Associate Professor of Medicine Vanderbilt-Ingram Cancer Center, Nashville, TN Nashville, Tennessee, United States
Introduction: Despite therapeutic advances, multiple myeloma (MM) remains incurable. BCMA targeting immunotherapies, such as bispecific T-cell engagers (TCE) and autologous CAR-T, provide clinical benefit, but relapses are common. TCE require chronic therapy and are complicated by a high rate of infections. Autologous CAR-T require apheresis, are hampered by prolonged manufacturing times, including manufacturing failures, bridging therapy and as a result potential adverse events. Therefore, patient (pt) focused, safe and off the shelf therapies are needed for MM pts.
P-BCMA-ALLO1 is an allogeneic BCMA targeting CAR-T manufactured from healthy donor T-cells with non-viral transposon-based integration (piggyBac®) to express a human anti-BCMA VH-based CAR to produce a T stem cell memory-rich product. Cas-CLOVER™ Site-Specific Gene Editing eliminates endogenous T cell receptor expression to prevent graft-vs-host disease (GvHD), as well as the beta-2 microglobulin gene, to reduce MHC class I expression and potential host-vs-graft response. P-BCMA-ALLO1 is available as an “off-the-shelf” CAR-T and is being evaluated in a phase 1 clinical trial in RRMM pts.
Methods: The primary objective is to determine the maximum tolerated dose of P-BCMA-ALLO1. The key secondary objective is to evaluate the anti-myeloma activity. Eligible pts (aged ≥18 y) were diagnosed with MM per IMWG criteria, had measurable disease, and have received prior treatment with a proteasome inhibitor, an immunomodulatory drug and an anti-CD38 antibody. The study is exploring escalating P-BCMA-ALLO1 doses and evaluating deeper lymphodepletion (LD) regimens. These “P” LD arms include: P1 - cyclophosphamide (cy) 500 mg/m²/day + fludarabine (flu) 30 mg/m²/day, P1.5 - cy 750 mg/m²/day + flu 30 mg/m²/day, and P2 - cy 1000 mg/m²/day + flu 30 mg/m²/day, for 3 days.
Results: A total of 34 pts have been dosed with P-BCMA-ALLO1 in P LD arms and have completed the DLT evaluation period. 17 pts received treatment in arm P1, 7 pts in P1.5, and 10 pts in P2 with a P-BCMA-ALLO1 cell dose of >2 × 10⁶ to < 6 × 10⁶ cells/kg on day 0. The median pt age is 66 years and median prior lines of therapy is 5. The median time from enrollment to study treatment was just 2 days and 100% of the intent to treat (ITT) population received P-BCMA-ALLO1. None of the pts required bridging therapy, highlighting the rapid accessibility of an off-the-shelf product. P-BCMA-ALLO1 was well tolerated with no DLT or GvHD. Most common grade (G) ≥ 3 TEAEs were neutropenia (61%), leukopenia (55%), lymphopenia (45%), thrombocytopenia (39%), anemia (30%) and febrile neutropenia (24%). Ten of the 34 pts (29%) developed CRS (G≤2) and one pt (2.9%) developed G2 ICANS.
Conclusions: In summary, P-BCMA-ALLO1 is a well-tolerated allogeneic CAR-T that is available “on-demand” and demonstrates low rates of CRS and ICANS. Enrollment is ongoing and updated safety and efficacy data will be presented at the meeting.
