AbstractPurpose:Chimeric antigen receptor T cells (CAR-T) have demonstrated remarkable efficacy in multiple myeloma, but prolonged hematologic toxicity remains a common adverse event, and secondary myeloid malignancies are a significant safety concern.Experimental Design:We evaluated 213 patients with myeloma treated with B-cell maturation antigen–directed CAR-T at our center to characterize clinical, inflammatory, and myeloid clonal features associated with hematologic toxicity.Results:Patients with persistent grade ≥3 neutropenia or thrombocytopenia at day 100 (19%) had shorter progression-free survival (P = 0.0003) and overall survival (P P = 0.006). Serum cytokine analysis in patients with delayed myeloid recovery showed a signature of persistent inflammation and endothelial dysfunction. Finally, 9% developed secondary myeloid diseases, including 5% with high-grade myelodysplastic syndrome (MDS) requiring therapy, a median of 14.5 months after CAR-T. MDS was associated with clonal expansion of underlying TP53-mutated CH from a median variant allele frequency of 3.4% before CAR-T to 44.0%. Whereas patients with baseline TP53-mutated CH exhibited clonal evolution and a high incidence of MDS (67%), other CH mutations did not show similar expansion after CAR-T (P > 0.99).Conclusions:This study underscores the impact of hematologic toxicity and CH on B-cell maturation antigen CAR-T outcomes and suggests a potential role of CAR-T in influencing TP53 clonal dynamics and myeloid disease development.
Avigan et al. (Wed,) studied this question.
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