Background: A growing body of evidence has indicated impaired function or compositional changes of monocytes in inflammatory disorders, such as acute respiratory syndrome and covid-19. In myeloma tumor microenvironment, activation of type I interferon pathway and dysregulated expression of major histocompatibility complex type II genes are observed in classical monocytes, which result in loss of antigen presentation of monocytes. The proportions of BAFF+PD-L1+ monocytes in the bone marrow also correlate with survival of myeloma patients following chimeric antigen-receptor T cell therapy. Nevertheless, the mechanisms underlying PB and BM monocytes defects in myeloma remain poorly addressed, at least in part by the lack of large scale scRNA-seq studies. To resolve the heterogeneous bone marrow and peripheral blood monocyte subpopulations and their transcriptional factors between healthy donors and multiple myeloma patients. Methods: We conducted scRNA-seq on monocytes of 7 newly diagnosed myeloma patients and 12 healthy donors. Specifically, 3 and 5 bone marrow aspirates and 9 and 7 peripheral blood samples of 12 healthy controls and 7 newly diagnosed patients were obtained, respectively. Results: Heterogeneous bone marrow and peripheral blood monocyte subpopulations and their transcriptional factors were resolved. The function characteristics of monocyte were compared between MM patients and healthy donors, which indicated a stress signature induced by multiple myeloma. Furthermore, we identified two monocyte differentiation pathways, and discovered that bone marrow monocyte feature type I IFN-associated differentiation dysregulation in patients with MM as well as dysregulated patterns at transcriptome. Finally, we included 10 MM patients as a validation cohort, by tracking the stress signature over time in those patients undergoing first-line treatment, we founded that the stress signature was partially overcome by antitumor therapy. Conclusion: Our results provided further insight into transcriptional and differentiation changes occurring in the bone marrow and peripheral blood monocytes from patients with multiple myeloma and hint and mechanisms of immune evasion. Encore Abstract - previously submitted to EHA 2023 The research was funded by: This investigation was supported by the International Cooperation Projects of National Natural Science Foundation (grants 81920108006), CAMS Innovation Fund for Medical Sciences (CIFMS) (grants 2022-I2M-1-022), the National Natural Science Foundation (grants 81630007; grants 82270218, 81670202; grants 81900214), and the Atlas of Blood Cell Alliance. Keywords: genomics, epigenomics, and other -omics, microenvironment, multiple myeloma No conflicts of interests pertinent to the abstract.