Credit: Linda Bartlett
SAN FRANCISCO—Combination therapy involving a novel monoclonal antibody (mAb) produces encouraging activity in relapsed or refractory multiple myeloma (MM), according to researchers.
The team conducted a phase 1b trial testing the IgG1 mAb SAR650984 in combination with lenalidomide and dexamethasone (SAR-len-dex).
The treatment produced an overall response rate (ORR) of 58% and a higher ORR among patients who received the highest dose of SAR.
Furthermore, the combination had a “very manageable safety profile,” according to study investigator Thomas Martin, MD, of the University of California at San Francisco.
“The safety findings are really consistent with those of the individual drugs,” he said.
Dr Martin presented these findings at the 2014 ASH Annual Meeting as abstract 83.* The trial was sponsored by Sanofi (the company developing SAR), but investigators also received research funding from Karyopharm, Bristol Myers Squibb, Millennium, and Celgene.
Dr Martin explained that SAR is a humanized IgG1 mAb that binds selectively to a unique epitope on the human CD38 receptor, and it has 4 potential mechanisms of action: antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, direct apoptosis without crosslinking, and inhibition of CD38 enzyme activity.
He said there is “ample evidence” to suggest that SAR-len-dex would be active in MM. First, both lenalidomide and SAR have demonstrated single-agent activity in MM. Second, lenalidomide can increase IL-2 production, which leads to enhanced antibody-dependent cellular cytotoxicity. And finally, SAR and lenalidomide showed additive effects in a mouse model of MM.
With that in mind, Dr Martin and his colleagues decided to test SAR-len-dex in patients with relapsed or refractory MM.
The team enrolled 31 patients and administered SAR at 3 different dose levels. Patients received 3 mg/kg (n=4), 5 mg/kg (n=3), or 10 mg/kg (n=24) every 2 weeks. They received lenalidomide at 25 mg on days 1-21 per 28-day cycle and dexamethasone at 40 mg once a week on days 1, 8, 15, and 22.
The patients’ median age was 59 (range, 45-74), the median time since diagnosis was 4 years (range, 1-12), the median number of prior treatment regimens was 7 (range, 2-14), and the median number of prior lines of therapy was 4 (range, 1-11).
“The median time from the last lenalidomide-containing regimen was 9 months,” Dr Martin noted. “Ninety-four percent of the patients had prior lenalidomide, and 74% of these patients were lenalidomide refractory.”
Of the 29% of patients who had received prior pomalidomide, all were refractory to it. The same was true of the 48% of patients who received carfilzomib. And of the 94% of patients who received prior bortezomib, 52% were refractory to it.
Adverse events
The maximum-tolerated dose of SAR was not reached. Treatment-emergent adverse events occurring in 30% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, diarrhea, fatigue, insomnia, muscle spasms, nausea, pneumonia, pyrexia, and upper respiratory tract infections.
Grade 3/4 events occurring in 5% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, fatigue, insomnia, and pneumonia.
“All of these events are commonly associated with the backbone treatment of lenalidomide and dexamethasone, and no unexpected or untoward adverse events were seen,” Dr Martin noted.
The most common SAR-associated adverse events were infusion reactions. About 35% of patients experienced an infusion reaction in cycle 1, and 10% did so in cycle 2.
Most reactions were grade 1 and 2 and did not lead to treatment discontinuation. Two patients did discontinue treatment due to grade 3 infusion reactions, but both events were ultimately resolved.
Response and survival
The ORR was 58% (n=18), and the clinical benefit rate was 65% (n=20). Two patients had a stringent complete response, 7 had a very good partial response, 9 had a partial response, 2 had a minimal response, 6 had stable disease, 4 progressed, and 1 was not evaluable.
Responses were seen at all dose levels, but the best responses occurred in patients who received the highest dose of SAR. Among patients who received the highest dose, the ORR was 68%, and the clinical benefit rate was 65%.
The ORR was 50% in patients who were refractory to prior treatment with an immunomodulatory drug, 40% in patients who were refractory to carfilzomib, and 33% in patients who were refractory to pomalidomide.
At 9 months of follow-up, the median progression-free survival was 6.2 months. The median progression-free survival was not reached for patients who had received 1 to 2 prior lines of therapy, and it was 5.8 months for patients who had received 3 or more prior lines of therapy.
“SAR in combination with lenalidomide/dexamethasone showed encouraging activity in this heavily pretreated population,” Dr Martin said in closing, adding that the combination compares favorably to other treatments tested in patients who received the same number of prior lines of therapy.
*Information in the abstract differs from that presented at the meeting.