Daratumumab is an anti-CD38 monoclonal antibody with lytic activity against 
multiple myeloma (MM) cells, including ADCC (antibody-dependent cellular 
cytotoxicity) and CDC (complement-dependent cytotoxicity). Owing to a marked 
heterogeneity of response to daratumumab therapy in MM, we investigated 
determinants of the sensitivity of MM cells toward daratumumab-mediated ADCC and 
CDC. In bone marrow samples from 144 MM patients, we observed no difference in 
daratumumab-mediated lysis between newly diagnosed or relapsed/refractory 
patients. However, we discovered, next to an expected effect of effector 
(natural killer cells/monocytes) to target (MM cells) ratio on ADCC, a 
significant association between CD38 expression and daratumumab-mediated ADCC 
(127 patients), as well as CDC (56 patients). Similarly, experiments with 
isogenic MM cell lines expressing different levels of CD38 revealed that the 
level of CD38 expression is an important determinant of daratumumab-mediated 
ADCC and CDC. Importantly, all-trans retinoic acid (ATRA) increased CD38 
expression levels but also reduced expression of the complement-inhibitory 
proteins CD55 and CD59 in both cell lines and primary MM samples. This resulted 
in a significant enhancement of the activity of daratumumab in vitro and in a 
humanized MM mouse model as well. Our results provide the preclinical rationale 
for further evaluation of daratumumab combined with ATRA in MM patients.