Multiple myeloma, currently an incurable common hematological malignancy, is notorious for its recurrence and drug resistance. Our work led to the hypothesis that intercellular communications between myeloma initiating cells (MICs, a.k.a. myeloma stem cell) and bone marrow stromal cells (BMSCs) during the biomechanical remodeling of cancer stem cell niches play a key role in myeloma initiation and drug resistance. MICs prime BMSCs via SDF-1 paracrine; the activated BMSCs provide stiffer micro-environment, which boosts sustainable tumor growth under drug treatments. Understanding this pro-oncogenetic positive-feedback loop is thus crucial to the cure of the disease.In this study we used a 3D multi-scale agent-based modeling (ABM) approach to investigate the role of MIC-BMSC interactions in tumor growth and drug responses. The model is composed of four agent types, each representing a cell type: MIC, BMSC, PC (cancer progenitor cells), and MM (matured cancer cells). At intracellular level, specific signaling pathways were inferred from functional proteomics (reverse phase protein array) and gene expression data, and encapsulated into corresponding agent as ODEs. Intercellular communications were simulated on the agent-to-agent interfaces. The SDF-1 paracrine was described by PDEs of mass transfer. Intercellular events were extended to tissue level as tumor growth by a cancer stem cell lineage model (which includes MIC, PC, and MM agents). By seamlessly incorporating multi-scale events, our model quantitatively illustrated the interruption of BMSC contraction reduces the change of forming drug-resistant MIC strains and suppresses MIC colonogenesis, which was experimentally validated. Our work answered how the biomechanical remodeling of cancer stem cell niches via intercellular communications between tumor and stromal cells affects myeloma drug responses and prognosis, provided insights into myeloma development mechanisms, and cast new light on novel drug candidates and treatment strategies targeting the MIC-BMSC interactions.