Multiple myeloma patients deemed to not be candidates for high-dose therapy followed by stem cell rescue who nonetheless need chemotherapy have traditionally received an oral regimen combining melphalan and prednisone. With the advent of novel agents, however, such as immunomodulatory drugs and proteasome inhibitors that are active in the relapsed/refractory setting, there has been an impetus to incorporate these new options into front-line therapy. Several phase II studies have recently revealed that addition of either thalidomide, lenalidomide, or bortezomib to melphalan and prednisone increased the overall and complete response rates, albeit at the cost of some increased toxicity. Randomized phase III studies of melphalan and prednisone with thalidomide have already shown that, compared to melphalan and prednisone alone, the three-drug regimen prolonged time to progression and overall survival in this population, thereby defining a new standard of care. Moreover, our increasing knowledge of the molecular role that cytogenetic abnormalities play in the biology of multiple myeloma and our growing chemotherapeutic armamentarium are beginning to allow us to rationally select therapies based on these characteristics of each patient's disease. Such a risk-and molecular-adapted strategy to the therapy of multiple myeloma promises to revolutionize and personalize our care of these patients and bring us closer to a cure for this disease.Using the diagnostic criteria recommended by the International Working Group, patients with multiple myeloma are classified as having either asymptomatic or symptomatic (Table 1) disease. 1 The latter population, generally considered candidates for a chemotherapy-based intervention, are then further divided into those who either are or are not eligible for high-dose chemotherapy followed by stem cell rescue. 2 Criteria that are weighed to help make this second distinction have generally included age, performance status, and co-morbid medical conditions. 2 There is some variability in these parameters and how they are applied, since studies examining stem cell transplantation have used different criteria. In regard to age, for example, which is the most objective of these measures, initial studies tended to enroll patients younger than 65 years of age, 3 while more recent studies suggest that transplant is safe in at least some who are over the age of 70 (for example 4,5 ). On the other hand, data suggesting that patients with poor-risk chromosomal features have a short time to progression after autologous transplantation have led to suggestions that even younger patients with these abnormalities may not be candidates for standard approaches. Nonetheless, as little as two years ago, there was general agreement that the standard of care for patients who were not eligible for transplantation and yet needed chemotherapy was melphalan