Multiple myeloma is a B-cell malignancy with a highly variable outcome. Despite the marked recent improvements in its management, especially due to the widespread application of high-dose treatment and autologous stem cell transplantation, relapses eventually occur in the majority of patients. Systematic research at University of Arkansas over the last 10 years, has revealed that the absence of unfavorable cytogenetic abnormalities (deletion of chromosome 13 and hypodiploidy), low beta-2 microglobulin levels prior to transplant, a normal lactate dehydrogenase level at diagnosis and early application of high-dose treatment (< 12 months of preceding standard treatment) define a subgroup of myeloma patients with a high likelihood of long (> 5 years) event-free survival; a sizable minority of these patients may be considered cured. Recognition of the importance of these prognostic factors should lead to routine cytogenetic evaluation of all patients and early referral to specialized transplant centers. Furthermore, patients with less favorable outcome should be identified early in their disease course and should be managed with novel and hopefully more effective treatments.