Multiple myeloma (MM), a malignancy of plasma cells, preferentially expands in the bone marrow, while inducing debilitating bone destruction, which often causes immobilization by bone fractures and/or lower limb paralysis through spinal compression by tumors. Osteocytes are sensors of mechanical stress and master regulatory cells of bone remodeling to interact with bone marrow cells through their dendritic processes. However, the roles of osteocytes in MM expansion has not been studied especially in condition with mechanical unloading in MM. In the present study, we therefore explored the impacts of immobilization or mechanical unloading on MM tumor expansion in bone. Right hind legs of mice were unilaterally immobilized by sciatic denervation or casting with adhesive bandage. MicroCT revealed substantial volume reduction of trabecular bone in the unloaded legs, in which osteoclast increased in number on the surface of the trabecular bone along with RANK ligand upregulation in osteocytes. Interestingly, when luciferase-transfected mouse 5TGM1 MM cells were inoculated into tibiae, 5TGM1 tumor expanded more rapidly in the immobilized hind legs with the denervation or casting than in intact hind legs as shown IVIS images. The acceleration of MM tumor growth by mechanical unloading was further confirmed by simultaneous MM cell inoculation into tibiae in both the unloaded (right) or intact (left) hind legs in the same mice. The acceleration of MM tumor growth by mechanical unloading was substantially suppressed by the anti-resorptive agent zoledronic acid or injection of the TAK1 inhibitor LLZ1640-2. Osteoclasts formed in vitro by RANK ligand directly enhanced MM cells, which was almost completely suppressed by the TAK1 inhibition. These results demonstrate that mechanical unloading aggravates bone destruction and MM tumor expansion, and suggest the causative role of TAK1 as well as osteocytic RANK ligand induction and thereby osteoclastogenesis in promotion of MM tumor expansion by mechanical unloading.