First-in-human phase 1 trial of trimeric APRIL (TriPRIL) CAR T cells in relapsed or refractory multiple myeloma: Clinical outcomes and biological correlates of disease response and resistance

Abstract Durable responses to currently available CAR T cell therapies for relapsed or refractory multiple myeloma (R/R MM) are limited in part by BCMA antigen escape and immunologic responses to the CAR construct. Moreover, effective therapies for patients (pts) who progress after receiving BCMA CAR T cells in R/R MM remain an unmet need. TriPRIL CAR T cells were developed to co-target BCMA and TACI using a trimeric form of their natural ligand APRIL, fused to the 4-1BB and CD3ζ intracellular signaling domains. Targeting multiple antigens using a single ligand-based CAR may minimize antigen-negative tumor escape and immune responses to the construct. We present both clinical and translational correlative studies from an ongoing, first-in-human, phase 1 clinical trial of autologous TriPRIL CAR T cells in pts with R/R MM (# NCT05020444). Eligible pts with R/R MM had received at least 3 prior lines of therapy or had triple class-refractory disease. Prior BCMA-targeting therapy was allowed. The primary endpoint was incidence of dose-limiting toxicities (DLTs) and adverse events. The study employed a 3+3 dose escalation design followed by dose expansion. If the target CAR T cell dose was not manufactured, pts could receive infusion at the lower dose level. TriPRIL CAR T cells were evaluated using flow cytometry and vector copy number. BCMA and TACI expression were assessed by flow cytometry on bone marrow plasma cells before and after infusion. To further explore the mechanisms of response and resistance, ex vivo CAR-T function, as well as soluble BCMA, TACI, APRIL, and BAFF, were evaluated. As of July 9, 2025, 11 pts had undergone leukapheresis and 10 pts had received TriPRIL CAR T infusion. Five pts were treated at dose level 1 (1 x10^8 CAR T cells) and 5 pts at dose level 2 (3 x10^8 CAR T cells). Among the infused pts, the median age was 73 years (range 62-82), and 8 pts were female (80%). Pts had received a median of 6 prior lines of therapy (range, 3-10). Six pts (60%) had received previous BCMA CAR T therapy. Six pts (60%) had high-risk cytogenetics, and 3 pts (30%) had extramedullary disease. No DLTs occurred at either dose level. Grade 1 or 2 CRS occurred in all pts (100%; Grade 1: 80%, Grade 2: 20%). One patient (10%) had Grade 2 ICANS. There were no Grade 3 or higher CRS or ICANS events, nor occurrences of Parkinsonism or cranial nerve palsies. The median follow-up time among pts who remain alive is 11.9 months (mo). The overall response rate (ORR) was 80% with a complete response (CR) rate of 60%. Four of the 6 pts (67%) who previously received BCMA CAR T cells achieved a CR. The median PFS was 8.4 mo (95% CI, 0.9-11.1) among the entire cohort and 8.4 mo (95% CI, 0.9-NE) among pts with prior BCMA CAR T. One patient with prior BCMA CAR T therapy was in an ongoing CR 14 mo post-TRiPRIL infusion. The median OS had not been reached (95% CI, 3.8-NE). CAR T expansion occurred in all pts (median peak expansion 2713 cells/μl blood), with persistence beyond mo 3 in 9 pts (90%). All 5 pts in remission at mo 6 had ongoing CAR T persistence at this timepoint. In contrast, one patient who did not respond had limited expansion (6 cells/μl blood), and CAR T cells did not persist beyond day 21. The only other non-responder had BCMA and TACI-negative plasma cells pre-infusion, having previously received BCMA CAR T therapy. Circulating CAR T cells from this patient remained functional, killing a BCMA-positive cell line ex vivo (RPMI-8226). Further correlative studies of bone marrow plasma found that soluble BCMA and TACI declined from baseline to D+28 post-infusion, in keeping with the destruction of target antigen. In contrast, soluble BAFF and APRIL increased. Furthermore, we identified soluble TriPRIL in the serum of responding pts post-infusion, which corresponded to peak CAR T cell expansion. TriPRIL CAR T cells demonstrated notable safety and a high response rate in heavily pretreated pts with R/R MM, including pts who previously received BCMA CAR T. TriPRIL is one of the first ligand-based CAR T cell therapies to show efficacy in an early phase clinical trial. Correlative studies demonstrated potential mechanisms of resistance, including the absence of both target antigens and a lack of sustained CAR T cell expansion in a patient recently treated with a bispecific antibody. Our findings support and inform the continued clinical development of TriPRIL CAR T cells. Updated data through November 2025 will be presented.