INCIDENCE, MITIGATION, AND MANAGEMENT OF NEUROLOGIC ADVERSE EVENTS IN PATIENTS WITH MULTIPLE MYELOMA TREATED WITH CILTACABTAGENE AUTOLEUCEL (CILTA-CEL) IN CARTITUDE-2

Abstract

Objective: Cilta-cel (JNJ-68284528) is a chimeric antigen receptor T cell (CAR-T) therapy with two B-cell maturation antigen (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 with multiple myeloma (MM) in various clinical settings. We describe the mitigation and management strategies implemented to identify and reduce the risk for neurologic adverse events in patients enrolled in Cohort A (progressive MM after 1-3 prior lines of therapy). Method and materials: Eligible patients (≥18 years of age) had MM per International Myeloma Working Group criteria, measurable disease, Eastern Cooperative Oncology Group performance status ≤1, progressive disease after 1-3 prior lines of therapy (including a proteasome inhibitor and an immunomodulatory drug), were lenalidomide refractory, and had not received BCMA-targeting agents. 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 adverse events include providing more effective bridging therapy to reduce tumor burden prior to lymphodepletion, frequent assessment of CAR-T related immune effector cellassociated neurotoxicity syndrome (ICANS) using the immune effector cellassociated encephalopathy tool, regular handwriting assessments to detect micrographia, and neuroimaging (brain MRI) and electroencephalogram for patients with prior neurologic disease. Management strategies include evaluating infectious and paraneoplastic etiologies upon observation of ICANS ≥grade 1, administration of tocilizumab (if concurrent with cytokine release syndrome [CRS], all grade of ICANS) and/or dexamethasone (grade 2/3) or methylprednisolone (grade 4). ICANS and CRS were graded by American Society for Transplantation and Cellular Therapy criteria; neurotoxicities not classified as ICANS were graded per common terminology criteria for adverse events, v5.0. Results: As of 15 Jan 2021 (median follow-up: 5.8 months [range: 2.5–9.8]), 20 patients in Cohort A received cilta-cel. Median age was 60 years (range: 38–75) and 65% were male. Neurotoxicities occurred in 4 patients (20%). Three patients had ICANS (grade 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 patients received supportive measures to treat ICANS, including levetiracetam and steroids; all 3 had concurrent CRS and all recovered. One patient developed isolated facial paralysis (grade 2) on Day 29 after cilta-cel infusion and recovered 51 days after onset following treatment with dexamethasone for 28 days. No movement or neurocognitive disorders were reported. Discussion: Early detection and management of neurologic adverse events can lead to better treatment outcomes. Conclusion: Neurologic adverse events were generally manageable in patients 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 patients from Cohort A.