Poseida Therapeutics' P-BCMA-ALLO1, an allogeneic BCMA-directed CAR-T therapy, is showing promise in treating relapsed/refractory multiple myeloma (MM). Data from an ongoing phase 1/1b clinical trial (NCT04960579), presented at the 21st International Myeloma Society Annual Meeting, reveal a high overall response rate (ORR) and a manageable safety profile, particularly with enhanced lymphodepletion regimens. This therapy addresses a critical need for patients who have failed or are ineligible for standard autologous CAR-T treatments.
Key Findings from the Phase 1/1b Trial
The trial included 72 heavily pretreated MM patients, half of whom had high-risk cytogenetics, and 43% had prior BCMA-targeted therapy or talquetamab. All patients received the P-BCMA-ALLO1 infusion. The primary endpoint was safety. No graft-versus-host disease was reported. Cytokine release syndrome (CRS) occurred in 27% of patients, mostly grade 1 or 2, with no grade 3 or higher events or neurotoxicity.
"Looking at the in vivo kinetics, we noticed that with higher lymphodepletion we noticed better in vivo expansion and persistence of P-BCMA-ALLO1. That actually correlated with the antimyeloma activity of this agent compared to the standard lymphodepletion, where overall response rate (ORR) was only 21%, " said Bhagirathbhai R. Dholaria, MD, an associate professor of medicine in malignant hematology & stem cell transplantation at Vanderbilt University Medical Center, and trial investigator.
Enhanced Lymphodepletion Improves Efficacy
The study explored different cell doses and lymphodepletion regimens. Enhanced lymphodepletion, particularly with cyclophosphamide at 750 mg/m2/day (Arm C), resulted in a 91% ORR. This arm is now selected for phase 1b expansion. In contrast, standard lymphodepletion showed an ORR of only 21%. These results suggest that optimizing lymphodepletion is crucial for P-BCMA-ALLO1's efficacy.
Addressing Unmet Needs in Multiple Myeloma
Despite advances in bispecific antibodies and CAR-T therapies, a significant unmet need remains for patients who have exhausted these options or are ineligible for autologous CAR-T therapy due to manufacturing delays or disease progression. Autologous CAR-T therapy can take 4-6 weeks from leukapheresis to cell infusion, a critical delay for high-risk patients. P-BCMA-ALLO1, as an allogeneic product, is readily available, eliminating the need for leukapheresis and bridging therapy.
Challenges and Future Directions
Early challenges included suboptimal expansion, persistence, and efficacy with standard lymphodepletion. However, dose escalation of cyclophosphamide, along with cell dose expansion, identified an optimal balance of safety and efficacy. Future research will focus on multiple cell dose infusions to improve the durability of responses, both in patients with and without prior BCMA-targeted therapies.
