The role of the bone marrow non-immune microenvironment (BME) in the transition from monoclonal gammopathy of undetermined significance (MGUS) into clinically active multiple myeloma (MM) remains incompletely defined. To address this, we performed single-cell RNA sequencing (scRNA-seq) of non-hematopoietic BME cells and MM cells from two genetically engineered mouse models (BIc{gamma}1 and MIc{gamma}1) that recapitulate MGUS to MM progression. Our analysis revealed distinct transcriptional trajectories in endothelial cells (EC) and mesenchymal stem cells (MSC), uncovering stage-specific BME-PC interactions that shape disease progression. EC adopted a stress phenotype during MGUS and transitioned into a proliferative, angiogenic state in MM. In parallel, MSC exhibited impaired differentiation capacity and an inflammatory transcriptional program that intensified during MM development. Notably, an interferon (IFN)-associated MM signature was detected in both EC and MSC from the BIc{gamma}1 model but was absent in the more aggressive MIc{gamma}1 model. We further show that treatment with bortezomib, lenalidomide, and dexamethasone (VRd) remodeled the BME by suppressing IFN-driven transcriptional programs, promoting an adaptive stress response in EC, and restoring osteogenic potential in MSC-shifting the niche toward a less tumor-permissive state. Importantly, elements of the IFN-related MM signature were validated in MSCs from newly diagnosed patients across the MGUS-to-MM spectrum, supporting the translational relevance of our findings. Together, these data define dynamic, targetable alterations in the non-immune BME during myeloma progression and highlight potential therapeutic strategies.