Incidence and management of CAR-T neurotoxicity in patients with multiple myeloma treated with ciltacabtagene autoleucel in CARTITUDE studies

Abstract

Chimeric antigen receptor (CAR) T-cell therapies are highly effective for multiple myeloma (MM) but their impressive efficacy is associated with treatment-related neurotoxicities in some patients. In CARTITUDE-1, 5% of patients with MM reported movement and neurocognitive treatment-emergent adverse events (MNTs) with ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen-targeted CAR T-cell therapy. We assessed the associated factors for MNTs in CARTITUDE-1. Based on common features, patients who experienced MNTs were characterized by the presence of a combination of at least two variables: high tumor burden, grade ≥2 cytokine release syndrome (CRS) or any grade immune effector cell-associated neurotoxicity syndrome (ICANS) after cilta-cel infusion, and high CAR T-cell expansion/persistence. Strategies were implemented across the cilta-cel development program to monitor and manage patients with MNTs, including enhanced bridging therapy to reduce baseline tumor burden, early aggressive treatment of CRS and ICANS, handwriting assessments for early symptom detection, and extended monitoring/reporting time for neurotoxicity beyond 100 days post-infusion. After successful implementation of these strategies, the incidence of MNTs was reduced from 5% to <1% across the cilta-cel program, supporting its favorable benefit–risk profile for treatment of MM.

Toxicity management strategies for next-generation novel therapeutics in multiple myeloma

“…Perhaps uniquely, five patients reportedly developed movement disorders, neurocognitive events, and personality changes MNT after recovery from CRS and/or typical ICANS. 75 Common features of this group included high tumor burden, grade ⩾ 2 CRS, ICANS, and high CAR-T cell expansion/persistence. Lab features included higher absolute lymphocyte counts, absolute CD4+ T-cells and CAR-T cell persistence at days 14, 21, and 28.…”

“…Those receiving Cilta-cel and who develop MNT-associated symptoms may be less responsive to steroids, however, hence early stratification of these patients to receive other cytokine therapy beyond steroids/tocilizumab, appropriate full neurologic and infectious evaluation, including CSF exam and seizure prophylaxis are recommended. 75 …”

Evaluating the Therapeutic Potential of Idecabtagene Vicleucel in the Treatment of Multiple Myeloma: Evidence to Date

“… 77 , 87 , 88 Late-onset movement disorders, cognitive impairment and personality changes have also been described, particularly in patients with high tumor burden, coexisting CRS (grade ≥2) or ICANS (any grade), and high CAR-T expansion. 89 Rare instances of fatal cerebral edema have also been described. 90 , 91 It is thought to result from an overproduction of various cytokines, including IL-2, IL-6, IL-10, IL-15, IFN-γ, TNF-α, GM-CSF, and MCP-1, as well as endothelial cell dysfunction and disruption of the blood–brain barrier (BBB).…”

T-Cell-Based Cellular Immunotherapy of Multiple Myeloma: Current Developments

“…Grade 2 or higher ICANS are treated with corticosteroids [ 55 , 56 ]. Following treatment with ciltacabtagene autoleucel in CARTITUDE-1, 5% of patients experienced neurotoxicities described as movement and neurocognitive treatment-emergent adverse events (MNTs) [ 59 ]. These MNTs were categorized into movement disorders, cognitive impairments and personality changes and had median onset of 17 days (range 3–94) after recovery of CRS and ICANS [ 59 ].…”

“…Following treatment with ciltacabtagene autoleucel in CARTITUDE-1, 5% of patients experienced neurotoxicities described as movement and neurocognitive treatment-emergent adverse events (MNTs) [ 59 ]. These MNTs were categorized into movement disorders, cognitive impairments and personality changes and had median onset of 17 days (range 3–94) after recovery of CRS and ICANS [ 59 ]. One of these cases of MNTs included a patient that developed worsening parkinsonism approximately 3 months following cilta-cel infusion.…”