Evaluating BCMA-Targeting CAR T-Cell Therapy bb21217 in Relapsed/Refractory Myeloma

In a phase I trial, the B-cell maturation antigen (BCMA)–targeting chimeric antigen receptor (CAR) T-cell therapy bb21217 demonstrated “encouraging” efficacy in patients with relapsed/refractory multiple myeloma, with adverse events (AEs) consistent with other CAR T-cell therapies. Updates from this trial were presented at the 2021 American Society of Hematology Annual Meeting by Noopur Raje, MD.

bb21217 uses the same CAR molecule as idecabtagene vicleucel (ide-cel), which is an FDA-approved CAR T-cell therapy for the treatment of patients with relapsed/refractory myeloma after four or more previous lines of therapy. During ex vivo culture, a PI3K inhibitor is added to the bb21217 CAR molecule.

This treatment was tested in the multicenter phase I CRB-402 trial, which enrolled patients with relapsed/refractory myeloma who had either received ≥3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who were double-refractory to both drug classes. During the dose-expansion arm, patients were required to also have prior exposure to an anti-CD38 antibody and to be refractory to their last line of therapy.

Prior to CAR T-cell infusion, patients underwent lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2). Patients received a single infusion of bb21217 at doses of 150, 300 or 450×106 CAR T cells/kg (150, n =12; 300, n = 14; 450, n = 46). Median follow-up was nine months.

As of data cut-off, 72 patients had received treatment. Patients had a median of six prior lines of therapy (range = 3-17), including 49 (68%) who had triple-refractory disease. Three-quarters of patients developed cytokine release syndrome (CRS). While most cases were grade 1-2 (n = 51), one patient experienced grade 3 CRS and two patients died from CRS-related causes. Median time to first onset of CRS was two days. In addition, 15% of patients developed neurotoxicity after a median of seven days.

Thirty of 37 patients (81%) with six-month follow-up had detectable CAR+ T cells; at one year post-infusion, nine of 15 patients (60%) had CAR+ T cells.

Fifteen patients who achieved a complete response were evaluable for measurable residual disease (MRD) status. Fourteen of these patients were MRD-negative. According to an analysis of peripheral blood samples from 15 days post-infusion, patients with greater CD8+ CAR+ T cells expressing CD27 and CD28 had significantly longer durations of response compared with patients with lower levels of expression (p = 0.0024). “This suggests less differentiated, more proliferative CAR+ T cells at peak expansion are associated with prolonged disease response,” the authors noted.

“Adverse events [with bb21217] are consistent with known toxicities of CAR T-cell therapies,” the authors concluded, adding that efficacy results are also encouraging. “Patients with higher levels of proliferative, less differentiated memory like CAR+ T-cells at peak expansion are more likely to experience prolonged durations of response, continuing to support the hypothesis that the memory like T-cell phenotype associated with bb21217 results in prolonged duration of response.”