Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab.
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.


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.
Dept. of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.
Michael S
MS
van der Veer
Michel
M
de Weers
Berris
B
van Kessel
Joost M
JM
Bakker
Shulamiet
S
Wittebol
Paul W H I
PW
Parren
Henk M
HM
Lokhorst
Tuna
T
Mutis
D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology; D003165:Complement System Proteins / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D007167:Immunotherapy; D000077269:Lenalidomide; D009101:Multiple Myeloma / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; C556306:daratumumab; D013792:Thalidomide; D003165:Complement System Proteins; D000077269:Lenalidomide