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)
Authors: Van De Donk Niels W.C.J. , Sidana Surbhi , Schecter Jordan M. , Jackson Carolyn Chang , Lendvai Nikoletta , De Braganca Kevin C , Slaughter Ana , Lonardi Carolina , Vlummens Philip , Varsos Helen , Corsale Christina , Madduri Deepu , Jadidi Shirin , Gu Junchen , Zhao Hao , Li Katherine , Lee Erin , Marquez Loreta , Zhao Man , Yeh Tzu-min , Chen Diana , Florendo Erika , Patel Nitin , Akram Muhammad , Gellego Perez-Larraya Jaime , Rodriguez Otero Paula 
Published: December 2023

Introduction: Cilta-cel is a dual-binding, BCMA-targeting CAR-T cell therapy that has shown high rates of deep and durable response in patients (pts) with relapsed/refractory multiple myeloma (RRMM), and significantly prolonged PFS vs SOC in pts with lenalidomide-refractory MM after 1-3 prior lines of therapy (LOT; HR, 0.26) in the phase 3 CARTITUDE-4 trial. CAR-T therapies are associated with AEs related to immune activation, including neurologic toxicities (Gonzalez Castro. Neuro-Oncol Pract. 2020). Here, we describe the clinical experience with presentation and management of cranial neuropathy (CNP) in pts treated with cilta-cel in the CARTITUDE-1, CARTITUDE-2 Cohorts A, B, and C, and CARTITUDE-4 studies.

Methods: CARTITUDE-1 and CARTITUDE-2 Cohort C pts had ≥3 prior LOT, incl PIs, IMiDs, and anti-CD38 mAbs, or were double-refractory to PI and IMiD; CARTITUDE-2 Cohort C pts also had non-cellular anti-BCMA therapy. CARTITUDE-2 Cohort B pts relapsed within 12 months of initial therapy. CARTITUDE-2 Cohort A and CARTITUDE-4 pts had 1-3 prior LOT, incl PI and IMiD, and were lenalidomide-refractory. After apheresis, pts received bridging therapy, then 1 cilta-cel infusion (target dose 0.75×10 6 CAR+ viable T cells/kg) 5-7 days (d) after lymphodepletion. Pts presenting with signs/symptoms of cranial nerve impairment commonly underwent a diagnostic workup that included CSF analysis and brain MRI at investigator discretion. Correlative data were available for pts in CARTITUDE-4: cilta-cel levels and T cell memory phenotypes in peripheral blood were assessed by flow cytometry, and serum cytokines were measured using multiplex sandwich immunoassays on the Meso Scale Discovery platform.

Results: Of the 332 pts infused with cilta-cel as study treatment in CARTITUDE-1, CARTITUDE-2 (Cohorts A, B, and C), and CARTITUDE-4, 21 (6.3%) developed CNP (TABLE); most cases were grade (gr) 2 (n=3 gr 3). 6 pts had CNP that affected both sides; most unilateral impairments were left-sided. Median time to onset was 22 d (range 17-101; 81% had onset on d 22 +/- 5). Cranial nerve (CN) VII was involved in all pts; 2 pts had additional CNs involved (1 CN III [gr 3], 2 CN V [gr 3]). Twelve pts had concurrent neurologic symptoms/neurotoxicities (headache, n=7; n=1 each for dysgeusia, parosmia, restlessness, peripheral sensory neuropathy, polyneuropathy, amnesia, aphasia, agitation, depressed level of consciousness).

Clinical characteristics of pts with or without CNP were comparable. In the 21 pts with CNP, median age was 64 years; 81% were male; at baseline, 1 pt had high disease burden (BM 95% plasma cells), 4 had plasmacytomas (1 bone-based); 1 pt had ISS stage III. Most pts responded to bridging therapy. Six pts had an infection after cilta-cel infusion and prior to CNP onset (bacterial, n=5; CMV, n=2; both, n=1). CRS rate was comparable between pts with vs without CNP. 90% of pts with CNP had preceding CRS (all gr 1/2; median onset, d 7; median duration, 3 d); 13 received tocilizumab for CRS. One pt had preceding gr 2 ICANS; no pts had movement/neurocognitive TEAEs (MNT) at any time.

CSF analysis and brain MRI were performed in 14 and 17 pts, respectively. No evidence of infectious or malignant etiology was identified in any of these cases; MRI showed facial nerve enhancement in 7 pts, in whom there were no other significant findings. Most CNP cases were treated with corticosteroids for median 13 d. CNP resolved in 19/21 pts 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 (C max) and greater exposure to CAR+ T cells (AUC 0-CNP onset) than those without CNP (FIGURE). Pts with CNP had a trend toward higher peak concentration and exposure level (AUC 0-CNP onset) of IL-6, IL-10, and IL-2Rα, but not in IFNγ. The differentiation pattern of memory T cells from apheresis to the time of peak CAR+ T expansion (T max) was comparable in pts with vs without CNP; CAR+ T cells at T max were dominant with central memory T cells in both groups.

Conclusions:Ptstreated with CAR-T cells, including cilta-cel, may experience CNP.The pathogenesis of the events in these 3 studies was unknown/idiopathic, but it is important to rule out etiology of infection or MM progression. Most cases were low-grade and resolved with a limited course of corticosteroids. CNP in CARTITUDE-4 was associated with higher exposure to CAR-T cells before onset, but no predictive clinical factors have been established.