A phase 1/2 study of mRNA-2808 in participants with relapsed or refractory multiple myeloma.

Abstract

TPS7580 Background: Multiple myeloma (MM) remains mostly incurable despite therapeutic advances and relapsed or refractory multiple myeloma (RRMM) remains a significant unmet need. mRNA-2808 is an intravenously (IV) administered mRNA-encoded, multiplexed T-cell engager (TCE) that delivers in vivo translation of three distinct TCEs targeting BCMA, GPRC5D, and FcRH5. This multiplexed approach aims to enhance immune-mediated cytotoxicity, overcome tumor heterogeneity and target-mediated resistance. Previous preclinical studies of mRNA-2808 have demonstrated efficient in vivo translation of TCEs, potent activity against both primary MM cells ex vivo and murine tumor xenografts in vivo , and target-cell depletion in non-human primates. Taken together, this supports the clinical evaluation of mRNA-2808. Methods: This ongoing, first-in-human, open-label, multicenter Phase 1/2 study evaluates the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of mRNA-2808 administered to participants with RRMM. Key eligibility criteria include RRMM with prior exposure to a proteasome inhibitor, an IMiD, and an anti-CD38 monoclonal antibody and are either triple-class refractory or have progressed on or within 60 days of their last line of therapy, have measurable disease including bone marrow plasma cells >30% or plasmacytoma ≥2cm in size, and ECOG PS 0-2. Prior exposure to BCMA, GPRC5D, or FcRH5 targeted therapies is allowed. The study comprises two parts: Part 1 (dose escalation) to determine the recommended Phase 2 dose(s) (RP2D) and Part 2 (dose expansion) to further assess safety and efficacy of selected RP2D(s). The dose-escalation in Part 1 will proceed in 2 phases: Accelerated Titration Phase (single participant per dose level (DL)) and Standard Titration Phase (at least 3 participants per DL). The Accelerated Titration Phase will continue until a dose limiting toxicity (DLT) or a clinically significant AE of ≥Grade 2 is observed. If a ≥Grade 2 CRS and/or ≥Grade 2 neurotoxicity including ICANS occurs, step-up dosing will be implemented. During the Standard Titration Phase, dosing decisions will be guided by a Bayesian Optimal Interval design based on the observed DLT rate from the current cohort and recommendations from the Safety Review Committee. During Cycle 1 (28-day cycles), mRNA-2808 will be administered IV weekly, and during Cycles 2-12 every 2 weeks. Treatment with mRNA-2808 will continue for up to 12 cycles. Participants who achieve at least a partial response by the end of Cycle 5 may transition to a 4-week dosing schedule at the Investigator’s discretion. Additional exploratory endpoints will evaluate surrogates of efficacy, mechanism of action, and characterize exposure. Dose Levels 1 and 2 have been completed without DLT and dose escalation is ongoing (NCT07116616). Clinical trial information: NCT07116616 .