What are the latest updates from the phase I trial of P-BCMA-ALLO1 for the treatment of RRMM?

The Multiple Myeloma Hub spoke with Mehmet Hakan Kocoglu, University of Maryland, Baltimore, US. We asked, What are the latest updates from the phase I trial of P-BCMA-ALLO1 for relapsed/refractory multiple myeloma (RRMM)?

In this interview, Mehmet Hakan Kocoglu discussed the latest updates from the phase I trial of P-BCMA-ALLO1 (NCT04960579) for RRMM, focusing on the key efficacy and safety data for this allogeneic B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy.

Key learnings

• Autologous CAR T cells are limited by manufacturing logistics and need for bridging therapy.¹
• Bispecific antibodies can be used as bridging therapy but require frequent (weekly/biweekly) infusions and are associated with risk of infection.^2,3
• The use of allogeneic CAR T cells offers the theoretical advantage of an ‘off-the-shelf’ approach without the need for multiple treatments.¹
• P-BCMA-ALLO1 is an allogenic BCMA-targeting CAR T-cell therapy that uses a non‑viral, transposon-based gene insertion method combined with gene editing to eliminate endogenous TCR and MHC I expression, aiming to reduce graft-vs-host/host-vs-graft risks.⁴
• In contrast to currently approved CAR T-cell therapies developed using a lentiviral approach, the transposon-based approach enriches for stem-cell memory / central memory-like T-cell subsets, which is associated with improved CAR T-cell persistence.¹
• An open-label, phase I/Ib trial, P-BCMA-ALLO1-001 (NCT04960579), is ongoing across the United States to investigate the safety and efficacy of P-BCMA-ALLO1 in triple-class-refractory patients with RRMM.⁴
• Initial data demonstrate a short (1 day) median time from enrolment to participants receiving therapy, without the need for bridging therapy.⁴
• In analyses to date, more than 50% of patients had high-genetic-risk disease and 40% had extramedullary disease. 50% of patients had received prior BCMA-directed therapy, with one-third exposed to both BCMA- and GPRC5D-targeting therapies.
• Cytokine release syndrome (CRS) was observed in 39% of patients, and immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in 14–15% of patients; no Grade ≥3 events were reported for either CRS or ICANS.⁴
• Hematological adverse events were observed, consistent with other agents, including neutropenia, anemia, thrombocytopenia, and lymphopenia.⁴
• No instances of graft-versus-host disease or rejection were recorded.⁴
• The overall response rate (ORR) was close to 90% for the whole patient population, 100% in BCMA-naïve patients, and 80% in patients exposed to BCMA- and GPRC5D-targeting therapies.⁴
• Correlation analyses in the study suggested good persistence and expansion of CAR T cells, with good functionality and durable remissions. P-BCMA-ALLO1 also shows promise in multiple myeloma that has developed anti-BCMA resistance.
• P-BCMA-ALLO1 shows promise in difficult-to-treat populations with RRMM. Data will continue to be accrued through the phase I/Ib P-BCMA-ALLO1-001 trial, with long-term (15 years) safety due to be monitored in a separate follow-up study (NCT03741127). To date, P-BCMA-ALLO1 has received FDA orphan drug designation and regenerative medicine advanced therapy (RMAT) designation. 

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