IKEMA is an ongoing, phase 3, randomized, open-label, parallel-group study evaluating the effect of adding isatuximab (Isa) to carfilzomib and dexamethasone (Kd) in patients with relapsed/refractory multiple myeloma (RRMM), which reached its interim analysis milestone. The study examines the efficacy of Isa plus Kd and its impact on prolonging progression-free survival (PFS) compared with Kd alone, its primary end point. Secondary outcome measures include assessing overall response rate (ORR), very good partial response (VGPR) or better, complete response (CR), and minimal residual disease (MRD) negativity, as well as overall survival (OS) in both treatment arms of the study, as well as safety.
The study enrolled 302 patients, randomized to 2 treatment arms, with 179 patients in the Isa-Kd arm and 123 patients in the Kd arm. Eligibility criteria included having undergone 1 to 3 prior lines of treatment, of which 93% had prior proteasome inhibitor therapy in the Isa-Kd group and 85% in the Kd group and 76% had prior immunomodulatory drug therapy in the Isa-Kd group and 81% in the Kd group. Patients could not have previous exposure to carfilzomib and could not be refractory to anti-CD38 monoclonal antibody treatment. The baseline patient characteristics were similar in both arms; the median age was 64 years, ranging from 33 to 90 years, and 25.8% had stage 1 disease, 59.6% had stage 2 disease, and 7.9% had stage 3 disease. In addition, 24% of patients had high-risk cytogenetics. The patients were assigned randomly in a 3:2 ratio and stratified based on their International Staging System stage and the number of prior treatments in the Isa-Kd arm or the Kd arm. The therapy was administered in 28-day cycles, with the Isa-Kd arm receiving isatuximab 10 mg/kg intravenously weekly for 4 weeks, then every other week, and both the Isa-Kd arm and the Kd arm received carfilzomib 20 mg/m2 days 1 and 2, and all subsequent doses at 56 mg/m2 twice-weekly for 3 of 4 weeks, and dexamethasone 20 mg twice-weekly. The patients continued treatment unless they experienced disease progression or intolerable adverse events.
At the time of the interim analysis of the study, median PFS had not been reached in the Isa-Kd group and was 19.2 months in the Kd group; Isa-Kd resulted in a 47% risk reduction in progression or death versus Kd (P = .0007). The PFS benefit was seen across nearly every subgroup. The ORR (≥partial response) was not significantly different between the 2 arms at 86.6% for Isa-Kd and 82.9% for Kd. The ≥VGPR rate was significantly better in the Isa-Kd group versus the Kd group (72.6% vs 56.1%, respectively; P = .001). The CR rates were 39.7% and 27.6% in the Isa-Kd versus Kd arms, respectively. The MRD-negativity rates were significantly better in the Isa-Kd arm versus the Kd arm (29.6% vs 13.0%, respectively; P = .0004). The time to next treatment was significantly delayed in the Isa-Kd arm. OS was immature at the time of analysis, with 17.3% of patients in the Isa-Kd arm and 20.3% in the Kd arm recorded as dead at the time of the analysis. The median duration of follow-up was 20.7 months, but the study is ongoing.
The patients continued treatment unless they experienced disease progression or intolerable adverse events, with 52.0% of Isa-Kd patients remaining on treatment and 30.9% of Kd patients. The reasons for discontinuation of treatment included progression of disease in 29.1% of patients in the Isa-Kd arm and 39.8% of patients in the Kd arm or unacceptable adverse events that affected 8.5% of patients in the Isa-Kd arm and 13.9% of patients in the Kd arm, respectively. The grade ≥3 adverse events were reported in 76.8% of the Isa-Kd group versus 67.2% of the Kd group. Serious adverse events in the Isa-Kd arm were reported in 59.3% and 57.4% of Kd, and fatal adverse events were similar in both arms, at 3.4% and 3.3%. Adverse respiratory events of grade ≥3 were reported in 32.2% of patients in the Isa-Kd arm and 23.8% in the Kd arm. Grade ≥3 cardiac failure was seen in 4.0% of the Isa-Kd–treated patients and 4.1% of the Kd-treated patients, with grade 3-4 thrombocytopenia in 29.9% versus 23.8% and grade 3-4 in 19.2% versus 7.4% of patients treated with Isa-Kd versus Kd, respectively.
The interim results of the IKEMA study demonstrate treatment of relapsed multiple myeloma with the addition of Isa to Kd leads to a clear improvement in PFS with a tolerable safety profile, with final results currently pending.
Reference
Abstract and Oral Presentation LB2603. EHA 2020. June 12, 2020. Isatuximab plus carfilzomib and dexamethasone in relapsed/refractory multiple myeloma (IKEMA) interim analysis of a phase 3, randomized, open-label study.