CD38 is a glycoprotein expressed at a low level in myeloid and lymphoid tissues. However, it is highly and homogeneously expressed in plasma cells (PC) in multiple myeloma. Daratumumab is a human CD38-specific IgG1 antibody available for the treatment of multiple myeloma in Colombia. It has been authorized in relapsed/refractory disease as front-line treatment for non-eligible stem cell transplantation patients by INVIMA (Instituto Nacional de Vigilancia de Medicamentos y Alimentos) that is the regulatory agency. Daratumumab treatment has been associated with the negativization of the expression of CD38 in PC, demonstrating a resistance mechanism under the clonal evolution theory. We report the case of a 63-year-old male, diagnosed with a relapsed/refractory multiple myeloma, heavily treated, who expressed strong CD38 marker at the beginning of the treatment, with a posterior negativization of CD38 after four cycles of treatment with daratumumab.