Daratumumab is a CD38-directed monoclonal antibody approved as monotherapy for the treatment of multiple myeloma (MM). Results from recent randomized trials have demonstrated synergy between daratumumab and lenalidomide and bortezomib in the treatment of relapsed MM.
In addition to a direct anti-CD38 effect, induction of complement dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis (ADCP) are thought to be mechanisms of activity of daratumumab.
Previously, Pallach and colleagues reported that combination regimens of therapeutic antibodies and chemotherapy could overcome resistance to macrophage-mediated killing in lymphoid malignancy; specifically cyclophosphamide was shown to induce an acute secretory response that led to macrophage infiltration and phagocytic activity in bone marrow.1 Rigalou and colleagues sought to build on this work by studying the effects on macrophage-induced ADCP of drugs likely to be used in combination with daratumumab in MM.
They were able to show that cyclophosphamide, lenalidomide, and bortezomib were able individually and in combination to enhance the percentage of daratumumab clearance of MM1S cells (P<0.01), an effect that was partially reversed by incubation of macrophage co-cultures with cytochalasin D (P<0.01), which indicates that ADCP is a likely mechanism of tumor cell clearance. Downregulation of CD47 on chemotherapy-treated MM1S cells was also observed, which could enhance phagocytosis.
These effects “may explain in part the dramatic synergy observed between lenalidomide, bortezomib, and daratumumab in clinical trials, and provides a rationale for combining cyclophosphamide with daratumumab in the clinic,” the authors concluded.
Rigalou A, et al. ASH 2016. Abstract 2101.
- Pallasch CP, et al. Cell. 2014;156(3):590-602.