Mezigdomide Plus Elranatamab Produces Significant Response in Early MELT-MM Analysis

The investigational combination of mezigdomide and elranatamab-bcmm (Elrexfio; Pfizer) produced an overall response rate (ORR) of 100% among 13 evaluable patients with relapsed or refractory multiple myeloma (RRMM), according to updated results from part 1 of the phase 1/2 MELT-MM trial (NCT06645678). Twelve patients (92.3%) achieved a complete response (CR) or better, and responses emerged within a median of 17 days.¹

These findings were presented at the 23rd International Myeloma Society Annual Meeting. Investigators selected both mezigdomide doses evaluated in part 1 for the trial’s randomized expansion.¹

Combining CELMoD and Bispecific Antibody Activity

Mezigdomide is an investigational oral cereblon E3 ligase modulator (CELMoD) designed to induce rapid degradation of the transcription factors Ikaros and Aiolos. This activity produces direct antimyeloma effects while stimulating immune-cell function. In an earlier phase 1/2 study, mezigdomide plus dexamethasone demonstrated activity in heavily pretreated patients, including those with disease resistant to established drug classes.²

Elranatamab is a bispecific antibody that binds B-cell maturation antigen on myeloma cells and CD3 on T cells, redirecting T-cell activity toward malignant plasma cells. It is FDA approved for adults with RRMM who have received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody.³

The MELT-MM combination is based on evidence that mezigdomide may strengthen T-cell effector function and reduce markers associated with T-cell exhaustion, potentially supporting elranatamab activity in patients with a high tumor burden. The combination remains investigational.¹

Responses Observed Across Both Dose Cohorts

MELT-MM is an ongoing, open-label, multinational phase 1/2 trial. Part 1 was designed to evaluate safety, tolerability, and preliminary efficacy while identifying recommended phase 2 doses. Eligible patients had measurable RRMM after at least 2 prior lines of therapy that included lenalidomide and a proteasome inhibitor. All were naïve to BCMA-directed therapy and had an Eastern Cooperative Oncology Group performance status of 2 or lower.¹

Following an elranatamab lead-in, patients received mezigdomide at either 0.3 mg or 0.6 mg on days 1 through 21 of each 28-day cycle. Elranatamab was administered weekly during cycles 1 through 6, with response-based reductions in dosing frequency during subsequent cycles.¹

Fifteen patients enrolled between December 2024 and the April 2026 data cutoff. Thirteen were evaluable for safety and efficacy, including 7 treated with mezigdomide 0.3 mg and 6 treated with 0.6 mg. Patients had received a median of 4 prior lines of therapy. More than half had previously received an anti-CD38 antibody, 30.8% had received a non-BCMA bispecific antibody, and 30.8% had extramedullary disease.¹

All 13 evaluable patients responded, and 12 achieved CR or better. Among 8 patients with stringent CR and available minimal residual disease (MRD) results, 7 (87.5%) achieved MRD negativity. The median time to first response was 17 days, and median progression-free survival was not reached after a median follow-up of 10 months.¹

Although these findings suggest substantial early activity, the analysis cannot establish the durability of response or support comparisons with other regimens because it included only 13 evaluable patients and lacked a control group.

Safety Findings Highlight Monitoring Needs

Cytokine release syndrome occurred in 10 patients (76.9%), but all events were grade 1 or 2. No immune effector cell–associated neurotoxicity syndrome events occurred. These toxicities warrant close surveillance because elranatamab carries boxed warnings for serious or fatal cytokine release syndrome and neurologic toxicity.³

Fatigue was the most common nonhematologic adverse event, occurring in 84.6% of patients; one patient experienced grade 3 or 4 fatigue. Six patients (46.2%) developed infections, including 2 cases of cytomegalovirus disease. No febrile neutropenia was reported.¹

Both dose-limiting toxicities occurred in the 0.6-mg cohort: 1 case of reversible grade 4 thrombocytopenia and 1 case of reversible grade 3 acute kidney injury. Hematologic toxicities were otherwise consistent with the known safety profile of mezigdomide. Previous clinical experience has identified neutropenia and infections as important considerations with mezigdomide-based treatment.²

For pharmacists, the findings reinforce the need for coordinated monitoring of blood counts, infection symptoms, renal function, and immune-mediated toxicities when CELMoD agents are combined with T-cell–engaging therapies. Cytomegalovirus disease in 2 of 13 patients also supports careful evaluation of infection risk and institutional monitoring practices as the regimen advances.

Part 2 will randomly assign patients to mezigdomide 0.3 mg or 0.6 mg, stratified by International Myeloma Working Group Frailty Score. The expansion is expected to clarify dose selection and determine whether the depth of response observed in part 1 is maintained in a larger population.¹

REFERENCES

1. Byun JM, Cho H, Min CK, et al. Phase I/II study of mezigdomide and elranatamab for relapsed/refractory multiple myeloma patients (MELT-MM): updated results from part 1. Presented at: 23rd International Myeloma Society Annual Meeting; September 2026. Abstract OA-52.

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

3. Elrexfio (elranatamab-bcmm) injection, for subcutaneous use. Prescribing information. Pfizer; revised 2025. https://labeling.pfizer.com/ShowLabeling.aspx?id=19669

4. Lesokhin AM, Tomasson MH, Arnulf B, et al. Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results. Nat Med. 2023;29(9):2259-2267. doi:10.1038/s41591-023-02528-9

5. ClinicalTrials.gov. Study of mezigdomide and elranatamab in relapsed/refractory multiple myeloma (MELT-MM). NCT06645678. Updated December 3, 2025. Accessed September 22, 2026. https://clinicaltrials.gov/study/NCT06645678?term=NCT06645678&rank=1