Project Summary (Project 1) To improve overall outcome in multiple myeloma (MM), in the current funding period this project achieved two major goals: 1: Defined the role of transplant in the era of novel agents –establishing integration of transplant with novel agents as the standard of care for newly-diagnosed patients 2: Redefined Complete Remission, establishing the feasibility of measuring minimal residual disease (MRD) using sequencing-based method and its significant impact on prolongation of PFS. In this renewal application, we now propose to build upon our highly successful collaborative clinical study to address the next most important question, whether less intense maintenance (1-drug) provides adequate benefit compared to more intense maintenance (2-drug) and whether MRD negative status should be the ultimate goal. We hypothesize that achieving MRD negative status will lead to long- term disease free survival, and that irrespective of how one gets to MRD negative status, the overall outcome will be similar. To achieve these goals, in Specific Aim 1 we will perform a large 1,260 patient study utilizing lenalidomide, ixazomib, and dexamethasone with daratumumab (RID-Dara) as induction and consolidation post high-dose therapy. Those not achieving MRD negative status will receive 2nd HDT. All MRD negative patients will be randomized to lenalidomide versus lenalidomide plus daratumumab maintenance. The study will also evaluate MRD status at various time points and investigate whether early versus late MRD status will affect overall outcome. In specific Aim 2, we will redefine new risk stratification incorporating MRD status and all genomic/epigenomic correlates.