Enhancing the Safety of Ciltacabtagene Autoleucel in Relapsed Multiple Myeloma (MM):Identification of Potentially Modifiable Risk-Factors Associated with Delayed Neurotoxicity and Non-Relapse Mortality

Introduction Ciltacabtagene autoleucel (cilta-cel) has shown high efficacy in relapsed MM, but further efforts are needed to mitigate non-ICANS delayed neurotoxicity (DNT) and non-relapse mortality (NRM). Identifying risk factors for DNT and NRM may aid risk mitigation and clinical decision making. Methods In this multi-center retrospective study from the US MM Immunotherapy Consortium, we evaluated 761 patients treated at 15 centers receiving standard of care cilta-cel for relapsed MM between May 2022 to December 2024. Risk factors for DNT, particularly Parkinsonism and NRM, were evaluated by univariable and multivariable analysis. NRM events post-disease progression were censored. Results The median age was 65 (range: 30-88) with median prior lines of therapy (pLoT) being 5 (range: 1-23). Cilta-cel was used in earlier relapse (1-3 pLoT) in 16% of patients. High-risk cytogenetics (del 17p, t(14;16), t(4;14)) were present in 39%, with extramedullary disease (EMD) in 27%, and R-ISS stage III in 18%. 86% patients received bridging therapy, with ≥ partial response seen in 33%; median follow-up was 10.1 months, response rate was 92%, and CR rate was 70%. DNT was seen in 10% of patients: Parkinsonism (2.9%, n=22), cranial nerve palsy (4.6%, n=35), other DNT (2.4%). Risk of DNT was higher in patients who did not respond to bridging therapy (Any DNT: 12% vs 6%; Parkinsonism: 5% vs 0.5%, p 3000/uL: 68% vs 14% (p 3000 vs ≤ 3000/uL: 12% vs 1%, p 2500 vs ≤ 2500uL: 9% vs 1%, p 3000/uL (OR: 12.7, p 3000/uL for Parkinsonism. Peak ALC could be a biomarker to identify patients for interventions. Effective bridging strategies are needed to decrease Parkinsonism and NRM risk with cilta-cel.