MULTIPLE MYELOMA (MM) is a clonal B-cell neo-plasm that affects terminally differentiated B cells (ie, plasma cells) and may proceed through different phases: an inactive phase in which tumor cells are nonproliferating mature plasma cells, an active phase with a small percentage (1%) of proliferating plasmablastic cells, and a fulminant phase with the frequent occurrence of extramedullary proliferation and an increase in plasmablastic cells. During the past years, considerable progress has been made in identifying some of the critical components of neoplastic transformation in MM. This review intends to propose a model of a stepwise malignant transformation during MM pathogenesis. Both diagnostic and therapeutic implications of this model will be discussed.