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Investigational mezigdomide triplet evaluated in phase 3 SUCCESSOR-2 trial for relapsed or refractory multiple myeloma.

In patients exposed to anti-CD38 antibodies and lenalidomide, investigators reported improved progression-free survival and deeper responses versus carfilzomib–dexamethasone, with safety consistent with prior mezigdomide studies and known carfilzomib toxicity.

  • Meletios A Dimopoulos, MD; Fredrik Schjesvold, MD; Chengcheng Fu, MD; Monique A Hartley-Brown, MD; Cesar Gomez, MD; Donna Reece, MD; et al.

  • June 14, 2026

  • The Lancet
  • The Lancet, Volume 408, Issue 10551, Pages 219–233
  • 10.1016/S0140-6736(26)01088-3

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Evidence before this study

We searched PubMed, with no language restrictions, for articles published between Jan 1, 2016, and April 22, 2026. Specific search terms included “multiple myeloma”, “relapsed”, “refractory”, “mezigdomide”, “lenalidomide”, and “CD38”. This approach identified clinical trials and real-world analyses evaluating treatments for relapsed or refractory multiple myeloma, including in patients exposed to anti-CD38 antibodies or lenalidomide. Real-world evidence showed that exposure or refractoriness to anti-CD38 antibodies and lenalidomide is associated with poor outcomes in this population. Despite anti-CD38 antibody-based and lenalidomide-based therapies being standards of care in frontline and early-relapse settings, no published prospective studies specifically focused on patients universally exposed to both agents as early as first relapse. Clinical trials in this setting are ongoing, including those evaluating T-cell-redirecting therapies. Real-world data showed heterogeneous treatment patterns, with carfilzomib plus dexamethasone among the most frequently used combinations, and median progression-free survival (PFS) of only 6·3 months across treatment regimens, highlighting a substantial unmet need for effective, accessible regimens with differentiated mechanisms of action suitable for routine clinical use. Mezigdomide is an oral cereblon E3 ligase modulator, specifically optimised for maximal and rapid degradation of Ikaros and Aiolos target proteins, leading to increased myeloma cell killing and superior immunostimulatory activity when compared with immunomodulatory drugs. Phase 1/2 data have shown that mezigdomide has promising activity in the relapsed or refractory setting, including in combination with carfilzomib–dexamethasone, supporting further prospective evaluation.

Added value of this study

SUCCESSOR-2 is the first phase 3 randomised trial specifically designed to evaluate mezigdomide–carfilzomib–dexamethasone versus carfilzomib–dexamethasone in patients with relapsed or refractory multiple myeloma who were universally exposed to both anti-CD38 antibodies and lenalidomide. Its inferentially seamless design enabled prospective, randomised dose optimisation within a single confirmatory trial. Carfilzomib–dexamethasone was selected as the comparator as an approved, guideline-recommended option in early relapse; furthermore, it is among the most frequently used regimens in patients previously treated with anti-CD38 antibodies and lenalidomide in real-world practice. The addition of mezigdomide to carfilzomib–dexamethasone allowed for evaluation of the specific contribution of mezigdomide to the efficacy and safety of the combination. After a median follow-up of 10·6 months, mezigdomide–carfilzomib–dexamethasone showed superior efficacy versus carfilzomib–dexamethasone, reducing the risk of progression or death by 52%, with the median PFS more than doubled. Mezigdomide–carfilzomib–dexamethasone induced deep responses, doubling the very good partial response or better rate and tripling the complete response or better rate of carfilzomib–dexamethasone. The safety profile of mezigdomide–carfilzomib–dexamethasone was consistent with previous mezigdomide studies, with neutropenia being the most common grade 3 or 4 adverse event, and with the known toxicity profile of carfilzomib.

Implications of all the available evidence

Taken together with previous real-world evidence and data from early-phase clinical trials, the results of SUCCESSOR-2 showed that mezigdomide–carfilzomib–dexamethasone substantially improves outcomes versus carfilzomib–dexamethasone in a growing and under-studied population of patients with relapsed or refractory multiple myeloma who are predominantly refractory to anti-CD38 antibodies and lenalidomide. These findings address a major evidence gap in early relapse and support mezigdomide–carfilzomib–dexamethasone as a potent, differentiated combination that addresses distinct clinical needs in the evolving relapsed or refractory multiple myeloma treatment paradigm at early relapse. Mezigdomide is under active investigation across additional combinations and multiple myeloma populations.

Source: The Lancet

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