Monoclonal gammopathy of undetermined significance (MGUS) is a benign condition with 30% of patient developing symptomatic multiple myeloma (MM). The events leading to the transformation from MGUS to MM remain unclear, however several evidences have supported the idea that the immune system, in patients with MGUS, may play a role in controlling the progression to MM; and the identification of antigenic targets could open the way for future immunotherapeutic approaches to delay or prevent such progression. To identify target antigens that are recognized by the immune system in MGUS, we have screened a cDNA expression library, produced from purified CD138+ bone marrow myeloma cells, with high dilution (1:500) serum from 3 MGUS patients with stable disease for 1 to 4 years. Using this approach we were able to identify a panel of 11 gene products to which an antibody response was observed in serum from individuals with MGUS. Responses appeared to be directed against intracellular proteins involved in variety of cellular functions such as apoptosis (SON, Hip1), DNA and RNA binding (KIAA0530, GPATC4), signal transduction regulators (AKAP11), transcriptional co-repressors (IRF2BP2), developmental proteins (OFD1) and proteins involved in the ubiquitin-proteosome pathway (PSMC1). Interestingly PSMC1, the 26S subunit of proteosome, has recently emerged as a potential target for antimyeloma therapies and AKAP11 located on the 13q14.11, a locus frequently involved in the pathogenesis of aggressive MM. Importantly, two of these identified genes with antibody response have been previously identified by SEREX screenings; KIAA0530 has been reported to induce a strong antibody response in solid tumors such as head and neck, testicular, breast and colorectal cancers and SON, a protein involved in apoptosis with similarities to oncoproteins such as myc and mos, has been previously reported by us to induce an antibody response associated with a complete response after donor lymphocyte infusion in patients with MM. Our studies are now focused on testing these proteins in a series of MGUS serum at different stages of disease as well as in early stage myeloma. Although preliminary, these data open the possibility to identify target antigens that are important in the disease process of MGUS and may allow us to design future vaccines and immunotherapeutic approaches targeting these antigens in MGUS as well as in MM.