Multiple myeloma (MM) remains incurable despite important recent advances in 
treatment due to its inherent resistance, characterized by highly complex and 
heterogeneous molecular abnormalities, as well as the support from myeloma bone 
marrow (BM) microenvironment. A novel therapeutic strategy that effectively 
targets specific molecules on myeloma cells and also potentially overcomes tumor 
microenvironment-mediated drug resistance and the downstream effects of genetic 
instability is thus urgently needed. Over the last 2 years, an anti-CD38 
monoclonal antibody daratumumab (DARA) has emerged as a breakthrough targeted 
therapy for patients with MM. Early-stage clinical trials have found DARA to be 
safe and to have encouraging clinical activity as a single agent and in 
combination with lenalidomide in heavily pretreated, relapsed patients in whom 
other novel agents (such as bortezomib, thalidomide and lenalidomide) as well as 
stem cell transplant has already failed. DARA may, therefore, be the first mAb 
with significant anti-MM activity both as a monotherapy and in combination. It 
is currently being further evaluated both alone and in combination with 
conventional and novel anti-MM agents as part of prospective clinical trials. 
This review discusses the preclinical and clinical development of DARA, its 
pathophysiological basis, and its prospects for future use in MM.