Dr Byun on Updated Data From MELT-MM With Mezigdomide and Elranatamab in Multiple Myeloma

“One of the major pitfalls of T-cell engagers is that they ultimately lead to T-cell exhaustion, which leads to resistance. Based on [the] mechanism of action and preclinical data, we hypothesized that adding mezigdomide would reverse the T-cell exhaustion and enhance T-cell fitness [so we could] ultimately achieve [a] deeper and more durable response.”

Ja Min Byun, MD, PhD, an assistant professor in the Department of Internal Medicine at Seoul National University College of Medicine and a hematologist-oncologist at the Center for Hematological Oncology at Seoul National University Hospital, discussed updated results from part 1 of the investigator-initiated phase 1b/2 MELT-MM trial (NCT06645678), presented at the 2026 International Myeloma Society Annual Meeting, evaluating the cereblon E3 ligase modulatory drug (CELMoD) mezigdomide plus the BCMA x CD3 bispecific antibody elranatamab (Elrexfio) in patients with relapsed/refractory multiple myeloma.

BCMA-directed T-cell engagers have transformed the multiple myeloma treatment landscape, but according to Byun, high tumor burden can limit elranatamab’s single-agent efficacy, and sustained exposure drives T-cell exhaustion and resistance. Preclinical data showing mezigdomide restores elranatamab’s cytotoxicity under high tumor burden provided the rationale for combining the two agents, she explained.

Investigators enrolled 15 patients between December 2024 and October 2025; the 13 who received both agents, split across mezigdomide 0.3-mg (n = 7) and 0.6-mg (n = 6) cohorts, comprised the efficacy-evaluable population. At a median follow-up of 13.7 months (range, 8.6-19.3) the objective response rate was 100% (n = 13 of 13), with a stringent complete response (CR) rate of 92.3% (n = 12 of 13), Byun reported. Median time to response was 17 days, and 10 of 11 evaluable patients (90.9%) achieved minimal residual disease–negative CR at the 10⁻⁵ threshold; duration of response was not yet calculable given the limited follow-up, she said.

The safety profile was consistent with other BCMA-containing regimens, according to Byun. Neutropenia (84.6%) was the most common adverse effect and did not translate into febrile neutropenia, and fatigue (84.6%), associated with both agents, was manageable, she said. Six of 13 patients developed an infection, 4 of whom had grade 3/4 events, Byun noted.

Correlative analyses supported the mechanism: mezigdomide sustained elranatamab-driven T-cell activation without raising cytokine release syndrome risk, and reversed TIGIT and PD-1 upregulation on T cells, in preclinical models and patient samples, Byun said.

Part 2, a randomized expansion comparing the two mezigdomide doses in combination with elranatamab, is now enrolling patients in Singapore and Korea, and Byun said she has high hopes for the doublet moving forward.