To characterize clinical phenotypes and immune mechanisms in patients with non-Immune Effector Cell-Associated Neurotoxicity Syndrome (non-ICANS) neurotoxicity following BCMA-directed CAR T-cell therapy (BCMA CAR-T).

BCMA CAR-T has transformed the treatment of multiple myeloma (MM). However, neurological complications beyond classical ICANS remain poorly understood. 

We evaluated patients with MM treated with ciltacabtagene autoleucel (cilta-cel) or idecabtagene vicleucel for non-ICANS neurotoxicity, including cases of movement and neurocognitive treatment-emergent adverse events (MNT), neuropathy (NEU), and encephalopathy. Blood and CSF immune profiles were analyzed using Olink^® discovery proteomics and flow cytometry.

22/191 patients (11.5%; all following cilta-cel; median age, 65; 18 males) were identified, including 8, 13, and 1 MNT, NEU, and encephalopathy case(s), respectively. Absolute lymphocyte count (ALC) >3×10³ cells/µL between day +7-14 strongly predicted non-ICANS neurotoxicity (OR 7.1, p<0.001). ALC was substantially higher in MNT versus NEU, even 3 months after CAR-T (p=0.031). CSF pleocytosis with CAR-T cell predominance was common in MNT but not NEU (median cell count, 172/µL vs. 1/µL, p=0.013). Serum and CSF proteomics showed evidence of enhanced cytotoxicity, T-cell activation, and apoptosis in MNT versus NEU. Longitudinal CAR-T cell profiling in an MNT case revealed a memory precursor effector cell-like (MPEC-like) phenotype not observed in NEU. Despite immunosuppression, one MNT patient died and all others experienced neurological sequelae, while 9/13 NEU patients achieved complete recovery.

Non-ICANS neurotoxicity is associated with high CAR-T cell expansion. While NEU shows good recovery over time, CSF evidence of cytotoxicity and cell death supports CAR-T-cell-mediated neuronal injury as a mechanism of MNT.