Bone destruction is a prominent feature of multiple myeloma, but conflicting 
data exist on the expression and pathophysiologic involvement of the bone 
remodeling ligand RANKL in this disease and the potential therapeutic benefits 
of its targeted inhibition. Here, we show that RANKL is expressed by primary 
multiple myeloma and chronic lymphocytic leukemia (CLL) cells, whereas release 
of soluble RANKL was observed exclusively with multiple myeloma cells and was 
strongly influenced by posttranscriptional/posttranslational regulation. 
Signaling via RANKL into multiple myeloma and CLL cells induced release of 
cytokines involved in disease pathophysiology. Both the effects of RANKL on 
osteoclastogenesis and cytokine production by malignant cells could be blocked 
by disruption of RANK-RANKL interaction with denosumab. As we aimed to combine 
neutralization of RANKL with induction of antibody-dependent cellular 
cytotoxicity of natural killer (NK) cells against RANKL-expressing malignant 
cells and as denosumab does not stimulate NK reactivity, we generated RANK-Fc 
fusion proteins with modified Fc moieties. The latter displayed similar capacity 
compared with denosumab to neutralize the effects of RANKL on osteoclastogenesis 
in vitro, but also potently stimulated NK cell reactivity against primary 
RANKL-expressing malignant B cells, which was dependent on their engineered 
affinity to CD16. Our findings introduce Fc-optimized RANK-Ig fusion proteins as 
attractive tools to neutralize the detrimental function of RANKL while at the 
same time potently stimulating NK cell antitumor immunity.