Hematological toxicity is a common toxicity of CAR-T cell therapies, being particularly severe in relapsed/refractory (R/R) multiple myeloma (MM) patients treated with BCMA CAR-T cells; still its etiology is poorly understood. In this study we aimed to explain the mechanisms underlying severe and long-lasting cytopenia in a cohort of 50 patients treated with BCMA-CAR T-cell therapy at the University Clinica of Navarra. The overall incidence of any grade cytopenias was 95.74%, with grade ≥3 thrombopenia and neutropenia in 57% and 53% of patients one month after infusion, and median time to recovery to grade 1 neutropenia of 1.5 months. To understand the cause of cytopenias, an ex-vivo myeloid differentiation model subjected to the paracrine effect of activated BCMA CAR-T cells. HSPCs cells were differentiated following an optimized protocol in the presence of supernatants from activated BCMA CAR-T cells (spCAR) or control T lymphocytes (spUTD). Phenotypic analysis with flow cytometry showed that HSPCs differentiated with spCAR presented more immature phenotypes, with reduced expression of granulocytic, monocytic and erythroid maturation-associated markers. Transcriptomic analysis at single cell level, performed using 10x Genomics, revealed that clusters integrated by cells differentiated with spCAR are enriched in TFs relevant in early hematopoiesis, such as GATA2. Moreover, GRNs analysis identified regulons that modulate monocytic and neutrophil maturation, such as KLF6, being less active in cells differentiated with spCAR. Overall, our study contributes to understand the molecular mechanisms behind cytopenias observed after CAR-T cell treatment, suggesting that CAR-T activation negatively influences the hematopoietic differentiation through paracrine signalling.