Multiple myeloma (MM) is a malignant plasma cell disorder characterized by the abnormal expansion and accumulation of clonal plasma cells in the bone marrow in association with production of monoclonal immunoglobulin and its fragment (as protein), and MM remains an incurable disease. Recently extramedullary relapse of MM is more frequent especially in patients treated with stem cell transplantation and/or novel drugs. This review focuses the incidence of extramedullary relapse in MM, mechanisms involved in extramedullary myeloma spread, tumor characteristics at extramedullary sites as well as prognosis and response to therapy.