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Figure 3: Lenalidomide alone, or in combination with a variety of therapeutic monoclonal antibodies, increases NK-cell-mediated killing of multiple myeloma cells. Lenalidomide (LEN) increases IL-2 secretion from by-standing T helper cells which augments NK cell activity. Lenalidomide, as described previously, upregulates Fas expression and costimulatory molecules on MM cells leading to greater Fas-mediated apoptosis. Lenalidomide has also been shown to augment the ADCC effect of various monoclonal antibodies like Rituximab (anti-CD20), GA-101 (glycoengineered anti-CD20), and CT-011 (anti-PDL-1). CT-011 blocks PD-1 ligand on the MM cells, interfering with binding to PD-1 and inhibiting NK cell activity. Binding of the anti-CD20 antibodies to their targets on MM cells increases complement-dependent cytotoxicity (CDC), as well as NK-cell recognition and killing of the MM cells. IPH2101 is an anti-inhibitory KIR that has been shown in combination with lenalidomide to increase NK-cell killing as well, as blocking the inhibitory signals allows for NK activation and detection of the tumor cells.