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There has been no improvement in the treatment of multiple myeloma (MM) during the last decades and two meta-analyses of randomized trials recorded no significant survival benefit for combination chemotherapy compared to the classic melphalan-prednisone combination. However the past 15 years has seen several innovative strategies which have dramatically modified the management of MM. In younger patients, high-dose therapy with autologous stem cell transplantation is considered to be superior to conventional chemotherapy and is used as part of front-line therapy. A number of issues have been addressed in recent trials in order to improve the results of autologous transplantation (source of stem cells, conditioning regimen, impact of double transplants, maintenance therapy). Bisphosphonates reduce the incidence of skeletal-related events and improve the quality of life. Recombinant erythropoietin reduces red blood cell transfusion need and improves the quality of life. Thalidomide has been introduced more recently. Phase II studies with thalidomide alone or combined with dexamethasone have shown impressive response rates and this drug is currently being evaluated as part of front-line therapy. Finally, analysis of prognostic factors such as β2 microglobulin and cytogenetics define subgroups of patients with a completely different outcome and help the process of selecting therapeutics strategies.