Multiple Myeloma (MM) is a still lethal disease in 2012 characterized by the accumulation in the bone marrow of a clone of malignant plasma cells (MMC for multiple myeloma cells). High dose chemotherapy (HDC) and hematopoietic stem cell (HSC) transplantation, in association with novel drugs as proteasome inhibitor (Bortezomib) or immunomodulatory agents (Lenalidomide and Thalidomide) have allowed survival improvement. Genomic instability is a characteristic feature of myeloma cells. Although there has been substantial work performed on the genetics of myeloma, little is known about the epigenetic changes leading to disease progression. Recent studies have shown that epigenetic modifications such as DNA methylation play a role by silencing various cancer-related genes in MM. DNA methyltransferase (DNMT) inhibitors or histone deacetylase (HDAC) inhibitors are now being used in the treatment of some hematologic malignancies, including MM. Here, we describe the results of a microarray-based genome-wide screen for genes responding to DNMT inhibition and HDAC inhibition in MM cell lines. Based on the results of our microarray assay, we built new “DNA methylation gene score” and “histone acetylation gene score” that make it possible identification of myeloma patients that will be sensitive to DNMT inhibitors or HDAC inhibitors. In our project, we plan to realize the proof of concept on our large panel of myeloma cell lines and primary myeloma cells. We will test DNMT inhibitors or HDAC inhibitors alone or in association with conventional treatment of MM and correlate the drug toxicity with the “DNA methylation gene score” and “histone acetylation gene score”. There are 2000 newly-diagnosed patients with MM in France, about 20000 in EU, and the costs of myeloma treatments are among the highest of cancer treatment costs. This work could deliver new tools to progress in the treatment of MM patients and maximize the benefit/cost ratio.