Schematic overview of MBD. The intercellular interactions between bone marrow stromal cells (BMSCs) and MM cells, along with the involvement of immune cells, such as Th17 cells, induce cytokine release (interleukin-1b [IL-1b], IL-3, IL-6, IL-11, and IL-17) and secretion of proosteoclastogenic factors such as tumor necrosis factor α (TNF-α), chemokine (C-C motif) ligand 3 (CCL3), stromal cell derived factor-1α (SDF-1α), and annexin 2 in the bone marrow microenvironment. These cytokines promote increased osteoclast activity and inhibit osteoblastogenesis. Adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) on BMSCs and very late antigen-4 (VLA-4) on MM cells mediate cell-to-cell contact. Notch, expressed by MM cells, binds to Jagged, expressed by neighboring MM cells and BMSCs, and activates intracellular cascades favoring RANKL production. RANKL, expressed by both BMSCs and MM cells, binds directly to RANK on osteoclast precursors and promotes osteoclastogenesis. Syndecan-1 on MM cells binds and inactivates osteoprotogerin (OPG), the RANKL soluble decoy receptor. Osteoclasts also produce factors sustaining MM cell growth and survival, such as osteopontin. Furthermore, osteocytes and MM cells produce soluble factors that inhibit osteoblastogenesis such as DKK-1, sFRP-2, and sclerostin. Activin-A secreted by BMSCs also impedes osteoblast production. EphB4 on osteoblasts and BMSCs binds to EphrinB2 on osteoclasts and results in bidirectional signaling that ultimately induces osteoclastogenesis and impedes osteoblastogenesis. Moreover, myeloma cells and osteoclasts produce semaphorin-4D (Sema-4D) and further inhibit the osteoblasts. Osteocyte apoptosis increases RANKL and sclerostin production to increase osteoclast activity, suppress osteoblast differentiation, and increase myeloma growth through bidirectional Notch signaling. BAFF, B cell–activating factor; HGF, hepatocyte growth factor. Professional illustration by Somersault18:24.