Phase I/II study of mezigdomide and elranatamab for relapsed/refractory multiple myeloma patients (MELT-MM): Initial results from part 1

Abstract Background: Despite significant advances, multiple myeloma (MM) remains incurable and new therapies are needed to improve outcomes. Mezigdomide (MEZI) is a high potent CELMODTM agent with enhanced tumoricidal and immune-modulatory effects by inducing rapid degradation of Ikaros/Aiolos. Elranatamab (ELRA) is a BCMA-CD3 bispecific antibody, approved for use in many parts of the world based on its durable response with a manageable safety profiles in patients with R/R MM. Considering (1) the cell autonomous and immunomodulatory effects of MEZI; (2) that MEZI may reverse and prevent T-cell exhaustion/ dysfunction when used with T-cell engagers; and (3) the fact that BCMA expression persists through disease relapses, we expect the combination of MEZI plus ELRA will yield promising results in R/R setting based on NK-cell / T-cell modulation, anti-proliferation and tumor apoptosis. Study design and Methods: MELT-MM is an ongoing, open-label, single arm, multinational phase I/II study estimated to enroll ~ 75 patients and registered on clinicaltrials.gov as NCT06645678. The study constitutes parts: a phase I safety cohort (part 1) to determine the optimal recommended phase 2 dose (RP2D) of mezigdomide and to assess safety and tolerability MEZI plus ELRA; and phase II expansion cohort (part 2) to determine the efficacy of this novel-novel combination based. After initial ELRA lead-in schedule (cycle 0, 2 weeks), each cycle consists of 28 days. For cycles 1-6, ELRA is be given weekly. For cycles 7-12, ELRA is be given every 2 weeks for those achieving PR or better response. For cycles 13-24, ELRA is be given monthly for those achieving CR or better response. MEZI is given on days 1-21 at a chosen dose. Three different doses of MEZI, starting from 0.3mg → 0.6mg → 1mg are to be tested in a traditional 3+3 design to determine RP2D. Primary prophylaxis with pegylated GCSF is used in all patients. Participants who have completed the planned 24 cycles and have achieved PR or better response per IMWG will roll over to maintenance phase. Participants will receive MEZI (without ELRA) until confirmed PD by investigator, unacceptable toxicity as assessed by the investigator and/or withdrawal of consent. Key inclusion criteria include 2 prior lines of antimyeloma therapy including lenalidomide and at least 1 proteasome inhibitor, age ≥19 years, diagnosis of MM according to IMWG criteria, an ECOG performance status ≤2, and measurable disease. Key exclusion criteria include prior treatment with a BCMA-targeted therapy (including antibody drug conjugates), prior treatment with mezigdomide, known CNS involvement with myeloma, or active infection. Patients with extramedullary disease are allowed to participate if there is a measurable disease in serum and/or urine. Results: A total of 11 patients (8 in MEZI dose level 0.3mg; 3 in MEZI dose level 0.6mg) have been enrolled in Part 1 and dosed. The median age at enrollment was 70 (range 54-76), with median 4 prior lines of therapy (range 2-6). Five (45.5%) had prior anti-CD38 exposure, and 3 (27.3%) had prior non-BCMA BsAbs exposure. Among 8 patients in dose level 0.3mg, 2 were DLT non-evaluable and there were no DLT events. Among 3 patients in dose level 0.6mg, 2 patients with IMWG frailty score 2 experienced DLT: 1) grade 4 thrombocytopenia related to study drugs at C1D15 that lasted for 6 days; and 2) grade 3 acute kidney injury in relation to parainfluenza pneumonia that lasted for 11 days (study drugs not related). Additional patients will be recruited to dose level 0.6mg. Response was evaluable in 10 patients: ORR 90%, VGPR or better 60%, and CR or better 50%. For those treated for > 3 cycles (N=7, median follow-up 5.6 months), the ORR was 100%, VGPR or better 100%, and CR or better 71.4%. Cytokine release syndrome was observed in 6 patients (54.5%), and all were grade 1. There were no cases of neurologic adverse events. Other than the DLT events, there was 1 event of CMV disease but no other safety signals including infection and cytopenias during DLT period. Conclusion: In patients with R/R MM, initial results suggest that the combination of MEZI + ELRA is clinically feasible and show therapeutic potential.