Incidence, mitigation, and management of neurologic adverse events in patients with multiple myeloma (MM) treated with ciltacabtagene autoleucel (cilta-cel) in CARTITUDE-2.
Authors: Einsele Hermann , Parekh Samir S. , Madduri Deepu , Santomasso Bianca , Gállego Pérez De Larraya Jaime , van de Donk Niels W.C.J. , Arnulf Bertrand , Mateos Maria-Victoria , De Braganca Kevin C. , Varsos Helen , Carrasco-Alfonso Marlene , Akram Muhammad , Lendvai Nikoletta , Jackson Carolyn Chang , Olyslager Yunsi , Zudaire Enrique , Li Claire , Geng Dong , Jakubowiak Andrzej J. , Cohen Adam D. 
Published: June 2021

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Background: Cilta-cel (JNJ-68284528) is a chimeric antigen receptor T (CAR-T)-cell therapy with 2 BCMA-targeting, single-domain antibodies designed to confer high avidity binding. CARTITUDE-2 (NCT04133636) is a phase 2, multicohort, open-label study assessing the efficacy and safety of cilta-cel in patients (pts) with MM in various clinical settings. Here, we describe the mitigation and management strategies implemented to identify and reduce the risk for neurologic adverse events (AEs) in Cohort A pts (progressive MM after 1−3 prior lines of therapy). Methods: Eligible pts (≥18 years of age) had MM per IMWG criteria, measurable disease, ECOG ≤1, progressive disease after 1−3 prior lines of therapy (including a PI and IMiD) and were lenalidomide refractory (no prior BCMA-targeting agent). Cilta-cel (0.75×106 [range 0.5–1.0×106] CAR+ viable T cells/kg) was given as a single infusion 5–7 days after start of lymphodepletion (cyclophosphamide 300 mg/m2 + fludarabine 30 mg/m2 daily for 3 days). Monitoring and mitigation strategies for neurologic AEs include providing more effective bridging therapy to reduce tumor burden prior to lymphodepletion, frequent assessment of CAR-T-related ICANS using the ICE tool, regular handwriting assessments to detect micrographia, and neuroimaging (brain MRI) and EEG for pts with prior neurologic disease. Management strategies include evaluating infectious and paraneoplastic etiologies upon observation of ICANS ≥Grade (gr) 1, administration of tocilizumab (if concurrent CRS, all gr of ICANS) and/or dexamethasone (gr 2/3) or methylprednisolone (gr 4). ICANS and CRS were graded by ASTCT criteria; neurotoxicities not classified as ICANS were graded per CTCAE Version 5.0. Results: As of 15 Jan 2021 (median follow-up: 5.8 months [range: 2.5–9.8 months]), 20 pts in Cohort A received cilta-cel. Median age was 60 years (range: 38–75); 65% were male. Neurotoxicities occurred in 4 pts (20%). Three pts had ICANS (gr 1/2); median time to onset of symptoms was 8 days (range: 7–11) and median duration was 2 days (range: 1–2). Two of the 3 pts received supportive measures to treat ICANS, including levetiracetam and steroids; all 3 had concurrent CRS and all recovered. One pt developed isolated facial paralysis (gr 2) on Day 29 after cilta-cel infusion, and recovered 51 days after the onset of event following treatment with dexamethasone for 28 days. No movement or neurocognitive disorders were reported. Conclusions: Neurologic AEs were generally manageable in pts with MM following treatment with cilta-cel. With a median of 5.8 months of follow-up, there were no movement or neurocognitive disorders in pts from Cohort A. These results suggest that early detection and management of neurologic AEs can lead to better treatment outcomes. Clinical trial information: NCT04133636.