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SAN FRANCISCO – Combining anti-CD38 monoclonal antibodies with standard antimyeloma therapies proved highly active without excessive toxicity in newly diagnosed as well as relapsed or refractory multiple myeloma in a pair of phase Ib studies.
“These anti-CD38 antibodies are the next blockbuster class of agents,” Dr. Thomas Martin III, lead author of one of the studies, said during a press briefing at the annual meeting of the American Society of Hematology. “These are the next agents that are really going to show some benefit for myeloma patients. And the next 5 years are going to be really fun moving them from the refractory setting to the less refractory setting to the frontline setting.”
Three agents are in development that target CD38, a cell surface glycoprotein that is strongly expressed in multiple myeloma. All three – daratumumab, SAR650984, and MOR202 – bind to a different part of the anti-CD39 receptor, but “whether that makes any clinical difference, we certainly don’t know at this point in time,” said Dr. Martin of the University of California, San Francisco.
Immunomodulatory drugs (IMiDs) and proteasome inhibitors (PI) are the current blockbuster agents in myeloma and have advanced overall survival from about 3 years to 7-10 years. But all patients still relapse after IMiD and PI failure, and survival outcomes remain poor at a median of about 9 months for those with advanced relapsed/refractory disease. Further, myeloma has failed to respond like the B-cell lymphomas to anti-CD20 antibodies such as rituximab (Rituxan).
Dr. Martin and his associates launched a phase Ib dose-escalation trial to evaluate SAR650984 in combination with standard doses of lenalidomide (Revlimid) and dexamethasone in adults with relapsed or refractory multiple myeloma failing at least two prior therapies.
SAR650984 was given intravenously on days 1 and 15 of a 28-day cycle at 3 mg/kg to 4 patients (cohort 1), 5 mg/kg to 3 patients (cohort 2), and 10 mg/kg to 6 patients (cohort 3) plus an additional 18 patients in an expansion cohort.
All 31 patients were heavily pretreated, with 94% previously treated with lenalidomide or bortezomib (Velcade), 29% with pomalidomide (Pomalyst), and 48% with carfilzomib (Kyprolis). Many (84%) were considered double refractory, or relapsed and refractory, to their last IMiD therapy, Dr. Martin reported.
Despite this, nearly two-thirds (58%) had a response, including two stringent complete responses, seven very good partial responses, and nine partial responses. The overall response rate (ORR) was 25% in cohort 1, 67% in cohort 2, and 63% at the 10-mg dose level or double what was seen as a single agent, he said. The clinical benefit rates were 50%, 67%, and 67%.
In addition, the ORR was 50% in patients who were IMiD relapsed and refractory and 33% in patients pomalidomide relapsed and refractory, he reported.
At 9 months’ follow-up, median progression-free survival was 6.2 months and had not been reached in patients who received fewer than three lines of prior therapy.
The most common treatment-related adverse events were infusion reactions, fatigue, nausea, upper respiratory tract infection, and diarrhea. Infusion reactions occurred about a third of the time, typically in the first or second cycle, and were mostly mild (grade 1 or 2), Dr. Martin said. Only two patients discontinued treatment because of infusion reactions, one for a serious grade 3 anaphylactic reaction in cycle 1 and the other for a nonserious grade 3 maculopapular rash in cycle 2.
Daratumumab
The second highlighted study looked at the benefit and safety of adding daratumumab to commonly used backbone regimens in patients with newly diagnosed, relapsed, or treatment-resistant myeloma.
Single-agent daratumumab has shown activity in prior studies and received breakthrough therapy designation in May 2013 for patients with multiple myeloma after at least three prior lines of therapy including a proteasome inhibitor and an IMiD or those double refractory to a PI and IMiD.
In the four-arm, open-label study, daratumumab was given at a starting dose of 16 mg/kg in combination with bortezomib-dexamethasone (VD), bortezomib-thalidomide-dexamethasone (VTD), bortezomib-melphalan-prednisone (VMP), and pomalidomide-dexamethasone (POM-D). Treatment was for 18 three-week cycles or until transplantation in the VD and VTD arms, for 9 six-week cycles in the VMP arm, and was given in four-week cycles until disease progression in the POM-D arm.
Newly diagnosed patients were included in the VD and VTD arms irrespective of transplant eligibility, while patients in the VMP arm were newly diagnosed and transplant ineligible. Patients in the POM-D arm were relapsed/refractory to two or more lines of therapy including two consecutive cycles of lenalidomide and bortezomib. In all, 24 patients were evaluable for efficacy.
The ORR in newly diagnosed patients was 100%, including partial responses and very good partial responses, and 50% in the relapsed group, including one complete response, study coauthor Dr. María-Victoria Mateos said at the briefing.
Daratumumab does not appear to have a negative effect on stem cell mobilization, with five patients electively taken off study for autologous stem cell transplantation after cycle 4.
Three of the seven patients in the POM-D arm dropped out (one because of physician decision and two because of disease progression).
The addition of daratumumab to the various backbones was well tolerated in all evaluable patients and did not result in significant additional toxicity, said Dr. Mateos of University Hospital of Salamanca, Spain.
Adverse events possibly or probably related to daratumumab included one grade 3 neutropenia in the VD arm, one grade 3 thrombocytopenia in the VMP arm, and one serious infectious pneumonia in the POM-D arm. There were a few infusion-related reactions, but most were grade 1 or 2 and occurred within the first infusions, she said.
“This is a very new and exciting concept in multiple myeloma, as we are seeing that combining this precision approach with the standard of care is leading to more effective treatment without increased toxicity,” Dr. Philippe Moreau, lead study author, of University Hospital of Nantes, France, said in a statement. “By targeting a simple molecule expressed by the cancer cells, this therapy has the potential to become a potent addition to conventional treatment.”
Dr. Brad S. Kahl, press briefing moderator, of the University of Wisconsin-Madison, was enthusiastic about the potential for anti-CD38 antibodies to transform the treatment of multiple myeloma.
“Obviously it’s very, very early, probably too early to plant a victory flag in the ground,” he said. “Having said that, the early data is very promising and totally justifies all the comments about bringing these drugs forward, aggressively moving them into the front line.”
Phase III studies are ongoing or will be initiated shortly with daratumumab plus VD in relapsed myeloma (MMY3004-CASTOR), with VMP in non–transplant eligible patients (MMY3007-ALCYONE), and with VTD as induction therapy (MMY3006/IFM-HOVON-CASSIOPEIA).
SAN FRANCISCO – Combining anti-CD38 monoclonal antibodies with standard antimyeloma therapies proved highly active without excessive toxicity in newly diagnosed as well as relapsed or refractory multiple myeloma in a pair of phase Ib studies.
“These anti-CD38 antibodies are the next blockbuster class of agents,” Dr. Thomas Martin III, lead author of one of the studies, said during a press briefing at the annual meeting of the American Society of Hematology. “These are the next agents that are really going to show some benefit for myeloma patients. And the next 5 years are going to be really fun moving them from the refractory setting to the less refractory setting to the frontline setting.”
Three agents are in development that target CD38, a cell surface glycoprotein that is strongly expressed in multiple myeloma. All three – daratumumab, SAR650984, and MOR202 – bind to a different part of the anti-CD39 receptor, but “whether that makes any clinical difference, we certainly don’t know at this point in time,” said Dr. Martin of the University of California, San Francisco.
Immunomodulatory drugs (IMiDs) and proteasome inhibitors (PI) are the current blockbuster agents in myeloma and have advanced overall survival from about 3 years to 7-10 years. But all patients still relapse after IMiD and PI failure, and survival outcomes remain poor at a median of about 9 months for those with advanced relapsed/refractory disease. Further, myeloma has failed to respond like the B-cell lymphomas to anti-CD20 antibodies such as rituximab (Rituxan).
Dr. Martin and his associates launched a phase Ib dose-escalation trial to evaluate SAR650984 in combination with standard doses of lenalidomide (Revlimid) and dexamethasone in adults with relapsed or refractory multiple myeloma failing at least two prior therapies.
SAR650984 was given intravenously on days 1 and 15 of a 28-day cycle at 3 mg/kg to 4 patients (cohort 1), 5 mg/kg to 3 patients (cohort 2), and 10 mg/kg to 6 patients (cohort 3) plus an additional 18 patients in an expansion cohort.
All 31 patients were heavily pretreated, with 94% previously treated with lenalidomide or bortezomib (Velcade), 29% with pomalidomide (Pomalyst), and 48% with carfilzomib (Kyprolis). Many (84%) were considered double refractory, or relapsed and refractory, to their last IMiD therapy, Dr. Martin reported.
Despite this, nearly two-thirds (58%) had a response, including two stringent complete responses, seven very good partial responses, and nine partial responses. The overall response rate (ORR) was 25% in cohort 1, 67% in cohort 2, and 63% at the 10-mg dose level or double what was seen as a single agent, he said. The clinical benefit rates were 50%, 67%, and 67%.
In addition, the ORR was 50% in patients who were IMiD relapsed and refractory and 33% in patients pomalidomide relapsed and refractory, he reported.
At 9 months’ follow-up, median progression-free survival was 6.2 months and had not been reached in patients who received fewer than three lines of prior therapy.
The most common treatment-related adverse events were infusion reactions, fatigue, nausea, upper respiratory tract infection, and diarrhea. Infusion reactions occurred about a third of the time, typically in the first or second cycle, and were mostly mild (grade 1 or 2), Dr. Martin said. Only two patients discontinued treatment because of infusion reactions, one for a serious grade 3 anaphylactic reaction in cycle 1 and the other for a nonserious grade 3 maculopapular rash in cycle 2.
Daratumumab
The second highlighted study looked at the benefit and safety of adding daratumumab to commonly used backbone regimens in patients with newly diagnosed, relapsed, or treatment-resistant myeloma.
Single-agent daratumumab has shown activity in prior studies and received breakthrough therapy designation in May 2013 for patients with multiple myeloma after at least three prior lines of therapy including a proteasome inhibitor and an IMiD or those double refractory to a PI and IMiD.
In the four-arm, open-label study, daratumumab was given at a starting dose of 16 mg/kg in combination with bortezomib-dexamethasone (VD), bortezomib-thalidomide-dexamethasone (VTD), bortezomib-melphalan-prednisone (VMP), and pomalidomide-dexamethasone (POM-D). Treatment was for 18 three-week cycles or until transplantation in the VD and VTD arms, for 9 six-week cycles in the VMP arm, and was given in four-week cycles until disease progression in the POM-D arm.
Newly diagnosed patients were included in the VD and VTD arms irrespective of transplant eligibility, while patients in the VMP arm were newly diagnosed and transplant ineligible. Patients in the POM-D arm were relapsed/refractory to two or more lines of therapy including two consecutive cycles of lenalidomide and bortezomib. In all, 24 patients were evaluable for efficacy.
The ORR in newly diagnosed patients was 100%, including partial responses and very good partial responses, and 50% in the relapsed group, including one complete response, study coauthor Dr. María-Victoria Mateos said at the briefing.
Daratumumab does not appear to have a negative effect on stem cell mobilization, with five patients electively taken off study for autologous stem cell transplantation after cycle 4.
Three of the seven patients in the POM-D arm dropped out (one because of physician decision and two because of disease progression).
The addition of daratumumab to the various backbones was well tolerated in all evaluable patients and did not result in significant additional toxicity, said Dr. Mateos of University Hospital of Salamanca, Spain.
Adverse events possibly or probably related to daratumumab included one grade 3 neutropenia in the VD arm, one grade 3 thrombocytopenia in the VMP arm, and one serious infectious pneumonia in the POM-D arm. There were a few infusion-related reactions, but most were grade 1 or 2 and occurred within the first infusions, she said.
“This is a very new and exciting concept in multiple myeloma, as we are seeing that combining this precision approach with the standard of care is leading to more effective treatment without increased toxicity,” Dr. Philippe Moreau, lead study author, of University Hospital of Nantes, France, said in a statement. “By targeting a simple molecule expressed by the cancer cells, this therapy has the potential to become a potent addition to conventional treatment.”
Dr. Brad S. Kahl, press briefing moderator, of the University of Wisconsin-Madison, was enthusiastic about the potential for anti-CD38 antibodies to transform the treatment of multiple myeloma.
“Obviously it’s very, very early, probably too early to plant a victory flag in the ground,” he said. “Having said that, the early data is very promising and totally justifies all the comments about bringing these drugs forward, aggressively moving them into the front line.”
Phase III studies are ongoing or will be initiated shortly with daratumumab plus VD in relapsed myeloma (MMY3004-CASTOR), with VMP in non–transplant eligible patients (MMY3007-ALCYONE), and with VTD as induction therapy (MMY3006/IFM-HOVON-CASSIOPEIA).
SAN FRANCISCO – Combining anti-CD38 monoclonal antibodies with standard antimyeloma therapies proved highly active without excessive toxicity in newly diagnosed as well as relapsed or refractory multiple myeloma in a pair of phase Ib studies.
“These anti-CD38 antibodies are the next blockbuster class of agents,” Dr. Thomas Martin III, lead author of one of the studies, said during a press briefing at the annual meeting of the American Society of Hematology. “These are the next agents that are really going to show some benefit for myeloma patients. And the next 5 years are going to be really fun moving them from the refractory setting to the less refractory setting to the frontline setting.”
Three agents are in development that target CD38, a cell surface glycoprotein that is strongly expressed in multiple myeloma. All three – daratumumab, SAR650984, and MOR202 – bind to a different part of the anti-CD39 receptor, but “whether that makes any clinical difference, we certainly don’t know at this point in time,” said Dr. Martin of the University of California, San Francisco.
Immunomodulatory drugs (IMiDs) and proteasome inhibitors (PI) are the current blockbuster agents in myeloma and have advanced overall survival from about 3 years to 7-10 years. But all patients still relapse after IMiD and PI failure, and survival outcomes remain poor at a median of about 9 months for those with advanced relapsed/refractory disease. Further, myeloma has failed to respond like the B-cell lymphomas to anti-CD20 antibodies such as rituximab (Rituxan).
Dr. Martin and his associates launched a phase Ib dose-escalation trial to evaluate SAR650984 in combination with standard doses of lenalidomide (Revlimid) and dexamethasone in adults with relapsed or refractory multiple myeloma failing at least two prior therapies.
SAR650984 was given intravenously on days 1 and 15 of a 28-day cycle at 3 mg/kg to 4 patients (cohort 1), 5 mg/kg to 3 patients (cohort 2), and 10 mg/kg to 6 patients (cohort 3) plus an additional 18 patients in an expansion cohort.
All 31 patients were heavily pretreated, with 94% previously treated with lenalidomide or bortezomib (Velcade), 29% with pomalidomide (Pomalyst), and 48% with carfilzomib (Kyprolis). Many (84%) were considered double refractory, or relapsed and refractory, to their last IMiD therapy, Dr. Martin reported.
Despite this, nearly two-thirds (58%) had a response, including two stringent complete responses, seven very good partial responses, and nine partial responses. The overall response rate (ORR) was 25% in cohort 1, 67% in cohort 2, and 63% at the 10-mg dose level or double what was seen as a single agent, he said. The clinical benefit rates were 50%, 67%, and 67%.
In addition, the ORR was 50% in patients who were IMiD relapsed and refractory and 33% in patients pomalidomide relapsed and refractory, he reported.
At 9 months’ follow-up, median progression-free survival was 6.2 months and had not been reached in patients who received fewer than three lines of prior therapy.
The most common treatment-related adverse events were infusion reactions, fatigue, nausea, upper respiratory tract infection, and diarrhea. Infusion reactions occurred about a third of the time, typically in the first or second cycle, and were mostly mild (grade 1 or 2), Dr. Martin said. Only two patients discontinued treatment because of infusion reactions, one for a serious grade 3 anaphylactic reaction in cycle 1 and the other for a nonserious grade 3 maculopapular rash in cycle 2.
Daratumumab
The second highlighted study looked at the benefit and safety of adding daratumumab to commonly used backbone regimens in patients with newly diagnosed, relapsed, or treatment-resistant myeloma.
Single-agent daratumumab has shown activity in prior studies and received breakthrough therapy designation in May 2013 for patients with multiple myeloma after at least three prior lines of therapy including a proteasome inhibitor and an IMiD or those double refractory to a PI and IMiD.
In the four-arm, open-label study, daratumumab was given at a starting dose of 16 mg/kg in combination with bortezomib-dexamethasone (VD), bortezomib-thalidomide-dexamethasone (VTD), bortezomib-melphalan-prednisone (VMP), and pomalidomide-dexamethasone (POM-D). Treatment was for 18 three-week cycles or until transplantation in the VD and VTD arms, for 9 six-week cycles in the VMP arm, and was given in four-week cycles until disease progression in the POM-D arm.
Newly diagnosed patients were included in the VD and VTD arms irrespective of transplant eligibility, while patients in the VMP arm were newly diagnosed and transplant ineligible. Patients in the POM-D arm were relapsed/refractory to two or more lines of therapy including two consecutive cycles of lenalidomide and bortezomib. In all, 24 patients were evaluable for efficacy.
The ORR in newly diagnosed patients was 100%, including partial responses and very good partial responses, and 50% in the relapsed group, including one complete response, study coauthor Dr. María-Victoria Mateos said at the briefing.
Daratumumab does not appear to have a negative effect on stem cell mobilization, with five patients electively taken off study for autologous stem cell transplantation after cycle 4.
Three of the seven patients in the POM-D arm dropped out (one because of physician decision and two because of disease progression).
The addition of daratumumab to the various backbones was well tolerated in all evaluable patients and did not result in significant additional toxicity, said Dr. Mateos of University Hospital of Salamanca, Spain.
Adverse events possibly or probably related to daratumumab included one grade 3 neutropenia in the VD arm, one grade 3 thrombocytopenia in the VMP arm, and one serious infectious pneumonia in the POM-D arm. There were a few infusion-related reactions, but most were grade 1 or 2 and occurred within the first infusions, she said.
“This is a very new and exciting concept in multiple myeloma, as we are seeing that combining this precision approach with the standard of care is leading to more effective treatment without increased toxicity,” Dr. Philippe Moreau, lead study author, of University Hospital of Nantes, France, said in a statement. “By targeting a simple molecule expressed by the cancer cells, this therapy has the potential to become a potent addition to conventional treatment.”
Dr. Brad S. Kahl, press briefing moderator, of the University of Wisconsin-Madison, was enthusiastic about the potential for anti-CD38 antibodies to transform the treatment of multiple myeloma.
“Obviously it’s very, very early, probably too early to plant a victory flag in the ground,” he said. “Having said that, the early data is very promising and totally justifies all the comments about bringing these drugs forward, aggressively moving them into the front line.”
Phase III studies are ongoing or will be initiated shortly with daratumumab plus VD in relapsed myeloma (MMY3004-CASTOR), with VMP in non–transplant eligible patients (MMY3007-ALCYONE), and with VTD as induction therapy (MMY3006/IFM-HOVON-CASSIOPEIA).
AT ASH 2014
Key clinical point: The investigational anti-CD38 antibodies SAR650984 and daratumumab in combination with standard regimens were highly active in untreated and relapsed/refractory multiple myeloma.
Major finding: Overall response rates were 58% in patients treated with SAR650984, and 100% and 50%, respectively, in newly diagnosed and relapsed patients given daratumumab.
Data source: Two phase Ib studies in patients with newly diagnosed or relapsed/refractory multiple myeloma.
Disclosures: Sanofi Oncology sponsored the SAR650984 study. Dr. Martin reported research funding from Sanofi and serving as a speaker for Novartis. Genmab sponsored the daratumumab study. Dr. Mateos and Dr. Moreau reported ties with Janssen. Dr. Kahl reported ties with numerous drug companies.
