Multiple myeloma (MM) is a malignant blood cancer that results from the infiltration69 of abnormal clonal plasma cells into the bone marrow and immune evasion.1 Risk70 factors include increased age, male gender, family background and mostly genetic71 modifications, such as chromosomal translocations and hyperdiploidy 1,2. In72 patients with disease double refractory to a proteasome inhibitor (PI) and an73 immunomodulatory drug (IMiD), life expectancy is around 9 months 3.74 Over the last years, researchers have put great effort on the clinical development of75 innovative and more efficacious drugs, such as immunomodulators (e.g.76 lenalidomide), proteasome inhibitors (e.g. bortezomib), histone deacetylase inhibitors77 (e.g. panobinostat), and monoclonal antibodies (e.g.daratumumab, elotuzumab) 3,78 4. Many studies have focused on CD38, a 46-kDa type II multifunctional79 transmembrane glycoprotein that plays an important role in hemato-oncology80 malignancies, from both lymphoid and myeloid origin, such as chronic81 lymphoproliferative leukemia and myeloma 5, 6. However, CD38 receptors are also82 present, with lower expression, in normal cells, such as red blood cells (RBCs),83 myeloid cells and platelets 7, 8. Human CD38 acts as an enzyme with cyclase and84 hydrolase activities, mediates lymphocyte endothelial adhesion and promotes85 proliferation of both T and B immune cells 3, 9, 10. Thus, the presence of this86 receptor is recognized as a prognostic factor and a potential therapy target as its87 overexpression is associated with decreased immune function and disease88 progression in patients with myeloma 11, 12.89 Daratumumab, a fully human IgG1 monoclonal antibody, approved by the US Food90 and Drug Administration (FDA) in November 2015, and by the European Medicinal91 Agency (EMA) in May 2016, has brought an important rescue for heavily treated92 patients with relapsed and refractory multiple myeloma (RRMM). Two studies, phase93 1/2 GEN501 and phase 2 SIRIUS, were completed to access the efficacy and safety94 of daratumumab monotherapy in patients with RRMM, which received a median of 595 prior lines of therapy, being 86.5% double refractory to a proteasome inhibitor (PI)

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