T-cell expression of programmed death receptor-1 (PD-1) down-regulates the 
immune response against malignancy by interacting with cognate ligands (eg, 
PD-L1) on tumor cells; however, little is known regarding PD-1 and natural 
killer (NK) cells. NK cells exert cytotoxicity against multiple myeloma (MM), an 
effect enhanced through novel therapies. We show that NK cells from MM patients 
express PD-1 whereas normal NK cells do not and confirm PD-L1 on primary MM 
cells. Engagement of PD-1 with PD-L1 should down-modulate the NK-cell versus MM 
effect. We demonstrate that CT-011, a novel anti-PD-1 antibody, enhances human 
NK-cell function against autologous, primary MM cells, seemingly through effects 
on NK-cell trafficking, immune complex formation with MM cells, and cytotoxicity 
specifically toward PD-L1(+) MM tumor cells but not normal cells. We show that 
lenalidomide down-regulates PD-L1 on primary MM cells and may augment CT-011's 
enhancement of NK-cell function against MM. We demonstrate a role for the 
PD-1/PD-L1 signaling axis in the NK-cell immune response against MM and a role 
for CT-011 in enhancing the NK-cell versus MM effect. A phase 2 clinical trial 
of CT-011 in combination with lenalidomide for patients with MM should be 
considered.