Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma

Abstract

Background: Preclinical studies suggest that bb2121, a chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen (BCMA), has potential for the treatment of multiple myeloma.

Methods: In this phase 1 study involving patients with relapsed or refractory multiple myeloma, we administered bb2121 as a single infusion at doses of 50×10⁶, 150×10⁶, 450×10⁶, or 800×10⁶ CAR-positive (CAR+) T cells in the dose-escalation phase and 150×10⁶ to 450×10⁶ CAR+ T cells in the expansion phase. Patients had received at least three previous lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or were refractory to both drug classes. The primary end point was safety.

Results: Results for the first 33 consecutive patients who received a bb2121 infusion are reported. The data-cutoff date was 6.2 months after the last infusion date. Hematologic toxic effects were the most common events of grade 3 or higher, including neutropenia (in 85% of the patients), leukopenia (in 58%), anemia (in 45%), and thrombocytopenia (in 45%). A total of 25 patients (76%) had cytokine release syndrome, which was of grade 1 or 2 in 23 patients (70%) and grade 3 in 2 patients (6%). Neurologic toxic effects occurred in 14 patients (42%) and were of grade 1 or 2 in 13 patients (39%). One patient (3%) had a reversible grade 4 neurologic toxic effect. The objective response rate was 85%, including 15 patients (45%) with complete responses. Six of the 15 patients who had a complete response have had a relapse. The median progression-free survival was 11.8 months (95% confidence interval, 6.2 to 17.8). All 16 patients who had a response (partial response or better) and who could be evaluated for minimal residual disease (MRD) had MRD-negative status (≤10^-4 nucleated cells). CAR T-cell expansion was associated with responses, and CAR T cells persisted up to 1 year after the infusion.

Conclusions: We report the initial toxicity profile of a BCMA-directed cellular immunotherapy for patients with relapsed or refractory multiple myeloma. Antitumor activity was documented. (Funded by Bluebird Bio and Celgene; CRB-401 ClinicalTrials.gov number, NCT02658929.).

Figure 1.. Response to bb2121 Infusion.

Shown are the best responses among individual patients according to dose (50×10⁶ to 800×10⁶) of chimeric antigen receptor–positive (CAR+) T cells. All responses were confirmed and assessed according to the International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma (details on the criteria for disease response are provided in the Supplementary Appendix). Asterisks indicate patients with a high tumor burden (≥50% bone marrow plasma cells). MRD denotes minimal residual disease.

Figure 2.. Objective Response Rate and Progression-free Survival.

Panel A shows the rate of objective response (confirmed partial response or better) according to characteristics at baseline and during treatment. One patient who received 205×10⁶ CAR+ T cells is included in the 450×10⁶ dose group. Tumor burden was determined by the investigator, with a high burden defined as at least 50% CD138-positive cells by central laboratory analysis (first preference) or by local analysis of bone marrow plasma cells (second preference). In the absence of both, tumor burden was determined by the safety review committee. The cytogenetic risk profile was reported by investigators on the basis of local assessment of bone marrow obtained at screening. High risk was defined by the presence of the following abnormalities: del(17p), t(4;14), or t(14;16). AUC_0–28d denotes area under the curve during the first 28 days after the infusion, BCMA B-cell maturation antigen, and C_max maximum concentration. Panel B shows the rate of progression-free survival among patients who received less than 150×10⁶ CAR+ T cells and those who received at least 150×10⁶ CAR+ T cells. NE denotes could not be estimated.

Figure 3.. Correlation of CAR T-Cell Expansion with Dose and Response.

Panel A shows cellular kinetics as measured by median vector transgene copies per microgram of genomic DNA in CD3-enriched peripheral blood, according to dose group. Patients with a postbaseline vector transgene copy value were included. One patient received 205×10⁶ CAR+ T cells instead of the planned 450×10⁶ and was included in the 450×10⁶ dose group. I bars indicate 95% confidence intervals. LLOQ denotes lower limit of quantitation. Panel B shows the correlation between peak vector transgene copies per microgram of genomic DNA after infusion and the occurrence of tumor response in patients with at least 1 month of cellular kinetics data (33 patients). Horizontal lines indicate the medians. Circles indicate individual patients according to dose. The P value is based on a two-sided Wilcoxon rank-sum test.