Bone provides a unique microenvironment for myeloma (MM) cell growth and survival, including niches to foster clonogenic MM cells. MM cells stimulate bone resorption while suppressing bone formation to alter the microenvironment in bone where they colonize, which favors tumor growth and survival, thereby forming a vicious cycle between tumor progression and bone destruction. In spite of recent clinical application of new anti-MM agents, MM is still incurable with progressive bone loss. Therefore, the development of novel therapeutic options yielding better survival outcomes with bone restoration is urgently needed. We have found that the serine/threonine kinase Pim-2 is constitutively over-expressed as a pro-survival mediator in MM cells, and that its expression is further up-regulated in MM cells in cocultures with bone marrow stromal cells (BMSCs) or osteoclasts (OCs). The cocultures also induced Pim-2 expression in BMSCs and OCs besides MM cells to progress bone destruction, indicating the critical role of Pim-2 in MM growth and bone destruction. We recently found TGF-b-activated kinase-1 (TAK-1) as an upstream mediator responsible for Pim-2 up-regulation in these cells. TAK-1 inhibition not only directly suppressed MM cell growth but also decreased VCAM-1 and RANKL expression and IL-6 production in BMSCs, and impaired MM cell adhesion to BMSCs to reduce BMSC support for MM cell growth. In addition, TAK-1 inhibition was able to restore osteoblastogenesis suppressed by MM cells and abolish RANKL-induced osteoclastogenesis. Thus, TAK1 may become an efficacious therapeutic target in MM to suppress tumor burden while restoring bone. In contrast to the osteoblast precursors BMSCs, mature osteoblasts with bone formation induced MM cell death over time along with Pim-2 reduction followed by AMPK phosphorylation with mitochondrial damage in MM cells. These results suggest that restoration of bone formation may create a non-permissive niche for MM cells to induce their energy crisis.