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

• Published in: Haematologica (Roma) Vol. 96; no. 2; pp. 284 - 290
• Main Authors: VAN DER VEER, Michael S, DE WEERS, Michel, VAN KESSEL, Berris, BAKKER, Joost M, WITTEBOL, Shulamiet, PARREN, Paul W. H. I, LOKHORST, Henk M, MUTIS, Tuna
• Format: Journal Article
• Language: English
• Published: Pavia Ferrata Storti Foundation 01-02-2011
• Subjects: Antibodies, Monoclonal - administration & dosage; Antibody-Dependent Cell Cytotoxicity - immunology; Antibody-dependent cell-mediated cytotoxicity; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; Autografts; Biological and medical sciences; Bone marrow; Bone Marrow - immunology; Bone Marrow - pathology; CD38 antigen; Complement System Proteins - immunology; Cytotoxicity; Cytotoxicity, Immunologic - immunology; Drugs; Effector cells; Hematologic and hematopoietic diseases; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunomodulation; Immunopathology; Immunophenotyping; Immunotherapy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Leukocytes (mononuclear); Medical sciences; Monoclonal antibodies; Multiple myeloma; Multiple Myeloma - immunology; Multiple Myeloma - metabolism; Multiple Myeloma - therapy; Original; Peripheral blood mononuclear cells; Thalidomide - administration & dosage; Thalidomide - analogs & derivatives; Tumor cell lines; Tumor Cells, Cultured; Antineoplastic agent; Human; Immunopathology; multiple myeloma; Hematology; Lenalidomide; B cell neoplasm; Malignant hemopathy; Monoclonal antibody; Lymphoid neoplasm; Myeloma; Treatment; Immunoglobulinopathy; Efficiency; Lymphoproliferative syndrome; Immunotherapy; daratumumab; Cancer
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2010.030759

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.
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.
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.
Our results indicate that powerful and complementary effects may be achieved by combining lenalidomide and daratumumab in the clinical management of multiple myeloma.