CCL3/CCR1 participates in the vicious cycle that allows myeloma cells to establish themselves in bone. CCR1 inhibition can break this cycle at multiple points. Expression of RANKL on bone marrow stromal cells (SCs) and OBs stimulates OC maturation (a). CCL3 is one of several key OC-activating factors produced by MM cells (b). MM-produced CCL3 leads to up-regulation of RANKL on SCs and OBs and concomitantly inhibits OB formation (c). Activated OCs enhance MM cell survival via direct integrin-mediated cell-cell interactions and by production of soluble factors, such as CCL3 (d). OC precursors and mature OCs express high levels of CCL3, which stimulates OC maturation via a CCR1-dependent pathway (e). CCR1 is expressed on many cell types in this cycle, including OC precursors, activated OCs, OBs, and, in some cases, MM cells; inhibition by CCR1 antagonists has the potential to break this pathogenic cycle at multiple points.