Until 2007, frontline chemotherapy with melphalan and prednisone (MP) was considered as the standard of care in the treatment of elderly patients with multiple myeloma (MM). Recently, several prospective randomized studies comparing MP with the same combination plus new agents such as thalidomide (MPT) or bortezomib (MPV) clearly showed that MPT and MPV were superior to MP in terms of progression-free and overall survival. Melphalan-prednisone-lenalidomide (MPR) is currently compared to MP in one prospective trial and will also probably be superior to MP. Lenalidomide plus low-dose dexamethasone is a promising combination. Thus, at least four highly active new treatment options are now available to treat elderly patients with MM. The goal of future trials will be to determine the best treatment strategy in this group of patients.