Stage-specific disruption of erythropoiesis leads to anemia in newly diagnosed multiple myeloma patients

Background Multiple myeloma (MM) associated anemia affects over 60% of patients and correlates with poor prognosis. While most studies focus on the impact of microenvironment on erythropoiesis in MM, the stage-specific erythroid cell defects and their underlying molecular mechanisms remain poorly characterized. Method Clinical data were collected from 300 patients with newly diagnosed multiple myeloma (NDMM) and 300 healthy controls. Phenotypic and transcriptomic profiles of bone marrow early and late erythropoiesis were compared between healthy donors (HDs) and NDMM patients with anemia (NDMM-A). Furthermore, in vitro erythroid culture assays were performed to verify the intrinsic erythropoietic impairments in NDMM-A patients. Results Primary erythropoiesis profiles from bone marrow revealed a global reduction in erythroblasts across all maturation stages, along with significantly impaired colony-forming capacity of erythroid progenitors in NDMM patients. Transcriptomic profiling identified stage-specific dysregulation in the early and late erythropoiesis of NDMM-A patients. Erythroid progenitors exhibited downregulation of cell-cycle regulators (e.g., CDC20, AURKB) and key erythropoietic transcription factors (e.g., GATA1, GFI1B), accompanied by upregulation of immune-response genes (OAS3, OAS2). Conversely, terminal erythroblasts showed upregulation of genes involved in oxidative phosphorylation and the p53 pathway. In vitro assays confirmed intrinsic defects in erythroblasts derived from NDMM patients’ CD34+ cells, including poor proliferation, increased apoptosis rate, and defective enucleation. Conclusion These findings demonstrate that both cell-intrinsic impairments and external responses drive stage-specific erythropoietic failure in NDMM, providing new insights for therapeutic strategies.