With the accelerated FDA approval in December 2015 of the anti-CD38 monoclonal antibody daratumumab (Darzalex) for patients with multiple myeloma who received ≥3 previous therapies, studies of the drug presented at ASH 2015 were of great interest.
Daratumumab, Lenalidomide, and Dexamethasone
Torben Plesner, MD, Vejle Hospital, Denmark, reported that the combination of daratumumab, lenalidomide, and dexamethasone in the phase 1/2 GEN503 trial, produced “deep, durable responses,” suggesting that the drug is “the rituximab of myeloma.”
“It is very effective when given with other core treatments, with no added toxicity,” Dr Plesner said.
He updated the safety and efficacy data from the GEN503 trial of daratumumab, lenalidomide, and dexamethasone in 32 patients with relapsed or refractory multiple myeloma. The overall response rate was 81%, with 34% of patients achieving a complete response or better and 63% achieving a very good partial response (VGPR) or better. The median response duration was not reached, and 91% of patients were free of disease progression at 12 months.
Although the overall survival (OS) data are immature, 90% of patients were alive, and 72% were free of progression at 18 months.
The main toxicities included neutropenia (84%), muscle spasms (44%), cough (50%), and diarrhea (44%).
Daratumumab, Pomalidomide, and Dexamethasone
The phase 1b MMY1001 trial evaluated daratumumab in combination with pomalidomide (Pomalyst) and dexamethasone in 98 patients with relapsed or refractory multiple myeloma and at least 2 previous lines of treatment. Many patients were refractory to a proteasome inhibitor and an immunomodulating drug (IMiD).
Ajai Chari, MD, Director of Clinical Research, Multiple Myeloma Program, Mount Sinai School of Medicine, NY, reported that the response rate was 71% overall and 67% in patients with double-refractory disease; 43% of the patients achieved a VGPR or better, and 73% of patients had a clinical benefit.
“At a median follow-up of 4.2 months, 47 of 53 (89%) responders had not progressed.” Serious adverse events occurred in 42% of patients.
“Daratumumab can be safely combined with pom/dex [pomalidomide plus dexamethasone],” Dr Chari concluded. “We observed no new safety signals.”
Daratumumab as a single agent was also very active in an analysis of the combined data set of 148 patients receiving daratumumab in the GEN501 and SIRIUS trials.
Saad Z. Usmani, MD, Director of Clinical Research in Hematologic Malignancies, Levine Cancer Institute, Charlotte, NC, reported, “Daratumumab induced rapid, deep, and durable responses in a heavily pretreated/highly refractory population. A remarkable depth of response was observed in patients who were refractory to newer agents, including pomalidomide and carfilzomib [Kyprolis].”
The overall response rate was 31%, and 13% of the patients achieved a VGPR or better. The median OS was 19.9 months, and the 1-year survival rate was 69%. The median OS has not been reached in the responders.
“Daratumumab conferred an overall survival benefit, even in patients who achieved stable disease or minimal response,” Dr Usmani emphasized.
Sagar Lonial, MD, Professor and Executive Vice Chair, Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, said that daratumumab monotherapy “demonstrated significant activity, and not only this, but very prolonged duration of remission and overall survival in patients, even beyond the time when their response to anti-CD38 antibody is gone. This suggests that immunomodulation may be an important part of the long-term outcome of patients.”