Mezigdomide Regimen Improves PFS in Pretreated R/R Multiple Myeloma

At the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, Paul G. Richardson, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, presented findings from the phase 3 SUCCESSOR-2 trial (NCT05552976) evaluating mezigdomide (CC-92480), carfilzomib (Kyprolis), and dexamethasone (MeziKd) versus carfilzomib and dexamethasone (Kd) in patients with anti-CD38 monoclonal antibody (mAb)– and lenalidomide (Revlimid; LEN)–exposed relapsed/refractory multiple myeloma (RRMM).

MeziKd significantly reduced the risk of progression or death by 52% vs Kd (HR, 0.48; 95% CI, 0.36-0.63; P <.0001), with a median progression-free survival (PFS) of 18.0 months vs 8.3 months at a median follow-up of 10.6 months. The PFS benefit was consistent across all prespecified subgroups, including patients with high-risk cytogenetics; soft-tissue plasmacytomas; extramedullary disease; and those refractory to anti-CD38 mAbs, LEN, or both.

The addition of mezigdomide to Kd substantially deepened responses. The overall response rate (ORR) was 80.2% with MeziKd vs 53.4% with Kd. MeziKd tripled the rate of complete response (CR) or better (26.7% vs 8.9%) and nearly doubled the rate of very good partial response (VGPR) or better (60.1% vs 30.9%). The 12-month duration of response was 72% (95% CI, 65%-78%) with MeziKd vs 54% (95% CI, 41%-66%) with Kd. Minimal residual disease analysis is ongoing, and results will be reported in future presentations.

The clinical benefit of MeziKd extended beyond first progression. Median PFS2 was 23.6 months with MeziKd vs 13.0 months with Kd (HR, 0.53; 95% CI, 0.39-0.72), indicating the survival benefit was sustained even after subsequent lines of therapy. A planned futility analysis of overall survival (OS) showed a positive trend favoring MeziKd (HR, 0.79; 95% CI, 0.54-1.15), with death events occurring in 21.5% vs 26.7% of patients in the MeziKd and Kd arms, respectively. OS data continue to mature.

SUCCESSOR-2 enrolled adult patients who had received at least 1 prior line of antimyeloma therapy, including prior treatment with LEN and an anti-CD38 mAb. The confirmatory analysis group comprised 479 patients randomized 3:2 to MeziKd (n = 288) or Kd (n = 191). In the MeziKd arm, patients received mezigdomide at 1.0 mg orally once daily on days 1 through 21 of each 28-day cycle, combined with carfilzomib at 56 mg/m² intravenously on days 1, 8, and 15 (and days 1 and 15 in later cycles), plus dexamethasone 40 mg on days 8, 15, and 22. The primary end point was PFS per independent review committee assessment. At baseline, the median number of prior lines of therapy was 2.0 in both arms (range, 1-9); 86% of patients were refractory to anti-CD38 mAbs, 93% were refractory to their last line of treatment, and more than 92% in each arm had received triple-class therapy.

The safety profile of MeziKd was consistent with prior mezigdomide studies, with no new safety signals. Neutropenia was the most common grade 3/4 adverse event, occurring in 61.1% of patients in the MeziKd arm vs 9.1% with Kd, and was effectively managed with dose interruptions or modifications and/or granulocyte colony-stimulating factor. Grade 3/4 thrombocytopenia was lower with MeziKd (39.2%) than with Kd (22.6%). Grade 5 treatment-emergent adverse events (TEAEs) were observed in 7.3% of patients receiving MeziKd vs 4.3% with Kd, with the majority occurring in the context of disease progression. Although any-grade infections were more frequent with MeziKd (72.9%) than Kd (53.8%), grade 4 infections were infrequent (5.6% vs 0.5%), and most infections were managed with standard clinical practice and supportive care, with a low incidence of fatal infections (2.4% vs 1.1%). Discontinuations due to AEs were infrequent.

Investigators concluded that oral mezigdomide combined with weekly intravenous carfilzomib represents a potential new standard of care for RRMM that can be deployed across diverse treatment settings, including community practice. Key anticipated data readouts at the 2026 ASCO Annual Meeting, including CELMoD-based regimen data across myeloma subpopulations, were featured in a CancerNetwork® preview published ahead of the conference.

Reference

Richardson PG, Schjesvold F, Fu C, et al. Mezigdomide, carfilzomib, and dexamethasone vs carfilzomib and dexamethasone in relapsed/refractory multiple myeloma: results from the phase 3 SUCCESSOR-2 trial. J Clin Oncol. 2026;44(suppl 17):LBA7506. doi:10.1200/JCO.2026.44.17_suppl.LBA7506