BCMA-directed CAR T-cell therapy in patients with multiple myeloma and CNS involvement

Abstract

We investigated B-cell maturation antigen-directed chimeric antigen receptor T-cell (CAR-T) therapy in patients with relapsed or refractory multiple myeloma (MM) and central nervous system (CNS) involvement. Ten patients received either idecabtagene vicleucel (n = 6) or ciltacabtagene autoleucel (n = 4), where brain/cranial nerve and/or spinal cord involvement/leptomeningeal disease were evident on either magnetic resonance imaging (100%) and/or cerebrospinal fluid (40%). Eight patients had their CNS diagnosis before CAR-T therapy, and two were diagnosed within 14 days post-infusion. Seven received CNS-directed therapy during bridging before CAR-T therapy. There were no excess toxicities: no cytokine release syndrome grade ≥3; 10% immune effector cell-associated neurotoxicity syndrome (ICANS) grade 3; and no ICANS grade 4. Two patients experienced delayed but treatable neurotoxicity, with no reported parkinsonian side effects. The best overall response rate was 80% (≥70% very good partial response) and a 100% CNS response. With a median follow-up of 381 days, patients with CNS myeloma diagnosed before CAR-T therapy (n = 8) had a median overall survival and progression-free survival (PFS) of 13.3 and 6.3 months, respectively. Best outcomes were observed in 4 patients who had a response to bridging therapy, suggesting that optimizing pre-CAR-T therapy may be key for improved outcomes. Our study suggests that CAR-T therapy in patients with CNS MM is safe and feasible, and screening for CNS involvement before CAR-T therapy could be warranted in high-risk patients. The excellent initial response but relatively short PFS suggests consideration for post-CAR-T maintenance. Larger studies are needed to confirm these findings.

Graphical abstract

Figure 1.

BCMA CAR T-cell therapy recipients with CRS and ICANS. CRS grade 1 and 2 were 60% and 20%, respectively. No grade 3 to 4 CRS was observed. ICANS grade 1 and 3 were 20% and 10%, respectively, all of which reversed. No grade 4 ICANS was observed.

Figure 2.

PFS and OS for patients with MM with CNS involvement treated with CAR T-cell therapy. (A) PFS analysis of patients diagnosed with CNS myeloma before CAR T-cell therapy (n = 8): the median PFS was 6.3 months (95% confidence interval [CI], 1.9-10.7), and PFS at 6 months was 62.5%. PFS was not calculable for the 2 patients who were diagnosed with CNS myeloma after CAR T-cell therapy, so they were excluded from this analysis. (B) OS analysis. (Bi) OS of patients diagnosed with CNS myeloma before CAR T-cell therapy (n = 8): the median OS was 13.3 months; OS at 6 months and 1 year was 87.5% and 75%, respectively. (Bii) OS of patients with CNS myeloma diagnosed before CAR T-cell therapy or after CAR T-cell therapy (n = 10): the median OS was 13.5 months (95% CI, 6.0-21.1); OS at 6 months and 1 year was 90% and 70%, respectively.