Non-ICANS Neurologic Events in Patients With Relapsed/Refractory Multiple Myeloma Treated With Ciltacabtagene Autoleucel: Clinical Presentation and Management in CARTITUDE Studies.

B-cell maturation antigen-targeting chimeric antigen receptor (CAR) T-cell therapies have demonstrated remarkable efficacy in relapsed/refractory multiple myeloma (RRMM). However, emerging non-immune effector cell-associated neurotoxicity syndrome (non-ICANS) neurologic events-including cranial nerve palsy (CNP) and immune effector cell (IEC)-parkinsonism (also called movement and neurocognitive toxicity)-warrant vigilance. This review summarizes clinical findings from the CARTITUDE trials, which evaluated ciltacabtagene autoleucel in > 300 patients with RRMM. CNP occurred in 6.3% of patients, with a lower incidence in more heavily pretreated patients (≥ 3 prior lines of treatment [pLOT]: 3% vs. 1-3 pLOT: 9%). Median CNP onset was day 22 postinfusion; most cases were low grade, and 90% recovered completely. IEC-parkinsonism involves motor, cognitive, and personality changes; lower incidence was observed in less heavily pretreated patients (1% vs. 6%). Median time to onset was 56 days postinfusion; however, with greater awareness, IEC-parkinsonism may be recognized earlier. Emerging data suggest that early, aggressive intervention may result in better outcomes. High CAR-T cell expansion is associated with increased risk of CNP and IEC-parkinsonism. In the early postinfusion period (days 10-28), absolute lymphocyte count (ALC) strongly correlates with circulating CAR-T cell levels and could help identify patients at increased risk of neurologic events. Prophylactic interventions, including a short course of steroids, triggered by elevated ALC before symptom onset, are under investigation. Education of patients, caregivers (including family), local oncologists, and neurologists seeing patients outside CAR-T infusion centers is essential to facilitate timely recognition, referral to the CAR-T center, and management.