Thalidomide, administered orally, bortezomib (Velcade) intravenously and lenalidomide (Revlimid), also orally, are three agents that act on myeloma relapse. Thalidomide acts by a variety of mechanisms and is toxic to the peripheral nervous system as well as teratogenic. It acts in synergy with dexamethasone. Recent results prove that its use as first-line treatment combined with oral conventional "MP" chemotherapy improves survival in patients older than 65 years. Its use as first-line treatment with this chemotherapy appears likely. Bortezomib is the first drug in the proteasome inhibitor class. It too is toxic to the peripheral nervous system and synergistic with dexamethasone. Several studies show its efficacy as first-line 'induction treatment' with dexamethasone, in patients to receive a subsequent autologous stem cell transplantation. The combination of bortezomib and "MP" is also promising. Lenalidomide, a structural analog of thalidomide, is effective in relapsing patients. Its toxicity is essentially hematologic. It is also synergistic with dexamethasone and promising as first-line treatment. These different drugs can be used successively at relapse, making myeloma a chronic disease. They can also be used together for greater effectiveness. These combinations will replace conventional chemotherapies in the future.