In the last decades CD38 has emerged as an attractive target for multiple myeloma (MM). CD38 is a novel multifunctional glycoprotein that acts as a receptor, adhesion molecule interacting with CD31 and as an ectoenzyme. As an ectoenzyme, CD38 functions as a metabolic sensor catalyzing the extracellular conversion of NAD+ to the immunosuppressive factor adenosine (ADO). Other ectoenzymes, CD73 and CD203a, together with CD38, are also involved in the alternative axis of extracellular production of ADO, bypassing the canonical pathway mediated by CD39. CD38 is ubiquitously expressed in the bone marrow microenvironment; however, only MM cells display a very high surface density, which lead to the development of several anti-CD38 monoclonal antibodies (mAbs). The efficacy of anti-CD38 mAbs depends from the presence of CD38 on the surface of MM and immune-microenvironment cells. Interestingly, it has been reported that several drugs like lenalidomide, panobinostat, the all-trans retinoic acid and the DNA methyltransferase inhibitors may increase the expression of CD38. Hence, the possibility to modulate CD38 by increasing its expression on MM cells is the pre-requisite to potentiate the clinical efficacy of the anti-CD38 mAbs and to design clinical trials with the combination of anti-CD38 mAbs and these drugs.MM is a hematological cancer characterized by the accumulation and proliferation of malignant plasma cells (PCs) in the BM [9]. The close interaction between PCs and BM microenvironment cells creates a permissive niche for tumor survival and disease progression, characterized by osteolytic bone disease and immune-suppression [10]. Both soluble factors and cell-to-cell contact mechanisms are involved in this cross-talk. Among the surface molecules, which allow the adhesion to the microenvironment, MM cells highly express CD38 [11], which made it an attractive therapeutic target for mAbs [12,13]. Several studies demonstrated that only PCs strongly express CD38 antigens in BM, and that no PCs are detectable in either CD38 neg cell fraction or fraction of cells weakly expressing CD38 antigens (CD38 low ) [14,15]. However, activated B cell, T cells and NK cells up-regulate CD38 surface expression to levels similar to that found on PCs [16].CD38 is a 45-kDa type II transmembrane glycoprotein, which plays a dual role as a receptor and ectoenzyme [17]. It is expressed on normal cell subsets, such as T cells, NK cells, B cells, and dendritic cells [18]. It is involved in T cell activation and proliferation, B cell differentiation, and neutrophils and monocytes chemotaxis, [17,19,20]. In addition, CD38 interacts with the non-substrate ligand CD31, which is constitutively expressed by endothelial cells [21]. Interestingly, a co-expression of CD38 and CD31 was also demonstrated in MM cells but not on PC leukemia [22]. Accordingly, we have recently reported that extra-medullary MM cells can also lose the expression of CD38 [23].As ectoenzyme, CD38 acts like a metabolic sensor which catalyzes the extracellular conversion of NAD...