ASCO 2026: SUCCESSOR-2 Phase 3 — Mezigdomide + Carfilzomib Halves Disease Progression in Heavily Pretreated Multiple Myeloma

The Phase 3 SUCCESSOR-2 trial, presented at ASCO 2026 Annual Meeting, evaluated mezigdomide (MEZIKD) — a novel cereblon E3 ligase modulator (CELMoD) — combined with carfilzomib and dexamethasone (MeziKd) versus carfilzomib and dexamethasone alone (Kd) in 479 patients with relapsed or refractory multiple myeloma. The population was heavily pretreated: 92.1% were triple-class exposed, 85.8% were anti-CD38 antibody refractory, and 85.8% were lenalidomide refractory with a median of 2 prior lines of therapy — representing a highly challenging treatment setting where few effective options exist. MeziKd achieved a median PFS of 18.0 months versus 8.3 months with Kd alone (HR 0.48; p<0.0001), representing a 52% reduction in the risk of progression or death. The objective response rate was 80.2% (MeziKd) vs. 53.4% (Kd), with complete response or better achieved in 26.7% vs. 8.9% of patients. The safety profile of mezigdomide was manageable with expected CELMoD-class adverse events. Mezigdomide works by recruiting cereblon to degrade IKZF1 and IKZF3 transcription factors critical for myeloma cell survival — with greater potency and activity in lenalidomide/pomalidomide-resistant settings than older IMiD drugs. These results support mezigdomide as a meaningful new combination backbone for patients with anti-CD38-refractory, IMiD-exposed myeloma, establishing a new standard in this population.