Abstract Introduction: BCMA-directed CAR-T cell 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%. Notably, cilta-cel conferred a median progression-free survival (PFS) of 34.9 months and a 27-month overall survival (OS) of 70.4%. Despite this, relapse after BCMA CAR-T occurs in most responders and remains a major clinical challenge. Among various salvage therapies being explored, repeat BCMA CAR-T therapy represents a promising approach. However, there is limited data on the efficacy and safety of a second BCMA CAR-T therapy. We identified 9 patients treated with cilta-cel after a prior BCMA CAR-T cell with 7 achieving a durable response. Here we report their clinical characteristics, outcomes, and an exploratory analysis of serum biomarkers of response. Method: We identified a cohort of 9 patients with RRMM who received a BCMA CAR-T at our institution between 2019-2022, followed by a second BCMA CAR-T cell therapy using cilta-cel at the time of a later relapse. We assessed patient outcomes including PFS, OS and toxicity profile following a second CAR-T with cilta-cel. All patients had a follow up of at least 6 months after cilta-cel. Treatment responses were defined according to the International Myeloma Working Group. We further examined the serum proteome of a subset of patients at three time points (day 0, day 28 and 6 months) after cilta-cel infusion. We analyzed proteins differentially expressed between responders (relapse 6 months) and non-responders (relapse 6 months) to identify putative biomarkers of response to a second BCMA CAR-T cell therapy. Results: Patients had a median age of 67 (42-81) at the time of last follow-up. Three patients had high risk disease based on cytogenetics. One patient had an acquired TP53 variant. Prior to receiving cilta-cel, patients had received a median of 8 (range 5-11) lines of treatment including the first CAR-T therapy. For the first CAR-T cell therapy, 4 patients received an investigational BCMA-directed CAR-T at the recommended doses of the product, and 5 patients received ide-cel. The time between CAR-T therapies ranged from 7.5-60 months, with all patients receiving at least 1 and up to 6 lines of treatment including bridging therapy. The overall response rate to the first CAR-T was 88% with 6 patients achieving ≥ VGPR (n=3 VGPR; n= 2 CR; n= 1 sCR) and 2 patients achieving a partial response. The median PFS was 17.1 months (95% CI 10-NR). At a median follow-up of 26.9 months (6.0-35.9 months) after cilta-cel 7 out of 9 patients had achieved a response (n=3 CR; n=3 VGPR; n=1 PR) with a median PFS of 31 months (95% CI 9.4-NR) and a 24-month PFS of 62%. Refractory disease was observed in two patients; notably, one had also exhibited resistance to the initial CAR-T treatment. The 24-month and 30-month OS rate was 100% and 80%, respectively. Analysis of the serum proteome in 6 patients at the time of receiving cilta-cel revealed differentially expressed proteins associated with clinical outcome, enriched in specific immune regulatory and cell adhesion pathways. Grade ≥2 cytokine-release syndrome after cilta-cel was seen in 4 out of 9 patients (n=3 G2; n=1 G3). No ICANS was seen. One patient developed atypical, delayed neurotoxicity manifesting as Guillain-Barré syndrome and cranial nerve palsy. None developed movement and neurocognitive adverse events. Early (90 days) hematologic toxicities were seen in all patients. In patients with a response, prolonged (90 days) grade 3 neutropenia was seen in 1 and thrombocytopenia in 3 patients. Severe hypogammaglobulinemia was seen in 1 patient in the first 6 months after cilta-cel. Conclusion: We provide data demonstrating the efficacy and safety of a second BCMA-directed CAR-T therapy with cilta-cel in RRMM, especially in patients previously responsive to a similar CAR-T product. Our findings also put forth intriguing and testable hypotheses for identifying potential immunologic and serum biomarkers of response to this treatment approach. As multiple BCMA CAR-T cell therapies are being explored in earlier stages of disease it is important to know whether subsequent treatment with a different BCMA CAR-T product can prove effective. This work highlights the need to better understand sequencing of these agents and further expand their use in clinical practice.
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