Dose-Finding Phase 2 Trial of Single-Agent Isatuximab in Relapsed/Refractory Multiple Myeloma
Isatuximab (SAR650984) is a humanized monoclonal antibody that selectively targets CD38 on myeloma cells, eliciting antimyeloma immune effects. A phase 1/2 trial evaluated the safety and efficacy of isatuximab monotherapy in patients with relapsed and/or refractory multiple myeloma (RRMM).1 A phase 2 dose-finding study was subsequently added to evaluate single-agent isatuximab in RRMM. The preliminary analysis results of this trial were presented by Martin and colleagues at the 2015 ASH meeting.2 Eligible patients who had received ?3 therapies or were double-refractory to immunomodulatory drugs and proteasome inhibitors or prior treatment with alkylators were randomized to 1 of 3 treatment groups: A—3 mg/kg every 2 weeks (n = 23), B—10 mg/kg every 2 weeks (n = 26), and C—10 mg/kg every 2 weeks x 4 doses then every 4 weeks (n = 24); a fourth treatment group (D) was enrolled at a higher isatuximab dose of 20 mg/kg weekly x 4 doses then every 2 weeks (n = 25). Treatment cycles were 28 days in all 4 groups.
The patient population was heavily pretreated with a median 5 prior lines of therapy, including 87% to 96% who were double-refractory and 32% to 48% who were quadruple-refractory, including to pomalidomide, lenalidomide, pomalidomide, and/or carfilzomib. At data cut-off, 53.1% had discontinued treatment due to disease progression, 6.3% due to adverse events, and 4.2% due to other reasons. Dose delays were required in 17% of patients, and 7.3% of dose interruptions of isatuximab were reported in 7.3% of patients. Drug-related treatment-related adverse events (TEAEs) included anemia in 100% of patients, thrombocytopenia in 65%, and neutropenia in 40%; grade 3/4 adverse events were reported in <30% of patients. The most common nonhematologic drug-related TEAEs that occurred in >5% of patients were nausea, fatigue, cough, and dyspnea. Infusion-associated reactions (IARs) occurred in 49% of the patients and included chills, dyspnea, nausea, chest discomfort, flushing, and cough. IARs were predominantly grade 1/2 in severity and limited mainly to cycle 1. The most common serious TEAEs reported were pneumonia and sepsis. Six deaths were reported, 4 due to disease progression, and 2 due to serious adverse events unrelated to study therapy (cardiopulmonary arrest and cerebral hemorrhage). The overall response rate was 9% in group A, 20% in group B, 29% in group C, and 24% in group D.
Based on these results, the optimal dose and dosing schedule for isatuximab still needs to be established in an expanded population. In general, this agent was well-tolerated and demonstrated promising single-agent activity in heavily pretreated RRMM patients. Isatuximab will be advanced to phase 3 testing.
- Martin TG, et al. ASCO 2014. Abstract 8532.
- Martin T, et al. ASH 2015. Abstract 509.