BACKGROUND: In our efforts to develop novel effective treatment regimens for 
multiple myeloma we evaluated the potential benefits of combining the 
immunomodulatory drug lenalidomide with daratumumab. Daratumumab is a novel 
human CD38 monoclonal antibody which kills CD38+ multiple myeloma cells via 
antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity 
and apoptosis.
DESIGN AND METHODS: To explore the effect of lenalidomide combined with 
daratumumab, we first carried out standard antibody-dependent cell-mediated 
cytotoxicity and complement-dependent cytotoxicity assays in which the CD38+ 
multiple myeloma cell line UM-9 and primary multiple myeloma cells isolated from 
patients were used as target cells. We also tested the effect of lenalidomide on 
daratumumab-dependent cell-mediated-cytotoxicity and complement-dependent 
cytotoxicity of multiple myeloma cells directly in the bone marrow mononuclear 
cells of multiple myeloma patients. Finally, we determined the 
daratumumab-dependent cell-mediated cytotoxicity using peripheral blood 
mononuclear cells of multiple myeloma patients receiving lenalidomide treatment.
RESULTS: Daratumumab-dependent cell-mediated cytotoxicity of purified primary 
multiple myeloma cells, as well as of the UM-9 cell line, was significantly 
augmented by lenalidomide pre-treatment of the effector cells derived from 
peripheral blood mononuclear cells from healthy individuals. More importantly, 
we demonstrated a clear synergy between lenalidomide and daratumumab-induced 
antibody-dependent cell-mediated cytotoxicity directly in the bone marrow 
mononuclear cells of multiple myeloma patients, indicating that lenalidomide can 
also potentiate the daratumumab-dependent lysis of myeloma cells by activating 
the autologous effector cells within the natural environment of malignant cells. 
Finally, daratumumab-dependent cell-mediated cytotoxicity was significantly 
up-regulated in peripheral blood mononuclear cells derived from 3 multiple 
myeloma patients during lenalidomide treatment.
CONCLUSIONS: Our results indicate that powerful and complementary effects may be 
achieved by combining lenalidomide and daratumumab in the clinical management of 
multiple myeloma.