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Clinical Activity of P-BCMA-ALLO1, an Allogeneic BCMA Targeting CAR-T, in Patients with Relapsed Refractory Multiple Myeloma (RRMM) and Extramedullary Disease
Abstract   Peer reviewed

Clinical Activity of P-BCMA-ALLO1, an Allogeneic BCMA Targeting CAR-T, in Patients with Relapsed Refractory Multiple Myeloma (RRMM) and Extramedullary Disease

Siddhartha Ganguly, Caitlin Costello, Mehmet H. Kocoglu, Andrew Kin, Leyla Shune, Jose C Carlos Cruz, Aravind Ramakrishnan, Christopher Strouse, Edward A Faber, Ehsan Malek, …
Transplantation and cellular therapy, Vol.31(2 Supplement), pp.S404-S404
02/2025
DOI: 10.1016/j.jtct.2025.01.622

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Abstract

Extramedullary disease (EMD), an aggressive form of multiple myeloma (MM) described as proliferation of a malignant plasma cell clone independent of the bone marrow microenvironment, is a high-risk feature with a poorer prognosis than disease without EMD. Patients (pts) with EMD are underrepresented in clinical trials of bispecific t-cell engagers (TCE) and CAR-T. Autologous BCMA-targeted CAR-T appear to have inferior clinical activity in pts with EMD. Novel, effective and convenient treatments are needed to treat this high-risk subset. P-BCMA-ALLO1 is an allogeneic (allo) BCMA targeting CAR-T produced from healthy donor T-cells via non-viral transposon-based integration to produce a T stem cell memory-rich product. The Cas CLOVER™ gene editing system is used to ablate the TCR beta chain and partially knock out the beta-2 microglobulin gene to prevent graft vs host disease (GVHD) and attenuate host vs graft respectively. P-BCMA-ALLO1 expresses a novel human VH anti-BCMA CAR with a 4-1-BB costimulatory domain. P-BCMA-ALLO1 is being evaluated in a phase 1 clinical trial (NCT04960579) in relapsed/refractory multiple myeloma (RRMM). To examine clinical activity of P-BCMA-ALLO1 in pts with RRMM and EMD. The study uses 3+3 dose escalation to evaluate safety and MTD/RDE in adults with RRMM who received ≥ 3 prior lines of therapy including a PI, IMiD and CD38 mAb or are triple refractory if they have received 2 prior lines of therapy. Prior BCMA targeted therapy was allowed. A key secondary objective is evaluating the anti-myeloma effect of P-BCMA-ALLO1. As the optimal lymphodepletion (LD) regimen for allo CAR-T has not been determined, the study evaluates several LD regimens. Pts receive a 3-day LD regimen of fludarabine 30 mg/m2/day plus cyclophosphamide 300 mg/m2/day (arm S), 500 mg/m2/day (arm A), 1000 mg/m2/day (arm B) or 750 mg/m2/day (arm C). P-BCMA-ALLO1 was administered at dose of approximately 2 × 106 cells/kg after a 2-day rest period. As of September 6, 2024, 52 pts have enrolled in arms A, B and C, 17 of whom had EMD, including both BCMA-experienced and BCMA-naive pts. P-BCMA-ALLO1 was well tolerated with no GVHD, ≥grade (G) 3 cytokine release syndrome or ≥G3 immune effector cell neurotoxicity syndrome. The most common toxicities were cytopenias related to LD. The ORR in the 17 pts with EMD was 58.8%. Twenty-three pts were treated in arm C with a 91% ORR including 100% (N=9/9) ORR in BCMA-naïve pts and 86% (N=12/14) ORR in pts with prior BCMA/GPRC5D auto CAR-T and/or TCE-treatments. The 8 pts with EMD in Arm C had an ORR of 88% (7/8). Arm C has been selected for phase 1b expansion. P-BCMA-ALLO1 when administered with optimized LD in arm C is a safe and effective therapy for pts with EMD. We will continue to enroll pts with EMD to further assess P-BCMA-ALLO1 activity in this high-risk subgroup. Updated safety and efficacy data will be presented at the conference.

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