SUCCESSOR-2 Study Shows PFS Benefit With Mezigdomide in Relapsed Myeloma

Oral mezigdomide combined with carfilzomib (Kyprolis) and dexamethasone (MeziKd) significantly improved progression-free survival (PFS) compared with carfilzomib and dexamethasone alone (Kd) in patients with relapsed or refractory multiple myeloma, according to interim results from the phase 2/3 SUCCESSOR-2 trial (NCT05552976), which were announced by Bristol Myers Squibb.¹

The randomized, open-label, multicenter study evaluating MeziKd vs Kd met its primary end point of a statistically significant and clinically meaningful improvement PFS in the phase 3 portion of the study. Patients will continue to be followed to assess overall survival and longer-term safety.

Detailed efficacy data, including HRs and median PFS, were not disclosed in the announcement. The company stated that safety findings observed in the trial were consistent with the known safety profile of mezigdomide and with the established toxicities of the combination regimen.

“These data underscore the potential of MeziKd as an oral regimen that could address a key unmet need for patients previously exposed to anti-CD38 and lenalidomide [Revlimid],” Paul G. Richardson, MD, stated in a news release. Richardson is director of clinical research and clinical program leader at the Jerome Lipper Multiple Myeloma Center, the Dana-Farber Cancer Institute, and the RJ Corman Professor of Medicine at Harvard Medical School in Boston, Massachusetts.

CELMoDs Meet Rising Need in Myeloma

Relapsed or refractory multiple myeloma remains a therapeutic challenge despite substantial progress over the past 2 decades. Although combinations incorporating proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, and cellular therapies have improved outcomes, most patients ultimately relapse and require additional lines of therapy. Continued development of novel agents and mechanisms of action therefore remains an important priority in the treatment landscape.²

Mezigdomide is an investigational cereblon E3 ligase modulator (CELMoD) designed to enhance the degradation of transcription factors such as Ikaros and Aiolos, which are critical regulators of myeloma cell survival and immune function. CELMoD agents represent an evolution of immunomodulatory drugs such as lenalidomide and pomalidomide (Pomalyst), with the goal of achieving more potent antimyeloma activity and immunomodulatory effects.³

In the phase 1/2 CC-92480-MM-001 trial (NCT03374085), mezigdomide 1.0 mg once daily for 21 days of a 28-day cycle plus dexamethasone demonstrated promising efficacy in heavily pretreated patients, with adverse events that were primarily myelotoxic in nature.⁴

SUCCESSOR-2 Study Design

In the SUCCESSOR-2 trial, mezigdomide was evaluated in combination with the proteasome inhibitor carfilzomib and dexamethasone in patients whose disease had relapsed or become refractory after prior therapy. According to the study investigators, the regimen may address an unmet need for patients previously exposed to both anti-CD38 monoclonal antibodies and lenalidomide, a population that continues to grow as these therapies are used earlier in the treatment sequence.

SUCCESSOR-2 is an inferential seamless international phase 2/3 study designed to evaluate both efficacy and safety of the triplet regimen. Key secondary end points include 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.

In stage 1 of the trial, patients were randomly assigned 3:3:3:2 to 3 different doses of mezigdomide plus Kd or Kd alone.⁵ In stage 2, patients were randomly assigned 3:2 to the selected dose of mezigdomide or Kd. Full results from the phase 3 analysis have not yet been presented publicly, and additional details regarding patient characteristics, response rates, and subgroup outcomes are expected to be reported at a future scientific meeting.¹

In an interview, Richardson said that the dose optimization followed by randomization “is the first trial of its kind to reflect in results…this dose optimization strategy followed by phase 3 comparison.”

“Why that's so valuable is because obviously we're confident about the dose and schedule,” he said. “…We provide the FDA with a strategy or a framework for which they can feel very comfortable approving this approach and improving the therapy for patients.”

The related phase 3 SUCCESSOR-1 trial (NCT05519085) is investigating mezigdomide, bortezomib (Velcade), and dexamethasone vs pomalidomide, bortezomib, and dexamethasone in patients with relapsed/refractory multiple myeloma.

The SUCCESSOR-2 results represent the first positive phase 3 study involving mezigdomide, according to Bristol Myers Squibb.¹ If confirmed in future analyses and regulatory review, the regimen could expand treatment options for patients with previously treated multiple myeloma, particularly those with prior exposure to commonly used agents earlier in the disease course.

REFERENCES

1. Bristol Myers Squibb announces positive phase 3 results from the SUCCESSOR-2 study of oral mezigdomide in relapsed or refractory multiple myeloma. News release. Bristol Myers Squibb. March 9, 2026. Accessed March 9, 2026. https://tinyurl.com/mubr9veh

2. Rajkumar SV. Multiple myeloma: 2024 update on diagnosis, risk-stratification, and management. Am J Hematol. 2024;99(9):1802-1824. doi:10.1002/ajh.27422

3. Chamberlain PP, Hamann LG. Development of targeted protein degradation therapeutics. Nat Chem Biol. 2019;15(10):937-944. doi:10.1038/s41589-019-0362-y

4. Richardson PG, Trudel S, Popat R, et al; CC-92480-MM-001 Study Investigators. Mezigdomide plus dexamethasone in relapsed and refractory multiple myeloma. N Engl J Med. 2023;389(11):1009-1022. doi:10.1056/NEJMoa2303194

5. Richardson PG, Amatangelo M, Berenson JR, et al. A phase 3, two-stage, randomized study of mezigdomide, carfilzomib, and dexamethasone (MeziKd) versus carfilzomib and dexamethasone (Kd) in relapsed/refractory multiple myeloma (RRMM): SUCCESSOR-2. J Clin Oncol. 2023;41(suppl 16):TPS8070. doi:10.1200/JCO.2023.41.16_suppl.TPS8070