Background
Phase 3, open-label, randomised controlled trial (160 sites, 26 countries; two-stage inferentially seamless design). N=479 analysed with relapsed/refractory multiple myeloma after ≥1 prior regimen including an anti-CD38 antibody and lenalidomide. 86% were anti-CD38-refractory and 76% lenalidomide-refractory; median 2 prior lines. Mezigdomide is a next-generation cereblon E3 ligase modulator (CELMoD).
Results
Interventions and follow up: Arm A: Mezigdomide 1.0mg PO days 1–21 of each 28-day cycle + carfilzomib 56mg/m² weekly + dexamethasone 40mg weekly (n=288)
Arm B: Carfilzomib (56mg/m² twice weekly or 70mg/m² weekly) + dexamethasone (n=191)
Primary endpoint: PFS
mFollow up: 10.6 months
Results: PFS: 18.0 vs 8.3mo, HR 0.48, 95% CI 0.36–0.63, P<.0001
OS: NR (immature); deaths 22% vs 27%, mostly due to disease progression
Arm B: Carfilzomib (56mg/m² twice weekly or 70mg/m² weekly) + dexamethasone (n=191)
Primary endpoint: PFS
mFollow up: 10.6 months
Results: PFS: 18.0 vs 8.3mo, HR 0.48, 95% CI 0.36–0.63, P<.0001
OS: NR (immature); deaths 22% vs 27%, mostly due to disease progression
Adverse events
Grade 3–4 (any): 84% vs 56%
Hematologic: neutropenia 61% vs 9%
Infections: 34% vs 16%
Treatment-related grade 5: 3% (8 patients) vs 1% (1 patient)
Hematologic: neutropenia 61% vs 9%
Infections: 34% vs 16%
Treatment-related grade 5: 3% (8 patients) vs 1% (1 patient)
Conclusions
Mezigdomide–carfilzomib–dexamethasone more than doubled median PFS versus Kd (18.0 vs 8.3mo; HR 0.48) as early as first relapse in a heavily anti-CD38/lenalidomide-refractory population, with higher grade 3–4 toxicity (notably neutropenia and infections) that was mostly manageable with supportive care. The first phase 3 win for the CELMoD class.
Key Limitations
Open-label; short median follow-up (10.6mo) with immature OS; the Kd comparator lacks an anti-CD38 or immunomodulatory backbone (although most patients were already CD38-refractory); higher infection and grade 5 toxicity with the triplet; mezigdomide remains investigational; optimal sequencing versus T-cell-redirecting therapies (bispecifics, CAR-T) is undefined.
Clinical Context
First phase 3 data for mezigdomide, a CELMoD that Bristol Myers Squibb is developing and that Paul Richardson has described as “CAR-T in a pill.” Investigational — not FDA or EMA approved as of mid-2026; results are to be submitted to regulators. It targets the rapidly growing anti-CD38/lenalidomide-refractory population at first relapse, where options are limited. The sibling CELMoD iberdomide is under FDA review (PDUFA Aug 2026). ESMO-MCBS pending.