Isatuximab Plus Pomalidomide/Low-Dose Dexamethasone Versus Pomalidomide/Low-Dose Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma (ICARIA-MM): Characterization of Subsequent Antimyeloma Therapies

Introduction: Based on the primary analysis of the Phase 3 ICARIA-MM study (NCT02990338), isatuximab (Isa), an anti-CD38 monoclonal antibody, is approved in combination with pomalidomide and dexamethasone (Pd) in several countries for patients with relapsed and refractory multiple myeloma (RRMM) who have received at least 2 prior treatments, including lenalidomide and a proteasome inhibitor. Here, we describe updated, longer-term efficacy data following subsequent therapy.

Methods: Patients were randomized 1:1 to Isa-Pd (n=154) or Pd (n=153), with stratification by age (<75 vs ≥75) and number of prior lines (2–3 versus more than >3). Isa 10 mg/kg was administered weekly for the first 4-week cycle and every 2 weeks thereafter. In each cycle, both treatment arms received pomalidomide 4 mg (days 1-21) and weekly dexamethasone 40 mg (days 1, 8, 15, and 22). Treatment was given until progressive disease, unacceptable adverse events, or patient choice. The final overall survival analysis was planned when 220 death events occurred.

Results: As of March 14, 2022, 16 (10.4%) patients receiving Isa-Pd and 3 (2.0%) patients receiving Pd were still on treatment; 101 (65.6%) and 117 (76.5%) patients, respectively, discontinued treatment due to progressive disease. Median treatment duration was longer with Isa-Pd vs Pd (47.6 vs 24.0 weeks). After a median 52.4 months of follow-up, a clinically meaningful overall survival (OS) benefit was observed in favor of Isa-Pd vs Pd after 220 events (Jan 27, 2022; median: 24.6 vs 17.7 months; hazard ratio 0.776 [95% CI: 0.594–1.1015]; one-sided P=0.0319; significance level: P=0.02). Further antimyeloma treatment was given to 102 (66.2%) patients receiving Isa-Pd and 119 (77.8%) patients receiving Pd (regardless of the reason for treatment discontinuation in both arms), with a median of 2 and 1 further regimens, respectively. Of the patients receiving subsequent therapy, 22.5% (23/102) in the Isa-Pd arm and 59.7% (71/119) in the Pd arm received daratumumab. The most common further antimyeloma treatments for patients in the Isa-Pd arm were corticosteroids (n=88/102; 86.3%), alkylating agents (n=71/102; 69.6%), and proteasome inhibitors (n=70/102; 68.6%); the most common treatment received in the first subsequent line was a proteasome inhibitor (n=54/102; 52.9%). The most common further antimyeloma treatments for patients in the Pd arm were corticosteroids (n=94/119; 79.0%), monoclonal antibodies (n=75/119; 63.0%), and proteasome inhibitors (n=69/119; 58.0%); the most common treatment received in the first subsequent line was daratumumab (n=52/119; 43.7%). The overall response rate (ORR) for the first subsequent line of therapy was 28.8% (23/80) for the Isa-Pd arm and 35.3% (30/85) for the Pd arm. The ORR for patients receiving daratumumab-based regimens as the first subsequent line was 25.0% (2/8) for the Isa-Pd arm and 40.5% (17/42) for the Pd arm. The ORR for patients receiving daratumumab as monotherapy or with steroids in any subsequent line was 12.5% (1/8) for the Isa-Pd arm and 36.7% (11/30) for the Pd arm. The ORR for patients receiving daratumumab in combination with immunomodulatory agents, alkylating agents, or proteasome inhibitors in any subsequent line was 28.6% (4/14) for the Isa-Pd arm and 44.8% (13/29) for the Pd arm. Progression-free survival (PFS) on first subsequent line for patients receiving daratumumab was 2.2 months for the Isa-Pd arm and 5.7 months for the Pd arm. PFS on first subsequent line for patients receiving treatment excluding daratumumab was 4.6 months for the Isa-Pd arm and 5.2 months for the Pd arm.

Conclusions: This analysis demonstrates that the majority of patients with RRMM require multiple lines of subsequent therapy, even after receiving a triplet combination that includes a monoclonal antibody. The immediate use of an anti-CD38 monoclonal antibody with currently available combinations appears to be less effective in the Isa-Pd arm. The more frequent use of subsequent daratumumab in Pd (59.7%) compared with Isa-Pd (22.5%) may have affected the power to detect statistically significant OS given the sample size, as well as reflecting the efficacy of this approach in the management of RRMM.

Funding: Sanofi.