Active Extramedullary Disease Predicts ICANS and Early ICAHT after CAR-T Therapy in Multiple Myeloma

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Introduction BCMA-targeted CAR-T therapy has revolutionized treatment for multiple myeloma (MM), showing remarkable efficacy in clinical trials . However, both trial and real-world data indicate that patients (pts) with extramedullary disease (EMD) – whether paraskeletal or true – experience lower response rates and shorter response durations compared to those without EMD (Dima BCJ 2024). This study evaluated the impact of active EMD on CAR-T therapy toxicity in MM pts. Methods Our analysis included 96 pts treated with idecabtagene vicleucel (n=32, 33%) and ciltacabtagene autoleucel (n=64, 67%) as standard of care at our institution between Aug 2021 and Aug 2024. All pts underwent pre-treatment PET/CT. Multivariable (MV) regression models adjusted for bone marrow plasma cell percentage (BMPC), EMD, high-risk cytogenetic abnormality (HRCA) status, product type, and age. Results The median pt age was 64 yrs (range 31-79) and 47% (n=45) were female. Pre-treatment PET/CT identified active EMD in 34% of pts (n=33), including 22 with true EMD and 11 with paraskeletal disease. Most pts (97%, n=93) had ECOG performance status 0-1, and 50% (n=48) had a HRCA, including t(4;14), t(14;16), t(14;20), del(17p), or amp(1q). The median number of prior therapy lines was 5 (IQR 5-7). Pts with active EMD had higher rates of early immune effector cell-associated hemophagocytic syndrome (ICAHT; grade 2+: 48% vs 8.8%, p<.001; grade 3+: 26% vs 1.5%, p<.001) and immune effector cell-associated neurotoxicity (ICANS; grade 2+: 27% vs 5.7%, p=.008; grade 3+: 15% vs 1.5%, p=.018) compared to those without active EMD ( Panel A ). Cytokine release syndrome (CRS) rates were similar between groups (grade 2+: 46% vs 41%, p=.7). Inflammatory markers ( Panel B ), including peak ferritin (2598 vs 565 ng/mL, p<.001), CRP (109 vs 62 mg/L, p=.003), and IL6 (1530 vs 155 pg/mL, p=.008) were higher in EMD pts. MV analysis ( Panel C ) identified EMD as an independent predictor of grade 2+ ICANS (aOR 5.82, p=.028), grade 2+ ICAHT (aOR 15.1, p<.001), grade 3+ ICANS (aOR 22.8, p=.020), grade 3+ ICAHT (aOR 21.7, p=.008), and neutropenic days (+5.3, p<.001). Competing risk analysis suggested a trend toward higher 1-yr treatment-related mortality in EMD pts (19% vs 5.1%, p=.2). EMD was independently associated with worse overall (aHR 6.26, p<.001) and progression-free survival (aHR 2.27, p=.039). Conclusion While EMD is recognized for its association with poor long-term outcomes, our study is the first to link EMD with increased short-term toxicity and systemic inflammation following CAR-T therapy. These findings emphasize the need for careful pt selection when considering CAR-T therapy for MM pts with active EMD, and suggest that earlier intervention, when the EMD burden is lower, may be beneficial. Further research is needed to explore whether targeted EMD therapies, such as radiation, can reduce the risks associated with CAR-T treatment.

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