Project Summary – Overall Program Dana-Farber Cancer Institute This renewal application stems from our successful renewal of our program project grant funded in 2017, which brings together a talented group of investigators with expertise in basic biology (DFCI and Whitehead Institute at MIT), clinical science (IFM), as well as genomic and cell signaling (DFCI and Broad Institute). During the prior years of funding period, we have 1. Defined the role of transplant in the era of novel agents; 2 Established the role of molecular minimal residual disease (MRD) in myeloma; 3. Identified and validated number of novel genomic and epigenomic targets; and 4. Defined patterns of clonal evolution and mutational signatures being utilized in MM. Our program has also developed novel targeted sequencing platform, deciphered the genomic landscape and chronology of copy number alterations in MM, developed a pipeline to identify mutations using RNA-seq, and developed a publicly available data analysis portal (Canevolve.org). Building on these advances, the overall specific objectives of the program are 1) to determine whether high-dose therapy provides benefit if MRD negative status is achieved, to define the role of sustained MRD negativity in 716 patients randomized clinical study, and to develop novel risk model (Project 1). Clinically annotated patient samples from IFM/DFCI 2009 and the proposed clinical trial will be utilized to study genomic and epigenomic correlates (All Projects) Project 2 will advance our understanding of the regulation of transcriptional condensates and their biochemical environment. Project 3 will identify and validate the long non-coding RNA dependencies responsible for continued MM cell growth and develop strategies to interrupt their activities as a novel therapeutic approach. New targeted therapeutic agents will be translated to clinical trials to improve patient outcome. Project 4 will define the impact of clonal complexity and identify mediators of genomic instability underlying disease progression in MM and develop novel inhibitors targeting genomic instability. These 4 projects will be supported by Administrative and Communication Core (1), Clinical and Tissue Core (2); Epigenomics Core (3); Genomic Sequencing Core (4); and Biostatistical and Bioinformatics Cores (5). This unique collaborative effort will improve our understanding of myeloma biology and define a new treatment paradigm for this presently incurable disease.