Mezigdomide Triplet Improves PFS in Relapsed Myeloma

Mezigdomide plus carfilzomib and dexamethasone significantly improved progression-free survival (PFS) compared with carfilzomib and dexamethasone alone in patients with previously treated multiple myeloma, according to findings from the phase 3 SUCCESSOR-2 trial published in The Lancet.

The trial evaluated mezigdomide, a cereblon E3 ligase modulator, in combination with carfilzomib and dexamethasone for patients whose treatment options may be limited after exposure to anti-CD38 antibodies and lenalidomide. The investigators reported that mezigdomide–carfilzomib–dexamethasone provided a clinically meaningful benefit as early as first relapse in a population described as predominantly triple-class-exposed, anti-CD38 antibody-refractory, and lenalidomide-refractory.

SUCCESSOR-2 was an open-label, randomized controlled trial conducted at 160 hospital-based sites in 26 countries using a two-stage, inferentially seamless design. Eligible adults had measurable multiple myeloma, had received at least 1 previous regimen that included anti-CD38 antibodies and lenalidomide, had achieved minimal response or better on that regimen, and had documented disease progression during or after their most recent treatment.

Between February 3, 2023, and November 28, 2025, 762 patients were assessed for eligibility. A total of 606 patients were enrolled, and 479 were included in the analysis, including 288 assigned to mezigdomide–carfilzomib–dexamethasone and 191 assigned to carfilzomib–dexamethasone. At a median follow-up of 10.6 months, median PFS was 18.0 months with mezigdomide–carfilzomib–dexamethasone compared with 8.3 months with carfilzomib–dexamethasone alone (hazard ratio, 0.48; 95% CI, 0.36 -0.63; P<0.0001).

Grade 3 or 4 adverse events occurred in 84% of patients receiving mezigdomide–carfilzomib–dexamethasone and 56% of those receiving carfilzomib–dexamethasone. Deaths occurred in 22% and 27% of patients, respectively, mainly because of disease progression. The investigators concluded that the PFS benefit was accompanied by higher rates of grade 3 or 4 adverse events, including infections, which were mostly manageable with standard clinical practice and supportive care. They also reported that the findings support the regimen as a treatment option as early as first relapse for a predominantly triple-class-exposed, anti-CD38 antibody-refractory, and lenalidomide-refractory population.

Source: Dimopoulos MA, Schjesvold F, Fu C, et al.; SUCCESSOR-2 Trial Investigators. Mezigdomide, carfilzomib, and dexamethasone versus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma (SUCCESSOR-2): a phase 3, open-label, randomized controlled trial. Lancet. 2026;408(10551):219-233. doi:10.1016/S0140-6736(26)01088-3