The iperactivation of self-renewal mechanisms, like Hedgehog (HH) pathway, which govern the refuel of Multiple Myeloma neoplastic clone, is critical to relapse events. The bulk of current knowledge is mainly based on the CD138+ cells molecular characterization, but in the light of the recent evidences, which attributed growing relevance to immature precursor clones, we become aware that multiple myeloma disease heterogeneity have more deepen roots. Here, we report on a high-throughput transcriptome study of gene expression profiles in newly diagnosed MM patients analyzed both in the CD138+ plasmacell fraction and in the CD19+ B cells compartment. Resulted data demonstrated that Hedgehog pathway, and in particular, a 10 HH-genes signature was heterogeneously expressed among MM patients, both in mature plasmacells and also in B cells at transcriptional level. Interestingly, this signature divide patients in two subgroups, and it seems that exists a sort of “ying-yang effect” between mature and immature cell compartments that are tightly regulate in order to express this relevant self-renewal pathway according to their maturation state. 144 samples have been analyzed: 126 BM-CD138+, 7 BM-B cells and 11 PBL-B cells; the homogeneity of samples has been ensured by the immunomagnetic enrichment procedure: only >90% pure cells have been employed.