Importantly, daratumumab monotherapy is effective and well tolerated in heavily pre-treated lenalidomide and bortezomib-refractory myeloma patients. However, approximately 60% of patients do not achieve a partial response, and ultimately all patients, also those achieving complete response, will develop progressive disease during daratumumab therapy. Factors that determine the susceptibility of MM cells to daratumumab include levels of the target antigen CD38, and expression levels of the complement inhibitory proteins CD55 and CD59. At the time of progression, there is a reduced level of CD38 on the MM cells, whereas CD55 and CD59 levels are increased. This indicates that these factors are also involved in the development of daratumumab-resistant disease.