Lenalidomide-induced pure red cell aplasia: clinical characteristics and mechanistic analysis [scRNA-seq]

The RVd therapy, combining lenalidomide, bortezomib, and dexamethasone, is a mainstay treatment for multiple myeloma, typically eliciting immune activation and myeloma cell clearance, alleviating anemia and associated symptoms. In a unique multiple myeloma case, the patient developed pure red cell aplasia (PRCA) following RVd treatment, despite the absence of common PRCA triggers. In vitro analyses revealed severe erythropoiesis impairment in this patient, with lenalidomide emerging as a pivotal disruptor of erythroid development, potentially driving PRCA. Single-cell transcriptome analysis unveiled a notable increase in hyperactive cluster of differentiation (CD)8+ T cells in the patient's bone marrow. The few remaining erythroid progenitors in the patient's bone marrow exhibited developmental dysfunction and immune-related pathway activation. Unexpectedly, these erythroid cells displayed abnormally high expression of major histocompatibility class I (MHCI). Functional assays demonstrated that the addition of lenalidomide further augmented MHCI expression in the patient's erythroid progenitors. Drug-induced increases in antigen presentation by immune erythrocytes emerged as the potential driving force behind hyperactive T cell attacks and subsequent development of PRCA. This study not only elucidates the mechanism underlying lenalidomide-induced PRCA in this rare case, but also underscore the importance of considering the MHCI gene in erythroid cells during clinical trials and drug administration.