This retrospective real-world study of two US databases reports low rates of new-onset non-ICANS neurologic events after cilta-cel in RRMM patients—parkinsonism occurred in about 1% of patients with ≥4 prior lines of therapy and cranial nerve palsies in ~1–5%, with no parkinsonism seen in the 1–3…

While not mechanistic, the finding that CAR-T therapy can produce rare parkinsonism cases points to immune-mediated or neuroinflammatory routes to parkinsonism and is useful for surveillance and hypothesis generation for translational studies exploring inflammation-driven or iatrogenic PD…

INTRODUCTION: Ciltacabtagene autoleucel (cilta-cel) is a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy approved in the USA for relapsed or refractory multiple myeloma (RRMM) as early as following first relapse, based on pivotal CARTITUDE-1 (≥ 4 prior lines of therapy [LOT]) and CARTITUDE-4 (1-3 prior LOT) trials, which reported high response rates and prolonged survival. In CARTITUDE-1 and CARTITUDE-4, rates of all-grade parkinsonism were 6% and < 1%, respectively, while rates of cranial nerve palsy were 3% and 9%, respectively. This study aimed to characterize new-onset nonimmune effector cell-associated neurotoxicity syndrome (non-ICANS) neurologic events (NEs) among patients with RRMM receiving cilta-cel after 1-3 or ≥ 4 prior LOT. METHODS: This retrospective study used two real-world data sources: open and closed insurance claims from the Komodo Research Database (February 2021-November 2024), and electronic medical records from Loopback Analytics (February 2021-December 2024). New-onset non-ICANS NEs, including parkinsonism, cranial nerve palsy, and Guillain-Barré syndrome, were assessed from cilta-cel infusion until the end of clinical activity, death, or end of data availability. Analyses were conducted separately by database and stratified by LOT. RESULTS: In patients with 1-3 prior LOT (Komodo: 124; Loopback: 79), over a median follow-up of 3.4-3.5 months, cranial nerve palsy occurred in 5.6% and 5.1% in Komodo and Loopback, respectively, with no parkinsonism or Guillain-Barré syndrome observed. In patients with ≥ 4 prior LOT (Komodo: 524; Loopback: 191), over a median follow-up of 13.2-13.3 months, parkinsonism occurred in 1.0% in both databases, cranial nerve palsy in 4.6% and 1.0%, and Guillain-Barré syndrome in 0.2% and 0.5% in Komodo and Loopback, respectively. CONCLUSIONS: In this real-world study, rates of non-ICANS NEs post-cilta-cel infusion across two databases were comparable to or lower than prior trials or real-world studies, reinforcing the favorable risk-benefit profile of cilta-cel in routine practice. Graphical Abstract available for this article.