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Combo should be standard in MM, doc says
ATLANTA—Study results “strongly support” a new standard of care for transplant-ineligible patients with newly diagnosed multiple myeloma (MM), according to a speaker at the 2017 ASH Annual Meeting.
The study, ALCYONE, suggests treatment with bortezomib, melphalan, and prednisone (VMP) can be improved by the addition of daratumumab (D).
D-VMP produced deeper responses and prolonged progression-free survival (PFS) when compared to VMP.
“In this first phase 3, randomized study with a monoclonal antibody in newly diagnosed multiple myeloma, daratumumab reduced the risk of progression or death by 50%,” said Maria-Victoria Mateos, MD, PhD, of University Hospital of Salamanca in Spain.
“No new safety signals were observed [with D-VMP], except for higher infectious events that resolved. I would say the results of this study strongly support daratumumab in combination with VMP as a standard of care in transplant-ineligible, newly diagnosed multiple myeloma.”
Dr Mateos presented results from ALCYONE as a late-breaking abstract (LBA-4) at the ASH Annual Meeting. The study was simultaneously published in NEJM. The research was supported by Janssen Research and Development.
Patients and treatment
ALCYONE enrolled 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with autologous stem cell transplant.
Patients were randomized to receive VMP or D-VMP. They were stratified by International Staging System (I, II, III), region (Europe vs other), and age (<75 vs ≥75 years).
All patients received up to 9 cycles of VMP:
- Bortezomib at 1.3 mg/m2 twice weekly on weeks 1, 2, 4, and 5 of cycle 1 and once weekly on weeks 1, 2, 4, and 5 of cycles 2 through 9
- Melphalan at 9 mg/m2 once daily on days 1 to 4 of each cycle
- Prednisone at 60 mg/m2 once daily on days 1 to 4 of each cycle.
Patients in the daratumumab arm received the drug at 16 mg/kg once-weekly for the first cycle, every 3 weeks for cycles 2 to 9, and every 4 weeks thereafter, until disease progression. These patients also received dexamethasone (to manage infusion reactions) at 20 mg on the same schedule.
Baseline characteristics were similar between the VMP (n=356) and D-VMP (n=350) arms. The median age was 71 in both arms (range, 50-91 in the VMP arm and 40-93 in the D-VMP arm). Males made up 47% of the VMP arm and 46% of the D-VMP arm.
Forty-nine percent of patients in the VMP arm and 52% in the D-VMP arm had an ECOG performance status of 1. Twenty-eight percent and 22%, respectively, had a status of 0.
The median follow-up was 16.5 months (range, 0.1-28.1). At the clinical cutoff date (June 12, 2017), 5% of patients in the VMP arm were still on study treatment, as were 71% of patients in the D-VMP arm.
Response and survival
“I would like to note that the benefit of the addition of daratumumab was observed since the beginning of the treatment,” Dr Mateos said.
The overall response rate was 74% in the VMP arm and 91% in the D-VMP arm (P<0.0001). The median duration of response was 21.3 months in the VMP arm and was not reached in the D-VMP arm.
The rate of complete response was 24% in the VMP arm and 43% in the D-VMP arm (P<0.0001). Six percent of patients in the VMP arm and 22% in the D-VMP arm were negative for minimal residual disease (P<0.0001).
The hazard ratio for disease progression or death in the D-VMP arm versus the VMP arm was 0.50 (P<0.0001).
The median PFS was 18.1 months in the VMP arm and was not reached in the D-VMP arm. The 12-month PFS was 76% and 87%, respectively. And the 18-month PFS was 50% and 72%, respectively.
D-VMP prolonged PFS regardless of patient sex, age, cytogenetic risk, ECOG performance status, baseline renal function, and other factors.
The median overall survival was not reached in either treatment arm. There were 48 deaths in the VMP arm and 45 in the D-VMP arm.
Adverse events
The most common treatment-emergent adverse events (TEAEs; in the D-VMP and VMP arms, respectively) were neutropenia (50% and 53%), thrombocytopenia (49% and 54%), anemia (28% and 38%), peripheral sensory neuropathy (28% and 34%), upper respiratory tract infection (26% and 14%), diarrhea (24% and 25%), pyrexia (23% and 21%), and nausea (21% and 22%).
The most common grade 3/4 TEAEs (in the D-VMP and VMP arms, respectively) were neutropenia (40% and 39%), thrombocytopenia (34% and 38%), and anemia (16% and 20%).
There were 6 deaths due to TEAEs in the D-VMP arm and 5 such deaths in the VMP arm.
The rate of grade 3/4 infections was higher in the D-VMP arm than the VMP arm—23% and 15%, respectively. The most common of these was pneumonia, with rates of 11% and 4%, respectively.
Infections resolved in 88% of cases in the D-VMP arm and 87% of cases in the VMP arm. Rates of treatment discontinuation due to infection were 0.9% and 1.4%, respectively. One patient in each group stopped treatment due to pneumonia.
Twenty-eight percent of patients in the D-VMP arm had infusion-related reactions (15% grade 3 and 2% grade 4). Most of these reactions occurred during the first infusion. Five patients (1.4%) discontinued daratumumab due to infusion-related reactions. 
ATLANTA—Study results “strongly support” a new standard of care for transplant-ineligible patients with newly diagnosed multiple myeloma (MM), according to a speaker at the 2017 ASH Annual Meeting.
The study, ALCYONE, suggests treatment with bortezomib, melphalan, and prednisone (VMP) can be improved by the addition of daratumumab (D).
D-VMP produced deeper responses and prolonged progression-free survival (PFS) when compared to VMP.
“In this first phase 3, randomized study with a monoclonal antibody in newly diagnosed multiple myeloma, daratumumab reduced the risk of progression or death by 50%,” said Maria-Victoria Mateos, MD, PhD, of University Hospital of Salamanca in Spain.
“No new safety signals were observed [with D-VMP], except for higher infectious events that resolved. I would say the results of this study strongly support daratumumab in combination with VMP as a standard of care in transplant-ineligible, newly diagnosed multiple myeloma.”
Dr Mateos presented results from ALCYONE as a late-breaking abstract (LBA-4) at the ASH Annual Meeting. The study was simultaneously published in NEJM. The research was supported by Janssen Research and Development.
Patients and treatment
ALCYONE enrolled 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with autologous stem cell transplant.
Patients were randomized to receive VMP or D-VMP. They were stratified by International Staging System (I, II, III), region (Europe vs other), and age (<75 vs ≥75 years).
All patients received up to 9 cycles of VMP:
- Bortezomib at 1.3 mg/m2 twice weekly on weeks 1, 2, 4, and 5 of cycle 1 and once weekly on weeks 1, 2, 4, and 5 of cycles 2 through 9
- Melphalan at 9 mg/m2 once daily on days 1 to 4 of each cycle
- Prednisone at 60 mg/m2 once daily on days 1 to 4 of each cycle.
Patients in the daratumumab arm received the drug at 16 mg/kg once-weekly for the first cycle, every 3 weeks for cycles 2 to 9, and every 4 weeks thereafter, until disease progression. These patients also received dexamethasone (to manage infusion reactions) at 20 mg on the same schedule.
Baseline characteristics were similar between the VMP (n=356) and D-VMP (n=350) arms. The median age was 71 in both arms (range, 50-91 in the VMP arm and 40-93 in the D-VMP arm). Males made up 47% of the VMP arm and 46% of the D-VMP arm.
Forty-nine percent of patients in the VMP arm and 52% in the D-VMP arm had an ECOG performance status of 1. Twenty-eight percent and 22%, respectively, had a status of 0.
The median follow-up was 16.5 months (range, 0.1-28.1). At the clinical cutoff date (June 12, 2017), 5% of patients in the VMP arm were still on study treatment, as were 71% of patients in the D-VMP arm.
Response and survival
“I would like to note that the benefit of the addition of daratumumab was observed since the beginning of the treatment,” Dr Mateos said.
The overall response rate was 74% in the VMP arm and 91% in the D-VMP arm (P<0.0001). The median duration of response was 21.3 months in the VMP arm and was not reached in the D-VMP arm.
The rate of complete response was 24% in the VMP arm and 43% in the D-VMP arm (P<0.0001). Six percent of patients in the VMP arm and 22% in the D-VMP arm were negative for minimal residual disease (P<0.0001).
The hazard ratio for disease progression or death in the D-VMP arm versus the VMP arm was 0.50 (P<0.0001).
The median PFS was 18.1 months in the VMP arm and was not reached in the D-VMP arm. The 12-month PFS was 76% and 87%, respectively. And the 18-month PFS was 50% and 72%, respectively.
D-VMP prolonged PFS regardless of patient sex, age, cytogenetic risk, ECOG performance status, baseline renal function, and other factors.
The median overall survival was not reached in either treatment arm. There were 48 deaths in the VMP arm and 45 in the D-VMP arm.
Adverse events
The most common treatment-emergent adverse events (TEAEs; in the D-VMP and VMP arms, respectively) were neutropenia (50% and 53%), thrombocytopenia (49% and 54%), anemia (28% and 38%), peripheral sensory neuropathy (28% and 34%), upper respiratory tract infection (26% and 14%), diarrhea (24% and 25%), pyrexia (23% and 21%), and nausea (21% and 22%).
The most common grade 3/4 TEAEs (in the D-VMP and VMP arms, respectively) were neutropenia (40% and 39%), thrombocytopenia (34% and 38%), and anemia (16% and 20%).
There were 6 deaths due to TEAEs in the D-VMP arm and 5 such deaths in the VMP arm.
The rate of grade 3/4 infections was higher in the D-VMP arm than the VMP arm—23% and 15%, respectively. The most common of these was pneumonia, with rates of 11% and 4%, respectively.
Infections resolved in 88% of cases in the D-VMP arm and 87% of cases in the VMP arm. Rates of treatment discontinuation due to infection were 0.9% and 1.4%, respectively. One patient in each group stopped treatment due to pneumonia.
Twenty-eight percent of patients in the D-VMP arm had infusion-related reactions (15% grade 3 and 2% grade 4). Most of these reactions occurred during the first infusion. Five patients (1.4%) discontinued daratumumab due to infusion-related reactions.
ATLANTA—Study results “strongly support” a new standard of care for transplant-ineligible patients with newly diagnosed multiple myeloma (MM), according to a speaker at the 2017 ASH Annual Meeting.
The study, ALCYONE, suggests treatment with bortezomib, melphalan, and prednisone (VMP) can be improved by the addition of daratumumab (D).
D-VMP produced deeper responses and prolonged progression-free survival (PFS) when compared to VMP.
“In this first phase 3, randomized study with a monoclonal antibody in newly diagnosed multiple myeloma, daratumumab reduced the risk of progression or death by 50%,” said Maria-Victoria Mateos, MD, PhD, of University Hospital of Salamanca in Spain.
“No new safety signals were observed [with D-VMP], except for higher infectious events that resolved. I would say the results of this study strongly support daratumumab in combination with VMP as a standard of care in transplant-ineligible, newly diagnosed multiple myeloma.”
Dr Mateos presented results from ALCYONE as a late-breaking abstract (LBA-4) at the ASH Annual Meeting. The study was simultaneously published in NEJM. The research was supported by Janssen Research and Development.
Patients and treatment
ALCYONE enrolled 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with autologous stem cell transplant.
Patients were randomized to receive VMP or D-VMP. They were stratified by International Staging System (I, II, III), region (Europe vs other), and age (<75 vs ≥75 years).
All patients received up to 9 cycles of VMP:
- Bortezomib at 1.3 mg/m2 twice weekly on weeks 1, 2, 4, and 5 of cycle 1 and once weekly on weeks 1, 2, 4, and 5 of cycles 2 through 9
- Melphalan at 9 mg/m2 once daily on days 1 to 4 of each cycle
- Prednisone at 60 mg/m2 once daily on days 1 to 4 of each cycle.
Patients in the daratumumab arm received the drug at 16 mg/kg once-weekly for the first cycle, every 3 weeks for cycles 2 to 9, and every 4 weeks thereafter, until disease progression. These patients also received dexamethasone (to manage infusion reactions) at 20 mg on the same schedule.
Baseline characteristics were similar between the VMP (n=356) and D-VMP (n=350) arms. The median age was 71 in both arms (range, 50-91 in the VMP arm and 40-93 in the D-VMP arm). Males made up 47% of the VMP arm and 46% of the D-VMP arm.
Forty-nine percent of patients in the VMP arm and 52% in the D-VMP arm had an ECOG performance status of 1. Twenty-eight percent and 22%, respectively, had a status of 0.
The median follow-up was 16.5 months (range, 0.1-28.1). At the clinical cutoff date (June 12, 2017), 5% of patients in the VMP arm were still on study treatment, as were 71% of patients in the D-VMP arm.
Response and survival
“I would like to note that the benefit of the addition of daratumumab was observed since the beginning of the treatment,” Dr Mateos said.
The overall response rate was 74% in the VMP arm and 91% in the D-VMP arm (P<0.0001). The median duration of response was 21.3 months in the VMP arm and was not reached in the D-VMP arm.
The rate of complete response was 24% in the VMP arm and 43% in the D-VMP arm (P<0.0001). Six percent of patients in the VMP arm and 22% in the D-VMP arm were negative for minimal residual disease (P<0.0001).
The hazard ratio for disease progression or death in the D-VMP arm versus the VMP arm was 0.50 (P<0.0001).
The median PFS was 18.1 months in the VMP arm and was not reached in the D-VMP arm. The 12-month PFS was 76% and 87%, respectively. And the 18-month PFS was 50% and 72%, respectively.
D-VMP prolonged PFS regardless of patient sex, age, cytogenetic risk, ECOG performance status, baseline renal function, and other factors.
The median overall survival was not reached in either treatment arm. There were 48 deaths in the VMP arm and 45 in the D-VMP arm.
Adverse events
The most common treatment-emergent adverse events (TEAEs; in the D-VMP and VMP arms, respectively) were neutropenia (50% and 53%), thrombocytopenia (49% and 54%), anemia (28% and 38%), peripheral sensory neuropathy (28% and 34%), upper respiratory tract infection (26% and 14%), diarrhea (24% and 25%), pyrexia (23% and 21%), and nausea (21% and 22%).
The most common grade 3/4 TEAEs (in the D-VMP and VMP arms, respectively) were neutropenia (40% and 39%), thrombocytopenia (34% and 38%), and anemia (16% and 20%).
There were 6 deaths due to TEAEs in the D-VMP arm and 5 such deaths in the VMP arm.
The rate of grade 3/4 infections was higher in the D-VMP arm than the VMP arm—23% and 15%, respectively. The most common of these was pneumonia, with rates of 11% and 4%, respectively.
Infections resolved in 88% of cases in the D-VMP arm and 87% of cases in the VMP arm. Rates of treatment discontinuation due to infection were 0.9% and 1.4%, respectively. One patient in each group stopped treatment due to pneumonia.
Twenty-eight percent of patients in the D-VMP arm had infusion-related reactions (15% grade 3 and 2% grade 4). Most of these reactions occurred during the first infusion. Five patients (1.4%) discontinued daratumumab due to infusion-related reactions.
VIDEO: Daratumumab gives kick to standard first-line myeloma therapy
ATLANTA – The VMP regimen, consisting of bortezomib, melphalan, and prednisone, is a standard of care in Europe for frontline therapy for patients with multiple myeloma who, for reasons of age or infirmity, are not good candidates for autologous stem cell transplant.
In this video interview at the annual meeting of the American Society of Hematology, Jesus San-Miguel, MD, of the Clinical University of Navarra in Pamplona, Spain, discusses the results of the phase 3 international ALCYONE trial, comparing VMP with the same regimen plus the addition of the anti-CD38 monoclonal antibody daratumumab (Darzalex).
Adding daratumumab to VMP regimen as first-line therapy for 706 patients with multiple myeloma cut in half the risk of disease progression or death and substantially improved the rate of minimal residual disease negativity, Dr. San-Miguel reported. There were no new safety signals from adding the monoclonal antibody to VMP.
The ALCYONE study was supported by Janssen Research & Development. Dr. San-Miguel reported serving as an adviser to the company and several others.
ATLANTA – The VMP regimen, consisting of bortezomib, melphalan, and prednisone, is a standard of care in Europe for frontline therapy for patients with multiple myeloma who, for reasons of age or infirmity, are not good candidates for autologous stem cell transplant.
In this video interview at the annual meeting of the American Society of Hematology, Jesus San-Miguel, MD, of the Clinical University of Navarra in Pamplona, Spain, discusses the results of the phase 3 international ALCYONE trial, comparing VMP with the same regimen plus the addition of the anti-CD38 monoclonal antibody daratumumab (Darzalex).
Adding daratumumab to VMP regimen as first-line therapy for 706 patients with multiple myeloma cut in half the risk of disease progression or death and substantially improved the rate of minimal residual disease negativity, Dr. San-Miguel reported. There were no new safety signals from adding the monoclonal antibody to VMP.
The ALCYONE study was supported by Janssen Research & Development. Dr. San-Miguel reported serving as an adviser to the company and several others.
ATLANTA – The VMP regimen, consisting of bortezomib, melphalan, and prednisone, is a standard of care in Europe for frontline therapy for patients with multiple myeloma who, for reasons of age or infirmity, are not good candidates for autologous stem cell transplant.
In this video interview at the annual meeting of the American Society of Hematology, Jesus San-Miguel, MD, of the Clinical University of Navarra in Pamplona, Spain, discusses the results of the phase 3 international ALCYONE trial, comparing VMP with the same regimen plus the addition of the anti-CD38 monoclonal antibody daratumumab (Darzalex).
Adding daratumumab to VMP regimen as first-line therapy for 706 patients with multiple myeloma cut in half the risk of disease progression or death and substantially improved the rate of minimal residual disease negativity, Dr. San-Miguel reported. There were no new safety signals from adding the monoclonal antibody to VMP.
The ALCYONE study was supported by Janssen Research & Development. Dr. San-Miguel reported serving as an adviser to the company and several others.
REPORTING FROM ASH 2017
Daratumumab plus VMP boosts PFS, MRD-negativity in de novo myeloma
ATLANTA – Adding the anti-CD38 monoclonal antibody daratumumab (Darzalex) to the standard VMP regimen as first-line therapy for patients with multiple myeloma cut in half the risk of disease progression or death and substantially improved the rate of minimal residual disease (MRD) negativity, investigators in the ALCYONE trial reported.
This difference translated into a hazard ratio for progression or death with D-VMP of 0.50 (P less than .0001), said Jesus San-Miguel, MD, from the Clinical University of Navarra in Pamplona, Spain.
“This result clearly indicated for the first time that, in a phase 3 randomized study conducted with a monoclonal antibody in newly diagnosed myeloma patients, the addition of daratumumab to the standard of care reduced the risk of progression or death by 50%, and this is associated with significantly deeper responses, including a threefold higher MRD negativity rate,” he said at a media briefing prior to presentation of the data in a late-breaking abstract session at the annual meeting of the American Society of Hematology.
The VMP regimen is used more commonly in Europe than the United States as first-line therapy for patients with previously untreated multiple myeloma who are aged 65 years or older or are otherwise not suitable candidates for autologous stem cell transplants (ASCT).
In the ALCYONE trial, patients who met this definition were enrolled and stratified by International Staging System scores, region, and age (younger or older than 75 years) and were then randomized to 6-week cycles of VMP, with or without daratumumab. In the experimental arm, daratumumab was given at 16 mg/kg IV weekly for cycle 1, every 3 weeks for cycles 2-9, and every 4 weeks for cycles 10 and beyond (post VMP-treatment phase) until disease progression.
As noted before, the primary endpoint of investigator-assessed PFS significantly favored the addition of daratumumab. Dr. San-Miguel attributed this difference to the overall response rates, which were 91%, including 43% complete responses with daratumumab, vs. 74% ORR with 24% CR, without the monoclonal antibody.
The rate of MRD negativity, measured with a threshold sensitivity of 10–5, was also significantly higher with daratumumab at 22% vs. 6% (P less than .0001).
Among all patients who achieved MRD negativity, regardless of treatment, there was a lower risk of progression or death, Dr. San-Miguel said.
The rate of treatment discontinuation because of infection was higher with VMP (1.4%) than with D-VMP (0.9%). One patient in each trial arm discontinued therapy because of pneumonia. Rates of any serious adverse event were higher with D-VMP (42%, compared with 33%). Infusion-related reactions occurred in 27.7% of patients assigned to daratumumab.
Rates of grade 3 or 4 hematologic and nonhematologic toxicities were generally similar between the treatment arms, and there were no new safety signals with daratumumab, Dr. San-Miguel said.
The ALCYONE trial is one of several ongoing studies looking at the addition of daratumumab to standard therapies in the frontline, including the phase 3 MAIA trial (with daratumumab added to lenalidomide and dexamethasone), the phase 3 CASSIOPEIA trial (with the antibody added to bortezomib, thalidomide, and dexamethasone), the phase 2 GRIFFIN trial (with daratumumab plus lenalidomide, bortezomib, and dexamethasone), and the phase 2 LYRA trial (with the antibody added to cyclophosphamide, bortezomib, and dexamethasone).
The ALCYONE study was supported by Janssen Research & Development. Dr. San-Miguel reported serving as an adviser to the company and several others. Multiple coauthors disclosed similar relationships.
SOURCE: Mateos MV et al. ASH Abstract LBA-4.
ATLANTA – Adding the anti-CD38 monoclonal antibody daratumumab (Darzalex) to the standard VMP regimen as first-line therapy for patients with multiple myeloma cut in half the risk of disease progression or death and substantially improved the rate of minimal residual disease (MRD) negativity, investigators in the ALCYONE trial reported.
This difference translated into a hazard ratio for progression or death with D-VMP of 0.50 (P less than .0001), said Jesus San-Miguel, MD, from the Clinical University of Navarra in Pamplona, Spain.
“This result clearly indicated for the first time that, in a phase 3 randomized study conducted with a monoclonal antibody in newly diagnosed myeloma patients, the addition of daratumumab to the standard of care reduced the risk of progression or death by 50%, and this is associated with significantly deeper responses, including a threefold higher MRD negativity rate,” he said at a media briefing prior to presentation of the data in a late-breaking abstract session at the annual meeting of the American Society of Hematology.
The VMP regimen is used more commonly in Europe than the United States as first-line therapy for patients with previously untreated multiple myeloma who are aged 65 years or older or are otherwise not suitable candidates for autologous stem cell transplants (ASCT).
In the ALCYONE trial, patients who met this definition were enrolled and stratified by International Staging System scores, region, and age (younger or older than 75 years) and were then randomized to 6-week cycles of VMP, with or without daratumumab. In the experimental arm, daratumumab was given at 16 mg/kg IV weekly for cycle 1, every 3 weeks for cycles 2-9, and every 4 weeks for cycles 10 and beyond (post VMP-treatment phase) until disease progression.
As noted before, the primary endpoint of investigator-assessed PFS significantly favored the addition of daratumumab. Dr. San-Miguel attributed this difference to the overall response rates, which were 91%, including 43% complete responses with daratumumab, vs. 74% ORR with 24% CR, without the monoclonal antibody.
The rate of MRD negativity, measured with a threshold sensitivity of 10–5, was also significantly higher with daratumumab at 22% vs. 6% (P less than .0001).
Among all patients who achieved MRD negativity, regardless of treatment, there was a lower risk of progression or death, Dr. San-Miguel said.
The rate of treatment discontinuation because of infection was higher with VMP (1.4%) than with D-VMP (0.9%). One patient in each trial arm discontinued therapy because of pneumonia. Rates of any serious adverse event were higher with D-VMP (42%, compared with 33%). Infusion-related reactions occurred in 27.7% of patients assigned to daratumumab.
Rates of grade 3 or 4 hematologic and nonhematologic toxicities were generally similar between the treatment arms, and there were no new safety signals with daratumumab, Dr. San-Miguel said.
The ALCYONE trial is one of several ongoing studies looking at the addition of daratumumab to standard therapies in the frontline, including the phase 3 MAIA trial (with daratumumab added to lenalidomide and dexamethasone), the phase 3 CASSIOPEIA trial (with the antibody added to bortezomib, thalidomide, and dexamethasone), the phase 2 GRIFFIN trial (with daratumumab plus lenalidomide, bortezomib, and dexamethasone), and the phase 2 LYRA trial (with the antibody added to cyclophosphamide, bortezomib, and dexamethasone).
The ALCYONE study was supported by Janssen Research & Development. Dr. San-Miguel reported serving as an adviser to the company and several others. Multiple coauthors disclosed similar relationships.
SOURCE: Mateos MV et al. ASH Abstract LBA-4.
ATLANTA – Adding the anti-CD38 monoclonal antibody daratumumab (Darzalex) to the standard VMP regimen as first-line therapy for patients with multiple myeloma cut in half the risk of disease progression or death and substantially improved the rate of minimal residual disease (MRD) negativity, investigators in the ALCYONE trial reported.
This difference translated into a hazard ratio for progression or death with D-VMP of 0.50 (P less than .0001), said Jesus San-Miguel, MD, from the Clinical University of Navarra in Pamplona, Spain.
“This result clearly indicated for the first time that, in a phase 3 randomized study conducted with a monoclonal antibody in newly diagnosed myeloma patients, the addition of daratumumab to the standard of care reduced the risk of progression or death by 50%, and this is associated with significantly deeper responses, including a threefold higher MRD negativity rate,” he said at a media briefing prior to presentation of the data in a late-breaking abstract session at the annual meeting of the American Society of Hematology.
The VMP regimen is used more commonly in Europe than the United States as first-line therapy for patients with previously untreated multiple myeloma who are aged 65 years or older or are otherwise not suitable candidates for autologous stem cell transplants (ASCT).
In the ALCYONE trial, patients who met this definition were enrolled and stratified by International Staging System scores, region, and age (younger or older than 75 years) and were then randomized to 6-week cycles of VMP, with or without daratumumab. In the experimental arm, daratumumab was given at 16 mg/kg IV weekly for cycle 1, every 3 weeks for cycles 2-9, and every 4 weeks for cycles 10 and beyond (post VMP-treatment phase) until disease progression.
As noted before, the primary endpoint of investigator-assessed PFS significantly favored the addition of daratumumab. Dr. San-Miguel attributed this difference to the overall response rates, which were 91%, including 43% complete responses with daratumumab, vs. 74% ORR with 24% CR, without the monoclonal antibody.
The rate of MRD negativity, measured with a threshold sensitivity of 10–5, was also significantly higher with daratumumab at 22% vs. 6% (P less than .0001).
Among all patients who achieved MRD negativity, regardless of treatment, there was a lower risk of progression or death, Dr. San-Miguel said.
The rate of treatment discontinuation because of infection was higher with VMP (1.4%) than with D-VMP (0.9%). One patient in each trial arm discontinued therapy because of pneumonia. Rates of any serious adverse event were higher with D-VMP (42%, compared with 33%). Infusion-related reactions occurred in 27.7% of patients assigned to daratumumab.
Rates of grade 3 or 4 hematologic and nonhematologic toxicities were generally similar between the treatment arms, and there were no new safety signals with daratumumab, Dr. San-Miguel said.
The ALCYONE trial is one of several ongoing studies looking at the addition of daratumumab to standard therapies in the frontline, including the phase 3 MAIA trial (with daratumumab added to lenalidomide and dexamethasone), the phase 3 CASSIOPEIA trial (with the antibody added to bortezomib, thalidomide, and dexamethasone), the phase 2 GRIFFIN trial (with daratumumab plus lenalidomide, bortezomib, and dexamethasone), and the phase 2 LYRA trial (with the antibody added to cyclophosphamide, bortezomib, and dexamethasone).
The ALCYONE study was supported by Janssen Research & Development. Dr. San-Miguel reported serving as an adviser to the company and several others. Multiple coauthors disclosed similar relationships.
SOURCE: Mateos MV et al. ASH Abstract LBA-4.
REPORTING FROM ASH 2017
Key clinical point:
Major finding: The hazard ratio for progression or death with daratumumab plus VMP was 0.50 (P less than .0001).
Study details: Randomized phase 3 trial in 706 patients with multiple myeloma who were ineligible for transplant.
Disclosures: The ALCYONE study was supported by Janssen Research & Development. Dr. San-Miguel reported serving as an adviser to the company and several others. Multiple coauthors disclosed similar relationships.
Source: Mateos MV et al. ASH Abstract LBA-4.
Activating the Immune System to Treat Multiple Myeloma
Sagar Lonial, MD
Chief Medical Officer, Winship Cancer Institute of Emory University
Chair, Dept. of Hematology and Medical Oncology, Emory School of Medicine
Faculty/Faculty Disclosure
Dr. Lonial reports that he is a compensated consultant for Bristol-Myers Squibb; Celgene Corporation; Janssen Pharmaceuticals, Inc.; Merck & Co., Inc.; Millennium Pharmaceuticals, Inc.; Novartis Pharmaceuticals Corporation; and Onyx Pharmaceuticals, Inc.
Sagar Lonial, MD
Chief Medical Officer, Winship Cancer Institute of Emory University
Chair, Dept. of Hematology and Medical Oncology, Emory School of Medicine
Faculty/Faculty Disclosure
Dr. Lonial reports that he is a compensated consultant for Bristol-Myers Squibb; Celgene Corporation; Janssen Pharmaceuticals, Inc.; Merck & Co., Inc.; Millennium Pharmaceuticals, Inc.; Novartis Pharmaceuticals Corporation; and Onyx Pharmaceuticals, Inc.
Sagar Lonial, MD
Chief Medical Officer, Winship Cancer Institute of Emory University
Chair, Dept. of Hematology and Medical Oncology, Emory School of Medicine
Faculty/Faculty Disclosure
Dr. Lonial reports that he is a compensated consultant for Bristol-Myers Squibb; Celgene Corporation; Janssen Pharmaceuticals, Inc.; Merck & Co., Inc.; Millennium Pharmaceuticals, Inc.; Novartis Pharmaceuticals Corporation; and Onyx Pharmaceuticals, Inc.
FDA lifts partial hold on nivolumab trials
The US Food and Drug Administration (FDA) has lifted the partial clinical hold placed on 2 trials of the PD-1 immune checkpoint inhibitor nivolumab (Opdivo).
In these trials, CheckMate-039 (CA209 -039) and CA204142, researchers are investigating nivolumab-based combinations in patients with relapsed or refractory multiple myeloma (MM).
The partial clinical hold on these trials was a result of risks identified in studies involving another anti-PD-1 agent, pembrolizumab.
Data from the pembrolizumab trials suggested that risks outweigh benefits when PD-1/PD-L1 treatment is given to MM patients in combination with dexamethasone and pomalidomide or lenalidomide.
In addition, there could be an unfavorable risk-benefit ratio for MM patients receiving PD-1/PD-L1 treatments alone or in other combinations.
Therefore, the FDA placed a partial hold on the following nivolumab trials:
- CheckMate-602: A randomized, phase 3 trial of combinations of nivolumab, elotuzumab, pomalidomide, and dexamethasone in relapsed and refractory MM
- CheckMate-039: A phase 1 study intended to establish the tolerability of nivolumab and the combination of nivolumab and daratumumab, with or without pomalidomide and dexamethasone, in patients with relapsed or refractory MM
- CA204142: A phase 2 study of elotuzumab in combination with pomalidomide and low-dose dexamethasone, and in combination with nivolumab, in patients with MM who relapsed after or were refractory to prior treatment with lenalidomide.
After consulting with Bristol-Myers Squibb, the FDA decided to lift the hold on CheckMate-039 (CA209 -039) and CA204142. These trials will continue with amended protocols.
The third trial, CheckMate-602, remains on partial clinical hold. Bristol-Myers Squibb said it is continuing to work with the FDA to determine next steps for this trial.
CheckMate-602 is not enrolling new patients. However, patients who are experiencing clinical benefit are continuing to receive treatment.
The US Food and Drug Administration (FDA) has lifted the partial clinical hold placed on 2 trials of the PD-1 immune checkpoint inhibitor nivolumab (Opdivo).
In these trials, CheckMate-039 (CA209 -039) and CA204142, researchers are investigating nivolumab-based combinations in patients with relapsed or refractory multiple myeloma (MM).
The partial clinical hold on these trials was a result of risks identified in studies involving another anti-PD-1 agent, pembrolizumab.
Data from the pembrolizumab trials suggested that risks outweigh benefits when PD-1/PD-L1 treatment is given to MM patients in combination with dexamethasone and pomalidomide or lenalidomide.
In addition, there could be an unfavorable risk-benefit ratio for MM patients receiving PD-1/PD-L1 treatments alone or in other combinations.
Therefore, the FDA placed a partial hold on the following nivolumab trials:
- CheckMate-602: A randomized, phase 3 trial of combinations of nivolumab, elotuzumab, pomalidomide, and dexamethasone in relapsed and refractory MM
- CheckMate-039: A phase 1 study intended to establish the tolerability of nivolumab and the combination of nivolumab and daratumumab, with or without pomalidomide and dexamethasone, in patients with relapsed or refractory MM
- CA204142: A phase 2 study of elotuzumab in combination with pomalidomide and low-dose dexamethasone, and in combination with nivolumab, in patients with MM who relapsed after or were refractory to prior treatment with lenalidomide.
After consulting with Bristol-Myers Squibb, the FDA decided to lift the hold on CheckMate-039 (CA209 -039) and CA204142. These trials will continue with amended protocols.
The third trial, CheckMate-602, remains on partial clinical hold. Bristol-Myers Squibb said it is continuing to work with the FDA to determine next steps for this trial.
CheckMate-602 is not enrolling new patients. However, patients who are experiencing clinical benefit are continuing to receive treatment.
The US Food and Drug Administration (FDA) has lifted the partial clinical hold placed on 2 trials of the PD-1 immune checkpoint inhibitor nivolumab (Opdivo).
In these trials, CheckMate-039 (CA209 -039) and CA204142, researchers are investigating nivolumab-based combinations in patients with relapsed or refractory multiple myeloma (MM).
The partial clinical hold on these trials was a result of risks identified in studies involving another anti-PD-1 agent, pembrolizumab.
Data from the pembrolizumab trials suggested that risks outweigh benefits when PD-1/PD-L1 treatment is given to MM patients in combination with dexamethasone and pomalidomide or lenalidomide.
In addition, there could be an unfavorable risk-benefit ratio for MM patients receiving PD-1/PD-L1 treatments alone or in other combinations.
Therefore, the FDA placed a partial hold on the following nivolumab trials:
- CheckMate-602: A randomized, phase 3 trial of combinations of nivolumab, elotuzumab, pomalidomide, and dexamethasone in relapsed and refractory MM
- CheckMate-039: A phase 1 study intended to establish the tolerability of nivolumab and the combination of nivolumab and daratumumab, with or without pomalidomide and dexamethasone, in patients with relapsed or refractory MM
- CA204142: A phase 2 study of elotuzumab in combination with pomalidomide and low-dose dexamethasone, and in combination with nivolumab, in patients with MM who relapsed after or were refractory to prior treatment with lenalidomide.
After consulting with Bristol-Myers Squibb, the FDA decided to lift the hold on CheckMate-039 (CA209 -039) and CA204142. These trials will continue with amended protocols.
The third trial, CheckMate-602, remains on partial clinical hold. Bristol-Myers Squibb said it is continuing to work with the FDA to determine next steps for this trial.
CheckMate-602 is not enrolling new patients. However, patients who are experiencing clinical benefit are continuing to receive treatment.
Anti-BCMA CAR T-cell therapy being fast tracked at FDA
The Food and Drug Administration has granted breakthrough therapy designation to bb2121, a chimeric antigen receptor T-cell (CAR T) therapy that targets b-cell maturation antigen (BCMA) in patients with relapsed/refractory multiple myeloma.
The therapy, being developed jointly by Celgene and bluebird bio, will be given expedited review by the FDA under the program. Meanwhile, European drug officials have granted it Priority Medicines eligibility, which also provides accelerated review.
The decision to fast track the review of bb2121 is based on preliminary data from the ongoing phase I CRB-401 trial. As of May 2017, there was 1-month clinical response data from 18 patients with multiple myeloma who were infused with bb2121. The overall response rate was 89%, but was 100% for patients who had been treated with doses of 150 × 106 CAR+ T cells or higher, according to an abstract from the annual meeting of the American Society of Hematology. Five months of follow-up data on these patients, plus initial data on additional patients, will be presented at ASH 2017 on Dec. 11.
The Food and Drug Administration has granted breakthrough therapy designation to bb2121, a chimeric antigen receptor T-cell (CAR T) therapy that targets b-cell maturation antigen (BCMA) in patients with relapsed/refractory multiple myeloma.
The therapy, being developed jointly by Celgene and bluebird bio, will be given expedited review by the FDA under the program. Meanwhile, European drug officials have granted it Priority Medicines eligibility, which also provides accelerated review.
The decision to fast track the review of bb2121 is based on preliminary data from the ongoing phase I CRB-401 trial. As of May 2017, there was 1-month clinical response data from 18 patients with multiple myeloma who were infused with bb2121. The overall response rate was 89%, but was 100% for patients who had been treated with doses of 150 × 106 CAR+ T cells or higher, according to an abstract from the annual meeting of the American Society of Hematology. Five months of follow-up data on these patients, plus initial data on additional patients, will be presented at ASH 2017 on Dec. 11.
The Food and Drug Administration has granted breakthrough therapy designation to bb2121, a chimeric antigen receptor T-cell (CAR T) therapy that targets b-cell maturation antigen (BCMA) in patients with relapsed/refractory multiple myeloma.
The therapy, being developed jointly by Celgene and bluebird bio, will be given expedited review by the FDA under the program. Meanwhile, European drug officials have granted it Priority Medicines eligibility, which also provides accelerated review.
The decision to fast track the review of bb2121 is based on preliminary data from the ongoing phase I CRB-401 trial. As of May 2017, there was 1-month clinical response data from 18 patients with multiple myeloma who were infused with bb2121. The overall response rate was 89%, but was 100% for patients who had been treated with doses of 150 × 106 CAR+ T cells or higher, according to an abstract from the annual meeting of the American Society of Hematology. Five months of follow-up data on these patients, plus initial data on additional patients, will be presented at ASH 2017 on Dec. 11.
Enzyme may be target for MM treatment
The enzyme ADAR1 may be a therapeutic target for multiple myeloma (MM), according to research published in Nature Communications.
Investigators found that high ADAR1 levels correlate with reduced survival rates in MM patients.
The team also discovered that blocking ADAR1 reduced regeneration of high-risk MM in serially transplantable patient-derived xenografts.
The investigators believe that JAK2 inhibitors could be used to dampen ADAR1 activity and ultimately prevent progression or relapse in patients with MM.
“Despite new therapies, it’s virtually inevitable that a patient with multiple myeloma will experience relapse of the disease at some point,” said study author Catriona Jamieson, MD, PhD, of University of California, San Diego, in La Jolla.
“That’s why it’s exciting that this discovery may allow us to detect the disease earlier and address the root cause.”
Dr Jamieson and her colleagues knew that ADAR1 is normally expressed during fetal development to help blood cells form. The enzyme edits the sequence of RNA and is known to promote cancer progression and resistance to therapy.
With previous work, Dr Jamieson’s team described ADAR1’s contributions to chronic myeloid leukemia (CML). The enzyme’s RNA-editing activity boosts leukemic stem cells, giving rise to CML, increasing disease recurrence, and allowing CML to resist treatment.
For their current study, Dr Jamieson and her colleagues investigated ADAR1’s role in MM, first analyzing a database of nearly 800 MM patient samples.
The investigators found that patients with low ADAR1 levels in their tumor cells survived longer than patients with high ADAR1 levels.
While more than 90% of patients with low ADAR1 levels survived longer than 2 years after their initial diagnosis, fewer than 70% of patients with high ADAR1 levels did the same.
The investigators also created a humanized mouse model of MM and found that silencing the ADAR1 gene reduced the engraftment of MM.
“This is a difficult disease to model in animals; there isn’t a single gene we can manipulate to mimic multiple myeloma,” said study author Leslie A. Crews, PhD, of University of California, San Diego.
“This study is important, in part because we now have a new xenograft model that will, for the first time, allow us to apply new biomarkers to better predict disease progression and test new therapeutics.”
To advance their findings from this study, the investigators are exploring ways to leverage ADAR1 to detect MM progression as early as possible.
They are also testing inhibitors of JAK2, a molecule that influences ADAR1 activity, for their ability to eliminate cancer stem cells in MM models.
“Several major advances in recent years have been good news for multiple myeloma patients, but those new drugs only target terminally differentiated cancer cells and, thus, can only reduce the bulk of the tumor,” Dr Jamieson said.
“They don’t get to the root cause of disease development, progression, and relapse—cancer stem cells—the way inhibiting ADAR1 does. I like to call our approach ‘precision regenerative medicine.’”
The enzyme ADAR1 may be a therapeutic target for multiple myeloma (MM), according to research published in Nature Communications.
Investigators found that high ADAR1 levels correlate with reduced survival rates in MM patients.
The team also discovered that blocking ADAR1 reduced regeneration of high-risk MM in serially transplantable patient-derived xenografts.
The investigators believe that JAK2 inhibitors could be used to dampen ADAR1 activity and ultimately prevent progression or relapse in patients with MM.
“Despite new therapies, it’s virtually inevitable that a patient with multiple myeloma will experience relapse of the disease at some point,” said study author Catriona Jamieson, MD, PhD, of University of California, San Diego, in La Jolla.
“That’s why it’s exciting that this discovery may allow us to detect the disease earlier and address the root cause.”
Dr Jamieson and her colleagues knew that ADAR1 is normally expressed during fetal development to help blood cells form. The enzyme edits the sequence of RNA and is known to promote cancer progression and resistance to therapy.
With previous work, Dr Jamieson’s team described ADAR1’s contributions to chronic myeloid leukemia (CML). The enzyme’s RNA-editing activity boosts leukemic stem cells, giving rise to CML, increasing disease recurrence, and allowing CML to resist treatment.
For their current study, Dr Jamieson and her colleagues investigated ADAR1’s role in MM, first analyzing a database of nearly 800 MM patient samples.
The investigators found that patients with low ADAR1 levels in their tumor cells survived longer than patients with high ADAR1 levels.
While more than 90% of patients with low ADAR1 levels survived longer than 2 years after their initial diagnosis, fewer than 70% of patients with high ADAR1 levels did the same.
The investigators also created a humanized mouse model of MM and found that silencing the ADAR1 gene reduced the engraftment of MM.
“This is a difficult disease to model in animals; there isn’t a single gene we can manipulate to mimic multiple myeloma,” said study author Leslie A. Crews, PhD, of University of California, San Diego.
“This study is important, in part because we now have a new xenograft model that will, for the first time, allow us to apply new biomarkers to better predict disease progression and test new therapeutics.”
To advance their findings from this study, the investigators are exploring ways to leverage ADAR1 to detect MM progression as early as possible.
They are also testing inhibitors of JAK2, a molecule that influences ADAR1 activity, for their ability to eliminate cancer stem cells in MM models.
“Several major advances in recent years have been good news for multiple myeloma patients, but those new drugs only target terminally differentiated cancer cells and, thus, can only reduce the bulk of the tumor,” Dr Jamieson said.
“They don’t get to the root cause of disease development, progression, and relapse—cancer stem cells—the way inhibiting ADAR1 does. I like to call our approach ‘precision regenerative medicine.’”
The enzyme ADAR1 may be a therapeutic target for multiple myeloma (MM), according to research published in Nature Communications.
Investigators found that high ADAR1 levels correlate with reduced survival rates in MM patients.
The team also discovered that blocking ADAR1 reduced regeneration of high-risk MM in serially transplantable patient-derived xenografts.
The investigators believe that JAK2 inhibitors could be used to dampen ADAR1 activity and ultimately prevent progression or relapse in patients with MM.
“Despite new therapies, it’s virtually inevitable that a patient with multiple myeloma will experience relapse of the disease at some point,” said study author Catriona Jamieson, MD, PhD, of University of California, San Diego, in La Jolla.
“That’s why it’s exciting that this discovery may allow us to detect the disease earlier and address the root cause.”
Dr Jamieson and her colleagues knew that ADAR1 is normally expressed during fetal development to help blood cells form. The enzyme edits the sequence of RNA and is known to promote cancer progression and resistance to therapy.
With previous work, Dr Jamieson’s team described ADAR1’s contributions to chronic myeloid leukemia (CML). The enzyme’s RNA-editing activity boosts leukemic stem cells, giving rise to CML, increasing disease recurrence, and allowing CML to resist treatment.
For their current study, Dr Jamieson and her colleagues investigated ADAR1’s role in MM, first analyzing a database of nearly 800 MM patient samples.
The investigators found that patients with low ADAR1 levels in their tumor cells survived longer than patients with high ADAR1 levels.
While more than 90% of patients with low ADAR1 levels survived longer than 2 years after their initial diagnosis, fewer than 70% of patients with high ADAR1 levels did the same.
The investigators also created a humanized mouse model of MM and found that silencing the ADAR1 gene reduced the engraftment of MM.
“This is a difficult disease to model in animals; there isn’t a single gene we can manipulate to mimic multiple myeloma,” said study author Leslie A. Crews, PhD, of University of California, San Diego.
“This study is important, in part because we now have a new xenograft model that will, for the first time, allow us to apply new biomarkers to better predict disease progression and test new therapeutics.”
To advance their findings from this study, the investigators are exploring ways to leverage ADAR1 to detect MM progression as early as possible.
They are also testing inhibitors of JAK2, a molecule that influences ADAR1 activity, for their ability to eliminate cancer stem cells in MM models.
“Several major advances in recent years have been good news for multiple myeloma patients, but those new drugs only target terminally differentiated cancer cells and, thus, can only reduce the bulk of the tumor,” Dr Jamieson said.
“They don’t get to the root cause of disease development, progression, and relapse—cancer stem cells—the way inhibiting ADAR1 does. I like to call our approach ‘precision regenerative medicine.’”
Group develops MM-specific CAR T-cell therapy
Researchers say they have identified a multiple myeloma (MM)-specific target for chimeric antigen receptor (CAR) T-cell therapy.
The team unearthed an MM-specific monoclonal antibody (mAb) and designed a CAR that incorporates a fragment derived from that mAb.
The resulting CAR T-cell therapy exhibited anti-MM activity in vitro and in vivo but did not have a negative effect on normal hematopoietic cells.
The researchers described this work in Nature Medicine.
The team believed that new antigen epitopes could be discovered by thoroughly searching for cancer-specific mAbs and characterizing the antigens they recognize.
“We applied this strategy to identify novel therapeutic targets for multiple myeloma . . . ,” explained study author Naoki Hosen, MD, PhD, of Osaka University in Osaka, Japan.
The researchers screened more than 10,000 anti-MM mAb clones and identified MMG49 as an MM-specific mAb that recognizes a subset of integrin β7 molecules.
The team found that MMG49 reacted to MM cells—but not to normal hematopoietic cells—in MM patient samples.
This prompted the researchers to design a CAR that incorporates a fragment derived from MMG49.
When tested in vitro, MMG49 CAR T cells exhibited cytotoxic activity against cell lines expressing the MMG49 epitope and primary MM cell from patients’ bone marrow. However, MMG49 CAR T cells did not have cytotoxic effects on MMG49-negative cells or normal hematopoietic cells.
The researchers said MM cells were completely eradicated by MMG49 CAR T cells. But the therapy did not kill T cells, even when integrin β7 was activated by MAdCAM-1 and CXCL12.
In mouse models of MM, MMG49 CAR T cells significantly prolonged survival when compared to a CD19 CAR T-cell therapy. MMG49 CAR T cells eradicated MM cells and significantly decreased tumor burden in some mice, but some mice relapsed.
MMG49 CAR T cells did not affect normal hematopoietic cells in the mice, and the researchers said there were no unexpected side effects with the treatment.
“Our results also demonstrate that the active conformer of integrin β7 can serve as an immunotherapeutic target against MM, even though the expression of the protein itself is not specific to MM,” said study author Yukiko Matsunaga, PhD, of Princess Margaret Cancer Centre, University Health Network, in Toronto, Canada.
“Therefore, it’s highly plausible that there are other cancer immunotherapeutic targets that have yet to be identified in many cell-surface proteins that undergo conformational changes, even if the expression of the proteins themselves is not cancer-specific.”
Researchers say they have identified a multiple myeloma (MM)-specific target for chimeric antigen receptor (CAR) T-cell therapy.
The team unearthed an MM-specific monoclonal antibody (mAb) and designed a CAR that incorporates a fragment derived from that mAb.
The resulting CAR T-cell therapy exhibited anti-MM activity in vitro and in vivo but did not have a negative effect on normal hematopoietic cells.
The researchers described this work in Nature Medicine.
The team believed that new antigen epitopes could be discovered by thoroughly searching for cancer-specific mAbs and characterizing the antigens they recognize.
“We applied this strategy to identify novel therapeutic targets for multiple myeloma . . . ,” explained study author Naoki Hosen, MD, PhD, of Osaka University in Osaka, Japan.
The researchers screened more than 10,000 anti-MM mAb clones and identified MMG49 as an MM-specific mAb that recognizes a subset of integrin β7 molecules.
The team found that MMG49 reacted to MM cells—but not to normal hematopoietic cells—in MM patient samples.
This prompted the researchers to design a CAR that incorporates a fragment derived from MMG49.
When tested in vitro, MMG49 CAR T cells exhibited cytotoxic activity against cell lines expressing the MMG49 epitope and primary MM cell from patients’ bone marrow. However, MMG49 CAR T cells did not have cytotoxic effects on MMG49-negative cells or normal hematopoietic cells.
The researchers said MM cells were completely eradicated by MMG49 CAR T cells. But the therapy did not kill T cells, even when integrin β7 was activated by MAdCAM-1 and CXCL12.
In mouse models of MM, MMG49 CAR T cells significantly prolonged survival when compared to a CD19 CAR T-cell therapy. MMG49 CAR T cells eradicated MM cells and significantly decreased tumor burden in some mice, but some mice relapsed.
MMG49 CAR T cells did not affect normal hematopoietic cells in the mice, and the researchers said there were no unexpected side effects with the treatment.
“Our results also demonstrate that the active conformer of integrin β7 can serve as an immunotherapeutic target against MM, even though the expression of the protein itself is not specific to MM,” said study author Yukiko Matsunaga, PhD, of Princess Margaret Cancer Centre, University Health Network, in Toronto, Canada.
“Therefore, it’s highly plausible that there are other cancer immunotherapeutic targets that have yet to be identified in many cell-surface proteins that undergo conformational changes, even if the expression of the proteins themselves is not cancer-specific.”
Researchers say they have identified a multiple myeloma (MM)-specific target for chimeric antigen receptor (CAR) T-cell therapy.
The team unearthed an MM-specific monoclonal antibody (mAb) and designed a CAR that incorporates a fragment derived from that mAb.
The resulting CAR T-cell therapy exhibited anti-MM activity in vitro and in vivo but did not have a negative effect on normal hematopoietic cells.
The researchers described this work in Nature Medicine.
The team believed that new antigen epitopes could be discovered by thoroughly searching for cancer-specific mAbs and characterizing the antigens they recognize.
“We applied this strategy to identify novel therapeutic targets for multiple myeloma . . . ,” explained study author Naoki Hosen, MD, PhD, of Osaka University in Osaka, Japan.
The researchers screened more than 10,000 anti-MM mAb clones and identified MMG49 as an MM-specific mAb that recognizes a subset of integrin β7 molecules.
The team found that MMG49 reacted to MM cells—but not to normal hematopoietic cells—in MM patient samples.
This prompted the researchers to design a CAR that incorporates a fragment derived from MMG49.
When tested in vitro, MMG49 CAR T cells exhibited cytotoxic activity against cell lines expressing the MMG49 epitope and primary MM cell from patients’ bone marrow. However, MMG49 CAR T cells did not have cytotoxic effects on MMG49-negative cells or normal hematopoietic cells.
The researchers said MM cells were completely eradicated by MMG49 CAR T cells. But the therapy did not kill T cells, even when integrin β7 was activated by MAdCAM-1 and CXCL12.
In mouse models of MM, MMG49 CAR T cells significantly prolonged survival when compared to a CD19 CAR T-cell therapy. MMG49 CAR T cells eradicated MM cells and significantly decreased tumor burden in some mice, but some mice relapsed.
MMG49 CAR T cells did not affect normal hematopoietic cells in the mice, and the researchers said there were no unexpected side effects with the treatment.
“Our results also demonstrate that the active conformer of integrin β7 can serve as an immunotherapeutic target against MM, even though the expression of the protein itself is not specific to MM,” said study author Yukiko Matsunaga, PhD, of Princess Margaret Cancer Centre, University Health Network, in Toronto, Canada.
“Therefore, it’s highly plausible that there are other cancer immunotherapeutic targets that have yet to be identified in many cell-surface proteins that undergo conformational changes, even if the expression of the proteins themselves is not cancer-specific.”
GSI may boost BCMA CAR T-cell therapy efficacy in myeloma
NATIONAL HARBOR, MD. – Gamma secretase inhibition may lead to improved outcomes in multiple myeloma patients treated with B-cell maturation antigen (BCMA)–specific CAR T-cell therapy, according to Margot J. Pont, PhD.
In a preclinical myeloma model, gamma secretase inhibition (GSI) increased antitumor efficacy of BCMA-specific chimeric antigen receptor modified T-cells (BCMA CAR T), Dr. Pont of Fred Hutchinson Cancer Research Center, Seattle, reported at the annual meeting of the Society for Immunotherapy of Cancer.
BCMA is expressed in most multiple myeloma patients, and can be targeted by T cells that have been transduced with an anti-BCMA CAR. Other studies have shown efficacy of BCMA CAR T cells, and Dr. Pont and her colleagues have developed and optimized a CAR, based on a previously described single-chain variable fragment (scFv), that performs at least as well as a similar CAR developed previously by another group.
Previous studies have found that antigen down-regulation and escape can be an important escape mechanism by the tumor, so low-to-negative antigen expression could lead to failure in CAR T-cell recognition, resulting in relapse, she explained.
“We need the antigen density to be high enough,” she said, noting that BCMA, specifically, can be susceptible to antigen down-regulation, because its extracellular component is cleaved off the cell membrane by the enzyme gamma-secretase.
“That leads to two things: It reduces the surface expression of BCMA and it sheds soluble BCMA into the circulation, so you get high concentrations of soluble BCMA in the tumor microenvironment,” she said.
Inhibiting BCMA shedding with GSI can increase surface expression and reduce levels of soluble BCMA, thereby potentially enhancing the CAR activity.
First, soluble BCMA levels were measured in bone marrow sera from myeloma patients.
“We indeed saw high levels of soluble BCMA in these patients, and they roughly correlated with tumor burden. When culturing myeloma cell lines in vitro, we detected sBCMA in the culture supernatant within 24 hours,” Dr. Pont said, adding that the introduction of recombinant BCMA to the cultures showed that increasing levels of recombinant BCMA reduced staining of the CAR, demonstrating binding to the receptor.
Next, GSI was used to increase BCMA levels, and with increasing concentrations of the drug, BCMA surface expression was increased, she said, noting that this coincided with a reduction of soluble BCMA in the culture supernatant.
This also worked in patient samples, and was achieved with low doses of GSI, which upregulated surface BCMA levels on primary multiple myeloma by up to tenfold, she said.
In vivo testing of CAR T-cell efficacy was performed in tumor-bearing mice, which were treated with either BCMA-specific CAR T cells alone or in combination with GSI.
In this preclinical model of myeloma, RO4929097 increased BCMA on tumor cells in bone marrow and decreased soluble BCMA in peripheral blood. The myeloma-bearing mice treated with both BCMA CAR T cells and intermittent doses of RO4929097 experienced improved antitumor effects of the BCMA CAR T-cell therapy, as well as increased survival versus mice that did not receive RO4929097, she said.
“We’re currently optimizing these dosing regimens,” she said, concluding that “combining GSI and BCMA CAR T is an attractive option to improve the level of efficacy and prevent the outgrowth of BCMA-low tumor cells.”
Dr. Pont reported having no relevant financial disclosures.
NATIONAL HARBOR, MD. – Gamma secretase inhibition may lead to improved outcomes in multiple myeloma patients treated with B-cell maturation antigen (BCMA)–specific CAR T-cell therapy, according to Margot J. Pont, PhD.
In a preclinical myeloma model, gamma secretase inhibition (GSI) increased antitumor efficacy of BCMA-specific chimeric antigen receptor modified T-cells (BCMA CAR T), Dr. Pont of Fred Hutchinson Cancer Research Center, Seattle, reported at the annual meeting of the Society for Immunotherapy of Cancer.
BCMA is expressed in most multiple myeloma patients, and can be targeted by T cells that have been transduced with an anti-BCMA CAR. Other studies have shown efficacy of BCMA CAR T cells, and Dr. Pont and her colleagues have developed and optimized a CAR, based on a previously described single-chain variable fragment (scFv), that performs at least as well as a similar CAR developed previously by another group.
Previous studies have found that antigen down-regulation and escape can be an important escape mechanism by the tumor, so low-to-negative antigen expression could lead to failure in CAR T-cell recognition, resulting in relapse, she explained.
“We need the antigen density to be high enough,” she said, noting that BCMA, specifically, can be susceptible to antigen down-regulation, because its extracellular component is cleaved off the cell membrane by the enzyme gamma-secretase.
“That leads to two things: It reduces the surface expression of BCMA and it sheds soluble BCMA into the circulation, so you get high concentrations of soluble BCMA in the tumor microenvironment,” she said.
Inhibiting BCMA shedding with GSI can increase surface expression and reduce levels of soluble BCMA, thereby potentially enhancing the CAR activity.
First, soluble BCMA levels were measured in bone marrow sera from myeloma patients.
“We indeed saw high levels of soluble BCMA in these patients, and they roughly correlated with tumor burden. When culturing myeloma cell lines in vitro, we detected sBCMA in the culture supernatant within 24 hours,” Dr. Pont said, adding that the introduction of recombinant BCMA to the cultures showed that increasing levels of recombinant BCMA reduced staining of the CAR, demonstrating binding to the receptor.
Next, GSI was used to increase BCMA levels, and with increasing concentrations of the drug, BCMA surface expression was increased, she said, noting that this coincided with a reduction of soluble BCMA in the culture supernatant.
This also worked in patient samples, and was achieved with low doses of GSI, which upregulated surface BCMA levels on primary multiple myeloma by up to tenfold, she said.
In vivo testing of CAR T-cell efficacy was performed in tumor-bearing mice, which were treated with either BCMA-specific CAR T cells alone or in combination with GSI.
In this preclinical model of myeloma, RO4929097 increased BCMA on tumor cells in bone marrow and decreased soluble BCMA in peripheral blood. The myeloma-bearing mice treated with both BCMA CAR T cells and intermittent doses of RO4929097 experienced improved antitumor effects of the BCMA CAR T-cell therapy, as well as increased survival versus mice that did not receive RO4929097, she said.
“We’re currently optimizing these dosing regimens,” she said, concluding that “combining GSI and BCMA CAR T is an attractive option to improve the level of efficacy and prevent the outgrowth of BCMA-low tumor cells.”
Dr. Pont reported having no relevant financial disclosures.
NATIONAL HARBOR, MD. – Gamma secretase inhibition may lead to improved outcomes in multiple myeloma patients treated with B-cell maturation antigen (BCMA)–specific CAR T-cell therapy, according to Margot J. Pont, PhD.
In a preclinical myeloma model, gamma secretase inhibition (GSI) increased antitumor efficacy of BCMA-specific chimeric antigen receptor modified T-cells (BCMA CAR T), Dr. Pont of Fred Hutchinson Cancer Research Center, Seattle, reported at the annual meeting of the Society for Immunotherapy of Cancer.
BCMA is expressed in most multiple myeloma patients, and can be targeted by T cells that have been transduced with an anti-BCMA CAR. Other studies have shown efficacy of BCMA CAR T cells, and Dr. Pont and her colleagues have developed and optimized a CAR, based on a previously described single-chain variable fragment (scFv), that performs at least as well as a similar CAR developed previously by another group.
Previous studies have found that antigen down-regulation and escape can be an important escape mechanism by the tumor, so low-to-negative antigen expression could lead to failure in CAR T-cell recognition, resulting in relapse, she explained.
“We need the antigen density to be high enough,” she said, noting that BCMA, specifically, can be susceptible to antigen down-regulation, because its extracellular component is cleaved off the cell membrane by the enzyme gamma-secretase.
“That leads to two things: It reduces the surface expression of BCMA and it sheds soluble BCMA into the circulation, so you get high concentrations of soluble BCMA in the tumor microenvironment,” she said.
Inhibiting BCMA shedding with GSI can increase surface expression and reduce levels of soluble BCMA, thereby potentially enhancing the CAR activity.
First, soluble BCMA levels were measured in bone marrow sera from myeloma patients.
“We indeed saw high levels of soluble BCMA in these patients, and they roughly correlated with tumor burden. When culturing myeloma cell lines in vitro, we detected sBCMA in the culture supernatant within 24 hours,” Dr. Pont said, adding that the introduction of recombinant BCMA to the cultures showed that increasing levels of recombinant BCMA reduced staining of the CAR, demonstrating binding to the receptor.
Next, GSI was used to increase BCMA levels, and with increasing concentrations of the drug, BCMA surface expression was increased, she said, noting that this coincided with a reduction of soluble BCMA in the culture supernatant.
This also worked in patient samples, and was achieved with low doses of GSI, which upregulated surface BCMA levels on primary multiple myeloma by up to tenfold, she said.
In vivo testing of CAR T-cell efficacy was performed in tumor-bearing mice, which were treated with either BCMA-specific CAR T cells alone or in combination with GSI.
In this preclinical model of myeloma, RO4929097 increased BCMA on tumor cells in bone marrow and decreased soluble BCMA in peripheral blood. The myeloma-bearing mice treated with both BCMA CAR T cells and intermittent doses of RO4929097 experienced improved antitumor effects of the BCMA CAR T-cell therapy, as well as increased survival versus mice that did not receive RO4929097, she said.
“We’re currently optimizing these dosing regimens,” she said, concluding that “combining GSI and BCMA CAR T is an attractive option to improve the level of efficacy and prevent the outgrowth of BCMA-low tumor cells.”
Dr. Pont reported having no relevant financial disclosures.
AT SITC 2017
Team identifies genetic differences between MM patients
Researchers say they have identified significant genetic differences between African-American patients with multiple myeloma (MM) and Caucasian patients with the disease.
For example, the researchers found that African Americans were more likely to have mutations in BCL7A, BRWD3, and AUTS2, but Caucasians were more likely to have mutations in IRF4 and TP53.
“A cancer therapy that targets TP53 would not be as effective for African Americans with multiple myeloma as it would be for a white population because doctors would be trying to fix the wrong mutated gene,” said Zarko Manojlovic, PhD, of the University of Southern California in Los Angeles.
Dr Manojlovic and his colleagues conducted this research and detailed the results in PLOS Genetics.
The researchers analyzed genetic sequencing data and clinical data from 718 MM patients participating in the MMRF CoMMpass Study.
Race was reported by the patients, but the researchers also used the genetic data to determine that 127 patients were of African descent and 591 were of European descent. The researchers noted that the mean European admixture among self-reported African Americans was 31% (range; 11%-67.8%). And the mean west-African admixture among self-reported Caucasians was 0.1% (range; 0-34.3).
The African-American patients were significantly more likely than the Caucasians to have early onset MM (at ages 40-49)—11% and 4.6%, respectively (P=0.004). And Caucasians were significantly more likely than African Americans to have late-onset MM (at ages 70-79)—22% and 14%, respectively (P=0.04).
There was no significant difference in overall survival based on race, age of onset, or MM karyotype in this population.
Mutations in the following genes occurred at significantly higher frequencies in African-American patients than in Caucasians: RYR1, RPL10, PTCHD3, BCL7A, SPEF2, MYH13, ABI3BP, BRWD3, GRM7, AUTS2, PARP4, PLD1, ANKRD26, DDX17, and STXBP4.
On the other hand, Caucasians had a significantly higher frequency of mutations in IRF4 and TP53. In fact, there was a TP53 somatic mutation frequency of 6.3% in Caucasians and 1.6% in African Americans (P=0.035).
“One of the most surprising discoveries from this large cohort is that cancers from patients of European descent were 6 times more likely than their African-descent counterparts to have mutations in TP53, a known tumor suppressor gene,” Dr Manojlovic said.
“Biologically speaking, higher mutation rates in this gene should lead to overall lower survival rates among patients of European descent, but that does not correlate with what we see in clinical outcomes. Going forward, we hope to functionally validate these results for more insight into the underlying biology.”
“We in the cancer genomics community have a responsibility to ensure that our studies represent true population diversity so we can understand the role of ancestry and biology in health outcomes,” added study author John D. Carpten, PhD, of the University of Southern California.
“The new candidate myeloma genes we identified in the African-American population may have been overlooked because of the lack of diversity in previous genomic efforts. There are clearly molecular differences between African-American and Caucasian multiple myeloma cases, and it will be critical to pursue these observations to better improve clinical management of the disease for all patients.”
Researchers say they have identified significant genetic differences between African-American patients with multiple myeloma (MM) and Caucasian patients with the disease.
For example, the researchers found that African Americans were more likely to have mutations in BCL7A, BRWD3, and AUTS2, but Caucasians were more likely to have mutations in IRF4 and TP53.
“A cancer therapy that targets TP53 would not be as effective for African Americans with multiple myeloma as it would be for a white population because doctors would be trying to fix the wrong mutated gene,” said Zarko Manojlovic, PhD, of the University of Southern California in Los Angeles.
Dr Manojlovic and his colleagues conducted this research and detailed the results in PLOS Genetics.
The researchers analyzed genetic sequencing data and clinical data from 718 MM patients participating in the MMRF CoMMpass Study.
Race was reported by the patients, but the researchers also used the genetic data to determine that 127 patients were of African descent and 591 were of European descent. The researchers noted that the mean European admixture among self-reported African Americans was 31% (range; 11%-67.8%). And the mean west-African admixture among self-reported Caucasians was 0.1% (range; 0-34.3).
The African-American patients were significantly more likely than the Caucasians to have early onset MM (at ages 40-49)—11% and 4.6%, respectively (P=0.004). And Caucasians were significantly more likely than African Americans to have late-onset MM (at ages 70-79)—22% and 14%, respectively (P=0.04).
There was no significant difference in overall survival based on race, age of onset, or MM karyotype in this population.
Mutations in the following genes occurred at significantly higher frequencies in African-American patients than in Caucasians: RYR1, RPL10, PTCHD3, BCL7A, SPEF2, MYH13, ABI3BP, BRWD3, GRM7, AUTS2, PARP4, PLD1, ANKRD26, DDX17, and STXBP4.
On the other hand, Caucasians had a significantly higher frequency of mutations in IRF4 and TP53. In fact, there was a TP53 somatic mutation frequency of 6.3% in Caucasians and 1.6% in African Americans (P=0.035).
“One of the most surprising discoveries from this large cohort is that cancers from patients of European descent were 6 times more likely than their African-descent counterparts to have mutations in TP53, a known tumor suppressor gene,” Dr Manojlovic said.
“Biologically speaking, higher mutation rates in this gene should lead to overall lower survival rates among patients of European descent, but that does not correlate with what we see in clinical outcomes. Going forward, we hope to functionally validate these results for more insight into the underlying biology.”
“We in the cancer genomics community have a responsibility to ensure that our studies represent true population diversity so we can understand the role of ancestry and biology in health outcomes,” added study author John D. Carpten, PhD, of the University of Southern California.
“The new candidate myeloma genes we identified in the African-American population may have been overlooked because of the lack of diversity in previous genomic efforts. There are clearly molecular differences between African-American and Caucasian multiple myeloma cases, and it will be critical to pursue these observations to better improve clinical management of the disease for all patients.”
Researchers say they have identified significant genetic differences between African-American patients with multiple myeloma (MM) and Caucasian patients with the disease.
For example, the researchers found that African Americans were more likely to have mutations in BCL7A, BRWD3, and AUTS2, but Caucasians were more likely to have mutations in IRF4 and TP53.
“A cancer therapy that targets TP53 would not be as effective for African Americans with multiple myeloma as it would be for a white population because doctors would be trying to fix the wrong mutated gene,” said Zarko Manojlovic, PhD, of the University of Southern California in Los Angeles.
Dr Manojlovic and his colleagues conducted this research and detailed the results in PLOS Genetics.
The researchers analyzed genetic sequencing data and clinical data from 718 MM patients participating in the MMRF CoMMpass Study.
Race was reported by the patients, but the researchers also used the genetic data to determine that 127 patients were of African descent and 591 were of European descent. The researchers noted that the mean European admixture among self-reported African Americans was 31% (range; 11%-67.8%). And the mean west-African admixture among self-reported Caucasians was 0.1% (range; 0-34.3).
The African-American patients were significantly more likely than the Caucasians to have early onset MM (at ages 40-49)—11% and 4.6%, respectively (P=0.004). And Caucasians were significantly more likely than African Americans to have late-onset MM (at ages 70-79)—22% and 14%, respectively (P=0.04).
There was no significant difference in overall survival based on race, age of onset, or MM karyotype in this population.
Mutations in the following genes occurred at significantly higher frequencies in African-American patients than in Caucasians: RYR1, RPL10, PTCHD3, BCL7A, SPEF2, MYH13, ABI3BP, BRWD3, GRM7, AUTS2, PARP4, PLD1, ANKRD26, DDX17, and STXBP4.
On the other hand, Caucasians had a significantly higher frequency of mutations in IRF4 and TP53. In fact, there was a TP53 somatic mutation frequency of 6.3% in Caucasians and 1.6% in African Americans (P=0.035).
“One of the most surprising discoveries from this large cohort is that cancers from patients of European descent were 6 times more likely than their African-descent counterparts to have mutations in TP53, a known tumor suppressor gene,” Dr Manojlovic said.
“Biologically speaking, higher mutation rates in this gene should lead to overall lower survival rates among patients of European descent, but that does not correlate with what we see in clinical outcomes. Going forward, we hope to functionally validate these results for more insight into the underlying biology.”
“We in the cancer genomics community have a responsibility to ensure that our studies represent true population diversity so we can understand the role of ancestry and biology in health outcomes,” added study author John D. Carpten, PhD, of the University of Southern California.
“The new candidate myeloma genes we identified in the African-American population may have been overlooked because of the lack of diversity in previous genomic efforts. There are clearly molecular differences between African-American and Caucasian multiple myeloma cases, and it will be critical to pursue these observations to better improve clinical management of the disease for all patients.”