FDA Accepts NDA for Mezigdomide Combination in Relapsed/Refractory Multiple Myeloma

The FDA accepted a new drug application (NDA) for mezigdomide in combination with carfilzomib (Kyprolis) and dexamethasone (MeziKd) for the treatment of patients with relapsed or refractory multiple myeloma (R/R MM). The FDA assigned a Prescription Drug User Fee Act (PDUFA) target action date of May 13, 2027.¹

Mezigdomide is an oral cereblon E3 ligase modulator (CELMoD) being developed for the treatment of multiple myeloma. The NDA is supported by findings from the phase 3 SUCCESSOR-2 trial (NCT05552976), which evaluated MeziKd vs the doublet of carfilzomib plus dexamethasone (Kd) in patients with R/R MM, including those with disease relapse after first-line treatment with an anti-CD38 monoclonal antibody and lenalidomide (Revlimid).

Efficacy Findings

Results from SUCCESSOR-2 were presented as a late-breaking oral presentation at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting and were simultaneously published in The Lancet.^2,3

The trial met its primary end point of progression-free survival (PFS), with MeziKd showing a clinically meaningful and statistically significant improvement over Kd. The median PFS was 18.0 months with MeziKd vs 8.3 months with Kd (HR, 0.48; P <.0001), representing a 52% reduction in the risk of disease progression or death; PFS benefit was consistent across prespecified subgroups. Rates of response and complete response also favored MeziKd. Overall survival data were immature at the data cutoff, but a planned futility analysis showed a positive trend favoring MeziKd with an HR of 0.79 (95% CI, 0.54-1.15).

The safety profile of MeziKd was consistent with prior studies of mezigdomide and with the known safety profiles of the individual agents in the regimen. The most common hematologic toxicitiy was neutropenia, which occurred at grade 3 or 4 in 61.1% of patients compared with 9.1% with Kd. Higher-grade infections were also more common in the experimental arm.

Trial Design and Population

SUCCESSOR-2 is an inferential, seamless phase 3, multicenter, randomized, open-label study. Stage 1 of the trial led to a dose of 1.0 mg daily being selected for stage 2. In total, 479 patients were included in the analysis: 288 received MeziKd at the 1.0-mg dose of mezigdomide and 191 received Kd. Key secondary end points included overall survival, overall response rate, duration of response, time to progression, time to next treatment, minimal residual disease negativity, and health-related quality of life.

Across both treatment arms, the median patient age was 68 years, and 25.1% of patients were 75 years or older. The median number of prior therapies was 2. Most patients were heavily pretreated: 92.1% were triple class exposed, 85.8% were refractory to an anti-CD38 monoclonal antibody, and 75.8% were refractory to lenalidomide (Revlimid). Additionally, 37.2% of patients had prior exposure to pomalidomide (Pomalyst) and 7.3% had prior exposure to B-cell maturation antigen (BCMA)–targeted treatment.

At data cutoff, median follow-up was 10.6 months. At that time, 52.4% of patients in the MeziKd arm remained on treatment, compared with 31.4% of patients in the Kd arm.

Mechanism and Development Context

Mezigdomide is designed to modulate cereblon for rapid and maximal degradation of the Ikaros and Aiolos target proteins, resulting in greater antimyeloma activity and immune stimulation than traditional immunomodulatory agents.¹ Preclinical data suggest mezigdomide enhances T-cell function and can prevent and reverse an exhausted immune system. Mezigdomide is also being evaluated in the ongoing phase 3 SUCCESSOR-1 trial (NCT05519085) vs a standard-of-care bortezomib (Velcade), pomalidomide, and dexamethasone regimen in R/R MM.

Mezigdomide is the second CELMoD under review by the FDA, following the NDA acceptance of iberdomide in combination with daratumumab (Darzalex) and dexamethasone in February 2026.

“The FDA’s acceptance of our application for mezigdomide highlights the continued momentum of our targeted protein degradation programs, as we now have [2] distinct agents under review in relapsed or refractory multiple myeloma, which remains a persistent disease,” Cristian Massacesi, MD, executive vice president, chief medical officer, and head of development at Bristol Myers Squibb, stated in the news release.

Learn more about CELMoDs in an exclusive interview with Paul G. Richardson, MD.

REFERENCES

1. U.S. Food and Drug Administration accepts Bristol Myers Squibb's New Drug Application for mezigdomide in patients with relapsed or refractory multiple myeloma. News release. Bristol Myers Squibb. July 13, 2026. Accessed July 13, 2026. https://tinyurl.com/2hppz5vs

2. Richardson PG. Mezigdomide, carfilzomib, and dexamethasone (MeziKd) vs carfilzomib and dexamethasone (Kd) in relapsed/refractory multiple myeloma (RRMM): results from the phase 3 SUCCESSOR-2 trial. Presented at: ASCO Annual Meeting; May 29–June 2, 2026; Chicago, IL. Abstract LBA7506.

3. Dimopoulos MA, Schjesvold F, Fu C, et al. Mezigdomide, carfilzomib, and dexamethasone versus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma (SUCCESSOR-2): a phase 3, open-label, randomised controlled trial. Lancet. Published online June 14, 2026. doi:10.1016/S0140-6736(26)01088-3