Our long-term goal is to develop coherent experimental protocols and mathematical models for understanding the biomechanical interaction between myeloma-initiating cells (MICs, also known as myeloma stem cells) and bone marrow stromal cells (BMSCs, also known as bone marrow derived mesenchymal stem cells) regulating the MIC evolution We have recently shown that 1) BMSCs from myeloma patients (myeloma BMSCs) have higher stiffness and contractibility than normal BMSCs, 2) MICs form more colonies, adhere more tightly and become more resistant to drugs when they are co-cultured with myeloma BMSCs or on stiffer hydrogels, 3) MICs express much higher stromal cell-derivative factor-1 (SDF1) than the mature myeloma cells and 4) treatment of CXCR4 inhibitor, AMD3100, leads to decreased adherence of MICs to myeloma BMSCs and decreased colony formation of MICs. The goals of this study are to more fully characterize how the mechanical properties of myeloma BMSCs are influenced by the SDF1/CXCR4 signaling pathway, and to model the impact of such changes on MIC fate by novel mathematic models. A 3D multi-scale agent-based model (ABM) is proposed to investigate the role of cancer – stroma cell-to-cell interactions in multi-myeloma tumorigenesis. It includes: (a) Intracellular level: The intracellular signaling pathway features of myeloma initiating cells (MICs) and MM associated BMSCs may dominate biomechanically induced Multiple myeloma (MM) cancer cell phenotypes at intercellular level, cancer development and disease prognosis at the tissue level. (b) Intercellular level: Cell-to-cell interactions are the pivot chain linking intracellular level features of MIC and BMSC to intracellular biomechanical phenotype switch of MIC, BMSC, and progenitor cells (PCs) and MM. And (c) Tissue level: The cytokines secreted from MIC, PC and MM in the tissue level will regulate the proliferation and differentiation of MICs. By seamlessly incorporating multi-scale events, we 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. Drug synergism analysis also suggested interrupting the communications between cancer cells and their niches dramatically enhanced the drug efficacy against myeloma initiating cells, re-sensitized multiple myeloma to chemotherapies, and reduced risks of cancer relapse.