Several mechanisms are potentially involved in myeloma-induced inhibition of osteoblast formation and differentiation. Myeloma cells inhibit osteoblastogenesis by blocking Runx2 activity in mesenchymal and osteoprogenitor cells through the direct cell-to-cell contact with the involvement of VLA-4–VCAM-1 interaction. Soluble factors such as IL-7 may contribute to the suppression of Runx2 activity by myeloma cells. The direct production of the Wnt inhibitor DKK-1 by myeloma cells could inhibit osteoblast formation. Finally, IL-3 overproduction in the myeloma microenvironment may be involved in the inhibition of osteoblast formation and differentiation.