of only patients who underwent a health checkup,” the authors wrote.
Asked to comment on the results, George Han, MD, PhD, who was not involved with the study, told this news organization, “this is an interesting paper where the primary difference from previous studies is the new association between GVHD in hematopoietic stem cell transplant recipients and vitiligo.” Prior research had shown higher rates of vitiligo in HSCT recipients without making the GVHD distinction. Dr. Han is associate professor of dermatology in the Hofstra/Northwell Department of Dermatology, Hyde Park, New York.
Although GVHD may not be top-of-mind for dermatologists in daily practice, he said, the study enhances their understanding of vitiligo risk in HSCT recipients. “In some ways,” Dr. Han added, “the association makes sense, as the activated T cells from the graft attacking the skin in the HSCT recipient follow many of the mechanisms of vitiligo, including upregulating interferon gamma and the CXCR3/CXCL10 axis.”
Presently, he said, dermatologists worry more about solid organ recipients than about HSCT recipients because the long-term immunosuppression required by SOT increases the risk of squamous cell carcinoma (SCC). “However, the risk of skin cancers also seems to be elevated in HSCT recipients, and in this case the basal cell carcinoma (BCC):SCC ratio is not necessarily reversed as we see in solid organ transplant recipients. So the mechanisms are a bit less clear. Interestingly, acute and chronic GVHD have both been associated with increased risks of BCC and SCC/BCC, respectively.”
Overall, Dr. Han said, any transplant recipient should undergo yearly skin checks not only for skin cancers, but also for other skin conditions such as vitiligo. “It would be nice to see this codified into official guidelines, which can vary considerably but are overall more consistent in solid organ transplant recipients than in HSCT recipients. No such guidelines seem to be available for HSCTs.”
The study was funded by the Basic Research in Science & Engineering program through the National Research Foundation of Korea, which is funded by the country’s Ministry of Education. The study authors had no disclosures. Dr. Han reports no relevant financial interests.
published online in JAMA Dermatology December 13.
In the cohort study, the greatest risk occurred with hematopoietic stem cell transplants (HSCTs) and in cases involving GVHD. Kidney and liver transplants carried slight increases in risk.
“The findings suggest that early detection and management of vitiligo lesions can be improved by estimating the likelihood of its development in transplant recipients and implementing a multidisciplinary approach for monitoring,” wrote the authors, from the departments of dermatology and biostatistics, at the Catholic University of Korea, Seoul.
Using claims data from South Korea’s National Health Insurance Service database, the investigators compared vitiligo incidence among 23,829 patients who had undergone solid organ transplantation (SOT) or HSCT between 2010 and 2017 versus that of 119,145 age- and sex-matched controls. At a mean observation time of 4.79 years in the transplant group (and 5.12 years for controls), the adjusted hazard ratio (AHR) for vitiligo among patients who had undergone any transplant was 1.73. AHRs for HSCT, liver transplants, and kidney transplants were 12.69, 1.63, and 1.50, respectively.
Patients who had undergone allogeneic HSCT (AHR, 14.43) or autologous transplants (AHR, 5.71), as well as those with and without GVHD (24.09 and 8.21, respectively) had significantly higher vitiligo risk than the control group.
Among those with GVHD, HSCT recipients (AHR, 16.42) and those with allogeneic grafts (AHR, 16.81) had a higher vitiligo risk than that of control patients.
In a subgroup that included 10,355 transplant recipients who underwent posttransplant health checkups, investigators found the highest vitiligo risk — AHR, 25.09 versus controls — among HSCT recipients with comorbid GVHD. However, patients who underwent SOT, autologous HSCT, or HSCT without GVHD showed no increased vitiligo risk in this analysis. “The results of health checkup data analysis may differ from the initial analysis due to additional adjustments for lifestyle factors and inclusion of only patients who underwent a health checkup,” the authors wrote.
Asked to comment on the results, George Han, MD, PhD, who was not involved with the study, told this news organization, “this is an interesting paper where the primary difference from previous studies is the new association between GVHD in hematopoietic stem cell transplant recipients and vitiligo.” Prior research had shown higher rates of vitiligo in HSCT recipients without making the GVHD distinction. Dr. Han is associate professor of dermatology in the Hofstra/Northwell Department of Dermatology, Hyde Park, New York.
Although GVHD may not be top-of-mind for dermatologists in daily practice, he said, the study enhances their understanding of vitiligo risk in HSCT recipients. “In some ways,” Dr. Han added, “the association makes sense, as the activated T cells from the graft attacking the skin in the HSCT recipient follow many of the mechanisms of vitiligo, including upregulating interferon gamma and the CXCR3/CXCL10 axis.”
Presently, he said, dermatologists worry more about solid organ recipients than about HSCT recipients because the long-term immunosuppression required by SOT increases the risk of squamous cell carcinoma (SCC). “However, the risk of skin cancers also seems to be elevated in HSCT recipients, and in this case the basal cell carcinoma (BCC):SCC ratio is not necessarily reversed as we see in solid organ transplant recipients. So the mechanisms are a bit less clear. Interestingly, acute and chronic GVHD have both been associated with increased risks of BCC and SCC/BCC, respectively.”
Overall, Dr. Han said, any transplant recipient should undergo yearly skin checks not only for skin cancers, but also for other skin conditions such as vitiligo. “It would be nice to see this codified into official guidelines, which can vary considerably but are overall more consistent in solid organ transplant recipients than in HSCT recipients. No such guidelines seem to be available for HSCTs.”
The study was funded by the Basic Research in Science & Engineering program through the National Research Foundation of Korea, which is funded by the country’s Ministry of Education. The study authors had no disclosures. Dr. Han reports no relevant financial interests.
FROM JAMA DERMATOLOGY
No Benefit to Salvage Transplant in R/R Multiple Myeloma
Patients receiving a second, salvage-autologous stem cell transplant alongside lenalidomide-dexamethasone maintenance therapy did not demonstrate improved progression-free survival (PFS) or overall survival compared with patients who continued the two-drug regimen without salvage transplant, according to research presented at the American Society of Hematology annual meeting.
The primary phase 3 analysis, published in 2021, showed no survival benefit following salvage transplant at the time of relapse, though it only followed patients for a median of 37 months.
However, because a significant fraction of patients in the transplant arm — about 29% — did not undergo the planned salvage transplant before dropping out of the study, the researchers performed further analyses that “suggested a survival benefit in patients who actually received the transplant,” first author Marc-Andrea Baertsch, MD, of the German Cancer Research Center and University Hospital Heidelberg, reported at ASH.
Now, the latest analysis, which followed patients for a median of 99 months (8.25 years), confirmed the initial 2021 findings, Dr. Baertsch explained.
“The writing on the wall is clear: Don’t repeat a transplant at the time of relapse for those who have already gotten a transplant,” said Manni Mohyuddin, MD, of the University of Utah in Salt Lake City, who was not involved in the research. Dr. Mohyuddin added, however, that this finding doesn’t apply to those who haven’t yet gotten a transplant. “Data from other trials suggests a role of transplant in this situation, depending on the unique circumstances.”
The current trial included 282 adult patients, aged 75 years or younger, with relapsed or refractory multiple myeloma. Between 2010 and 2016, patients in the intention-to-treat analysis (n = 277) were randomized to lenalidomide-dexamethasone reinduction and maintenance, along with salvage high-dose chemotherapy with melphalan and autologous stem cell transplantation (n = 139) or just continuous lenalidomide-dexamethasone until progression (n = 138).
Patients in both arms received three cycles of lenalidomide-dexamethasone up front: 25 mg of lenalidomide on days 1 through 21, and 40 mg of dexamethasone on days 1, 8, 15, and 22 in 4-week cycles. Those in the salvage transplant arm then received high-dose chemotherapy with 200 mg/m2 of melphalan followed by transplant and 10 mg of lenalidomide maintenance therapy daily, while those in the control arm continued with receiving lenalidomide-dexamethasone.
All patients had received one to three prior lines of therapy, had good performance status, and had a time-to-disease-progression of at least 12 months after frontline autologous stem cell transplant.
In the primary 2021 study, patients in the salvage transplant group did not demonstrate a survival benefit (hazard ratio [HR] for PFS, 0.87; HR for overall survival, 0.81).
In the latest analysis, no survival benefit emerged after following patients for a median of about 8 years. Patients in the salvage transplant arm had a median PFS of 20.5 months vs 19.3 months in the continuous therapy arms (HR, 0.98; 95% CI, 0.76-1.27; P = .9). Median overall survival was 67.1 months in the salvage transplant arm and 62.7 months in the continuous treatment arm (HR, 0.89; 95% CI, 0.66 - 1.20; P = .44).
Time to first progression after frontline transplant was associated with a PFS benefit but did not predict an overall survival benefit, Dr. Baertsch noted.
When evaluating outcomes from the time of salvage transplant to account for the high number of dropouts, the PFS and overall survival findings held. Patients who received salvage transplant did not experience significantly improved PFS (HR, 0.91) or overall survival (76.3 months in the salvage group vs 65.9 months in the continuous treatment arm; HR, 0.80).
The lack of PFS and overall survival benefit occurred across all myeloma subgroups, Dr. Baertsch said.
Overall, the results indicate that “ a repeat transplant at the time of relapse for patients who had already gotten a transplant previously was no better than continuing a two-drug regimen,” Dr. Mohyuddin said.
However, he noted, “a lot has changed for myeloma care” since this trial was initially conducted. “We now have better regimens available that do not involve a transplant. If a repeat transplant couldn’t beat a two-drug regimen, it surely cannot beat a three drug or four drug regimen.”
Dr. Baertsch reported no disclosures.
A version of this article first appeared on Medscape.com.
Patients receiving a second, salvage-autologous stem cell transplant alongside lenalidomide-dexamethasone maintenance therapy did not demonstrate improved progression-free survival (PFS) or overall survival compared with patients who continued the two-drug regimen without salvage transplant, according to research presented at the American Society of Hematology annual meeting.
The primary phase 3 analysis, published in 2021, showed no survival benefit following salvage transplant at the time of relapse, though it only followed patients for a median of 37 months.
However, because a significant fraction of patients in the transplant arm — about 29% — did not undergo the planned salvage transplant before dropping out of the study, the researchers performed further analyses that “suggested a survival benefit in patients who actually received the transplant,” first author Marc-Andrea Baertsch, MD, of the German Cancer Research Center and University Hospital Heidelberg, reported at ASH.
Now, the latest analysis, which followed patients for a median of 99 months (8.25 years), confirmed the initial 2021 findings, Dr. Baertsch explained.
“The writing on the wall is clear: Don’t repeat a transplant at the time of relapse for those who have already gotten a transplant,” said Manni Mohyuddin, MD, of the University of Utah in Salt Lake City, who was not involved in the research. Dr. Mohyuddin added, however, that this finding doesn’t apply to those who haven’t yet gotten a transplant. “Data from other trials suggests a role of transplant in this situation, depending on the unique circumstances.”
The current trial included 282 adult patients, aged 75 years or younger, with relapsed or refractory multiple myeloma. Between 2010 and 2016, patients in the intention-to-treat analysis (n = 277) were randomized to lenalidomide-dexamethasone reinduction and maintenance, along with salvage high-dose chemotherapy with melphalan and autologous stem cell transplantation (n = 139) or just continuous lenalidomide-dexamethasone until progression (n = 138).
Patients in both arms received three cycles of lenalidomide-dexamethasone up front: 25 mg of lenalidomide on days 1 through 21, and 40 mg of dexamethasone on days 1, 8, 15, and 22 in 4-week cycles. Those in the salvage transplant arm then received high-dose chemotherapy with 200 mg/m2 of melphalan followed by transplant and 10 mg of lenalidomide maintenance therapy daily, while those in the control arm continued with receiving lenalidomide-dexamethasone.
All patients had received one to three prior lines of therapy, had good performance status, and had a time-to-disease-progression of at least 12 months after frontline autologous stem cell transplant.
In the primary 2021 study, patients in the salvage transplant group did not demonstrate a survival benefit (hazard ratio [HR] for PFS, 0.87; HR for overall survival, 0.81).
In the latest analysis, no survival benefit emerged after following patients for a median of about 8 years. Patients in the salvage transplant arm had a median PFS of 20.5 months vs 19.3 months in the continuous therapy arms (HR, 0.98; 95% CI, 0.76-1.27; P = .9). Median overall survival was 67.1 months in the salvage transplant arm and 62.7 months in the continuous treatment arm (HR, 0.89; 95% CI, 0.66 - 1.20; P = .44).
Time to first progression after frontline transplant was associated with a PFS benefit but did not predict an overall survival benefit, Dr. Baertsch noted.
When evaluating outcomes from the time of salvage transplant to account for the high number of dropouts, the PFS and overall survival findings held. Patients who received salvage transplant did not experience significantly improved PFS (HR, 0.91) or overall survival (76.3 months in the salvage group vs 65.9 months in the continuous treatment arm; HR, 0.80).
The lack of PFS and overall survival benefit occurred across all myeloma subgroups, Dr. Baertsch said.
Overall, the results indicate that “ a repeat transplant at the time of relapse for patients who had already gotten a transplant previously was no better than continuing a two-drug regimen,” Dr. Mohyuddin said.
However, he noted, “a lot has changed for myeloma care” since this trial was initially conducted. “We now have better regimens available that do not involve a transplant. If a repeat transplant couldn’t beat a two-drug regimen, it surely cannot beat a three drug or four drug regimen.”
Dr. Baertsch reported no disclosures.
A version of this article first appeared on Medscape.com.
Patients receiving a second, salvage-autologous stem cell transplant alongside lenalidomide-dexamethasone maintenance therapy did not demonstrate improved progression-free survival (PFS) or overall survival compared with patients who continued the two-drug regimen without salvage transplant, according to research presented at the American Society of Hematology annual meeting.
The primary phase 3 analysis, published in 2021, showed no survival benefit following salvage transplant at the time of relapse, though it only followed patients for a median of 37 months.
However, because a significant fraction of patients in the transplant arm — about 29% — did not undergo the planned salvage transplant before dropping out of the study, the researchers performed further analyses that “suggested a survival benefit in patients who actually received the transplant,” first author Marc-Andrea Baertsch, MD, of the German Cancer Research Center and University Hospital Heidelberg, reported at ASH.
Now, the latest analysis, which followed patients for a median of 99 months (8.25 years), confirmed the initial 2021 findings, Dr. Baertsch explained.
“The writing on the wall is clear: Don’t repeat a transplant at the time of relapse for those who have already gotten a transplant,” said Manni Mohyuddin, MD, of the University of Utah in Salt Lake City, who was not involved in the research. Dr. Mohyuddin added, however, that this finding doesn’t apply to those who haven’t yet gotten a transplant. “Data from other trials suggests a role of transplant in this situation, depending on the unique circumstances.”
The current trial included 282 adult patients, aged 75 years or younger, with relapsed or refractory multiple myeloma. Between 2010 and 2016, patients in the intention-to-treat analysis (n = 277) were randomized to lenalidomide-dexamethasone reinduction and maintenance, along with salvage high-dose chemotherapy with melphalan and autologous stem cell transplantation (n = 139) or just continuous lenalidomide-dexamethasone until progression (n = 138).
Patients in both arms received three cycles of lenalidomide-dexamethasone up front: 25 mg of lenalidomide on days 1 through 21, and 40 mg of dexamethasone on days 1, 8, 15, and 22 in 4-week cycles. Those in the salvage transplant arm then received high-dose chemotherapy with 200 mg/m2 of melphalan followed by transplant and 10 mg of lenalidomide maintenance therapy daily, while those in the control arm continued with receiving lenalidomide-dexamethasone.
All patients had received one to three prior lines of therapy, had good performance status, and had a time-to-disease-progression of at least 12 months after frontline autologous stem cell transplant.
In the primary 2021 study, patients in the salvage transplant group did not demonstrate a survival benefit (hazard ratio [HR] for PFS, 0.87; HR for overall survival, 0.81).
In the latest analysis, no survival benefit emerged after following patients for a median of about 8 years. Patients in the salvage transplant arm had a median PFS of 20.5 months vs 19.3 months in the continuous therapy arms (HR, 0.98; 95% CI, 0.76-1.27; P = .9). Median overall survival was 67.1 months in the salvage transplant arm and 62.7 months in the continuous treatment arm (HR, 0.89; 95% CI, 0.66 - 1.20; P = .44).
Time to first progression after frontline transplant was associated with a PFS benefit but did not predict an overall survival benefit, Dr. Baertsch noted.
When evaluating outcomes from the time of salvage transplant to account for the high number of dropouts, the PFS and overall survival findings held. Patients who received salvage transplant did not experience significantly improved PFS (HR, 0.91) or overall survival (76.3 months in the salvage group vs 65.9 months in the continuous treatment arm; HR, 0.80).
The lack of PFS and overall survival benefit occurred across all myeloma subgroups, Dr. Baertsch said.
Overall, the results indicate that “ a repeat transplant at the time of relapse for patients who had already gotten a transplant previously was no better than continuing a two-drug regimen,” Dr. Mohyuddin said.
However, he noted, “a lot has changed for myeloma care” since this trial was initially conducted. “We now have better regimens available that do not involve a transplant. If a repeat transplant couldn’t beat a two-drug regimen, it surely cannot beat a three drug or four drug regimen.”
Dr. Baertsch reported no disclosures.
A version of this article first appeared on Medscape.com.
FROM ASH 2023
SCD mortality rates improved for Black patients in 2010s
But the news is not all positive. Mortality rates still jumped markedly as patients transitioned from pediatric to adult care, lead author Kristine A. Karkoska, MD, a pediatric hematology/oncologist with the University of Cincinnati College of Medicine, said at the annual meeting of the American Society of Hematology.
“This reflects that young adults are getting lost to care, and then they’re presenting with acute, life-threatening complications,” she said. “We still need more emphasis on comprehensive lifetime sickle-cell care and the transition to adult clinics to improve mortality in young adults.”
According to Dr. Karkoska, researchers launched the analysis of sickle-cell mortality rates to update previously available data up to the year 2009, which showed improvements as current standard-of-care treatments were introduced. Updated numbers, she said, would reflect the influence of a rise in dedicated SCD clinics and a 2014 National Heart, Lung, and Blood Institute recommendation that all children with SCD be treated with hydroxyurea starting at 9 months.
For the study, Dr. Karkoska and colleagues analyzed mortality statistics from the period of 1979-2020 via a CDC database. They found that 5272 Black patients died of SCD from 2010 to 2020. The crude mortality rate was 1.1 per 100,000 Black people, lower than the 1.2 per 100,000 rate of 1999-2009 (P < .0001).
The researchers also found that from 2010 to 2020, the mortality rate jumped for patients in the 15-19 to 20-24 age group: It rose from 0.9 per 100,000 to 1.4 per 100,000, P < .0001).
The researchers also examined contributors to death other than SCD. In 39% of cases, underlying causes were noted: cardiovascular disease (28%), accidents (7%), cerebrovascular disease (7%), malignancy (6%), septicemia (4.8%), and renal disease (3.8%). The population of people with SCD is “getting older, and they’re developing a combination of both sickle-related chronic organ damage as well as non-sickle-related chronic disease,” Dr. Karkoska said.
She noted that limitations include a reliance on data that can be incomplete or inaccurate. She also mentioned that the study only focuses on Black patients, who make up the vast majority of those with SCD.
How good is the news about improved mortality numbers? One member of the audience at the ASH presentation was disappointed that they hadn’t gotten even better. “I was hoping to come here to be cheered up,” he said, “and I’m not.”
Three physicians who didn’t take part in the research but are familiar with the new study spoke in interviews about the findings.
Michael Bender, MD, PhD, director of the Odessa Brown Comprehensive Sickle Cell Clinic in Seattle, pointed out that mortality rates improve slowly over time, as new treatments enter the picture. When new therapies come along, he said, “it’s tough if someone’s already 40 years old and their body has gone through a lot. They’re not going to have as much benefit as someone who started [on therapy] when they were 5 years old, and they grew up with that improvement.”
Sickle cell specialist Asmaa Ferdjallah, MD, MPH, of the Mayo Clinic in Rochester, Minnesota, said that the data showing a spike in mortality rates during the pediatric-adult transition are not surprising but still “really hard to digest.”
“It is a testament to the fact that we are not meeting patients where they are,” she said. “We struggle immensely with the transition period. This is something that is difficult across all providers all over the country,” she said. “There are different ways to ensure a successful transition from the pediatric side to the adult side. Here at Mayo Clinic, we use a slow transition, and we rotate appointments with peds and adults until age 30.”
Sophie Miriam Lanzkron, MD, MHS, director of the Sickle Cell Center for Adults at Johns Hopkins Hospital, Baltimore, said increases in mortality in the post-pediatric period appear to be due in part to “lack of access to high-quality sickle cell care for adults because there aren’t enough hematologists.” Worsening disease due to aging is another factor, she said, and “there might also be some behavioral changes. Young people think they will live forever. Sometimes they choose not to adhere to medical recommendations, which for this population is very risky.”
Dr. Lanzkron said her team is developing a long-term patient registry that should provide more insight.
No study funding was reported. Dr. Karkoska had no disclosures. The other coauthor disclosed research funding and safety advisory board relationships with Novartis. Dr. Ferdjallah, Dr. Lanzkron, and Dr. Bender reported no disclosures.
But the news is not all positive. Mortality rates still jumped markedly as patients transitioned from pediatric to adult care, lead author Kristine A. Karkoska, MD, a pediatric hematology/oncologist with the University of Cincinnati College of Medicine, said at the annual meeting of the American Society of Hematology.
“This reflects that young adults are getting lost to care, and then they’re presenting with acute, life-threatening complications,” she said. “We still need more emphasis on comprehensive lifetime sickle-cell care and the transition to adult clinics to improve mortality in young adults.”
According to Dr. Karkoska, researchers launched the analysis of sickle-cell mortality rates to update previously available data up to the year 2009, which showed improvements as current standard-of-care treatments were introduced. Updated numbers, she said, would reflect the influence of a rise in dedicated SCD clinics and a 2014 National Heart, Lung, and Blood Institute recommendation that all children with SCD be treated with hydroxyurea starting at 9 months.
For the study, Dr. Karkoska and colleagues analyzed mortality statistics from the period of 1979-2020 via a CDC database. They found that 5272 Black patients died of SCD from 2010 to 2020. The crude mortality rate was 1.1 per 100,000 Black people, lower than the 1.2 per 100,000 rate of 1999-2009 (P < .0001).
The researchers also found that from 2010 to 2020, the mortality rate jumped for patients in the 15-19 to 20-24 age group: It rose from 0.9 per 100,000 to 1.4 per 100,000, P < .0001).
The researchers also examined contributors to death other than SCD. In 39% of cases, underlying causes were noted: cardiovascular disease (28%), accidents (7%), cerebrovascular disease (7%), malignancy (6%), septicemia (4.8%), and renal disease (3.8%). The population of people with SCD is “getting older, and they’re developing a combination of both sickle-related chronic organ damage as well as non-sickle-related chronic disease,” Dr. Karkoska said.
She noted that limitations include a reliance on data that can be incomplete or inaccurate. She also mentioned that the study only focuses on Black patients, who make up the vast majority of those with SCD.
How good is the news about improved mortality numbers? One member of the audience at the ASH presentation was disappointed that they hadn’t gotten even better. “I was hoping to come here to be cheered up,” he said, “and I’m not.”
Three physicians who didn’t take part in the research but are familiar with the new study spoke in interviews about the findings.
Michael Bender, MD, PhD, director of the Odessa Brown Comprehensive Sickle Cell Clinic in Seattle, pointed out that mortality rates improve slowly over time, as new treatments enter the picture. When new therapies come along, he said, “it’s tough if someone’s already 40 years old and their body has gone through a lot. They’re not going to have as much benefit as someone who started [on therapy] when they were 5 years old, and they grew up with that improvement.”
Sickle cell specialist Asmaa Ferdjallah, MD, MPH, of the Mayo Clinic in Rochester, Minnesota, said that the data showing a spike in mortality rates during the pediatric-adult transition are not surprising but still “really hard to digest.”
“It is a testament to the fact that we are not meeting patients where they are,” she said. “We struggle immensely with the transition period. This is something that is difficult across all providers all over the country,” she said. “There are different ways to ensure a successful transition from the pediatric side to the adult side. Here at Mayo Clinic, we use a slow transition, and we rotate appointments with peds and adults until age 30.”
Sophie Miriam Lanzkron, MD, MHS, director of the Sickle Cell Center for Adults at Johns Hopkins Hospital, Baltimore, said increases in mortality in the post-pediatric period appear to be due in part to “lack of access to high-quality sickle cell care for adults because there aren’t enough hematologists.” Worsening disease due to aging is another factor, she said, and “there might also be some behavioral changes. Young people think they will live forever. Sometimes they choose not to adhere to medical recommendations, which for this population is very risky.”
Dr. Lanzkron said her team is developing a long-term patient registry that should provide more insight.
No study funding was reported. Dr. Karkoska had no disclosures. The other coauthor disclosed research funding and safety advisory board relationships with Novartis. Dr. Ferdjallah, Dr. Lanzkron, and Dr. Bender reported no disclosures.
But the news is not all positive. Mortality rates still jumped markedly as patients transitioned from pediatric to adult care, lead author Kristine A. Karkoska, MD, a pediatric hematology/oncologist with the University of Cincinnati College of Medicine, said at the annual meeting of the American Society of Hematology.
“This reflects that young adults are getting lost to care, and then they’re presenting with acute, life-threatening complications,” she said. “We still need more emphasis on comprehensive lifetime sickle-cell care and the transition to adult clinics to improve mortality in young adults.”
According to Dr. Karkoska, researchers launched the analysis of sickle-cell mortality rates to update previously available data up to the year 2009, which showed improvements as current standard-of-care treatments were introduced. Updated numbers, she said, would reflect the influence of a rise in dedicated SCD clinics and a 2014 National Heart, Lung, and Blood Institute recommendation that all children with SCD be treated with hydroxyurea starting at 9 months.
For the study, Dr. Karkoska and colleagues analyzed mortality statistics from the period of 1979-2020 via a CDC database. They found that 5272 Black patients died of SCD from 2010 to 2020. The crude mortality rate was 1.1 per 100,000 Black people, lower than the 1.2 per 100,000 rate of 1999-2009 (P < .0001).
The researchers also found that from 2010 to 2020, the mortality rate jumped for patients in the 15-19 to 20-24 age group: It rose from 0.9 per 100,000 to 1.4 per 100,000, P < .0001).
The researchers also examined contributors to death other than SCD. In 39% of cases, underlying causes were noted: cardiovascular disease (28%), accidents (7%), cerebrovascular disease (7%), malignancy (6%), septicemia (4.8%), and renal disease (3.8%). The population of people with SCD is “getting older, and they’re developing a combination of both sickle-related chronic organ damage as well as non-sickle-related chronic disease,” Dr. Karkoska said.
She noted that limitations include a reliance on data that can be incomplete or inaccurate. She also mentioned that the study only focuses on Black patients, who make up the vast majority of those with SCD.
How good is the news about improved mortality numbers? One member of the audience at the ASH presentation was disappointed that they hadn’t gotten even better. “I was hoping to come here to be cheered up,” he said, “and I’m not.”
Three physicians who didn’t take part in the research but are familiar with the new study spoke in interviews about the findings.
Michael Bender, MD, PhD, director of the Odessa Brown Comprehensive Sickle Cell Clinic in Seattle, pointed out that mortality rates improve slowly over time, as new treatments enter the picture. When new therapies come along, he said, “it’s tough if someone’s already 40 years old and their body has gone through a lot. They’re not going to have as much benefit as someone who started [on therapy] when they were 5 years old, and they grew up with that improvement.”
Sickle cell specialist Asmaa Ferdjallah, MD, MPH, of the Mayo Clinic in Rochester, Minnesota, said that the data showing a spike in mortality rates during the pediatric-adult transition are not surprising but still “really hard to digest.”
“It is a testament to the fact that we are not meeting patients where they are,” she said. “We struggle immensely with the transition period. This is something that is difficult across all providers all over the country,” she said. “There are different ways to ensure a successful transition from the pediatric side to the adult side. Here at Mayo Clinic, we use a slow transition, and we rotate appointments with peds and adults until age 30.”
Sophie Miriam Lanzkron, MD, MHS, director of the Sickle Cell Center for Adults at Johns Hopkins Hospital, Baltimore, said increases in mortality in the post-pediatric period appear to be due in part to “lack of access to high-quality sickle cell care for adults because there aren’t enough hematologists.” Worsening disease due to aging is another factor, she said, and “there might also be some behavioral changes. Young people think they will live forever. Sometimes they choose not to adhere to medical recommendations, which for this population is very risky.”
Dr. Lanzkron said her team is developing a long-term patient registry that should provide more insight.
No study funding was reported. Dr. Karkoska had no disclosures. The other coauthor disclosed research funding and safety advisory board relationships with Novartis. Dr. Ferdjallah, Dr. Lanzkron, and Dr. Bender reported no disclosures.
FROM ASH 2023
MRD status predicts transplant benefit in NPM1-mutated AML
.
This survival benefit did not extend to patients who were MRD-negative after their second induction therapy, Jad Othman, MBBS, reported at the American Society of Hematology annual meeting.
The findings confirm the value of assessing MRD after induction chemotherapy to help identify patients with NPM1-mutated AML in first complete remission who are more likely to benefit from allogeneic transplant, said Dr. Othman, of King’s College London and Guy’s and St Thomas’ NHS Foundation Trust, London, and the University of Sydney, Australia.
Recently, updated European LeukemiaNet recommendations, which stratify patients with AML by favorable, intermediate, and adverse prognoses, now include a revised genetic-risk classification. This classification generally considers NPM1-mutated AML favorable risk. However, having a co-mutation with FLT3-ITD raises the risk to intermediate.
Despite this increased granularity in risk stratification, “it’s still not really clear who should have transplant in first remission with NPM1-mutated AML,” Dr. Othman said. “And there is still significant variation in practice, not just worldwide but even center to center.”
Although accumulating evidence suggests that MRD-negative patients with intermediate-risk AML are unlikely to benefit from allogeneic transplant in first complete remission, the presence of a FLT3-ITD mutation is often considered an indication for transplant, Othman explained. However, most studies supporting this view occurred before the development of sensitive molecular MRD measurement techniques.
The latest findings, from two sequential prospective randomized trials of intensive chemotherapy in adults aged 18-60 years with newly diagnosed AML may help clarify who will probably benefit from transplant and who won’t based on MRD status and relevant molecular features.
The first study (AML17), conducted from 2009 to 2014, selected patients for transplant in first complete remission using a validated risk score that incorporated features including age, sex, and response after therapy. The other (AML19), conducted from 2015 to 2020, selected patients with NPM1-mutated AML for transplant only if they tested positive for MRD in peripheral blood after their second course of treatment, regardless of FLT3-ITD status or other baseline risk factors.
Overall, the current analysis included the 737 patients with NPM1-mutated AML, 348 from AML17 and 389 from AML19, who were in complete remission after two courses of treatment and had an MRD sample at that point.
In AML17, 27% of MRD-positive patients (16 of 60) and 18% of MRD-negative patients (52 of 288) underwent transplant in first complete remission compared with 60% (50 of 83) and 16% (49 of 306), respectively, in AML19.
Among all 737 patients, Dr. Othman and colleagues did not observe an overall survival benefit among those who underwent transplant vs those who did not (hazard ratio [HR], 1.01) or among patients who were MRD-negative (HR, 0.82).
However, patients who were MRD-positive did have a significant survival advantage after transplant (HR, 0.39). In these patients, 3-year overall survival was 61% among those who underwent transplant vs 24% among those who did not.
In MRD-negative patients, transplant in first complete remission did not improve overall survival despite improved relapse-free survival (HR, 0.50). This outcome, Othman explained, probably occurred because most patients who did not undergo transplant and who relapsed were salvaged, with about two thirds undergoing a transplant during their second complete response.
Results in patients with NPM1 FLT3-ITD co-mutation mirrored those in the overall population: MRD-positive patients in first complete remission who underwent transplant demonstrated improved overall survival compared with those without transplant (HR, 0.52), but the overall survival benefit did not extend to MRD-negative patients (HR, 0.80).
The findings show that molecular MRD after induction chemotherapy can identify patients with NPM1-mutated AML who are more likely to benefit from transplant in first remission, Dr. Othman concluded. However, he noted, because only 16% of patients overall were older than 60 years, the results may not be generalizable to older patients.
A version of this article appeared on Medscape.com.
.
This survival benefit did not extend to patients who were MRD-negative after their second induction therapy, Jad Othman, MBBS, reported at the American Society of Hematology annual meeting.
The findings confirm the value of assessing MRD after induction chemotherapy to help identify patients with NPM1-mutated AML in first complete remission who are more likely to benefit from allogeneic transplant, said Dr. Othman, of King’s College London and Guy’s and St Thomas’ NHS Foundation Trust, London, and the University of Sydney, Australia.
Recently, updated European LeukemiaNet recommendations, which stratify patients with AML by favorable, intermediate, and adverse prognoses, now include a revised genetic-risk classification. This classification generally considers NPM1-mutated AML favorable risk. However, having a co-mutation with FLT3-ITD raises the risk to intermediate.
Despite this increased granularity in risk stratification, “it’s still not really clear who should have transplant in first remission with NPM1-mutated AML,” Dr. Othman said. “And there is still significant variation in practice, not just worldwide but even center to center.”
Although accumulating evidence suggests that MRD-negative patients with intermediate-risk AML are unlikely to benefit from allogeneic transplant in first complete remission, the presence of a FLT3-ITD mutation is often considered an indication for transplant, Othman explained. However, most studies supporting this view occurred before the development of sensitive molecular MRD measurement techniques.
The latest findings, from two sequential prospective randomized trials of intensive chemotherapy in adults aged 18-60 years with newly diagnosed AML may help clarify who will probably benefit from transplant and who won’t based on MRD status and relevant molecular features.
The first study (AML17), conducted from 2009 to 2014, selected patients for transplant in first complete remission using a validated risk score that incorporated features including age, sex, and response after therapy. The other (AML19), conducted from 2015 to 2020, selected patients with NPM1-mutated AML for transplant only if they tested positive for MRD in peripheral blood after their second course of treatment, regardless of FLT3-ITD status or other baseline risk factors.
Overall, the current analysis included the 737 patients with NPM1-mutated AML, 348 from AML17 and 389 from AML19, who were in complete remission after two courses of treatment and had an MRD sample at that point.
In AML17, 27% of MRD-positive patients (16 of 60) and 18% of MRD-negative patients (52 of 288) underwent transplant in first complete remission compared with 60% (50 of 83) and 16% (49 of 306), respectively, in AML19.
Among all 737 patients, Dr. Othman and colleagues did not observe an overall survival benefit among those who underwent transplant vs those who did not (hazard ratio [HR], 1.01) or among patients who were MRD-negative (HR, 0.82).
However, patients who were MRD-positive did have a significant survival advantage after transplant (HR, 0.39). In these patients, 3-year overall survival was 61% among those who underwent transplant vs 24% among those who did not.
In MRD-negative patients, transplant in first complete remission did not improve overall survival despite improved relapse-free survival (HR, 0.50). This outcome, Othman explained, probably occurred because most patients who did not undergo transplant and who relapsed were salvaged, with about two thirds undergoing a transplant during their second complete response.
Results in patients with NPM1 FLT3-ITD co-mutation mirrored those in the overall population: MRD-positive patients in first complete remission who underwent transplant demonstrated improved overall survival compared with those without transplant (HR, 0.52), but the overall survival benefit did not extend to MRD-negative patients (HR, 0.80).
The findings show that molecular MRD after induction chemotherapy can identify patients with NPM1-mutated AML who are more likely to benefit from transplant in first remission, Dr. Othman concluded. However, he noted, because only 16% of patients overall were older than 60 years, the results may not be generalizable to older patients.
A version of this article appeared on Medscape.com.
.
This survival benefit did not extend to patients who were MRD-negative after their second induction therapy, Jad Othman, MBBS, reported at the American Society of Hematology annual meeting.
The findings confirm the value of assessing MRD after induction chemotherapy to help identify patients with NPM1-mutated AML in first complete remission who are more likely to benefit from allogeneic transplant, said Dr. Othman, of King’s College London and Guy’s and St Thomas’ NHS Foundation Trust, London, and the University of Sydney, Australia.
Recently, updated European LeukemiaNet recommendations, which stratify patients with AML by favorable, intermediate, and adverse prognoses, now include a revised genetic-risk classification. This classification generally considers NPM1-mutated AML favorable risk. However, having a co-mutation with FLT3-ITD raises the risk to intermediate.
Despite this increased granularity in risk stratification, “it’s still not really clear who should have transplant in first remission with NPM1-mutated AML,” Dr. Othman said. “And there is still significant variation in practice, not just worldwide but even center to center.”
Although accumulating evidence suggests that MRD-negative patients with intermediate-risk AML are unlikely to benefit from allogeneic transplant in first complete remission, the presence of a FLT3-ITD mutation is often considered an indication for transplant, Othman explained. However, most studies supporting this view occurred before the development of sensitive molecular MRD measurement techniques.
The latest findings, from two sequential prospective randomized trials of intensive chemotherapy in adults aged 18-60 years with newly diagnosed AML may help clarify who will probably benefit from transplant and who won’t based on MRD status and relevant molecular features.
The first study (AML17), conducted from 2009 to 2014, selected patients for transplant in first complete remission using a validated risk score that incorporated features including age, sex, and response after therapy. The other (AML19), conducted from 2015 to 2020, selected patients with NPM1-mutated AML for transplant only if they tested positive for MRD in peripheral blood after their second course of treatment, regardless of FLT3-ITD status or other baseline risk factors.
Overall, the current analysis included the 737 patients with NPM1-mutated AML, 348 from AML17 and 389 from AML19, who were in complete remission after two courses of treatment and had an MRD sample at that point.
In AML17, 27% of MRD-positive patients (16 of 60) and 18% of MRD-negative patients (52 of 288) underwent transplant in first complete remission compared with 60% (50 of 83) and 16% (49 of 306), respectively, in AML19.
Among all 737 patients, Dr. Othman and colleagues did not observe an overall survival benefit among those who underwent transplant vs those who did not (hazard ratio [HR], 1.01) or among patients who were MRD-negative (HR, 0.82).
However, patients who were MRD-positive did have a significant survival advantage after transplant (HR, 0.39). In these patients, 3-year overall survival was 61% among those who underwent transplant vs 24% among those who did not.
In MRD-negative patients, transplant in first complete remission did not improve overall survival despite improved relapse-free survival (HR, 0.50). This outcome, Othman explained, probably occurred because most patients who did not undergo transplant and who relapsed were salvaged, with about two thirds undergoing a transplant during their second complete response.
Results in patients with NPM1 FLT3-ITD co-mutation mirrored those in the overall population: MRD-positive patients in first complete remission who underwent transplant demonstrated improved overall survival compared with those without transplant (HR, 0.52), but the overall survival benefit did not extend to MRD-negative patients (HR, 0.80).
The findings show that molecular MRD after induction chemotherapy can identify patients with NPM1-mutated AML who are more likely to benefit from transplant in first remission, Dr. Othman concluded. However, he noted, because only 16% of patients overall were older than 60 years, the results may not be generalizable to older patients.
A version of this article appeared on Medscape.com.
FROM ASH 2023
Sickle Cell: Good Outcomes for Haploidentical Transplants
Of 42 patients aged 15-45 who were fully treated, 95% survived to 2 years post transplant (overall survival, (95% CI, 81.5%-98.7%), and 88% reached the primary endpoint of event-free survival at 2 years (95% CI, 73.5%-94.8%), according to the findings, which were released at the annual meeting of the American Society of Hematology.
At an ASH news briefing, study lead author Adetola A. Kassim, MBBS, MS, of Vanderbilt University Medical Center, in Nashville, Tennessee, said the results support haploidentical stem cell transplants “as a suitable and tolerable curative therapy for adults with sickle cell disease and severe end-organ toxicity such as stroke or pulmonary hypertension, a population typically excluded from participating in gene therapy.”
Dr. Kassim added that the findings are especially promising since there are so many potential donors in stem-cell transplants: “Your siblings can be donors, your parents can be donors, your cousins can be donors. First-, second-, and third-degree relatives can be donors. So there’s really endless donors within the family.”
In an interview, Mayo Clinic SCD specialist Asmaa Ferdjallah, MD, MPH, of Mayo Clinic in Rochester, Minnesota, who was not involved with the study but is familiar with its findings, said stem cell transplant is the only option to cure SCD.
“This is advantageous because SCD is otherwise a chronic disease that is marked by chronic pain, risk of stroke, frequent interruptions of school/work due to sick days, and decreased life span,” she said. “Most patients, assuming they can tolerate the conditioning chemotherapy that is given before transplant, are eligible.”
Matched sibling donors are preferable, but they can be hard to find, she said. It hasn’t been clear whether half-matched donors are feasible options in SCD, she said. “This means that, if you are a patient with sickle cell disease, and you don’t have a suitable matched donor, haploidentical transplant is not a recommendation we can make outside of enrollment in a clinical trial.”
For the study, researchers enlisted 54 patients with SCD and prior stroke, recurrent acute chest syndrome or pain, chronic transfusion regimen, or tricuspid valve regurgitant jet velocity ≥2.7 m/sec. Participants had to have an HLA-haploidentical first-degree relative donor who would donate bone marrow.
“The median age was 22.8 years at enrollment; 47/54 (87%) of enrolled participants had hemoglobin SS disease, 40/54 (74.1%) had a Lansky/Karnofsky score of 90-100 at baseline, and 41/54 (75.9%) had an HLA match score of 4/8,” the researchers reported. “Recurrent vaso-occlusive pain episodes (38.9%), acute chest syndrome (16.8%), and overt stroke (16.7%) were the most common indications for transplant.”
“We knew going into this that we were going to get very high-risk patients,” Dr. Kassim said.
Forty-two patients went through with transplants. As for adverse events, 2 patients died, all within the first year, of organ failure and acute respiratory distress syndrome; 4.8% of participants had primary graft failure, and 2.4% had secondary graft failure before day 100. “The cumulative incidence of grades II-IV acute GVHD [graft-versus-host disease] at day 100 was 26.2% (95% CI, 14.0%-40.2%), and grades III-IV acute GVHD at day 100 was 4.8% (95% CI, 0.9%-14.4%).”
The outcomes are similar to those in transplants with matched sibling donors, Dr. Kassim said.
Dr. Ferdjallah said the new study is “robust” and impressive, although it’s small.
“As a clinician, these are the kind of outcomes I have been hoping for,” Dr. Ferdjallah said. “I have been very reluctant to suggest haploidentical transplant for my sickle cell disease patients. However, reviewing the results of this study with my motivated patients and families can help us both to use shared medical decision-making and come together with what is best for that specific patient.”
As for adverse events, she said they “confirm a fear of using haploidentical transplant, which is graft failure. Fortunately, out of 42 who proceeded to transplant, only 2 had primary graft failure and 1 had secondary graft failure. This is not overtly a large number. Of course, we would hope for more durable engraftment. The other side effects including GVHD and infection are all to be expected.”
As for cost, Dr. Kassim said the transplants run from $200,000 to $400,000 vs over $2 million for gene therapy, and Dr. Ferdjallah said insurance is likely to cover the treatment.
Moving ahead, Dr. Ferdjallah said she looks forward to getting study data about pediatric patients specifically. For now, “we should consider HLA-haploidentical seriously in patients with sickle cell disease and no available HLA-matched donors.”
Grants to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute and National Cancer Institute funded the study. Dr. Kassim had no disclosures. Some other authors disclosed various and multiple relationships with industry. Dr. Ferdjallah has no disclosures.
Of 42 patients aged 15-45 who were fully treated, 95% survived to 2 years post transplant (overall survival, (95% CI, 81.5%-98.7%), and 88% reached the primary endpoint of event-free survival at 2 years (95% CI, 73.5%-94.8%), according to the findings, which were released at the annual meeting of the American Society of Hematology.
At an ASH news briefing, study lead author Adetola A. Kassim, MBBS, MS, of Vanderbilt University Medical Center, in Nashville, Tennessee, said the results support haploidentical stem cell transplants “as a suitable and tolerable curative therapy for adults with sickle cell disease and severe end-organ toxicity such as stroke or pulmonary hypertension, a population typically excluded from participating in gene therapy.”
Dr. Kassim added that the findings are especially promising since there are so many potential donors in stem-cell transplants: “Your siblings can be donors, your parents can be donors, your cousins can be donors. First-, second-, and third-degree relatives can be donors. So there’s really endless donors within the family.”
In an interview, Mayo Clinic SCD specialist Asmaa Ferdjallah, MD, MPH, of Mayo Clinic in Rochester, Minnesota, who was not involved with the study but is familiar with its findings, said stem cell transplant is the only option to cure SCD.
“This is advantageous because SCD is otherwise a chronic disease that is marked by chronic pain, risk of stroke, frequent interruptions of school/work due to sick days, and decreased life span,” she said. “Most patients, assuming they can tolerate the conditioning chemotherapy that is given before transplant, are eligible.”
Matched sibling donors are preferable, but they can be hard to find, she said. It hasn’t been clear whether half-matched donors are feasible options in SCD, she said. “This means that, if you are a patient with sickle cell disease, and you don’t have a suitable matched donor, haploidentical transplant is not a recommendation we can make outside of enrollment in a clinical trial.”
For the study, researchers enlisted 54 patients with SCD and prior stroke, recurrent acute chest syndrome or pain, chronic transfusion regimen, or tricuspid valve regurgitant jet velocity ≥2.7 m/sec. Participants had to have an HLA-haploidentical first-degree relative donor who would donate bone marrow.
“The median age was 22.8 years at enrollment; 47/54 (87%) of enrolled participants had hemoglobin SS disease, 40/54 (74.1%) had a Lansky/Karnofsky score of 90-100 at baseline, and 41/54 (75.9%) had an HLA match score of 4/8,” the researchers reported. “Recurrent vaso-occlusive pain episodes (38.9%), acute chest syndrome (16.8%), and overt stroke (16.7%) were the most common indications for transplant.”
“We knew going into this that we were going to get very high-risk patients,” Dr. Kassim said.
Forty-two patients went through with transplants. As for adverse events, 2 patients died, all within the first year, of organ failure and acute respiratory distress syndrome; 4.8% of participants had primary graft failure, and 2.4% had secondary graft failure before day 100. “The cumulative incidence of grades II-IV acute GVHD [graft-versus-host disease] at day 100 was 26.2% (95% CI, 14.0%-40.2%), and grades III-IV acute GVHD at day 100 was 4.8% (95% CI, 0.9%-14.4%).”
The outcomes are similar to those in transplants with matched sibling donors, Dr. Kassim said.
Dr. Ferdjallah said the new study is “robust” and impressive, although it’s small.
“As a clinician, these are the kind of outcomes I have been hoping for,” Dr. Ferdjallah said. “I have been very reluctant to suggest haploidentical transplant for my sickle cell disease patients. However, reviewing the results of this study with my motivated patients and families can help us both to use shared medical decision-making and come together with what is best for that specific patient.”
As for adverse events, she said they “confirm a fear of using haploidentical transplant, which is graft failure. Fortunately, out of 42 who proceeded to transplant, only 2 had primary graft failure and 1 had secondary graft failure. This is not overtly a large number. Of course, we would hope for more durable engraftment. The other side effects including GVHD and infection are all to be expected.”
As for cost, Dr. Kassim said the transplants run from $200,000 to $400,000 vs over $2 million for gene therapy, and Dr. Ferdjallah said insurance is likely to cover the treatment.
Moving ahead, Dr. Ferdjallah said she looks forward to getting study data about pediatric patients specifically. For now, “we should consider HLA-haploidentical seriously in patients with sickle cell disease and no available HLA-matched donors.”
Grants to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute and National Cancer Institute funded the study. Dr. Kassim had no disclosures. Some other authors disclosed various and multiple relationships with industry. Dr. Ferdjallah has no disclosures.
Of 42 patients aged 15-45 who were fully treated, 95% survived to 2 years post transplant (overall survival, (95% CI, 81.5%-98.7%), and 88% reached the primary endpoint of event-free survival at 2 years (95% CI, 73.5%-94.8%), according to the findings, which were released at the annual meeting of the American Society of Hematology.
At an ASH news briefing, study lead author Adetola A. Kassim, MBBS, MS, of Vanderbilt University Medical Center, in Nashville, Tennessee, said the results support haploidentical stem cell transplants “as a suitable and tolerable curative therapy for adults with sickle cell disease and severe end-organ toxicity such as stroke or pulmonary hypertension, a population typically excluded from participating in gene therapy.”
Dr. Kassim added that the findings are especially promising since there are so many potential donors in stem-cell transplants: “Your siblings can be donors, your parents can be donors, your cousins can be donors. First-, second-, and third-degree relatives can be donors. So there’s really endless donors within the family.”
In an interview, Mayo Clinic SCD specialist Asmaa Ferdjallah, MD, MPH, of Mayo Clinic in Rochester, Minnesota, who was not involved with the study but is familiar with its findings, said stem cell transplant is the only option to cure SCD.
“This is advantageous because SCD is otherwise a chronic disease that is marked by chronic pain, risk of stroke, frequent interruptions of school/work due to sick days, and decreased life span,” she said. “Most patients, assuming they can tolerate the conditioning chemotherapy that is given before transplant, are eligible.”
Matched sibling donors are preferable, but they can be hard to find, she said. It hasn’t been clear whether half-matched donors are feasible options in SCD, she said. “This means that, if you are a patient with sickle cell disease, and you don’t have a suitable matched donor, haploidentical transplant is not a recommendation we can make outside of enrollment in a clinical trial.”
For the study, researchers enlisted 54 patients with SCD and prior stroke, recurrent acute chest syndrome or pain, chronic transfusion regimen, or tricuspid valve regurgitant jet velocity ≥2.7 m/sec. Participants had to have an HLA-haploidentical first-degree relative donor who would donate bone marrow.
“The median age was 22.8 years at enrollment; 47/54 (87%) of enrolled participants had hemoglobin SS disease, 40/54 (74.1%) had a Lansky/Karnofsky score of 90-100 at baseline, and 41/54 (75.9%) had an HLA match score of 4/8,” the researchers reported. “Recurrent vaso-occlusive pain episodes (38.9%), acute chest syndrome (16.8%), and overt stroke (16.7%) were the most common indications for transplant.”
“We knew going into this that we were going to get very high-risk patients,” Dr. Kassim said.
Forty-two patients went through with transplants. As for adverse events, 2 patients died, all within the first year, of organ failure and acute respiratory distress syndrome; 4.8% of participants had primary graft failure, and 2.4% had secondary graft failure before day 100. “The cumulative incidence of grades II-IV acute GVHD [graft-versus-host disease] at day 100 was 26.2% (95% CI, 14.0%-40.2%), and grades III-IV acute GVHD at day 100 was 4.8% (95% CI, 0.9%-14.4%).”
The outcomes are similar to those in transplants with matched sibling donors, Dr. Kassim said.
Dr. Ferdjallah said the new study is “robust” and impressive, although it’s small.
“As a clinician, these are the kind of outcomes I have been hoping for,” Dr. Ferdjallah said. “I have been very reluctant to suggest haploidentical transplant for my sickle cell disease patients. However, reviewing the results of this study with my motivated patients and families can help us both to use shared medical decision-making and come together with what is best for that specific patient.”
As for adverse events, she said they “confirm a fear of using haploidentical transplant, which is graft failure. Fortunately, out of 42 who proceeded to transplant, only 2 had primary graft failure and 1 had secondary graft failure. This is not overtly a large number. Of course, we would hope for more durable engraftment. The other side effects including GVHD and infection are all to be expected.”
As for cost, Dr. Kassim said the transplants run from $200,000 to $400,000 vs over $2 million for gene therapy, and Dr. Ferdjallah said insurance is likely to cover the treatment.
Moving ahead, Dr. Ferdjallah said she looks forward to getting study data about pediatric patients specifically. For now, “we should consider HLA-haploidentical seriously in patients with sickle cell disease and no available HLA-matched donors.”
Grants to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute and National Cancer Institute funded the study. Dr. Kassim had no disclosures. Some other authors disclosed various and multiple relationships with industry. Dr. Ferdjallah has no disclosures.
FROM ASH 2023
Measurable residual disease–guided therapy promising for CLL
The targeted therapy combination was also associated with better progression-free survival among patients with CLL with worse prognostic features, including immunoglobulin heavy chain variable (IGHV) unmutated disease and cytogenetic abnormalities, such as the 11q deletion, trisomy 12, and 13q deletion.
Personalizing treatment duration of ibrutinib-venetoclax, as determined by measurable residual disease (MRD), allowed more than half of patients assigned to the combination therapy to stop therapy by 3 years because they had achieved MRD negativity, reported Peter Hillmen, MBChB, PhD, from the Leeds Institute of Medical Research at St James’s University Hospital in Leeds, United Kingdom.
The shorter course of therapy could help to ameliorate toxicities and lower the risk for the development of drug-resistant disease, he said.
“This is the first trial to show that an MRD-guided approach with treatment beyond [MRD] negativity has a significant advantage over chemoimmunotherapy, both in terms of [progression-free] and overall survival. Over 90% of patients achieve an MRD-negative in this combination in the peripheral blood,” said Dr. Hillmen in a media briefing prior to his presentation of the data in an oral abstract session here at the American Society of Hematology annual meeting.
The study results were also published online in The New England Journal of Medicine to coincide with the presentation.
Adaptive Trial
The FLAIR study is a phase 3 open-label platform trial that initially compared ibrutinib-rituximab with fludarabine-cyclophosphamide-rituximab (FCR) in patients with untreated CLL. However, in 2017 the trial was adapted to include both an ibrutinib monotherapy and an ibrutinib-venetoclax arm with therapy duration determined by MRD.
At ASH 2023, Dr. Hillmen presented data from an interim analysis of 523 patients comparing ibrutinib-venetoclax with FCR.
In the ibrutinib-venetoclax group, patients received oral ibrutinib 420 mg daily, with venetoclax added after 2 months, beginning with a 20-mg dose ramped up to 400 mg in a weekly dose-escalation schedule. The combination could be given for 2-6 years, depending on MRD responses. FCR was delivered in up to six cycles of 28 days each. Two thirds of patients assigned to FCR completed all six cycles.
After a median follow-up of 43.7 months, 12 patients (4.6%) randomly assigned to ibrutinib-venetoclax had disease progression or died compared with 75 patients (28.5%) assigned to FCR. The estimated 3-year progression-free survival with ibrutinib-venetoclax was 97.2%, compared with 76.8% with FCR, translating into a hazard ratio (HR) for progression or death with the targeted therapy combination of 0.13 (P <.001).
Among patients with unmutated IGHV, the combination led to improved progression-free survival compared with FCR (hazard ratio [HR] for progression or death, 0.07); for patients with mutated IGHV, however, the combination did not improve progression-free survival (HR, 0.54; 95% CI, 0.21-1.38).
In all, eight patients (3.5%) assigned to ibrutinib-venetoclax and 23 assigned to FCR (9.5%) died.
The 3-year overall survival rates were 98% in the targeted therapy group vs 93% in the FCR group (HR for progression or death, 0.31).
At 2 years, 52.4% of patients assigned to ibrutinib-venetoclax had undetectable MRD in bone marrow compared with 49.8% with FCR. At 5 years, the respective percentages for MRD in bone marrow were 65.9% vs 49.8% and 92.7% vs 67.9% for MRD in peripheral blood.
The safety analysis showed higher rates of blood and lymphatic system disorders with FCR, whereas cardiac, metabolic/nutrition disorders, and eye disorders occurred more frequent with ibrutinib-venetoclax.
A total of 24 secondary cancers were diagnosed in 17 patients randomly assigned to ibrutinib-venetoclax and 45 secondary cancers among 34 patients randomly assigned to FCR. One patient assigned to ibrutinib-venetoclax developed myelodysplastic syndrome/acute myeloid leukemia (AML), as did eight patients assigned to FCR. One patient in the ibrutinib-venetoclax arm and four patients in the FCR arm had Richter’s transformation.
The incidence rate for other cancers was 2.6 per 100 person-years with ibrutinib-venetoclax compared with 5.4 per 100 person-years with FCR.
The most frequently occurring cancers in each arm were basal cell or squamous cell carcinomas. The incidence of myelodysplastic syndromes, AML lymphoma, and prostate/urologic cancers was higher among patients on FCR.
This research “unequivocally shows the superiority of targeted therapy over traditional cytotoxic chemotherapy,” commented briefing moderator Mikkael A. Sekeres, MD, from the University of Miami Miller School of Medicine.
The ibrutinib-venetoclax combination has the potential to reduce the incidence of myelodysplastic syndromes secondary to CLL therapy, Dr. Sekeres suggested.
“As someone who specializes in leukemia and myelodysplastic syndromes, I have the feeling I won’t be seeing these CLL patients in my clinic — years after being treated for CLL — much longer,” he said.
In an interview with this news organization, Lee Greenberger, PhD, said that “I think that duration-adapted therapy is a great story. Using MRD negativity is a perfectly justified way, I think, to go about a new combination that’s going to be really potent for CLL patients and probably give them many years of treatment and then to get off the drug, because ultimately the goal is to get cures.”
This combination, though highly efficacious, is unlikely to be curative; however, because even when MRD is undetectable, “it will come back,” said Dr. Greenberger, chief scientific officer for the Leukemia & Lymphoma Society.
Dr. Greenberger added that MRD testing of bone marrow, which provides a more detailed picture of MRD status than testing of peripheral blood, is feasible in academic medical centers but may be a barrier to MRD-adapted therapy in community oncology practices.
The FLAIR study is supported by grants from Cancer Research UK, Janssen, Pharmacyclics, and AbbVie. Dr. Hillmen disclosed employment and equity participation with Apellis Pharmaceuticals. Dr. Sekeres disclosed board activities for Geron, Novartis, and Bristol-Myers Squibb and owner of stock options Kurome. Dr. Greenberger reported no relevant financial disclosures.
A version of this article appeared on Medscape.com.
The targeted therapy combination was also associated with better progression-free survival among patients with CLL with worse prognostic features, including immunoglobulin heavy chain variable (IGHV) unmutated disease and cytogenetic abnormalities, such as the 11q deletion, trisomy 12, and 13q deletion.
Personalizing treatment duration of ibrutinib-venetoclax, as determined by measurable residual disease (MRD), allowed more than half of patients assigned to the combination therapy to stop therapy by 3 years because they had achieved MRD negativity, reported Peter Hillmen, MBChB, PhD, from the Leeds Institute of Medical Research at St James’s University Hospital in Leeds, United Kingdom.
The shorter course of therapy could help to ameliorate toxicities and lower the risk for the development of drug-resistant disease, he said.
“This is the first trial to show that an MRD-guided approach with treatment beyond [MRD] negativity has a significant advantage over chemoimmunotherapy, both in terms of [progression-free] and overall survival. Over 90% of patients achieve an MRD-negative in this combination in the peripheral blood,” said Dr. Hillmen in a media briefing prior to his presentation of the data in an oral abstract session here at the American Society of Hematology annual meeting.
The study results were also published online in The New England Journal of Medicine to coincide with the presentation.
Adaptive Trial
The FLAIR study is a phase 3 open-label platform trial that initially compared ibrutinib-rituximab with fludarabine-cyclophosphamide-rituximab (FCR) in patients with untreated CLL. However, in 2017 the trial was adapted to include both an ibrutinib monotherapy and an ibrutinib-venetoclax arm with therapy duration determined by MRD.
At ASH 2023, Dr. Hillmen presented data from an interim analysis of 523 patients comparing ibrutinib-venetoclax with FCR.
In the ibrutinib-venetoclax group, patients received oral ibrutinib 420 mg daily, with venetoclax added after 2 months, beginning with a 20-mg dose ramped up to 400 mg in a weekly dose-escalation schedule. The combination could be given for 2-6 years, depending on MRD responses. FCR was delivered in up to six cycles of 28 days each. Two thirds of patients assigned to FCR completed all six cycles.
After a median follow-up of 43.7 months, 12 patients (4.6%) randomly assigned to ibrutinib-venetoclax had disease progression or died compared with 75 patients (28.5%) assigned to FCR. The estimated 3-year progression-free survival with ibrutinib-venetoclax was 97.2%, compared with 76.8% with FCR, translating into a hazard ratio (HR) for progression or death with the targeted therapy combination of 0.13 (P <.001).
Among patients with unmutated IGHV, the combination led to improved progression-free survival compared with FCR (hazard ratio [HR] for progression or death, 0.07); for patients with mutated IGHV, however, the combination did not improve progression-free survival (HR, 0.54; 95% CI, 0.21-1.38).
In all, eight patients (3.5%) assigned to ibrutinib-venetoclax and 23 assigned to FCR (9.5%) died.
The 3-year overall survival rates were 98% in the targeted therapy group vs 93% in the FCR group (HR for progression or death, 0.31).
At 2 years, 52.4% of patients assigned to ibrutinib-venetoclax had undetectable MRD in bone marrow compared with 49.8% with FCR. At 5 years, the respective percentages for MRD in bone marrow were 65.9% vs 49.8% and 92.7% vs 67.9% for MRD in peripheral blood.
The safety analysis showed higher rates of blood and lymphatic system disorders with FCR, whereas cardiac, metabolic/nutrition disorders, and eye disorders occurred more frequent with ibrutinib-venetoclax.
A total of 24 secondary cancers were diagnosed in 17 patients randomly assigned to ibrutinib-venetoclax and 45 secondary cancers among 34 patients randomly assigned to FCR. One patient assigned to ibrutinib-venetoclax developed myelodysplastic syndrome/acute myeloid leukemia (AML), as did eight patients assigned to FCR. One patient in the ibrutinib-venetoclax arm and four patients in the FCR arm had Richter’s transformation.
The incidence rate for other cancers was 2.6 per 100 person-years with ibrutinib-venetoclax compared with 5.4 per 100 person-years with FCR.
The most frequently occurring cancers in each arm were basal cell or squamous cell carcinomas. The incidence of myelodysplastic syndromes, AML lymphoma, and prostate/urologic cancers was higher among patients on FCR.
This research “unequivocally shows the superiority of targeted therapy over traditional cytotoxic chemotherapy,” commented briefing moderator Mikkael A. Sekeres, MD, from the University of Miami Miller School of Medicine.
The ibrutinib-venetoclax combination has the potential to reduce the incidence of myelodysplastic syndromes secondary to CLL therapy, Dr. Sekeres suggested.
“As someone who specializes in leukemia and myelodysplastic syndromes, I have the feeling I won’t be seeing these CLL patients in my clinic — years after being treated for CLL — much longer,” he said.
In an interview with this news organization, Lee Greenberger, PhD, said that “I think that duration-adapted therapy is a great story. Using MRD negativity is a perfectly justified way, I think, to go about a new combination that’s going to be really potent for CLL patients and probably give them many years of treatment and then to get off the drug, because ultimately the goal is to get cures.”
This combination, though highly efficacious, is unlikely to be curative; however, because even when MRD is undetectable, “it will come back,” said Dr. Greenberger, chief scientific officer for the Leukemia & Lymphoma Society.
Dr. Greenberger added that MRD testing of bone marrow, which provides a more detailed picture of MRD status than testing of peripheral blood, is feasible in academic medical centers but may be a barrier to MRD-adapted therapy in community oncology practices.
The FLAIR study is supported by grants from Cancer Research UK, Janssen, Pharmacyclics, and AbbVie. Dr. Hillmen disclosed employment and equity participation with Apellis Pharmaceuticals. Dr. Sekeres disclosed board activities for Geron, Novartis, and Bristol-Myers Squibb and owner of stock options Kurome. Dr. Greenberger reported no relevant financial disclosures.
A version of this article appeared on Medscape.com.
The targeted therapy combination was also associated with better progression-free survival among patients with CLL with worse prognostic features, including immunoglobulin heavy chain variable (IGHV) unmutated disease and cytogenetic abnormalities, such as the 11q deletion, trisomy 12, and 13q deletion.
Personalizing treatment duration of ibrutinib-venetoclax, as determined by measurable residual disease (MRD), allowed more than half of patients assigned to the combination therapy to stop therapy by 3 years because they had achieved MRD negativity, reported Peter Hillmen, MBChB, PhD, from the Leeds Institute of Medical Research at St James’s University Hospital in Leeds, United Kingdom.
The shorter course of therapy could help to ameliorate toxicities and lower the risk for the development of drug-resistant disease, he said.
“This is the first trial to show that an MRD-guided approach with treatment beyond [MRD] negativity has a significant advantage over chemoimmunotherapy, both in terms of [progression-free] and overall survival. Over 90% of patients achieve an MRD-negative in this combination in the peripheral blood,” said Dr. Hillmen in a media briefing prior to his presentation of the data in an oral abstract session here at the American Society of Hematology annual meeting.
The study results were also published online in The New England Journal of Medicine to coincide with the presentation.
Adaptive Trial
The FLAIR study is a phase 3 open-label platform trial that initially compared ibrutinib-rituximab with fludarabine-cyclophosphamide-rituximab (FCR) in patients with untreated CLL. However, in 2017 the trial was adapted to include both an ibrutinib monotherapy and an ibrutinib-venetoclax arm with therapy duration determined by MRD.
At ASH 2023, Dr. Hillmen presented data from an interim analysis of 523 patients comparing ibrutinib-venetoclax with FCR.
In the ibrutinib-venetoclax group, patients received oral ibrutinib 420 mg daily, with venetoclax added after 2 months, beginning with a 20-mg dose ramped up to 400 mg in a weekly dose-escalation schedule. The combination could be given for 2-6 years, depending on MRD responses. FCR was delivered in up to six cycles of 28 days each. Two thirds of patients assigned to FCR completed all six cycles.
After a median follow-up of 43.7 months, 12 patients (4.6%) randomly assigned to ibrutinib-venetoclax had disease progression or died compared with 75 patients (28.5%) assigned to FCR. The estimated 3-year progression-free survival with ibrutinib-venetoclax was 97.2%, compared with 76.8% with FCR, translating into a hazard ratio (HR) for progression or death with the targeted therapy combination of 0.13 (P <.001).
Among patients with unmutated IGHV, the combination led to improved progression-free survival compared with FCR (hazard ratio [HR] for progression or death, 0.07); for patients with mutated IGHV, however, the combination did not improve progression-free survival (HR, 0.54; 95% CI, 0.21-1.38).
In all, eight patients (3.5%) assigned to ibrutinib-venetoclax and 23 assigned to FCR (9.5%) died.
The 3-year overall survival rates were 98% in the targeted therapy group vs 93% in the FCR group (HR for progression or death, 0.31).
At 2 years, 52.4% of patients assigned to ibrutinib-venetoclax had undetectable MRD in bone marrow compared with 49.8% with FCR. At 5 years, the respective percentages for MRD in bone marrow were 65.9% vs 49.8% and 92.7% vs 67.9% for MRD in peripheral blood.
The safety analysis showed higher rates of blood and lymphatic system disorders with FCR, whereas cardiac, metabolic/nutrition disorders, and eye disorders occurred more frequent with ibrutinib-venetoclax.
A total of 24 secondary cancers were diagnosed in 17 patients randomly assigned to ibrutinib-venetoclax and 45 secondary cancers among 34 patients randomly assigned to FCR. One patient assigned to ibrutinib-venetoclax developed myelodysplastic syndrome/acute myeloid leukemia (AML), as did eight patients assigned to FCR. One patient in the ibrutinib-venetoclax arm and four patients in the FCR arm had Richter’s transformation.
The incidence rate for other cancers was 2.6 per 100 person-years with ibrutinib-venetoclax compared with 5.4 per 100 person-years with FCR.
The most frequently occurring cancers in each arm were basal cell or squamous cell carcinomas. The incidence of myelodysplastic syndromes, AML lymphoma, and prostate/urologic cancers was higher among patients on FCR.
This research “unequivocally shows the superiority of targeted therapy over traditional cytotoxic chemotherapy,” commented briefing moderator Mikkael A. Sekeres, MD, from the University of Miami Miller School of Medicine.
The ibrutinib-venetoclax combination has the potential to reduce the incidence of myelodysplastic syndromes secondary to CLL therapy, Dr. Sekeres suggested.
“As someone who specializes in leukemia and myelodysplastic syndromes, I have the feeling I won’t be seeing these CLL patients in my clinic — years after being treated for CLL — much longer,” he said.
In an interview with this news organization, Lee Greenberger, PhD, said that “I think that duration-adapted therapy is a great story. Using MRD negativity is a perfectly justified way, I think, to go about a new combination that’s going to be really potent for CLL patients and probably give them many years of treatment and then to get off the drug, because ultimately the goal is to get cures.”
This combination, though highly efficacious, is unlikely to be curative; however, because even when MRD is undetectable, “it will come back,” said Dr. Greenberger, chief scientific officer for the Leukemia & Lymphoma Society.
Dr. Greenberger added that MRD testing of bone marrow, which provides a more detailed picture of MRD status than testing of peripheral blood, is feasible in academic medical centers but may be a barrier to MRD-adapted therapy in community oncology practices.
The FLAIR study is supported by grants from Cancer Research UK, Janssen, Pharmacyclics, and AbbVie. Dr. Hillmen disclosed employment and equity participation with Apellis Pharmaceuticals. Dr. Sekeres disclosed board activities for Geron, Novartis, and Bristol-Myers Squibb and owner of stock options Kurome. Dr. Greenberger reported no relevant financial disclosures.
A version of this article appeared on Medscape.com.
FROM ASH 2023
Mantle Cell Lymphoma: Drug Combo Improves PFS
Still, “in the countries where ibrutinib is indicated, this combination should be a new standard therapy for relapsed/refractory mantle cell lymphoma,” Michael Wang, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in a media briefing at the annual meeting of the American Society of Hematology.
Its use would be off label, according to the authors of the industry-funded trial, because no nation has approved the combination therapy for MCL, a rare, aggressive form of non-Hodgkin lymphoma.
As Dr. Wang noted, ibrutinib (a Bruton tyrosine kinase inhibitor) is approved by the Food and Drug Administration to treat MCL, while venetoclax (a BCL-2 inhibitor) is approved for chronic lymphocytic leukemia and previously untreated acute myeloid leukemia. “The combination of these two agents leverages complementary modes of action and has demonstrated synergistic anti-tumor activity in preclinical models of mantle cell lymphoma,” he said. And “in patients with relapsed/refractory mantle cell lymphoma, promising clinical activity has also been observed in early-phase studies.”
For the multinational, randomized, phase 3, double-blind SYMPATICO study, researchers assigned 267 adults with relapsed/refractory MCL after 1-5 prior therapies 1:1 to receive oral ibrutinib 560 mg daily with oral venetoclax (standard 5-wk ramp-up to a target dose of 400 mg once daily) or placebo for 2 years. Then they continued with ibrutinib alone until progressive disease or unacceptable toxicity.
The study began in 2017. The median age of patients was 68, and the numbers of patients in each group were 134 (both drugs) and 133 (ibrutinib plus placebo).
At a median of 51.2 months, median PFS — the primary endpoint — was higher in the combination group vs. ibrutinib alone (31.9 vs. 22.1 months, hazard ratio [HR]=0.65, 95% CI, 0.47–0.88, P = .0052). While overall survival was higher in the combination group vs. ibrutinib alone, an interim analysis found that the difference was not statistically significant (44.9 months vs. 38.6 months, 95% CI, HR = 0.85, 0.62-1.19, P = .3465).
When questioned about this finding at the ASH news briefing, Dr. Wang said that 170 events are needed for a full overall survival analysis, and there are just 144 now. The study may reach that point in early 2025, he said.
Over a median treatment duration of 22.0 months for the combination treatment and 17.7 months for ibrutinib alone, grade ≥ 3 adverse events occurred in 84% and 76% of patients, respectively. At 60%, the level of serious adverse events was the same in both groups.
In an interview, Brian T. Hill, MD, PhD, of Cleveland Clinic, noted that in general, MCL “has a pretty relentless pattern of relapses and disease progression without an easy cure in the vast majority of patients.”
Ibrutinib has revolutionized treatment over the past decade with generally manageable side effects, and clinicians are now turning to other Bruton tyrosine kinase inhibitors, he said. Still, “there is a need for improving the durability and the response rates second-line treatment or beyond,” Dr. Hill said.
The new study is important since it’s the first randomized trial “that demonstrates that additional venetoclax significantly improves not only response rates, but also progression-free survival with a trend toward overall survival,” he said. “The toxicity profile doesn’t really seem to be significantly more worse than what we might expect with each agent given individually.”
However, Dr. Hill noted that “it’s a relatively small study and relatively short follow-up.”
It may be difficult to get an ibrutinib-venetoclax combination approved today since ibrutinib is no longer the preferred Bruton tyrosine kinase inhibitor for clinicians, he said.
Pharmacyclics, maker of ibrutinib, is the study sponsor and Janssen is a collaborator.
Dr. Wang reports research funding Acerta Pharma, AstraZeneca, BeiGene, BioInvent, Celgene, Genentech, Innocare, Janssen, Juno Therapeutics, Kite Pharma, Lilly, Loxo Oncology, Molecular Templates, Oncternal, Pharmacyclics, and VelosBio. Other authors report multiple and various relationships with industry. Dr. Hill discloses research funding and consulting relationships with Pharmacyclics, AbbVie, BeiGene, and AstraZeneca.
Still, “in the countries where ibrutinib is indicated, this combination should be a new standard therapy for relapsed/refractory mantle cell lymphoma,” Michael Wang, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in a media briefing at the annual meeting of the American Society of Hematology.
Its use would be off label, according to the authors of the industry-funded trial, because no nation has approved the combination therapy for MCL, a rare, aggressive form of non-Hodgkin lymphoma.
As Dr. Wang noted, ibrutinib (a Bruton tyrosine kinase inhibitor) is approved by the Food and Drug Administration to treat MCL, while venetoclax (a BCL-2 inhibitor) is approved for chronic lymphocytic leukemia and previously untreated acute myeloid leukemia. “The combination of these two agents leverages complementary modes of action and has demonstrated synergistic anti-tumor activity in preclinical models of mantle cell lymphoma,” he said. And “in patients with relapsed/refractory mantle cell lymphoma, promising clinical activity has also been observed in early-phase studies.”
For the multinational, randomized, phase 3, double-blind SYMPATICO study, researchers assigned 267 adults with relapsed/refractory MCL after 1-5 prior therapies 1:1 to receive oral ibrutinib 560 mg daily with oral venetoclax (standard 5-wk ramp-up to a target dose of 400 mg once daily) or placebo for 2 years. Then they continued with ibrutinib alone until progressive disease or unacceptable toxicity.
The study began in 2017. The median age of patients was 68, and the numbers of patients in each group were 134 (both drugs) and 133 (ibrutinib plus placebo).
At a median of 51.2 months, median PFS — the primary endpoint — was higher in the combination group vs. ibrutinib alone (31.9 vs. 22.1 months, hazard ratio [HR]=0.65, 95% CI, 0.47–0.88, P = .0052). While overall survival was higher in the combination group vs. ibrutinib alone, an interim analysis found that the difference was not statistically significant (44.9 months vs. 38.6 months, 95% CI, HR = 0.85, 0.62-1.19, P = .3465).
When questioned about this finding at the ASH news briefing, Dr. Wang said that 170 events are needed for a full overall survival analysis, and there are just 144 now. The study may reach that point in early 2025, he said.
Over a median treatment duration of 22.0 months for the combination treatment and 17.7 months for ibrutinib alone, grade ≥ 3 adverse events occurred in 84% and 76% of patients, respectively. At 60%, the level of serious adverse events was the same in both groups.
In an interview, Brian T. Hill, MD, PhD, of Cleveland Clinic, noted that in general, MCL “has a pretty relentless pattern of relapses and disease progression without an easy cure in the vast majority of patients.”
Ibrutinib has revolutionized treatment over the past decade with generally manageable side effects, and clinicians are now turning to other Bruton tyrosine kinase inhibitors, he said. Still, “there is a need for improving the durability and the response rates second-line treatment or beyond,” Dr. Hill said.
The new study is important since it’s the first randomized trial “that demonstrates that additional venetoclax significantly improves not only response rates, but also progression-free survival with a trend toward overall survival,” he said. “The toxicity profile doesn’t really seem to be significantly more worse than what we might expect with each agent given individually.”
However, Dr. Hill noted that “it’s a relatively small study and relatively short follow-up.”
It may be difficult to get an ibrutinib-venetoclax combination approved today since ibrutinib is no longer the preferred Bruton tyrosine kinase inhibitor for clinicians, he said.
Pharmacyclics, maker of ibrutinib, is the study sponsor and Janssen is a collaborator.
Dr. Wang reports research funding Acerta Pharma, AstraZeneca, BeiGene, BioInvent, Celgene, Genentech, Innocare, Janssen, Juno Therapeutics, Kite Pharma, Lilly, Loxo Oncology, Molecular Templates, Oncternal, Pharmacyclics, and VelosBio. Other authors report multiple and various relationships with industry. Dr. Hill discloses research funding and consulting relationships with Pharmacyclics, AbbVie, BeiGene, and AstraZeneca.
Still, “in the countries where ibrutinib is indicated, this combination should be a new standard therapy for relapsed/refractory mantle cell lymphoma,” Michael Wang, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in a media briefing at the annual meeting of the American Society of Hematology.
Its use would be off label, according to the authors of the industry-funded trial, because no nation has approved the combination therapy for MCL, a rare, aggressive form of non-Hodgkin lymphoma.
As Dr. Wang noted, ibrutinib (a Bruton tyrosine kinase inhibitor) is approved by the Food and Drug Administration to treat MCL, while venetoclax (a BCL-2 inhibitor) is approved for chronic lymphocytic leukemia and previously untreated acute myeloid leukemia. “The combination of these two agents leverages complementary modes of action and has demonstrated synergistic anti-tumor activity in preclinical models of mantle cell lymphoma,” he said. And “in patients with relapsed/refractory mantle cell lymphoma, promising clinical activity has also been observed in early-phase studies.”
For the multinational, randomized, phase 3, double-blind SYMPATICO study, researchers assigned 267 adults with relapsed/refractory MCL after 1-5 prior therapies 1:1 to receive oral ibrutinib 560 mg daily with oral venetoclax (standard 5-wk ramp-up to a target dose of 400 mg once daily) or placebo for 2 years. Then they continued with ibrutinib alone until progressive disease or unacceptable toxicity.
The study began in 2017. The median age of patients was 68, and the numbers of patients in each group were 134 (both drugs) and 133 (ibrutinib plus placebo).
At a median of 51.2 months, median PFS — the primary endpoint — was higher in the combination group vs. ibrutinib alone (31.9 vs. 22.1 months, hazard ratio [HR]=0.65, 95% CI, 0.47–0.88, P = .0052). While overall survival was higher in the combination group vs. ibrutinib alone, an interim analysis found that the difference was not statistically significant (44.9 months vs. 38.6 months, 95% CI, HR = 0.85, 0.62-1.19, P = .3465).
When questioned about this finding at the ASH news briefing, Dr. Wang said that 170 events are needed for a full overall survival analysis, and there are just 144 now. The study may reach that point in early 2025, he said.
Over a median treatment duration of 22.0 months for the combination treatment and 17.7 months for ibrutinib alone, grade ≥ 3 adverse events occurred in 84% and 76% of patients, respectively. At 60%, the level of serious adverse events was the same in both groups.
In an interview, Brian T. Hill, MD, PhD, of Cleveland Clinic, noted that in general, MCL “has a pretty relentless pattern of relapses and disease progression without an easy cure in the vast majority of patients.”
Ibrutinib has revolutionized treatment over the past decade with generally manageable side effects, and clinicians are now turning to other Bruton tyrosine kinase inhibitors, he said. Still, “there is a need for improving the durability and the response rates second-line treatment or beyond,” Dr. Hill said.
The new study is important since it’s the first randomized trial “that demonstrates that additional venetoclax significantly improves not only response rates, but also progression-free survival with a trend toward overall survival,” he said. “The toxicity profile doesn’t really seem to be significantly more worse than what we might expect with each agent given individually.”
However, Dr. Hill noted that “it’s a relatively small study and relatively short follow-up.”
It may be difficult to get an ibrutinib-venetoclax combination approved today since ibrutinib is no longer the preferred Bruton tyrosine kinase inhibitor for clinicians, he said.
Pharmacyclics, maker of ibrutinib, is the study sponsor and Janssen is a collaborator.
Dr. Wang reports research funding Acerta Pharma, AstraZeneca, BeiGene, BioInvent, Celgene, Genentech, Innocare, Janssen, Juno Therapeutics, Kite Pharma, Lilly, Loxo Oncology, Molecular Templates, Oncternal, Pharmacyclics, and VelosBio. Other authors report multiple and various relationships with industry. Dr. Hill discloses research funding and consulting relationships with Pharmacyclics, AbbVie, BeiGene, and AstraZeneca.
FROM ASH 2023
Distinct toxicity profiles for anti-BCMA myeloma therapies
Among 1803 patients with multiple myeloma treated with either chimeric antigen receptor (CAR) T-cell constructs or a bispecific antibody, CAR T-cell therapy was associated with a “prominent” risk for both cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, while the antibody was associated with a high risk for infection-related mortality, reported Zimu Gong, MD, PhD, from the Cancer Center at Houston Methodist Hospital.“When we are selecting or sequencing these agents, because they are approved for almost identical indications, we need to carefully consider their unique toxicity profile,” he said in an oral abstract session at the annual meeting of the American Society of Hematology (ASH) here.
Going to the FAERS
Dr. Gong and colleagues drew on the FDA Adverse Event Reporting System (FAERS) database for data on toxicities associated with three BCMA-directed therapies: CAR T-cell treatments idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti), and the bispecific antibody teclistamab (Tecvayli).
They identified a total of 1803 cases with a total of 4423 reported adverse events.
The authors calculated a reporting odds ratio (ROR) by dividing the odds of a specific event occurring with an agent by the odds of the same event occurring with all other BCMA-directed agents in the FAERS database.
They found that the highest ROR for cytokine release syndrome was with ide-cel, at 1.8, compared with 0.74 with cilta-cel, and 0.63 with teclistamab. Ide-cel was also most strongly associated with risk for both immune effector cell-associated neurotoxicity syndrome, with an ROR of 1.38, compared with 1.04 with cilta-cel and 0.69 with teclistamab, and with non-immune effector cell-associated neurotoxicity, with an ROR of 2.19 vs 0.83 and 0.4, respectively.
There were 14 reported cases of Bell’s palsy, 13 of which were associated with cilta-cel and 1 with teclistamab, and 11 cases of Parkinsonism, including 7 occurring with cilta-cel, 4 with ide-cel, and none with teclistamab.
In contrast, risk for infection was highest with teclistamab, with an ROR of 4.38 compared with 1.3 with cilta-cel and 0.12 with ide-cel. The infections most commonly reported with teclistamab included pneumonia, sepsis, COVID-19 pneumonia, pneumocystis jirovecii pneumonia, cytomegalovirus reactive and cytomegalovirus pneumonia.
The antibody was also associated with the highest risk for nonrelapse mortality, with an ROR of 1.73 compared with 1.28 with cilta-cel and 0.13 with ide-cel.
There were 309 reported deaths. The investigators calculated nonrelapse mortality by excluding disease progress from cases with death as the final reported outcome. Ide-cell had the lowest odds ratio for non-relapse mortality, at 0.53, compared with 0.99 for cilta-cel, and 1.72 for teclistamab. The most common cause of nonrelapse deaths was toxicities associated with CAR T-cell therapy, and infections, Dr. Gong said.
Dr. Gong acknowledged that one of the major limitations of the study is the nature of the FAERS database itself, which includes both mandatory reports on adverse events, medication errors, and product quality complaints submitted as required by law by manufacturers, but also voluntarily reported by healthcare professionals and consumers.
In an interview with this news organization, David Miklos, MD, PhD, chief of the blood and marrow transplantation and cellular therapy division at Stanford University, who attended the session but was not involved in the study, commented that although the study showed differences among various anti-BCMA products in terms of adverse events, the analysis is only one of several that show different values.
“The concern I have about the FAERS database is simply the lack of validation, and maybe, with no disrespect to the institution, this is kind of like review scores on Amazon.com: not validated, nobody knows who put them out there, and we don’t even know if it’s true,” he said.
He noted that whatever the system, data collection and reporting is both time- and resource-consuming, and given the potential of cellular therapies to significantly improve survival may burden clinicians with requirements for decades of follow-up and reporting.
“Self-reporting isn’t the answer either,” said Dr. Miklos. Perhaps, he suggested, there is a role for apps with “patients self-reporting” and medical practitioners validating the reports.
Dr. Gong and colleagues did not report a study funding source. Dr. Gong had no conflict of interest disclosures. Dr. Miklos has disclosed serving as a director, officer, partner, employee, advisor, consultant, or trustee for: Kite-Gilead, Novartis, Juno-Celgene-Bristol-Myers Squibb, Adaptive Biotech, Pharmacyclics, and Janssen; received research funding from: Kite-Gilead, Novartis, Juno-Celgene-Bristol-Myers Squibb, Adaptive Biotech, Pharmacyclic; patents, royalties, or other intellectual property from Pharmacyclics, and travel support from Kite-Gilead, Novartis, Juno-Celgene-Bristol-Myers Squibb, Adaptive Biotech, Pharmacyclics, and Janssen.
A version of this article first appeared on Medscape.com.
Among 1803 patients with multiple myeloma treated with either chimeric antigen receptor (CAR) T-cell constructs or a bispecific antibody, CAR T-cell therapy was associated with a “prominent” risk for both cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, while the antibody was associated with a high risk for infection-related mortality, reported Zimu Gong, MD, PhD, from the Cancer Center at Houston Methodist Hospital.“When we are selecting or sequencing these agents, because they are approved for almost identical indications, we need to carefully consider their unique toxicity profile,” he said in an oral abstract session at the annual meeting of the American Society of Hematology (ASH) here.
Going to the FAERS
Dr. Gong and colleagues drew on the FDA Adverse Event Reporting System (FAERS) database for data on toxicities associated with three BCMA-directed therapies: CAR T-cell treatments idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti), and the bispecific antibody teclistamab (Tecvayli).
They identified a total of 1803 cases with a total of 4423 reported adverse events.
The authors calculated a reporting odds ratio (ROR) by dividing the odds of a specific event occurring with an agent by the odds of the same event occurring with all other BCMA-directed agents in the FAERS database.
They found that the highest ROR for cytokine release syndrome was with ide-cel, at 1.8, compared with 0.74 with cilta-cel, and 0.63 with teclistamab. Ide-cel was also most strongly associated with risk for both immune effector cell-associated neurotoxicity syndrome, with an ROR of 1.38, compared with 1.04 with cilta-cel and 0.69 with teclistamab, and with non-immune effector cell-associated neurotoxicity, with an ROR of 2.19 vs 0.83 and 0.4, respectively.
There were 14 reported cases of Bell’s palsy, 13 of which were associated with cilta-cel and 1 with teclistamab, and 11 cases of Parkinsonism, including 7 occurring with cilta-cel, 4 with ide-cel, and none with teclistamab.
In contrast, risk for infection was highest with teclistamab, with an ROR of 4.38 compared with 1.3 with cilta-cel and 0.12 with ide-cel. The infections most commonly reported with teclistamab included pneumonia, sepsis, COVID-19 pneumonia, pneumocystis jirovecii pneumonia, cytomegalovirus reactive and cytomegalovirus pneumonia.
The antibody was also associated with the highest risk for nonrelapse mortality, with an ROR of 1.73 compared with 1.28 with cilta-cel and 0.13 with ide-cel.
There were 309 reported deaths. The investigators calculated nonrelapse mortality by excluding disease progress from cases with death as the final reported outcome. Ide-cell had the lowest odds ratio for non-relapse mortality, at 0.53, compared with 0.99 for cilta-cel, and 1.72 for teclistamab. The most common cause of nonrelapse deaths was toxicities associated with CAR T-cell therapy, and infections, Dr. Gong said.
Dr. Gong acknowledged that one of the major limitations of the study is the nature of the FAERS database itself, which includes both mandatory reports on adverse events, medication errors, and product quality complaints submitted as required by law by manufacturers, but also voluntarily reported by healthcare professionals and consumers.
In an interview with this news organization, David Miklos, MD, PhD, chief of the blood and marrow transplantation and cellular therapy division at Stanford University, who attended the session but was not involved in the study, commented that although the study showed differences among various anti-BCMA products in terms of adverse events, the analysis is only one of several that show different values.
“The concern I have about the FAERS database is simply the lack of validation, and maybe, with no disrespect to the institution, this is kind of like review scores on Amazon.com: not validated, nobody knows who put them out there, and we don’t even know if it’s true,” he said.
He noted that whatever the system, data collection and reporting is both time- and resource-consuming, and given the potential of cellular therapies to significantly improve survival may burden clinicians with requirements for decades of follow-up and reporting.
“Self-reporting isn’t the answer either,” said Dr. Miklos. Perhaps, he suggested, there is a role for apps with “patients self-reporting” and medical practitioners validating the reports.
Dr. Gong and colleagues did not report a study funding source. Dr. Gong had no conflict of interest disclosures. Dr. Miklos has disclosed serving as a director, officer, partner, employee, advisor, consultant, or trustee for: Kite-Gilead, Novartis, Juno-Celgene-Bristol-Myers Squibb, Adaptive Biotech, Pharmacyclics, and Janssen; received research funding from: Kite-Gilead, Novartis, Juno-Celgene-Bristol-Myers Squibb, Adaptive Biotech, Pharmacyclic; patents, royalties, or other intellectual property from Pharmacyclics, and travel support from Kite-Gilead, Novartis, Juno-Celgene-Bristol-Myers Squibb, Adaptive Biotech, Pharmacyclics, and Janssen.
A version of this article first appeared on Medscape.com.
Among 1803 patients with multiple myeloma treated with either chimeric antigen receptor (CAR) T-cell constructs or a bispecific antibody, CAR T-cell therapy was associated with a “prominent” risk for both cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, while the antibody was associated with a high risk for infection-related mortality, reported Zimu Gong, MD, PhD, from the Cancer Center at Houston Methodist Hospital.“When we are selecting or sequencing these agents, because they are approved for almost identical indications, we need to carefully consider their unique toxicity profile,” he said in an oral abstract session at the annual meeting of the American Society of Hematology (ASH) here.
Going to the FAERS
Dr. Gong and colleagues drew on the FDA Adverse Event Reporting System (FAERS) database for data on toxicities associated with three BCMA-directed therapies: CAR T-cell treatments idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti), and the bispecific antibody teclistamab (Tecvayli).
They identified a total of 1803 cases with a total of 4423 reported adverse events.
The authors calculated a reporting odds ratio (ROR) by dividing the odds of a specific event occurring with an agent by the odds of the same event occurring with all other BCMA-directed agents in the FAERS database.
They found that the highest ROR for cytokine release syndrome was with ide-cel, at 1.8, compared with 0.74 with cilta-cel, and 0.63 with teclistamab. Ide-cel was also most strongly associated with risk for both immune effector cell-associated neurotoxicity syndrome, with an ROR of 1.38, compared with 1.04 with cilta-cel and 0.69 with teclistamab, and with non-immune effector cell-associated neurotoxicity, with an ROR of 2.19 vs 0.83 and 0.4, respectively.
There were 14 reported cases of Bell’s palsy, 13 of which were associated with cilta-cel and 1 with teclistamab, and 11 cases of Parkinsonism, including 7 occurring with cilta-cel, 4 with ide-cel, and none with teclistamab.
In contrast, risk for infection was highest with teclistamab, with an ROR of 4.38 compared with 1.3 with cilta-cel and 0.12 with ide-cel. The infections most commonly reported with teclistamab included pneumonia, sepsis, COVID-19 pneumonia, pneumocystis jirovecii pneumonia, cytomegalovirus reactive and cytomegalovirus pneumonia.
The antibody was also associated with the highest risk for nonrelapse mortality, with an ROR of 1.73 compared with 1.28 with cilta-cel and 0.13 with ide-cel.
There were 309 reported deaths. The investigators calculated nonrelapse mortality by excluding disease progress from cases with death as the final reported outcome. Ide-cell had the lowest odds ratio for non-relapse mortality, at 0.53, compared with 0.99 for cilta-cel, and 1.72 for teclistamab. The most common cause of nonrelapse deaths was toxicities associated with CAR T-cell therapy, and infections, Dr. Gong said.
Dr. Gong acknowledged that one of the major limitations of the study is the nature of the FAERS database itself, which includes both mandatory reports on adverse events, medication errors, and product quality complaints submitted as required by law by manufacturers, but also voluntarily reported by healthcare professionals and consumers.
In an interview with this news organization, David Miklos, MD, PhD, chief of the blood and marrow transplantation and cellular therapy division at Stanford University, who attended the session but was not involved in the study, commented that although the study showed differences among various anti-BCMA products in terms of adverse events, the analysis is only one of several that show different values.
“The concern I have about the FAERS database is simply the lack of validation, and maybe, with no disrespect to the institution, this is kind of like review scores on Amazon.com: not validated, nobody knows who put them out there, and we don’t even know if it’s true,” he said.
He noted that whatever the system, data collection and reporting is both time- and resource-consuming, and given the potential of cellular therapies to significantly improve survival may burden clinicians with requirements for decades of follow-up and reporting.
“Self-reporting isn’t the answer either,” said Dr. Miklos. Perhaps, he suggested, there is a role for apps with “patients self-reporting” and medical practitioners validating the reports.
Dr. Gong and colleagues did not report a study funding source. Dr. Gong had no conflict of interest disclosures. Dr. Miklos has disclosed serving as a director, officer, partner, employee, advisor, consultant, or trustee for: Kite-Gilead, Novartis, Juno-Celgene-Bristol-Myers Squibb, Adaptive Biotech, Pharmacyclics, and Janssen; received research funding from: Kite-Gilead, Novartis, Juno-Celgene-Bristol-Myers Squibb, Adaptive Biotech, Pharmacyclic; patents, royalties, or other intellectual property from Pharmacyclics, and travel support from Kite-Gilead, Novartis, Juno-Celgene-Bristol-Myers Squibb, Adaptive Biotech, Pharmacyclics, and Janssen.
A version of this article first appeared on Medscape.com.
FROM ASH 2023
Myeloma: Isatuximab Four-Drug Regimen Boosts MRD Negativity
“This [research] builds on our experience that four-drug combinations with a monoclonal antibody, proteasome inhibitor, immunomodulatory drug and steroids are superior to three-drug combinations,” Joseph Mikhael, MD, chief medical officer of the International Myeloma Foundation, said in an interview on the study.
“It also demonstrates the value of CD38 antibodies, and specifically isatuximab, in the frontline setting,” said Dr. Mikhael, professor at the Translational Genomics Research Institute (TGen), City of Hope Cancer Center in Goodyear, Ariz.
The findings were presented at the annual meeting of the American Society of Hematology.
The current standard of care for transplant-eligible, newly diagnosed MM consists of the quadruple combination of a CD38 monoclonal antibody, an immunomodulatory drug, a proteasome inhibitor, and a glucocorticoid, followed by high-dose melphalan and autologous stem-cell transplantation (ASCT).
Isatuximab already has approval in combination with the regimen of carfilzomib and dexamethasone (KRd) in the treatment of relapsed or refractory MM patients who have received prior lines of therapy.
To investigate the efficacy and safety of addition of isatuximab in the setting of transplant-eligible, newly diagnosed MM patients, first author Francesca Gay, MD, PhD, of the Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy, and colleagues conducted the multisite, phase-3 Iskia trial, enrolling 302 transplant-eligible newly diagnosed MM patients.
The patients were randomized to groups of 151 each to treatment either with IsaKRd or KRd alone. The treatment regimen for KRd included four cycles in induction including weekly carfilzomib at 56 mg on day 1, 8 and 15, lenalidomide 25 mg at day 1-21, and dexamethasone at 40 mg weekly, and the IsaKRd group included four 28-day cycles of isatuximab 10 mg/kg IV days 1, 8, 15, and 22 in cycle 1, followed by 10 mg/kg days 1, 15 in cycles 2-4.
The induction was followed by stem cell mobilization and collection and high dose chemotherapy, followed by four cycles of full-dose consolidation at the same doses and schedule as induction, followed by a light consolidation phase of 12 28-day cycles of reduced dose KRd.
Patients had a median age of 61 and 60 in the isatuximab versus KRd group, respectively, and characteristics were similar between the two arms.
With the current follow-up of a mean of 21 months, the primary endpoint was met, with the intention-to-treat analysis showing a rate of post-consolidation MRD negativity, as assessed with a next-generation sequencing (NGS) cut-off of 10-5, of 77% with isatuximab versus 67% with KRd alone (OR 1.67; P = .049).
With an NGS cut-off of 10-6, the respective rates were 67% vs. 48% (OR 2.29; P < .001).
“This difference in MRD negativity in the depth of response was seen despite the responses analyzed according to the conventional criteria being comparable in the two arms, with more than 90% of patients achieving at least a very good partial response and more than 70% achieving at least a complete response,” Dr. Gay noted.
For the key secondary endpoint of MRD negativity over time, the rates were also significantly higher with IsaKRd vs. KRd at post-induction (10-5 cut-off, 45% vs. 26%, OR 2.34; P < .001; 10-6 cut-off, 27% vs. 14%, OR 2.36, P = .004).
IsaKRd also had greater MRD negativity post-ASCT (10-5 cutoff 64% vs. 49%; P = .006; 10-6 cutoff, 52% vs. 27%, P < .001) and post-consolidation (10-5 cutoff, 77% vs. 67%; P = .049 and 10-6 cutoff, 67% vs. 48%, P < .001).
The increase in the MRD negativity in the IsaKRd group was observed in all subgroups of patients analyzed at the 10-5 and 10-6 cut-offs.
The improved post-consolidation rate of MRD negativity with IsaKRd was also observed among patients based on all levels of cytogenetic risk, which was not the case in the KRd alone arm, which showed a reduction in MRD negativity among very high-risk patients, Dr. Gay observed.
The study’s other key secondary endpoint of progression-free survival will be presented in the future, when longer-term outcomes are available.
As of the current follow-up, 17% of patients in the IsaKRd group had discontinued the study treatment versus 10% with KRd, with the leading cause of adverse events for 6% and 5%, respectively.
At least one hematologic adverse event occurred in 55% of patients treated with IsaKRd and 44% in the KRd alone group, with the most prominent grade 3-4 adverse events occurring more commonly with IsaKRd being neutropenia (36% vs. 22%) and thrombocytopenia (15% vs. 17%).
Non-hematologic grade 3-4 adverse events occurred in 41% of patients in the IsaKRd group versus 37% in KRd only, which included infections (15% vs. 11%), and gastrointestinal (7% vs. 5%), vascular (5% vs. 10%) and cardiac events (<1% vs. 3%).
Discontinuation for toxicity occurred in similar rates in both groups (6% in IsaKRd vs. 5% in KRd); with four treatment-related deaths occurring with IsaKRd (two COVID, one pneumonia, one pulmonary embolism) and one with KRd (septic shock).
“Treatment was tolerable with a toxicity profile that was similar to that in previous reports,” Dr. Gay said.
“In the context of these highly effective regimens that produce a high rate of response, the 10-6 MRD cutoff might be more informative than other result categories,” she added.
Longer follow-up will provide more insights in survival endpoints, and “the trial can potentially offer the opportunity to explore correlations between depth of MRD negativity and survival endpoints,” Dr. Gay noted.
Further commenting on the study, Irene Ghobrial, MD, of Medical Oncology, with the Dana-Farber Cancer Institute, Boston, said the results are encouraging.
“We’re seeing two phase three trials now showing us that indeed a CD38 antibody in addition to our triplet standards of care are making a huge difference in MRD response,” she said in an interview.
“So, I think the main message here is that the four-drug regimen is the way to go from now on in multiple myeloma.”
The study received funding from Sanofi and Amgen. Dr. Gay disclosed relationships with AbbVie; Bristol Myers Squibb/Celgene; Sanofi; Roche; GlaxoSmithKline; Pfizer; Oncopeptides; Takeda; Janssen; and Amgen. Dr. Mikhael reported ties with Amgen, BMS, Janssen, Sanofi and Takeda.
“This [research] builds on our experience that four-drug combinations with a monoclonal antibody, proteasome inhibitor, immunomodulatory drug and steroids are superior to three-drug combinations,” Joseph Mikhael, MD, chief medical officer of the International Myeloma Foundation, said in an interview on the study.
“It also demonstrates the value of CD38 antibodies, and specifically isatuximab, in the frontline setting,” said Dr. Mikhael, professor at the Translational Genomics Research Institute (TGen), City of Hope Cancer Center in Goodyear, Ariz.
The findings were presented at the annual meeting of the American Society of Hematology.
The current standard of care for transplant-eligible, newly diagnosed MM consists of the quadruple combination of a CD38 monoclonal antibody, an immunomodulatory drug, a proteasome inhibitor, and a glucocorticoid, followed by high-dose melphalan and autologous stem-cell transplantation (ASCT).
Isatuximab already has approval in combination with the regimen of carfilzomib and dexamethasone (KRd) in the treatment of relapsed or refractory MM patients who have received prior lines of therapy.
To investigate the efficacy and safety of addition of isatuximab in the setting of transplant-eligible, newly diagnosed MM patients, first author Francesca Gay, MD, PhD, of the Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy, and colleagues conducted the multisite, phase-3 Iskia trial, enrolling 302 transplant-eligible newly diagnosed MM patients.
The patients were randomized to groups of 151 each to treatment either with IsaKRd or KRd alone. The treatment regimen for KRd included four cycles in induction including weekly carfilzomib at 56 mg on day 1, 8 and 15, lenalidomide 25 mg at day 1-21, and dexamethasone at 40 mg weekly, and the IsaKRd group included four 28-day cycles of isatuximab 10 mg/kg IV days 1, 8, 15, and 22 in cycle 1, followed by 10 mg/kg days 1, 15 in cycles 2-4.
The induction was followed by stem cell mobilization and collection and high dose chemotherapy, followed by four cycles of full-dose consolidation at the same doses and schedule as induction, followed by a light consolidation phase of 12 28-day cycles of reduced dose KRd.
Patients had a median age of 61 and 60 in the isatuximab versus KRd group, respectively, and characteristics were similar between the two arms.
With the current follow-up of a mean of 21 months, the primary endpoint was met, with the intention-to-treat analysis showing a rate of post-consolidation MRD negativity, as assessed with a next-generation sequencing (NGS) cut-off of 10-5, of 77% with isatuximab versus 67% with KRd alone (OR 1.67; P = .049).
With an NGS cut-off of 10-6, the respective rates were 67% vs. 48% (OR 2.29; P < .001).
“This difference in MRD negativity in the depth of response was seen despite the responses analyzed according to the conventional criteria being comparable in the two arms, with more than 90% of patients achieving at least a very good partial response and more than 70% achieving at least a complete response,” Dr. Gay noted.
For the key secondary endpoint of MRD negativity over time, the rates were also significantly higher with IsaKRd vs. KRd at post-induction (10-5 cut-off, 45% vs. 26%, OR 2.34; P < .001; 10-6 cut-off, 27% vs. 14%, OR 2.36, P = .004).
IsaKRd also had greater MRD negativity post-ASCT (10-5 cutoff 64% vs. 49%; P = .006; 10-6 cutoff, 52% vs. 27%, P < .001) and post-consolidation (10-5 cutoff, 77% vs. 67%; P = .049 and 10-6 cutoff, 67% vs. 48%, P < .001).
The increase in the MRD negativity in the IsaKRd group was observed in all subgroups of patients analyzed at the 10-5 and 10-6 cut-offs.
The improved post-consolidation rate of MRD negativity with IsaKRd was also observed among patients based on all levels of cytogenetic risk, which was not the case in the KRd alone arm, which showed a reduction in MRD negativity among very high-risk patients, Dr. Gay observed.
The study’s other key secondary endpoint of progression-free survival will be presented in the future, when longer-term outcomes are available.
As of the current follow-up, 17% of patients in the IsaKRd group had discontinued the study treatment versus 10% with KRd, with the leading cause of adverse events for 6% and 5%, respectively.
At least one hematologic adverse event occurred in 55% of patients treated with IsaKRd and 44% in the KRd alone group, with the most prominent grade 3-4 adverse events occurring more commonly with IsaKRd being neutropenia (36% vs. 22%) and thrombocytopenia (15% vs. 17%).
Non-hematologic grade 3-4 adverse events occurred in 41% of patients in the IsaKRd group versus 37% in KRd only, which included infections (15% vs. 11%), and gastrointestinal (7% vs. 5%), vascular (5% vs. 10%) and cardiac events (<1% vs. 3%).
Discontinuation for toxicity occurred in similar rates in both groups (6% in IsaKRd vs. 5% in KRd); with four treatment-related deaths occurring with IsaKRd (two COVID, one pneumonia, one pulmonary embolism) and one with KRd (septic shock).
“Treatment was tolerable with a toxicity profile that was similar to that in previous reports,” Dr. Gay said.
“In the context of these highly effective regimens that produce a high rate of response, the 10-6 MRD cutoff might be more informative than other result categories,” she added.
Longer follow-up will provide more insights in survival endpoints, and “the trial can potentially offer the opportunity to explore correlations between depth of MRD negativity and survival endpoints,” Dr. Gay noted.
Further commenting on the study, Irene Ghobrial, MD, of Medical Oncology, with the Dana-Farber Cancer Institute, Boston, said the results are encouraging.
“We’re seeing two phase three trials now showing us that indeed a CD38 antibody in addition to our triplet standards of care are making a huge difference in MRD response,” she said in an interview.
“So, I think the main message here is that the four-drug regimen is the way to go from now on in multiple myeloma.”
The study received funding from Sanofi and Amgen. Dr. Gay disclosed relationships with AbbVie; Bristol Myers Squibb/Celgene; Sanofi; Roche; GlaxoSmithKline; Pfizer; Oncopeptides; Takeda; Janssen; and Amgen. Dr. Mikhael reported ties with Amgen, BMS, Janssen, Sanofi and Takeda.
“This [research] builds on our experience that four-drug combinations with a monoclonal antibody, proteasome inhibitor, immunomodulatory drug and steroids are superior to three-drug combinations,” Joseph Mikhael, MD, chief medical officer of the International Myeloma Foundation, said in an interview on the study.
“It also demonstrates the value of CD38 antibodies, and specifically isatuximab, in the frontline setting,” said Dr. Mikhael, professor at the Translational Genomics Research Institute (TGen), City of Hope Cancer Center in Goodyear, Ariz.
The findings were presented at the annual meeting of the American Society of Hematology.
The current standard of care for transplant-eligible, newly diagnosed MM consists of the quadruple combination of a CD38 monoclonal antibody, an immunomodulatory drug, a proteasome inhibitor, and a glucocorticoid, followed by high-dose melphalan and autologous stem-cell transplantation (ASCT).
Isatuximab already has approval in combination with the regimen of carfilzomib and dexamethasone (KRd) in the treatment of relapsed or refractory MM patients who have received prior lines of therapy.
To investigate the efficacy and safety of addition of isatuximab in the setting of transplant-eligible, newly diagnosed MM patients, first author Francesca Gay, MD, PhD, of the Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy, and colleagues conducted the multisite, phase-3 Iskia trial, enrolling 302 transplant-eligible newly diagnosed MM patients.
The patients were randomized to groups of 151 each to treatment either with IsaKRd or KRd alone. The treatment regimen for KRd included four cycles in induction including weekly carfilzomib at 56 mg on day 1, 8 and 15, lenalidomide 25 mg at day 1-21, and dexamethasone at 40 mg weekly, and the IsaKRd group included four 28-day cycles of isatuximab 10 mg/kg IV days 1, 8, 15, and 22 in cycle 1, followed by 10 mg/kg days 1, 15 in cycles 2-4.
The induction was followed by stem cell mobilization and collection and high dose chemotherapy, followed by four cycles of full-dose consolidation at the same doses and schedule as induction, followed by a light consolidation phase of 12 28-day cycles of reduced dose KRd.
Patients had a median age of 61 and 60 in the isatuximab versus KRd group, respectively, and characteristics were similar between the two arms.
With the current follow-up of a mean of 21 months, the primary endpoint was met, with the intention-to-treat analysis showing a rate of post-consolidation MRD negativity, as assessed with a next-generation sequencing (NGS) cut-off of 10-5, of 77% with isatuximab versus 67% with KRd alone (OR 1.67; P = .049).
With an NGS cut-off of 10-6, the respective rates were 67% vs. 48% (OR 2.29; P < .001).
“This difference in MRD negativity in the depth of response was seen despite the responses analyzed according to the conventional criteria being comparable in the two arms, with more than 90% of patients achieving at least a very good partial response and more than 70% achieving at least a complete response,” Dr. Gay noted.
For the key secondary endpoint of MRD negativity over time, the rates were also significantly higher with IsaKRd vs. KRd at post-induction (10-5 cut-off, 45% vs. 26%, OR 2.34; P < .001; 10-6 cut-off, 27% vs. 14%, OR 2.36, P = .004).
IsaKRd also had greater MRD negativity post-ASCT (10-5 cutoff 64% vs. 49%; P = .006; 10-6 cutoff, 52% vs. 27%, P < .001) and post-consolidation (10-5 cutoff, 77% vs. 67%; P = .049 and 10-6 cutoff, 67% vs. 48%, P < .001).
The increase in the MRD negativity in the IsaKRd group was observed in all subgroups of patients analyzed at the 10-5 and 10-6 cut-offs.
The improved post-consolidation rate of MRD negativity with IsaKRd was also observed among patients based on all levels of cytogenetic risk, which was not the case in the KRd alone arm, which showed a reduction in MRD negativity among very high-risk patients, Dr. Gay observed.
The study’s other key secondary endpoint of progression-free survival will be presented in the future, when longer-term outcomes are available.
As of the current follow-up, 17% of patients in the IsaKRd group had discontinued the study treatment versus 10% with KRd, with the leading cause of adverse events for 6% and 5%, respectively.
At least one hematologic adverse event occurred in 55% of patients treated with IsaKRd and 44% in the KRd alone group, with the most prominent grade 3-4 adverse events occurring more commonly with IsaKRd being neutropenia (36% vs. 22%) and thrombocytopenia (15% vs. 17%).
Non-hematologic grade 3-4 adverse events occurred in 41% of patients in the IsaKRd group versus 37% in KRd only, which included infections (15% vs. 11%), and gastrointestinal (7% vs. 5%), vascular (5% vs. 10%) and cardiac events (<1% vs. 3%).
Discontinuation for toxicity occurred in similar rates in both groups (6% in IsaKRd vs. 5% in KRd); with four treatment-related deaths occurring with IsaKRd (two COVID, one pneumonia, one pulmonary embolism) and one with KRd (septic shock).
“Treatment was tolerable with a toxicity profile that was similar to that in previous reports,” Dr. Gay said.
“In the context of these highly effective regimens that produce a high rate of response, the 10-6 MRD cutoff might be more informative than other result categories,” she added.
Longer follow-up will provide more insights in survival endpoints, and “the trial can potentially offer the opportunity to explore correlations between depth of MRD negativity and survival endpoints,” Dr. Gay noted.
Further commenting on the study, Irene Ghobrial, MD, of Medical Oncology, with the Dana-Farber Cancer Institute, Boston, said the results are encouraging.
“We’re seeing two phase three trials now showing us that indeed a CD38 antibody in addition to our triplet standards of care are making a huge difference in MRD response,” she said in an interview.
“So, I think the main message here is that the four-drug regimen is the way to go from now on in multiple myeloma.”
The study received funding from Sanofi and Amgen. Dr. Gay disclosed relationships with AbbVie; Bristol Myers Squibb/Celgene; Sanofi; Roche; GlaxoSmithKline; Pfizer; Oncopeptides; Takeda; Janssen; and Amgen. Dr. Mikhael reported ties with Amgen, BMS, Janssen, Sanofi and Takeda.
FROM ASH 2023