Paper Details

ABSTRACT

Background: T-cell engagers (TCEs) that target single antigens have shown significant efficacy in relapsed/refractory multiple myeloma (RRMM). However, antigen expression heterogeneity and antigen escape are mechanisms of resistance. mRNA-2808, a single drug product, is an investigational lipid nanoparticle-formulated multiplexed mRNA therapeutic designed to enable in vivo production of three distinct TCEs targeting the clinically validated antigens BCMA, GPRC5D, and FcRH5. To our knowledge, mRNA-2808 is the first multiplexed mRNA therapeutic encoding multiple distinct TCEs to be evaluated in humans. Simultaneous targeting of these antigens is intended to broaden antigen coverage and address antigen heterogeneity or escape. We report initial results from the first-in-human phase 1/2 mRNA-2808-P101 study in heavily pretreated RRMM.

Methods: mRNA-2808-P101 (NCT07116616) is an ongoing first-in-human phase 1/2 study evaluating escalating doses of mRNA-2808 in adult participants with triple class exposed RRMM. mRNA-2808 is administered IV without step-up dosing weekly for 4 weeks, then every other week until month 12. Key objectives are safety, dose-limiting toxicities (DLT), efficacy by IMWG criteria, pharmacokinetics and pharmacodynamics. Ligand binding assays were used to detect secreted TCE proteins and cytokines. Bone marrow aspirates were evaluated for BCMA, GPRC5D, and FcRH5 expression by flow cytometry.

Results: As of 29 June 2026, 12 pts had received mRNA-2808 across five dose levels (0.002–0.108 mg/kg). Follow-up duration ranges from 0.5-6.5 months. Median age was 72 (range 48-83), and 9 (75%) had extramedullary disease. The median number of prior lines of therapy was 10 (range 4-16); all pts had triple-class refractory RRMM, 11/12 received prior T-cell redirecting therapy (TCRT) including CAR-T or TCE; 10/12 received prior BCMA-targeted TCRT; 10/12 received prior GPRC5D-targeted TCRT; and 9/12 received both BCMA- and GPRC5D-targeted TCRT. None received prior FcRH5 TCRT.

No DLTs were observed. Among the 12 safety evaluable pts, treatment emergent adverse events (TEAEs) occurred in 91.7%, including grade ≥3 TEAEs in 83.3% and serious TEAEs in 25.0%; none led to death or treatment discontinuation. 41.7% had grade ≥3 events that were considered related (predominantly hematologic); no serious adverse events were considered related. The most common TEAEs considered related to treatment were dysgeusia (58.3%), palmar-plantar erythrodysesthesia (PPE) syndrome (41.7%), pyrexia (41.7%), anemia (25.0%), and neutrophil count decreased (25.0%). CRS occurred in 41.7%, and in all cases was grade 1 and resolved with a single dose of tocilizumab. No cases of immune effector cell-associated neurotoxicity syndrome (ICANS) or infusion-related reactions were reported.

Across all dose levels, 11 pts were response evaluable with at least one post-baseline assessment. Four had confirmed PR or better including 2 VGPRs and 2 PRs. All 4 responses were among the 9 pts treated at doses ≥0.018 mg/kg and all were ongoing at data cutoff. Responses were observed in pts with prior exposure to BCMA-targeted TCRT, GPRC5D-targeted TCRT, and both BCMA- and GPRC5D-targeted TCRT.

All 3 TCE proteins were detectable in plasma and exposure increased with dose level. Plasma cytokines, including IFNγ, IL-6, and IL-10, peaked approximately 12 hours post first dose. All participants tested by flow cytometry expressed BCMA, GPRC5D and FcRH5 on malignant plasma cells (mPCs) at baseline, but with high variability between participants.

Conclusions: mRNA-2808 yielded in vivo production of three targeted TCEs and demonstrated a manageable safety profile without step-up dosing. Encouraging responses were observed in heavily pretreated RRMM and in those who progressed on or following prior BCMA and/or GPRC5D directed therapy. Dose escalation is ongoing, and longer follow-up will be presented.