"Off-the-Shelf" CAR T Therapy Strikes Hard Against Relapsed Myeloma

Bone biopsy of multiple myeloma cells

Patients with relapsed/refractory multiple myeloma who were heavily pretreated achieved high response rates with the allogeneic BCMA-targeted CAR T-cell therapy P-BCMA-ALLO1 without undergoing invasive apheresis or bridging therapy or experiencing manufacturing delays, according to interim data from an ongoing phase 1/1b trial (NCT04960579) presented during the 21st International Myeloma Society Annual Meeting.¹

Among the 23 heavily pretreated patients in the optimized lymphodepletion arm (arm C), the overall response rate (ORR) with P-BCMA-ALLO1 was 91%; ORRs were 100%, 86% and 86%, respectively, in BCMA-naive patients (n = 9), patients who had received 1 or more prior BCMA-targeting therapies (n = 14), and those who had previously received talquetamab-tgvs (Talvey) and/or at least 1 BCMA-targeted treatment (n = 7) in arm C. The ORR for arms S (n = 24), A (n = 19), and B (n = 10) were 21%, 42%, and 70%, respectively.

The median time to response for pooled arms A and B was 16 days (95% CI, 15-22), with a median duration of response (DOR) of 232 days (95% CI, 158-308) for patients in these arms with at least 6 months of follow-up. Notably, the median DOR for arm C could not be estimated at the time of data cutoff as the median follow-up was less than 3.5 months.

“We are especially impressed with the higher lymphodepletion overall response rates, even among the patient who had prior exposure to other CAR T-cell therapy or bispecific therapies,” presenting study author Bhagirathbhai Dholaria, MBBS, stated in an oral presentation of the data. Dholaria is an associate professor of medicine in the Division of Hematology and Oncology at Vanderbilt University Medical Center in Nashville, Tennessee.

P-BCMA-ALLO1 is an investigational non-viral, stem cell memory T cell–rich CAR-T cell product that improves antitumor activity and cellular expansion as well as prolongs T cell persistence.

On September 17, 2024, the agent received regenerative medicine advanced therapy (RMAT) designation from the FDA for the treatment of patients with relapsed/refractory multiple myeloma.² P-BCMA-ALLO1 was previously granted orphan drug designation for the same indication in March, 2024.³

As an “off-the-shelf” therapy, P-BCMA-ALLO1 could provide a novel therapeutic avenue to treat patients with rapidly progressing multiple myeloma who are ineligible for autologous therapies, Dholaria explained. He added that, “In United States, we are now in a post-BCMA era when it comes to relapsed/refractory myeloma, and this is an area [where] normal therapies are urgently needed.”¹

Study Overview

Bhagirathbhai Dholaria, MBBS

The open-label, multicenter, dose-escalation and expansion trial evaluated the efficacy and safety of P-BCMA-ALLO1 in patients with relapsed/refractory multiple myeloma with prior exposure to 3 or more lines of therapy, including a prior proteasome inhibitor, immunomodulatory drugs and anti-CD38 monoclonal antibody.¹ Prior BCMA-targeted therapy was allowed, and an ECOG performance status (PS) of 0 or 1 was required.

As of September 6, 2024, 72 patients were enrolled in the intent-to-treat (ITT) population and were treated across 4 study arms (S, A, B and C) with 30 mg/m2 of fludarabine combined with varying doses of cyclophosphamide and P-BCMA-ALLO1. In addition to the 30 mg/m2 dose of fludarabine, on Arm S, patients were given 300 mg/m2 of daily cyclophosphamide and P-BCMA-ALLO1 ranging from 0.25 to 6 x 106 cells/kg; on Arm A, participants were treated with 500 mg/m2 of cyclophosphamide and 2 x 106 cells/kg of P-BCMA-ALLO1; on Arm B, patients were treated with 1000 mg/m2 of cyclophosphamide and 2 x 106 cells/kg P-BCMA-ALLO1; and on Arm C, patients were given 750 mg/m2 of cyclophosphamide plus a P-BCMA-ALLO1 dose of 2 x 106 cells/kg.

The study’s primary end points were safety, identification of the maximum tolerated dose, and recommended phase 2 dose. Key secondary end points included anti-myeloma activity and selection of the optimal cell dose or lymphodepletion regimen.

In the ITT population, the median age for all patients was 67 years (range, 33-85); within arm C, the median age was 61 years (range, 39-76). The majority of patients in these respective populations were female (54%; 52%), had an ECOG PS of 1 (71%; 62%), were White (67%; 62%), and had high-risk cytogenetic (69%: 62%). Extramedullary disease was present in 26% of patients in the ITT population and 38% of patients in arm C. The time since diagnosis was 5.6 years (range, 0.9-19.1) and 5.1 years (range, 1.0-15.1) in these respective populations.

Patients in both the ITT population and arm C were heavily pretreated, with a median number of 6 prior regimens (range, 2-22; range, 2-14). BCMA-and/or GPRC5D-directed therapy was previously administered to 43% of patients in the ITT population and 62% of patients in arm C. A total of 58% and 67%, respectively, underwent prior autologous stem cell transplantation.

Notably, all patients enrolled onto the study as of the data cutoff underwent lymphodepletion and infusion with P-BCMA-ALLO1. No patients required anti-myeloma bridging therapy or prophylaxis with steroids or tocilizumab. The median time from enrollment to the start of study treatment was 1 day, indicating rapid and convenient CAR T-cell administration without the need for apheresis.

Based on cellular kinetics, safety and efficacy, investigators determined that arm C was the optimized lymphodepletion arm. Accordingly, the dose-expansion portion of the trial is currently enrolling patients using the lymphodepletion regimen in arm C across 2 dosing cohorts, and dose optimization in arm C is ongoing.

Safety Profile

Regarding safety, P-BCMA-ALLO1 was considered well-tolerated in all patients (n = 77). Patients did not report any dose-limiting toxicities at dose level 6 x 106 of P-BCMA-ALLO1, grade 3 or higher cytokine release syndrome (CRS), or immune effector cell neurotoxicity syndrome (ICANS), graft vs host disease at any dose, Parkinsonism, cranial neuropathies, or hemophagocytic lymphohistiocytosis.

The overall incidence of CRS and ICANS was 27% and 7%, respectively. In arm C, grade 1/ 2 CRS was observed in 39% of patients, and 13% experienced grade 1/2 ICANS. The median time to onset for CRS was 7 days (range, 4-8); for ICANS, this was 4 days (range, 3-6). Notably, 82% of patients experienced rapid cytopenia recovery to grade 2 or lower by 30 days after infusion.

The incidence of infections was 48%, 30% of which were grade 1/2 and 17% of which were grade 3. The median days to onset for grade 1/2 infections was 11 (range, 4-36); for grade 3 infections the median time to onset was 27 days (range, 6-74).

Any-grade treatment-emergent adverse effects (TEAEs) occurred in 99% of patients, 86% of which were grade 3 or higher and 55% of which were treatment-related. Other TEAEs reported in at least 20% of all patients included neutropenia (any-grade, 68%; grade 3 or higher, 66%), leukopenia (62%; 61%), thrombocytopenia (52%; 33%), anemia (49%; 39%), fatigue (27%; 3%), hypokalemia, (26%; 3%), hypocalcemia (22%; 7%), constipation (22%; 0%), hypophosphatemia (21%; 3%), diarrhea (21%; 1%), and nausea (21%; 0%).

Grade 3 or higher TEAES were primarily associated with lymphodepletion and myeloma, and serious infections were infrequent.

Common treatment-related AEs included neutropenia (55%), leukopenia (36%), thrombocytopenia (18%), anemia (22%), fatigue (3%) and diarrhea (1%).

REFERENCES:

1. Dholaria B, Kocoglu M, 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).Presented at: 2024 International Myeloma Society Annual Meeting; September 25-28, 2024; Rio De Janeiro, Brazil. Abstract OA-04.

2. Poseida Therapeutics receives regenerative medicine advanced therapy (RMAT) designation from FDA for P-BCMA-ALLO1 to treat relapsed/refractory multiple myeloma. News release. Poseida Therapeutics. September 16, 2024. Accessed September 30, 2024. https://tinyurl.com/2s4hsfaa

2. Poseida Therapeutics announces FDA orphan drug designation granted to P-BCMA-ALLO1 for the treatment of multiple myeloma. News release. Poseida Therapeutics. March 13, 2024. Accessed September 30, 2024. https://tinyurl.com/4uzwu4jd