Clinical Experience with Cranial Nerve Impairment in the CARTITUDE-1, CARTITUDE-2 Cohorts A, B, and C, and Cartitude-4 Studies of Ciltacabtagene Autoleucel (Cilta-cel)

Background Cilta-cel, a BCMA-targeting CAR-T cell therapy, has shown high rates of deep and durable response in patients (pts) with relapsed/refractory multiple myeloma (RRMM). We describe presentation and management of cranial neuropathy (CNP) in pts treated with cilta-cel across the CARTITUDE-1, -2, and -4 trials. Methods Enrollment criteria and methods for the CARTITUDE trials have been previously reported. Pts presenting with signs of cranial nerve (CN) impairment commonly underwent a diagnostic workup including cerebrospinal fluid (CSF) analysis and brain MRI at investigator discretion. Correlative data were available for pts in CARTITUDE-4 to relate CNP to treatment factors. Results Of N=332 receiving cilta-cel across trials, 21 (6.3%) developed CNP; most cases were grade (gr) 2 (n=3 gr 3). 6 pts had CNP on both sides; most unilateral impairments were left-sided. Median time to onset was 22 days (d; range, 17-101). All pts had CN VII involvement; 2 had additional CNs involved (1 CN III [gr 3], 2 CN V [gr 3]). 12 pts had concurrent neurologic symptoms/neurotoxicities.Clinical characteristics of pts with or without CNP were comparable. In n=21 with CNP, median age was 64 years; 81% were male; at baseline, 1 pt had high disease burden (bone marrow 95% plasma cells), 4 had plasmacytomas (1 bone based); 1 pt had ISS stage III. Most responded to bridging therapy. 6 pts had an infection before CNP onset after cilta-cel infusion (bacterial, n=5; cytomegalovirus, n=2; both, n=1); CRS rate was comparable between groups. Of pts with CNP, 90% had preceding CRS (all gr 1/2; median onset, d 7; median duration, 3 d); 13 received tocilizumab for CRS. 1 pt had preceding gr 2 ICANS; none had movement/neurocognitive treatment-related adverse events at any time.Brain MRI and CSF analysis in 14 and 17 pts, respectively, demonstrated no evidence of infectiousor malignant etiology. Facial nerve enhancement was shown with MRI in 7 pts. Most cases were treated with corticosteroids for median 13 d. In 19/21 pts, CNP resolved within median 66 d, including the 3 pts with gr-3 CNP.In CARTITUDE-4, pts with CNP had significantly higher levels of CAR+ T-cell expansion and greater exposure to CAR+ T cells (AUC0-CNP onset) than those without (Figure). Pts with CNP trended toward higher peak concentration and exposure level (AUC0-CNP onset) of IL-6, IL-10, and IL-2Rα, but not in IFNγ. Differentiation pattern of memory T cells from apheresis to peak CAR+ T expansion (Tmax) was comparable; CAR+ T cells at Tmax were dominant with central memory T cells in both groups. Conclusions Pts treated with CAR-T may experience CNP of unknown/idiopathic origin, but infection or MM progression should be ruled out. Most cases were low grade and resolved with corticosteroids. Higher exposure to CAR-T cells before onset in CARTITUDE-4 was associated with CNP; no predictive clinical factors have been established.