Abstract Background Although the advances in Multiple Myeloma (MM) therapy, the disease remains incurable. The existence of Myeloma Propagating Cells (MPCs) is supposed to be one of the major causes of MM drug-resistance, leading to relapse. However, very little is known about the molecular characteristics of MPCs, even if some studies suggested that these cells have phenotypic characteristics resembling the memory B cells. Aim and methods In order to molecularly characterize the CD138+ neoplastic clone and the memory B cells located both in BM and in PBL, we collected the CD138+ and CD138-19+27+ cell fractions from bone marrow (BM) and peripheral blood (PBL) of 50 newly diagnosed MM patients (pts), 7 MGUS pts and 15 relapsed pts. For several pts we collected buccal swab sample as a negative control. The complete set of genomic aberrations was evaluated by SNP Array 6.0 and copy number analysis was performed with Genotyping Console software and Partek Genomics. Results Both BM and PBL CD138+ cell fractions showed exactly the same genomic macro-alterations. In the BM and PBL CD138-19+27+ cell fractions any macro-alteration was detected, whereas several micro-alterations (range: 1-834 Kb) unique of the memory B cells clone, were highlighted. These micro-alterations were located out of any genomic variants region and are presumably associated to the MM pathogenesis. The micro-alterations involved HMGCLL1, DLGAP2 and RCOR3, PRR16, TSC1, ETS1, RBFOX1 in CD138-19+27+ derived from PBL and BM, respectively. These genes participated in cholesterol metabolism, embryonic development and transcriptional regulation. Interestingly, three focal micro-deletions (involving SKT, CES1P1, MIR650) were shared both by the PBL and the BM memory B cells clones. The MIR650 gene is located on chr22 in the immunoglobulin lambda gene locus, thus directly controlling its expression. By applying a more stringent analysis, the CD138-19+27+ cell fraction obtained from all pts analyzed showed a unique micro-deletion (410 Kb) on chr 14, involving JAG2, BRF1, PACS2, NUDT4 and BTBD6. This deletion has been already described as involved in a pediatric syndrome of chr.14q, and its presence is correlated to a variety of developmental disorders and mental retardation. Conclusions These data suggested that the MM CD138+ clone might resume the end of the complex process of myelomagenesis, proven by the presence of numerous macro-alterations, which might be probably due to an established genomic instability. In contrast, the memory B cells, which lack these macro-alterations, have some intriguing micro-alterations, supporting the idea that these post germinal center cells might be involved in the transforming event that originate the neoplastic clone. Work supported by European LeukemiaNet, AIRC, AIL, PRIN, University of Bologna and BolognAIL. Citation Format: Marina Martello, Carolina Terragna, Giovanni Martinelli, Enrica Borsi, Elena Zamagni, Lucia Pantani, Paola Tacchetti, Beatrice Zannetti, Katia Mancuso, Flores Dico, Michele Cavo. Genomic characterization of the putative myeloma stem cells clone reveals alterations possibly correlated with the origin of disease. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3749. doi:10.1158/1538-7445.AM2013-3749