Extreme persistence of polyclonal CD8⁺ CAR T cells as a driver of marrow failure, neurotoxicity, and fatal immune collapse after ciltacabtagene autoleucel.

2561 Background: BCMA-directed chimeric antigen receptor (CAR) T-cell therapies induce deep responses in relapsed/refractory multiple myeloma (MM), but increasing potency has expanded the spectrum of treatment-related toxicities. While cytokine release syndrome and immune effector cell–associated neurotoxicity are well characterized, the consequences of extreme and prolonged CAR T-cell persistence remain poorly understood, particularly as CAR T-cell strategies are extended to solid tumors. Methods: We performed longitudinal, multi-compartment immunomonitoring in a patient with high-risk MM treated with ciltacabtagene autoleucel (cilta-cel) who developed an unusual leukemia-like clinical course. Peripheral blood (PB), bone marrow (BM), and cerebrospinal fluid (CSF) samples were analyzed by multiparameter flow cytometry, functional cytokine secretion assays, multiplex cytokine profiling, single-cell RNA sequencing with paired T-cell receptor (TCR) repertoire analysis, and lentiviral CAR integration site mapping. Results: Following cilta-cel infusion, the patient developed massive and persistent expansion of non-malignant CD8⁺ effector-memory CAR T cells, comprising >90% of circulating lymphocytes and ~95% of BM lymphocytes, with absence of detectable non-transduced T cells. Despite achieving complete remission of MM, extensive BM infiltration by CAR T cells was associated with marked marrow hypocellularity, trilineage hypoplasia, and prolonged pancytopenia. A distinct trafficking-competent CD8⁺ effector-memory subset (TEM5) was selectively enriched in CSF and associated with severe neurotoxicity and a local pro-inflammatory cytokine milieu. Single-cell transcriptomics demonstrated a highly migratory, cytotoxic effector program with suppressed proliferation, MAPK/TCR signaling, and tissue-residency signatures. TCR repertoire and integration site analyses confirmed polyclonality and excluded malignant transformation or insertional oncogenesis. Sustained CAR T-cell dominance coincided with profound hypogammaglobulinemia, failure of immune reconstitution, recurrent life-threatening infections, and ultimately fatal sepsis. Conclusions: These findings define a previously underrecognized toxicity paradigm of BCMA CAR T-cell therapy characterized by pathologic immune dominance and extreme persistence of cytotoxic CAR T cells, leading to marrow failure, neurotoxicity, and lethal immunosuppression. Extended multi-parametric immunomonitoring may identify patients at risk and inform risk-adapted management strategies, and this principle has potential implications for the design of next-generation CAR T-cell therapies, including for solid tumors.