Use of Cilta-Cel CAR T Cells Following Previous Use of a BCMA-Directed CAR T-Cell Product in Heavily Treated Patients with Relapsed/Refractory Multiple Myeloma: A Single Institution Case Series

Background: BCMA-directed CAR T-cell (CAR T) therapy has demonstrated remarkable efficacy in patients with relapsed/refractory multiple myeloma (rrMM). Pivotal trials such as the KarMMa and CARTITUDE studies using ide-cel and cilta-cel respectively, have shown ORR of 73% and 98%, leading to FDA approval of these products. Notably, ide-cel conferred a median overall survival (OS) of 19.4 months with a median duration of response (DOR) of 10.7 months. Similarly, cilta-cel conferred a median progression-free survival (PFS) of 34.9 months and a 27-month OS rate of 70%. Although these and real-world outcomes are promising, relapse after BCMA CAR T therapy occurs in 27-64% of responders and remains a challenge. Various salvage treatments are being explored including repeat BCMA CAR T therapy with a different product.

Method: This is a case series of 5 patients with rrMM from a single institution treated with BCMA-directed CAR T therapy between 2019-2022, followed by a second BCMA-directed CAR T therapy using cilta-cel at the time of relapse. Here we report the response and toxicity profile following the second CAR T therapy.

Results: Patients had a median age of 64 (40-76). 2 out of 5 patients had high risk disease based on cytogenetics. Prior to the second CAR T therapy with cilta-cel, patients had received a median of 7 (5-8) lines of treatment including the first CAR T therapy. For the first CAR T therapy, 3 patients received an investigational BCMA-directed CAR T therapy at the recommended doses of the product and 2 patients received ide-cel. At the time of subsequent relapse all patients eventually received a second CAR T therapy with cilta-cel. Overall response rate to the first CAR T-cell therapy was 80% with 4 patients achieving ≥ VGPR (n=2 VGPR; n= 2 sCR), and 1 patient with refractory disease. The median DOR was 16 months (7-22 months) for responders and the median PFS was 10 months after the first CAR T therapy. The time between two CAR T therapies ranged from 8-38 months, with all patients receiving at least 1 and up to 2 lines of treatment including bridging therapy before cilta-cel. At the time of this report, with follow-up ranging from 3.1-11 months after the second CAR T therapy, 4 out of 5 patients had achieved a response (n=3 CR; n=1 PR) with a 6-month PFS of 75%. One patient had refractory disease and required subsequent treatment. Notably, this was the same patient who had been refractory to the previous CAR T cell therapy. Grade 2 cytokine-release syndrome after cilta-cel was seen in 1 out of 5 patients. Hematologic toxicities were seen in all patients with grade 3-4 neutropenia in 5, grade 3 anemia in 3 and grade 4 thrombocytopenia in 2 patients. Prolonged grade 3-4 thrombocytopenia was seen in 1 responder requiring transfusions and thrombopoietin analogs.

Conclusion: This case series demonstrates the early efficacy and safety of a second BCMA-directed CAR T therapy, specifically in patients previously responsive to similar BCMA-directed therapy. This highlights the need to better understand the clinical utility of this approach, especially with ide-cel and cilta-cel being explored in earlier stages of disease, and to delineate the heterogenous disease course and mechanism of resistance post BCMA-directed CAR T therapy.