A late-breaking phase 3 trial presented at the 2026 EHA Congress and published simultaneously in The Lancet has established mezigdomide (CC-92480), elotuzumab, and dexamethasone (MEd) as a superior regimen to carfilzomib and dexamethasone (Kd) for patients who have exhausted standard triplet options.
SUCCESSOR-2 (NCT05552976) enrolled 479 patients with relapsed or refractory multiple myeloma who had received at least two prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody—a population that has historically had median progression-free survival of less than 9 months. Patients were randomly assigned 3:2 to MEd (n=288) or Kd (n=191).
The primary endpoint was reached decisively. Median progression-free survival was 18.0 months with MEd versus 8.3 months with Kd (hazard ratio 0.48 [95% CI 0.36–0.63]; p<0.0001), representing a 52% reduction in the relative risk of progression or death. Responses were deeper and more frequent in the MEd arm: overall response rate 67.7% versus 43.7%, with very good partial responses or better in 53.5% versus 27.2%.
Mezigdomide is a next-generation cereblon E3 ligase modulator (CELMoD agent) that degrades Ikaros family zinc fingers 1 and 3 (IKZF1/IKZF3) more potently than lenalidomide or pomalidomide and retains activity in patients who have become resistant to both. Pairing it with elotuzumab, which targets SLAMF7 on myeloma cells and natural killer cells, and dexamethasone exploits complementary immune mechanisms in a class already battered by prior IMiD exposure.
The safety profile was consistent with known risks. Grade 3 or worse adverse events occurred in 78% of MEd patients and 69% of Kd patients; the most common serious events in the MEd arm were neutropenia (67%) and infections (21%). No unexpected safety signals emerged beyond those established in earlier MEd dose-finding work.
Bristol-Myers Squibb is now preparing regulatory submissions in multiple jurisdictions. The data position MEd as a likely standard of care for the triple-class-exposed population ahead of CAR-T eligibility—a gap the current myeloma armamentarium has not adequately filled.