In an interim analysis of a phase III trial (SUCCESOR-2) reported in The Lancet, Dimopoulos et al found that the addition of the cereblon E3 ligase modulator mezigdomide to carfilzomib/dexamethasone significantly improved progression-free survival in previously treated patients with relapsed or refractory multiple myeloma.
Study Details
In stage I of the international open-label trial, mezigdomide dosing across three levels was optimized. In stage II, 479 eligible patients with at least one prior regimen (including anti-CD38 antibodies and lenalidomide) were randomly assigned between February 2023 and November 2025 to receive: mezigdomide at 1.0 mg on days 1 to 21 of each 28-day cycle, carfilzomib at 56 mg/m2 weekly, and oral or intravenous dexamethasone at 40 mg weekly (n = 288) or carfilzomib at 56 mg/m2 twice weekly or 70 mg/m2 weekly and dexamethasone at 20 mg twice weekly or 40 mg weekly (n = 191). The primary endpoint was progression-free survival among patients who received 1.0 mg mezigdomide plus carfilzomib/dexamethasone or carfilzomib/dexamethasone alone across both study stages.
Key Findings
Median follow-up was 10.6 months (interquartile range = 7.2–15.3 months).
Median progression-free survival was 18.0 months (95% confidence interval [CI] = 14.5–22.1 months) in the mezigdomide group vs 8.3 months (95% CI = 5.6–10.7 months) in the control group (hazard ratio [HR] = 0.48, 95% CI = 0.36–0.63, P < .0001).
Complete response or better was achieved in 27% vs 17% of patients. At interim overall survival analysis, death had occurred in 22% of the mezigdomide group vs 27% of the control group (HR = 0.79, 95% CI = 0.54–1.15).
Grade 3 or 4 adverse events occurred in 84% of the mezigdomide plus carfilzomib/dexamethasone group (most commonly neutropenia [61%]) vs 56% of the carfilzomib/dexamethasone group; grade 3 or 4 infections occurred in 34% vs 16%. Treatment-related death occurred in eight patients in the mezigdomide group vs one patient in the control group.
The investigators concluded: “[Mezigdomide/carfilzomib/dexamethasone] provided a significant [progression-free survival] benefit compared with [carfilzomib/dexamethasone] alone, with higher rates of grade 3 or 4 adverse events, including infections, which were mostly manageable with standard clinical practice and supportive care. These findings support [mezigdomide/carfilzomib/dexamethasone] as a clinically meaningful treatment option as early as first relapse in predominantly triple-class–exposed, anti-CD38 antibody–refractory and lenalidomide-refractory patients, a growing population with substantial unmet need.”
Meletios A. Dimopoulos, MD, of the Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Greece, is the corresponding author for The Lancet article.
DISCLOSURE: The study was funded by Bristol Myers Squibb. For full disclosures of the study authors, visit thelancet.com.
