As reported in The Lancet by Philippe Moreau, MD, and colleagues, the phase III IKEMA trial has shown that the addition of the anti-CD38 antibody isatuximab-irfc to carfilzomib and dexamethasone resulted in significantly improved progression-free survival in patients with relapsed or refractory multiple myeloma.

The trial supported the March 2021 approval of isatuximab for use in combination with carfilzomib and dexamethasone for the treatment of adults with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy.

Philippe Moreau, MD

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The open-label trial included 302 patients who had received one to three prior lines of therapy from sites in 16 countries. They were randomly assigned 3:2 between November 2017 and March 2019 to receive isatuximab at 10 mg/kg weekly in the first 28-day cycle and then every 2 weeks in subsequent cycles plus carfilzomib/dexamethasone (n = 179) or carfilzomib/dexamethasone alone (n = 123). In both groups, carfilzomib was given at 20 mg/m² on days 1 and 2 of cycle 1; at 56 mg/m² on days 8, 9, 15, and 16 of cycle 1; and then at 56 mg/m² on days 1, 2, 8, 9, 15, and 16 of subsequent cycles; dexamethasone was given at 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each cycle. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival in the intention-to-treat population on masked independent response committee assessment.

Progression-Free Survival

Median follow-up was 20.7 months (interquartile range = 19.4–22.1 months). Median progression-free survival was not reached in the isatuximab group vs 19.15 months (95% confidence interval [CI] = 15.77 months to not reached) in the control group (hazard ratio [HR] = 0.53, 99% CI = 0.32–0.89, P = .0007). Estimated progression-free survival at 2 years was 68.9% (95% CI = 60.7%–75.8%) vs 45.7% (95% CI = 35.2%–55.6%).

Objective response was observed in 87% vs 83% of patients (P = .19). Very good partial response or better occurred in 73% vs 56% (P = .0011), with complete response in 40% vs 28%. Measurable residual disease (MRD)-negative status was achieved in 30% vs 13% of patients (P = .0004). Complete response and MRD-negative response were observed in 20% vs 11%. The duration of response (HR = 0.43, 95% CI = 0.27–0.67) and the time to next treatment (HR = 0.57, 95% CI = 0.38–0.84) were longer in the isatuximab group. Overall, 26% vs 43% of patients received at least one subsequent antimyeloma therapy.

Progression-free survival-2 and overall survival data were not mature at the time of interim analysis; at the time of analysis, progression-free survival-2 events had occurred in 22% vs 28% of patients, and 17% vs 20% of patients had died.

Adverse Events

Grade ≥ 3 adverse events occurred in 77% of patients in the isatuximab group vs 67% of the control group, with the most common in the isatuximab group being overall respiratory infections (32% vs 24% in control group), thrombocytopenia (30% vs 24%), pneumonia (21% vs 14%), and hypertension (20% vs 20%). Serious adverse events occurred in 59% vs 57% of patients. Adverse events led to discontinuation of any component of study treatment in 8% vs 14%. Second primary malignancies occurred in 7% vs 5%. Adverse events led to death in 3% of patients in each group.

The investigators concluded: “The addition of isatuximab to carfilzomib/dexamethasone significantly improves progression-free survival and depth of response in patients with relapsed multiple myeloma, representing a new standard of care for this patient population.”

Dr. Moreau, of the Department of Hematology, University Hospital Hôtel-Dieu, Nantes, is the corresponding author of The Lancet article.

Disclosure: The study was funded by Sanofi. For full disclosures of the study authors, visit thelancet.com.