Multinational phase 3 trial of adding mezigdomide to carfilzomib and dexamethasone for relapsed or refractory multiple myeloma

Mezigdomide is a cereblon E3 ligase modulator inducing Ikaros and Aiolos degradation, resulting in myeloma cell cytotoxicity and immune stimulation. The phase 3 SUCCESSOR-2 trial, at 160 centers in 26 countries, evaluated addition of mezigdomide to carfilzomib-dexamethasone for adult patients with multiple myeloma who had received at least one previous regimen on which they had achieved minimal response or better, and had disease progression on or after their most recent treatment. Patients received oral mezigdomide plus intravenous carfilzomib and oral or intravenous dexamethasone. In stage 1 of the study, mezigdomide doing across three levels was optimized. In stage 2, patients were randomized to the selected mezigdomide dose (1.0 mg daily on days 1-21 of 28-day cycles) plus carfilzomib and dexamethasone or carfilzomib and dexamethasone alone. Primary endpoint was progression-free survival (PFS). The study included 479 patients who received mezigdomide-carfilzomib-dexamethasone (n=288) or carfilzomib-dexamethasome (n=191). At 10.6 months median follow-up, median PFS was 18.0 months with triplet therapy versus 8.3 month with doublet therapy (HR 0.48; p<0.0001), with grade 3 or 4 treatment-related adverse events in 84% versus 56%, and grade 5 TRAEs in 3% versus 1%. Death occurred in 22% versus 27%, mainly due to disease progression. The authors conclude that addition of mezigdomide to carfilzomib-dexamethasone improved PFS, with higher rates of TRAEs, in previously treated patients with multiple myeloma.