Off-the-Shelf CAR T-Cell Therapy P-BCMA-ALLO1 Is Efficacious in Relapsed/Refractory Multiple Myeloma

Bhagirathbhai Dholaria, MBBS

The investigational, BCMA-directed, allogeneic CAR T-cell therapy P-BCMA-ALLO1 may be an effective agent for patients with relapsed/refractory multiple myeloma, including those who experienced disease progression following treatment with other BCMA-directed therapies, according to Bhagirathbhai Dholaria, MBBS.

Data from cohort C of a phase 1 study (NCT04960579) presented during the 2025 Transplant and Cellular Therapy Meetings demonstrated that patients who received P-BCMA-ALLO1 (n = 32) experienced an objective response rate (ORR) of 88%. Notably, the ORR was 100% in patients who had not received previous BCMA-targeted therapy (n = 16) and 75% in patients who had received at least 1 prior anti-BCMA therapy (n = 16). The ORRs among patients who received a prior BCMA-directed bispecific antibody (n = 12) and at least 1 prior BCMA and GPRC5D therapy (n = 9) were 75% and 78%, respectively.

“[Our findings showed that] you can safely administer an allogeneic, nonviral vector, gene-edited CAR T-cell therapy in relapsed/refractory myeloma, even [with] a higher lymphodepletion regimen, and have an excellent safety profile in terms of cytokine release syndrome [CRS], liver toxicity, and infections,” Dholaria said in an interview with OncLive®. “The efficacy signal is there across cohorts, even in patients who had prior BCMA-targeted therapies. [However], we need long-term follow-up to determine if this efficacy persists.”

In the interview, Dholaria, an associate professor in the Division of Hematology Oncology at Vanderbilt University Medical Center in Nashville, Tennessee, discussed what separates P-BCMA-ALLO1 from other CAR T-cell therapies, key data he presented from the phase 1 study, and next steps for the agent’s development.

OncLive: What differentiates P-BCMA-ALLO1 from other CAR T-cell agents?

Dholaria: P-BCMA-ALLO1 is an allogenic cell therapy product manufactured from healthy donor T cells. Currently, FDA-approved CAR T products [such as] idecabtagene vicleucel [Abecma] or ciltacabtagene autoleucel [Carvykti], use patients’ own T cells to manufacture the CAR. These CARs are made from a healthy donor and because of that the cells are ready [for use immediately]. There is no apheresis or manufacturing delay in getting patients the CAR T-[cell] therapy.

There are several other manufacturing differences between P-BCMA-ALLO1 and other BCMA-targeted CAR T-cell therapies. Most importantly, the gene editing technology [used for P-BCMA-ALLO1] is a nonviral vector transposon-based technology which allows the CAR T to be manufactured in more of a T-cell memory phenotype, rather than an activated T cell, which is the common immunophenotype for viral vector-based CAR T cells. In the final CAR T product, the majority of the cells had a CAR gene because they were selected ex vivo and most of these T cells were central memory phenotype, which has been found to be more effective and more in vivo persistent, with less risk of CRS and neurotoxicity compared with other CAR T-cell products.

What were the key design features of this phase 1 study?

The purpose of this study was to determine the safety of P-BCMA-ALLO1 in patients with relapsed/refractory multiple myeloma [who underwent] 3 or more prior lines of therapy. This trial allowed patients who received other BCMA-targeted therapies, such as other CAR T-cell therapies or bispecific antibodies, [to enroll]. It truly represents the real-world patient population [which is] those with heavily pretreated multiple myeloma.

It [used] a 3+3 dose escalation treatment schema; we tested different cell doses and had several treatment arms with a different lymphodepleting regimen. Early on in the trial, we realized that the standard lymphodepletion [regimen of] 300 mg/m2 of cyclophosphamide and 30 mg/m2 of fludarabine was not adequate for better in vivo expansion and antitumor activity. We quickly moved on to a higher lymphodepletion [regimen] which uses higher doses of cyclophosphamide, ranging anywhere from 500 mg/m2 to 1000 mg/m2, with the same dose of fludarabine.

Which lymphodepleting regimen was used in cohort C and why?

Cohort C used 750 mg/m2 of cyclophosphamide for 3 days with 30 mg/m2 of fludarabine for 3 days. This cohort [contained] the most recently treated patients. We had a higher dose cohort than cohort C which used 1000 mg/m2 of cyclophosphamide [and] we noticed a higher degree of cytopenia and infections with that highest dose. We felt that the best balance of efficacy and toxicity could be achieved by finding an intermediate intensity of the fludarabine and cyclophosphamide doses.

What is the safety profile of P-BCMA-ALLO1?

The most important message in terms of safety in cohort C [n = 36] is that we did not report any grade 3 or higher CRS or immune effector cell-associated neurotoxicity syndrome. [There were no] patients with parkinsonism or other movement disorders, which have been described with autologous BCMA-targeted CAR T-cell therapies. The incidence of [any-grade] CRS was 42% and all of these events were grade 1 or 2. Neurotoxicity was reported in 14% of patients, and all [instances] were grade 1, which were quickly resolved with minimal steroids.

Another important safety aspect of cohort C was the [rate of] cytopenias. Because of the higher cyclophosphamide and fludarabine doses used in this lymphodepletion regimen, grade 3 or higher [treatment-related] neutropenia was reported in 50% of patients, grade 3 or higher [treatment-related] thrombocytopenia was reported in 36%, and grade 3 or higher [treatment-related] anemia was reported in 39%. We noticed that majority of cytopenias resolved by day 28 after P-BCMA-ALLO1 infusion. There were some infectious events reported, and grade 3 or higher infection complications were reported in only 14% of patients in this cohort.

How durable were the responses observed in cohort C?

The follow-up in cohort C was rather short, so we don’t have full data on the duration of response. [However], the responses were rapid. In fact, most patients had a response at the first disease evaluation, which was [approximately] 2 weeks after CAR T cell infusion. We noticed that in vivo the cells expanded within the first 7 to 10 days after infusion, and by month 3 or 4, most of the CAR T cells disappeared, except in a handful of patients where we saw even longer in vivo, persistent [cells], mainly in the bone marrow, even after the CAR T [cells] disappeared from peripheral blood circulation.

What are the future directions of this research?

We are moving to the phase 1b portion, dose expansion, with cohorts that are using the same lymphodepletion regimen as cohort C. We’ll be evaluating this CAR T product at 2 cell doses [and] phase 1b will focus on the BCMA-naive patient population. It will still include relapsed/refractory myeloma and triple-refractory cases, but patients must be BCMA naive [in order to] see if there’s a better efficacy signal in that patient population.

[Moreover], BCMA-relapsed myeloma is an area of unmet need in 2025. We have multiple BCMA-targeted therapies available, and these CAR T-cell therapies are moving into earlier lines of therapy, but when patients [relapse after] autologous BCMA CAR T-cell or bispecific antibody therapy, we need to have novel treatment options. P-BCMA-ALLO1 falls into that category of therapeutic agents which can potentially salvage these patients.

Reference

1. Dholaria B, Kocoglu MH, Kin A, et al. 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 (arm C). Presented at: 2025 Transplantation and Cellular Therapy Meetings; February 12-15, 2025; Honolulu, HI. Abstract 48.