Multiple myeloma (MM) is a hematologic malignancy whose progression may account for uncontrolled osteoclastogenesis promoted by the malignant plasma cells within the marrow microenvironment. Osteoclasts are multinucleated cells derived from the fusion of myeloid progenitors such as monocytes/macrophages, in response to specific differentiation factors released within the marrow niche, that are significantly deregulated in MM. In this malignancy DC-STAMP, a major fusogen protein enrolled by pre-osteoclasts, is highly expressed by peripheral macrophages, whereas dendritic cells and myeloma plasma cells show high fusogenic susceptibility and under specific conditions transdifferentiate to osteoclasts. In particular, the malignant plasma cells, besides altered ploidy, expression of cancer stem cell phenotype and high metastasizing capability, are able to express phenotypic markers of osteclasts, namely the proteolytic enzymes for the bone matrix, and to activate the β3 transcriptional pathway leading to ERK1/2 phosphorylation and initiation of the bone resorbing activity. Thus, based on the imbalanced osteoclast formation and activity that involve cells constitutively uncommitted to osteoclast differentiation, both homotypic and heterotypic cell fusions in myeloma marrow microenvironment represent a major pathogenetic event that drives the development and progression of the skeleton devastation typical of the myeloma bone disease.