High dose therapy (HDT) with autologous stem cell transplantation (ASCT) is the standard of care for eligible newly diagnosed MM patients. Several randomized studies demonstrated a survival advantage for patients undergoing transplantation, compared with conventional chemotherapy. Introduction of new drugs in this setting have markedly increased survival rates within the last 10 years. Efforts to further improve response rates and survival in those patients are still needed, mainly by increasing the depth of tumor reduction and the duration of response through more effective induction, consolidation and maintenance therapies. Nevertheless, this approach is currently challenged by the promising results of long-term treatment with novel agents. Recent data suggest that the upfront combination of a proteasome inhibitor plus one immunomodulatory drug (IMiD) is highly effective. The most promising 3-drug association might be Bortezomib, Lenalidomide and dexamethasone (VRD). Adjunction of a 4th drug is not proven to be more efficient. Consolidation and maintenance therapies are emerging in all trials with great results. For elderly patients, or not eligible for ASCT, the introduction of novel agents has also changed the management of the disease. Melphalan-prednisone-thalidomide and bortezomib-melphalan-prednisone are the two standards of care. Current trials are challenging the role of alkylators in the frontline setting. Maintenance therapy is also undergoing evaluation.