Aims: Multiple myeloma (MM) remains mostly incurable 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. Pre-clinical studies demonstrated efficient in vivo translation of TCEs, potent activity against primary MM cells ex vivo and murine tumor xenografts in vivo, and target-cell depletion in non-human primates. supporting clinical evaluation of mRNA-2808.
Methods: This ongoing, first-in-human, open-label, multicenter Phase 1/2 study evaluates safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of mRNA-2808 in participants with RRMM. Eligibility criteria include prior exposure to a proteasome inhibitor, IMiD, and anti-CD38 monoclonal antibody, are either triple-class refractory or have progressed on or within 60 days of their last therapy, have measurable disease (bone marrow plasma cells >30% or plasmacytoma ≥2cm), and ECOG PS 0-2. Prior BCMA-, GPRC5D-, or FcRH5-targeted therapy is allowed. Part 1 uses dose escalation (accelerated and standard titration phases, with optional step-up dosing), to determine the recommended Phase 2 dose(s) (RP2D) and Part 2 (dose expansion) to further assess safety and efficacy. During the standard titration phase, dosing decisions will be guided by a Bayesian optimal interval design based on the observed dose-limiting toxicity (DLT) rate and Safety Review Committee recommendations. mRNA-2808 will be administered IV weekly during Cycle 1 (28-day cycles), then every 2 weeks through Cycle 12 or every 4-weeks for participants achieving at least a partial response by the end of Cycle 5 at the Investigator’s discretion. Exploratory endpoints will evaluate surrogates of efficacy, mechanism of action, and exposure. Dose Levels 1 and 2 have been completed without DLT and dose escalation is ongoing. (NCT07116616)