Multiple Myeloma (MM) is a currently incurable rare malignant plasma cell disease, which invariably relapses despite therapy. The objective of OVER-MYR is to understand the causes of drug resistance and relapse, develop novel strategies to overcome these, provide proof of principal for phase I/II trial, and thus impact on MM-patient’s survival.Currently-used drugs target both MM cells (MMC) and cells of the bone marrow (BM) microenvironment or ‘niche’ that are critical for supporting MMC survival, proliferation and growth. Since patients repeatedly relapse after such treatments, the following mechanisms of relapse are considered and need to be investigated:i) drugs have spared specific subclones or subpopulations of MMCii) drugs induce alterations in cells of the ‘niche’ that promote drug-resistance.OVER-MYR integrates a network of outstanding researchers from 6 EU countries with internationally recognized experience in clinics and human and animal models of MM, who will jointly:WP1: Study the molecular alterations in primary MM and environment cells in samples obtained from a large number of patients at treatment inclusion and relapse, using high throughput techniques.WP2: Implement in vitro and in vivo models of drug resistance to evaluate molecular and cellular mechanisms and compare their characteristics with drug resistant cells isolated from patients.Combined results of WP1 and WP2 will permit the identification of 10 prominent (altered) candidate genes involved in MM relapse. Changes in drug resistance, cell survival and proliferation will be assessed in WP2 by modulating the expression of the selected genes.WP3: Determine how cells from the niche alter their functions in the presence of drugs, and how drug-altered cells impact on MM cells during therapy.WP4: Screen chemical libraries for drugs active on generated sensitive cell lines, develop innovative inhibitors and provide proof of principle for a phase I/II trial