Melphalan-prednisone-thalidomide (MPT) and melphalan-prednisone-bortezomib (MPV) currently appear to be the treatments of choice for a large proportion of elderly multiple myeloma (MM) patients ineligible for autologous stem cell transplantation (ASCT). It seems certain that in the near future cyclophosphamide-thalidomide-dexamethasone, with an attenuated dose of dexamethasone (CTDa), and melphalan-prednisone-lenalidomide (MPR) will also be proved superior to MP, thus providing four therapeutic options in this patient group. These options could lead to more personalized treatment approaches, based on patient comorbidities, as the three novel agents have somewhat different toxicity profiles. MP would be appropriate for only a minority of patients with poor performance status and/or significant comorbidities. Questions regarding the relative efficacy of different melphalan-based regimens or melphalan-based regimens versus dexamethasone-based regimens with low-dose dexamethasone will require further trials. Additionally, the important issue of maintenance treatment needs to be investigated. These new and emerging therapies provide multiple effective treatment options for MM patients and greatly enhanced treatment strategies for clinicians, all offering promise that has been sorely lacking over the past four decades.