Thomas G. Martin, MD
The CD38-specific monoclonal antibody SAR650984 demonstrated encouraging efficacy as a monotherapy and in combination with dexamethasone and lenalidomide without reaching a maximum tolerated dose in patients with heavily pretreated multiple myeloma, according to results from two early-phase clinical trials presented at the 2014 ASCO Annual Meeting.
"There's a handful of evidence to move forward with this combination. First, these drugs all have shown single-agent activity. Second, lenalidomide may increase serum IL-2 levels, and thus promote NK cell activity and enhance ADCC [antibody dependent cellular cytotoxicity]. And there's also data from xenograft models," Thomas G. Martin, MD, the associate director of the myeloma program at the University of California, San Francisco, explained during his presentation.
Single-agent SAR650984 was administered intravenously to 35 patients with relapsed/refractory multiple myeloma across a variety of doses ranging from 0.3 to 20 mg/kg, in a phase I study. Patients had a median age of 64 years and had received a median of 6 prior therapies, including immunomodulatory agents and proteasome inhibitors.
Across all doses, the overall response rate (ORR) was 24% with a stable disease (SD) rate of 41%. In patients receiving a dose ≥10mg/kg (n = 18), the ORR was 33% with a 39% SD rate.
The most common all-grade adverse events (AEs) were fatigue (48.6%), nausea (34.3%), pyrexia (28.6%), anemia (28.6%), cough (25.7%), headache (25.7%), upper respiratory infection and chills (22.9%), dyspnea (20%), constipation (17.1%), and diarrhea and vomiting (14.3%). The most common, greater than grade 3 AE was pneumonia (9%).
In a separate phase Ib study, 13 patients with relapsed/refractory multiple myeloma were treated with SAR650984 at either 3, 5, or 10 mg/kg every 2 weeks. Lenalidomide was administered at 25 mg on days 1 through 21, and dexamethasone was administered at 40 mg once per week in a 28-day cycle.
The ORR across all doses was 58%, which was comprised of 1 partial response (PR) at the 3-mg/kg dose, 1 PR and 1 very good PR (VGPR) in the 5-mg/kg arm, and 1 PR and 3 VGPRs in the 10-mg/kg cohort.
Based on these findings, an expansion cohort was opened that enrolled an additional 18 patients who received treatment with the 10-mg/kg dose of SAR650984. Altogether, in patients treated with the 10-mg/kg dose (n = 24), the ORR was 63% (25% VGPR, 38% PR). When considering minimal responses, the clinical benefit rate was 67%.
In an analysis of response rates based on prior therapy, it was found that patients refractory to lenalidomide (n = 25) had an ORR of 48% (20% VGPR, 28% PR). Those refractory to bortezomib (n = 16) had an ORR of 44% (25% VGPR, 19% PR) and those refractory to pomalidomide (n = 9) had an ORR of 33% (11% VGPR, 22% PR). Strikingly, in 6 patients that were nonrefractory to lenalidomide, the ORR was 100% (33% VGPR, 67% PR).
The most frequent AEs included nausea (19%), cough (19%), fatigue, muscle spasm, and infection (n = 16% each). Greater than grade 3 neutropenia occurred in 13% of patients and thrombocytopenia was apparent in 10%. One patient discontinued therapy after the first treatment due to a grade 3 infusion reaction.