Impact of autoimmune disease on outcomes after BCMA-directed CAR-T cell therapy for patients with multiple myeloma

Abstract

Abstract Background: Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) are BCMA-directed CAR T-cell therapies effective in relapsed/refractory multiple myeloma (RRMM), but cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) remain serious complications. Historically, patients with autoimmune disease (AD) were excluded from CAR-T trials. Concerns included impaired manufacturing, dysfunctional immune expansion, unregulated inflammation, and blood-brain barrier disruption. This study evaluates the impact of pre-existing AD on efficacy, survival, and toxicity of BCMA-directed CAR T cells in RRMM. Methods: A retrospective study was conducted at Moffitt Cancer Center to evaluate patients with RRMM who received ide-cel and cilta-cel between 2021 and 2024. Patients with clinically significant pre-existing AD defined as requiring medication management and/or immunosuppression for AD prior to CAR T-cell infusion were identified. Diagnoses included rheumatoid arthritis, Grave's disease, Sjogren's disease, scleroderma, psoriasis, Hashimoto's thyroiditis, autoimmune premature ovarian failure, immune-mediated colitis, immune-mediated hemolytic anemia, immune thrombocytopenic purpura, demyelinating polyneuropathy, Guillain-Barre syndrome, and polymyalgia rheumatica. The impact of AD on CRS, ICANS, PFS, and OS was evaluated. Additionally, associations with baseline biomarkers of inflammation and prognostic scores of comorbidity collected prior to lymphodepletion, including Sorror score, Endothelial Activation and Stress Index (EASIX), mEASIX, LDH, ferritin, CRP, and absolute lymphocyte count (ALC), were assessed between groups. Cox proportional hazards models were used to assess survival associations. Results: Among 176 patients who received ide-cel, 13 (7%) had a clinically significant pre-existing AD. Median age in this subgroup was 71 (range: 58–81) years, with 6 (46%) males. Among 78 patients who received cilta-cel, 7 (9%) had a clinically significant pre-existing AD; median age in this subgroup was 58 (range: 47–79) years and all patients were female. No significant differences were observed in baseline Sorror score, EASIX, mEASIX, ALC, LDH, Ferritin, or CRP between patients with and without AD who received either ide-cel or cilta-cel. For cilta-cel, a trend toward higher ferritin levels was noted in patients with AD (392 vs. 142 (ng/mL), (p=0.07), but was not statistically significant. For ide-cel, any grade (G) CRS occurred in 100% of patients with AD vs 85% of patients without AD (p = 0.2); severe CRS (G ≥3) occurred in 1 patient with AD vs 3 patients without AD. Any grade ICANS occurred in 3/13 (23%) of AD patients vs 39/163 (24%) of non-AD (p = 1). Severe ICANS (G ≥3) occurred in 1 patient with AD vs 14 (8.6%) patients without AD. Median ICANS duration was 1 (range: 1 – 6) day for 3 patients with AD vs 1 (range: 1 – 26) day for 39 non-AD patients (p = 1.0). For cilta-cel, any grade CRS occurred in 86% of patients in both groups, and severe CRS (G ≥3) in 0% vs 5.6% (p = 1.0) for AD vs non-AD (p = 1.0). One patient with AD experienced ICANS, which was severe (G ≥3), and lasted for 15 days; compared to 12 non-AD patients with any grade ICANS and 5 with severe ICANS, and overall lasted for 2 (range: 1-17) days. For ide-cel, patients with AD demonstrated a trend toward longer PFS compared to those without AD, although this did not reach statistical significance (HR 0.47, 95% CI 0.21 – 1.02, p = 0.06). OS was similar in both groups (p = 0.6). Among those with or without ICANS, OS did not differ between groups. For cilta-cel, there was no significant difference in PFS or OS in AD vs non-AD. Among those with or without ICANS, OS did not differ between groups. Conclusions: Pre-existing AD was not associated with increased incidence or severity of CRS or ICANS following ide-cel and cilta-cel. Baseline prognostic/comorbidity scores and inflammatory biomarkers were similar between groups. Neither PFS nor OS seem to be significantly different between groups. These findings suggest that AD may not adversely impact CAR-T outcomes and may not warrant exclusion from the therapy and should give reassurance to study these patients prospectively in future CAR-T trials. Future studies will need to explore how AD predisposes patients to complications, given the inherent immune dysregulation seen in these patients.