Multiple Myeloma (MM) is a hematological malignancy characterized by the abnormal proliferation and accumulation of clonal plasma cells (PCs) in the bone marrow (BM). Despite significant advances in treating MM patients, most patients eventually relapse and succumb to the disease. Understanding the mechanisms driving progression from precursor conditions into clinically active MM may contribute to implementing early curative approaches. Accumulating evidence indicates that the tumor formation and progression process is influenced not only by the malignant cells but also by the microenvironment components and interconnectedness between them. However, the understanding of the contribution of the non-immune BM microenvironment (BME) to disease progression and relapse remains largely unknown. Our aim was to identify the transcriptional changes in the endothelial cells (ECs) and mesenchymal stromal cells (MSCs) during the transition from premalignant stages to MM to identify potential mechanisms of transformation and therapeutic targets. To this end, ECs and MSCs were immunophenotypically isolated from BM samples of healthy aged donors (n=19) and patients with (MGUS, n=10), Smoldering Multiple Myeloma (SMM, n=13), and MM (n=36). Bulk RNA sequencing analysis of ECs revealed enrichment in terms related to cell cycle and fatty acid metabolism in MGUS, SMM, and MM patients compared to old adults. Indeed, a selective upregulation of pathways associated with calcium signaling, cytokines, and angiogenesis was detected in ECs from MM patients. Regarding MSCs, our results revealed an increase in bone remodeling, inflammation, oxidative defense, and DNA damage repair in MM patients. Interestingly, during the transition from MGUS to SMM, MSCs exhibited enrichment in functions associated with cell morphogenesis and epithelial transition, while lipid-related functions were decreased. To gain a deeper understanding, single-cell RNA sequencing analysis of BME and PCs was performed in unique immunocompetent murine models recapitulating the principal clinical, genetic, and immunological characteristics of MGUS and MM patients (Larrayoz et al., 2023). Using as a reference a previous BME characterization in mice we conducted (Ye et al., 2022) and in line with findings in human patients, our results unveiled a compromised BME characterized by the angiogenic profile of ECs and the increase in the immune-related state of MSCs associated with the progression of the disease. Furthermore, MGUS ECs displayed enrichment in ion homeostasis, immune response, and cell signaling-related pathways compared to healthy controls. While MM ECs exhibited a significant increase in immune terms, migration, and vascular-related pathways when compared to MGUS ECs, indicating a more angiogenic functional profile. Moreover, MSCs in the MGUS stage depicted significant activation of pathways related to immune defense, detoxification, lipid metabolism, and bone remodeling. Likewise, genes upregulated in MM MSCs were associated with calcium signaling, cytokines, and interferon response-related pathways, demonstrating the inflammatory signature of MSCs that may be in relation to the immune exhaustion underlying MM transformation. Finally, subsequent single-cell derived cell-to-cell interaction analysis using Liana was conducted to characterize the interactions between malignant PCs and their niche and delineate the communication dynamics of the tumor-BM ecosystem. Our results showed that PCs interact with ECs mainly through Itga1 and Cd44, while they communicate with MSCs mainly via Egfr and Sdc1. Remarkably, the interactions initiated during the MGUS stage between ECs and PCs persisted, and MM-specific interactions were involved in adhesion, migration, and angiogenesis pathways. In the crosstalk between PCs and MSCs, MGUS-specific interactions were associated with fat and bone-related processes. In contrast, MM-specific interactions were related to the extracellular matrix, collagen organization, and immune-related processes. In conclusion, our findings provide several novel insights into the transcriptional profiles of the non-immune BME during MM disease progression as well as the cellular interactions established with malignant PCs that can drive a pro-MM environment. Additional analyses are ongoing to further comprehend the BME's remodeling through MM development.