This chapter gives an account of the experience of the Arkansas myeloma program since 1989 with transplant-supported high-dose melphalan, novel agents, and prognostic factors as they relate to standard laboratory features, gene expression profiling, and magnetic resonance imaging (MRI). Incorporation of novel agents and new concepts, such as post-tandem transplant consolidation therapy, has improved the rate and duration of complete response and prolonged event-free and overall survival rates. With Total Therapy 2, median survival exceeds 8 years, while Total Therapy 3 with added bortezomib has sustained complete remissions in more than 90% of patients at 2 years which, when used as a survival surrogate in Total Therapy 2, assured a high 6-year survival rate of 75%. Gene expression profiling identified 15% of patients with very short survival. MRI-defined focal lesions are associated with poor outcome, while their resolution - although slower than the time course of attaining clinical complete remission - conferred superior survival. Representing a frequent source of recurrence, with genetic profiles (in both plasma and stromal cells) distinct from those in random bone-marrow samples, therapeutic efforts are directed at hastening onset and increasing frequency of focal lesion resolution.