Although multiple myeloma (MM) remains an incurable disease, there has been a concerted effort toward understanding its molecular pathogenesis, which has paved the way for the development of highly effective, novel therapeutic agents such as the immunomodulatory agents thalidomide and lenalidomide, and the proteasome inhibitor bortezomib. A better understanding of the molecular basis of chemotherapy resistance and the molecular sequelae of conventional cytotoxic and novel agents on MM cells and the bone marrow microenvironment has afforded the opportunity to study novel, rationally designed combination therapies in the clinic. These regimens have shown impressive activity in relapsed/refractory MM, and recent work has demonstrated unprecedented response rates in the first-line setting rivaling those seen with autologous stem cell transplantation. Recently presented results of 2 phase III clinical trials comparing melphalan/prednisone (MP) with MP and thalidomide (MP-Thal) in older patients with newly diagnosed MM have demonstrated superior progression-free survival and overall survival rates with MP-Thal, thus providing the first evidence that the improved response rates to these novel combination regimens will translate into better patient outcomes. Herein we review the early promising clinical activity of these regimens in patients with newly diagnosed MM.