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Purpose: Daratumumab and its use in combination with other agents is becoming a new standard of care for the treatment of multiple myeloma. We mechanistically studied how daratumumab acts on natural killer (NK) cells. Experimental Design: Quantities of NK cells in peripheral blood and/or bone marrow of patients with multiple myeloma or healthy donors were examined by flow cytometry. NK-cell apoptosis and the associated mechanism were assessed by flow cytometry and immunoblotting. Patients' NK cells were expanded in vitro using feeder cells. Combination treatment of daratumumab and expanded NK cells was performed using an MM.1S xenograft animal model. Results: CD38 -/low NK cells survived, whereas CD38 + NK cells were almost completely eliminated, in peripheral blood and bone marrow of daratumumab-treated multiple myeloma patients. NK-cell depletion occurred due to daratumumab-induced NK-cell fratricide via antibody-dependent cellular cytotoxicity. Consequently, CD38 -/low NK cells were more effective for eradicating multiple myeloma cells than were CD38 + NK cells in the presence of daratumumab. Blockade of CD38 with the F(ab) 2 fragments of daratumumab inhibited the antibody-mediated NK-cell fratricide. CD38 -/low NK cells displayed a significantly better potential for expansion than CD38 + NK cells, and the expanded NK cells derived from the former population were more cytotoxic than those derived from the latter against multiple myeloma cells. Therefore, infusion of ex vivo -expanded autologous NK cells from daratumumab-treated patients may improve the antibody therapy. Conclusions: We unravel a fratricide mechanism for daratumumab-mediated NK-cell depletion and provide a potential therapeutic strategy to overcome this side effect in daratumumab-treated patients with multiple myeloma. Clin Cancer Res; 24(16); 4006-17. ©2018 AACR .

Fratricide of NK Cells in Daratumumab Therapy for Multiple Myeloma Overcome by Ex Vivo–Expanded Autologous NK Cells