Interaction of MM cells and their BM milieu. Binding of MM cells to BMSCs triggers both adhesion- and cytokine-mediated MM cell growth, survival, drug resistance, and migration. MM cell binding to BMSCs up-regulates cytokine (IL-6, IGF-1, VEGF, SDF-1α) secretion from both BMSCs and MM cells. These cytokines subsequently activate 3 major signaling pathways (ERK, JAK/STAT3, and/or PI3-K/Akt), and their downstream targets including cytokines (IL-6, IGF-1, VEGF) and antiapoptotic proteins (Bcl-xL, IAPs, Mcl-1) in MM cells. Adhesion-mediated activation of NF-κB up-regulates adhesion molecules (ICAM-1, VCAM-1) on both MM cells and BMSCs, further enhancing adhesion of MM cells to BMSCs.