Our myeloma research group, which has developed number of new targets and novel therapies (DFCI), will partner with the world leaders in cooperative clinical and transplantation trials in MM (IFM) to pursue collaborative translational investigation. We will couple combination novel therapies with high dose therapy and transplantation and then delineate genomic and molecular correlates of clinical and biological outcomes. Project 1 will focus on defining the durability of responses to novel combination therapy on the one hand, and the additional value of high dose therapy on the other, by enrolling 1000 newly diagnosed patients between IFM and DFCI. This trial will provide 1000 samples from newly diagnosed and uniformly treated patients to comprehensively characterize the MM genome and epigenome, to define molecular events driving development and progression of MM (Project 2), as well as to identify novel therapeutic targets (Project 3), biomarkers, and preventative strategies (Project 4). In these collaborative studies the Sanger Institute in UK, with whole genome sequencing capabilities, along with research teams from DFCI and IFM, will perform molecular genetic analysis of patient samples and delineate patient subgroups most likely to respond and achieve prolonged survival (Projects 2 and 4). The clinically relevant novel targets identified using these high throughput genomic technologies will be validated and novel targeted therapies developed in Project 3. Project 4 will further analyze evolution of genomic changes at relapse and their clinical significance, as well as devise strategies to prevent genomic instability. These 4 projects will be supported by Administrative and Communication Core (A), Clinical and Tissue Core (B); Genomics Core (C); Genomic Sequencing Core (0), and Biostatistical and Bioinformatics Core (E). This unique collaborative effort will define a new treatment paradigm for this presently incurable disease.