A curative blueprint for myeloma requires multiple components. The first step is to define patients with “early myeloma” and initiate therapy prior to end-organ damage. These patients would have less tumor burden, genomic instability, and intraclonal heterogenetity than patients with more advanced myeloma. Highly active combination therapy for early myeloma could be delivered without dose delay or dose reduction. Cellular and molecular assays for minimal residual disease (MRD) could be used to define disease eradication, guide strategies for persistent disease modulation (maintenance therapy), and monitor for relapse prior to appearance of a monoclonal paraprotein.