A Phase 1 Study of P-BCMA-ALLO1, a Non-Viral, Allogeneic BCMA Directed CAR-T in Relapsed/Refractory Multiple Myeloma (RRMM): Results from Optimized Lymphodepletion Cohort

Introduction: P-BCMA-ALLO1 is an allogeneic BCMA targeting CAR-T for the treatment of RRMM. It is manufactured at an in-house GMP facility from healthy donor T cells using Cas-CLOVER™ gene editing and non-viral transposon-based integration (piggyBac® DNA Delivery System) to express a human anti-BCMA V_H-based CAR. These technologies enable P-BCMA-ALLO1 to be a T stem cell memory (T_SCM)-rich product with high purity characterized by near-100% CAR+ cells.

Methods: The P-BCMA-ALLO1-001 study (NCT04960579) is enrolling RRMM patients (pts) refractory to or who have relapsed following IMID, PI and CD38 mAb. Pts previously treated with BCMA-targeted therapy were allowed. The study employs a 3 + 3 dose escalation design to test multiple P-BCMA-ALLO1 doses from multiple product lots manufactured from different donors. Several lymphodepletion (LD) regimens are being investigated to enable optimal CAR-T expansion. The primary objective is to assess the safety and determine maximum tolerated dose of P-BCMA-ALLO1. The key secondary objective is to evaluate its anti-myeloma effect. Here, we present data on pts treated with a dose of approximately 2 x 10⁶ cells/kg, after completing a 3-day LD regimen (cyclophosphamide 750 mg/m²/day and fludarabine 30 mg/m²/day).

Results: At the time of data cutoff, 21 pts with 4+ weeks of follow up had been treated in this LD arm. None required bridging therapy and the median time from enrollment to start of study treatment was just 1 day (range: 0-9 days), highlighting the rapid availability of P-BCMA-ALLO1, being an off-the-shelf CAR-T. 100% of the intent to treat (ITT) population received P-BCMA-ALLO1.

The median pt age was 61 (39-76) years, 53% were female and 42% were minorities. The median time since multiple myeloma diagnosis was 7.0 (1.0-15.1) years. Pts were heavily pretreated, with a median of six (2-14) prior lines of therapy. 62% had undergone prior BCMA-targeted CAR-T and/or T cell engager (TCE) therapy, 29% had previously received both a BCMA-targeted CAR-T and/or TCE and Talquetamab. Thirteen (62%) pts had high-risk FISH anomalies.

P-BCMA-ALLO1 was well tolerated with no DLTs or GvHD. The most common treatment-emergent adverse events (TEAEs) were neutropenia (71%), leukopenia (67%), anemia (52%), thrombocytopenia (48%), and CRS (43%). The most common ≥ G3 TEAEs were neutropenia (67%), leukopenia (67%) anemia (43%), and thrombocytopenia (33%). Most AEs were considered unrelated to P-BCMA-ALLO1. Of nine (43%) pts with CRS, seven (33%) had G1 CRS and two (10%) had G2 CRS; no pt had > G3 CRS. Three (14%) pts experienced ICANS, all were G1.

P-BCMA-ALLO1 demonstrated an encouraging overall response rate (ORR) in all relevant pt subsets. The ORR in the ITT population was 90%, including 6 CR/sCR, 5 VGPRs, and 8 PRs. The ORR was 100% in BCMA naïve pts and 85% in pts who previously received BCMA-targeted therapy. The ORR was 83% in the subset of 6 pts who received both prior BCMA-targeted agents, and Talquetamab.

To assess whether BCMA expression impacted clinical activity, baseline BCMA levels (BCMA MESF on CD138+CD38+ bone marrow cells) were evaluated for 12 pts, showing a median MESF of 4,685 (2,125-23,537). The median BCMA MESF for the 6 BCMA-naïve pts tested was 8,859 (4,098-23,537), while the median for the 6 pts with prior BCMA therapy was 2744 (2125-5912). P-BCMA-ALLO1 cellular kinetics (CK) were assessed (n=15) using ddPCR demonstrating a median C_max of 49,430 (66-501,678) cp/µg of the CAR transcript at a median T_max of 10 (7-21) days. The median CK for the BCMA naïve pts (n=7) was 72.077 (10,904 – 501,678) cp/µg, while the median CK for BCMA exposed pts (n=8) was 27,878 (66 – 310,209) cp/µg. There was no statistical difference between these groups.

Conclusions: P-BCMA-ALLO1 is a non-viral, T_SCM-rich, allogeneic BCMA-targeting CAR-T quickly delivered to all eligible pts without the need for bridging therapy. P-BCMA-ALLO1 demonstrates a promising ORR and favorable safety profile when administered with optimized LD. It is highly active, regardless of prior exposure to BCMA-targeted autologous CAR-T or TCE therapy. As an allogeneic therapy, it also offers significant practical advantages over autologous CAR-T, which require apheresis, prolonged, often uncertain manufacturing, and bridging therapy; and TCE, which require chronic administration. The P-BCMA-ALLO1-001 clinical trial is actively enrolling pts. Updated safety and efficacy data will be presented at ASH 2024.