The phase 1/2 PRIME clinical trial is ongoing to assess the safety and efficacy of P-BCMA-101, an autologous B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy consisting of a large proportion of desirable stem-cell memory T-cells (Tscm), in patients with relapsed/refractory multiple myeloma (RRMM). Patients were eligible for inclusion if they had been exposed to ≥3 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or if they were double refractory. Through June 30, 2020, P-BCMA-101 had been administered to 53 patients, 67% of whom were male. The median age was 60 years and patients had received a median of 8 prior regimens, with 100% having received PIs and an IMiD, 93% having received daratumumab, and 67% having received autologous stem-cell transplant.
Initially, the PRIME study was a dose-escalation trial of single infusions of P-BCMA-101, but novel therapeutic strategies have since been incorporated. After T-cell harvest, patients receive a standard 3-day cyclophosphamide/fludarabine lymphodepletion regimen, followed by intravenous administration of manufactured P-BCMA-101. A median dose of 0.75 x 106 cells/kg was administered as follows: P-BCMA-101 infusions in biweekly cycles; the addition of rituximab (to prevent anti-CAR antibody development) or lenalidomide (to increase T-cell robustness) pre- and postlymphodepletion; and single administration.
A favorable safety profile was observed across the study, likely because of the gradual expansion of the Tscm cells (2-3 weeks vs 3-7 days for most CAR T-cells). Of 17% of patients who experienced cytokine release syndrome (CRS), none was grade 3, whereas 2 cases of neurotoxicity were reported. Similarly, peak elevations of CRS markers were modest; tocilizumab was required in only 4 patients. Other common adverse events included cytopenias/infections and constitutional symptoms (76% of patients experienced grade ≥3 neutropenia, 30% of patients experienced thrombocytopenia, and 30% of patients experienced anemia). No patient deaths, dose-limiting toxicities, or other unanticipated toxicities related to P-BCMA-101 were observed. Based on these results, an amended protocol allowed fully outpatient CAR T-cell administration. Circulating P-BCMA-101 cells were detected by polymerase chain reaction in blood, peaking at 2 to 3 weeks after infusion and remaining detectable for up to 1.5 years (ongoing at the time of last follow-up). Response correlated with the maximum serum concentration and area under the curve of cell expansion, but not with dose administered.
An overall response rate (ORR) of 67% was observed for 31 evaluable patients treated with single administration during the initial dose escalation. A clear dose-response curve was not observed, but indications of better response were seen at lower doses; therefore, further cohorts focused on lower doses. Of 4 patients subsequently treated with cyclic administration, rituximab, lenalidomide, or single administration at the lowest dose (all received P-BCMA-101 within approximately 2 months before data cutoff), all responded rapidly (100% ORR) and responses are ongoing. The safety profile for these 4 patients was similar to the overall population, with minimal CRS.
High response rates and low toxicity were observed in this phase 1/2 study of P-BCMA-101 CAR T-cells in patients with RRMM. Modifications to manufacturing seem to have improved efficacy in this ongoing study, whereas low doses with favorable safety allow outpatient administration.
Abstract 134. ASH 2020. December 5, 2020. Phase 1/2 Study of the Safety and Response of P-BCMA-101 CAR-T Cells in Patients with Relapsed/Refractory (r/r) Multiple Myeloma (MM) (PRIME) with Novel Therapeutic Strategies.