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Shaji K. Kumar, MD
Shaji K. Kumar, MD
Posted: Friday, June 26, 2026
Results from the phase III SUCCESSOR-2 trial suggest that the addition of mezigdomide to carfilzomib and dexamethasone may represent a new treatment standard for patients with relapsed or refractory multiple myeloma (RRMM) who have previously received both an anti-CD38 monoclonal antibody and lenalidomide.
Presented by Paul G. Richardson, MD, of Dana-Farber Cancer Institute, as a late-breaking abstract at the 2026 ASCO Annual Meeting, SUCCESSOR-2 is the first randomized phase III study evaluating mezigdomide, an oral cereblon E3 ligase modulator (CELMoD) designed to induce potent degradation of the transcription factors Ikaros and Aiolos, resulting in enhanced myeloma cell death and immune activation. The trial enrolled adults with RRMM who had received at least one prior line of therapy that included both lenalidomide and an anti-CD38 antibody.
Study Details
The study used a two-stage design. During stage 1, patients were randomly assigned to receive one of three mezigdomide dose levels (0.3, 0.6, or 1.0 mg) combined with carfilzomib and dexamethasone (MeziKd) or standard carfilzomib plus dexamethasone (Kd) to identify the optimal dose. The 1.0-mg mezigdomide dose was selected for stage 2 and became the basis for the primary efficacy comparison.
A total of 479 patients were included in the analysis, with 288 receiving MeziKd and 191 receiving Kd. The median number of prior therapies was two, 92.1% of patients were triple class–exposed, 85.8% were refractory to anti-CD38 therapy, and 75.8% were refractory to lenalidomide. More than one-third of patients had prior pomalidomide exposure, and 7.3% had received anti-BCMA therapy.
Key Findings
At a median follow-up of 10.6 months, MeziKd demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS), the study’s primary endpoint. Median PFS was 18.0 months (95% confidence interval [CI] = 14.5–22.1 months) with MeziKd compared with 8.3 months (95% CI = 5.6–10.7 months) with Kd (hazard ratio = 0.48; 95% CI = 0.36–0.63; P < .0001). The PFS benefit was consistent across key subgroups, including patients with more than two prior lines of therapy, high-risk cytogenetics, extramedullary disease, prior treatment refractoriness, and those aged 75 years or older.
Response outcomes also favored the mezigdomide-containing regimen. The overall response rate was 80.2% with MeziKd vs 53.4% with Kd, while complete response or better was achieved in 26.7% and 8.9% of patients, respectively. Deaths occurred in 21.5% of patients receiving MeziKd and 26.7% receiving Kd, most commonly due to progressive disease.
Toxicity was higher with the triplet regimen. Grade 3 or 4 treatment-emergent adverse events occurred in 83.7% of patients receiving MeziKd compared with 56.5% receiving Kd. Rates of grade 3 or 4 neutropenia (61.1% vs 9.1%) and infections (34.0% vs 15.6%) were also increased. However, grade 5 infections were uncommon in both groups (2.4% vs 1.1%).
The investigators concluded: “MeziKd showed a clinically meaningful PFS benefit as early as first relapse in predominantly triple-class-exposed, anti-CD38 [monoclonal antibody]– and [lenalidomide]-refractory patients, a population with significant unmet need.”
DISCLOSURE: The study was funded by Bristol Myers Squibb. For full disclosures of the study authors, visit coi.asco.org.
2026 ASCO Annual Meeting (Abstract LBA7506)
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