Proteasome inhibitors (PIs), namely bortezomib, have become a cornerstone 
therapy for multiple myeloma (MM), potently reducing tumor burden and inhibiting 
pathologic bone destruction. In clinical trials, carfilzomib, a next generation 
epoxyketone-based irreversible PI, has exhibited potent anti-myeloma efficacy 
and decreased side effects compared with bortezomib. Carfilzomib and its orally 
bioavailable analog oprozomib, effectively decreased MM cell viability following 
continual or transient treatment mimicking in vivo pharmacokinetics. 
Interactions between myeloma cells and the bone marrow (BM) microenvironment 
augment the number and activity of bone-resorbing osteoclasts (OCs) while 
inhibiting bone-forming osteoblasts (OBs), resulting in increased tumor growth 
and osteolytic lesions. At clinically relevant concentrations, carfilzomib and 
oprozomib directly inhibited OC formation and bone resorption in vitro, while 
enhancing osteogenic differentiation and matrix mineralization. Accordingly, 
carfilzomib and oprozomib increased trabecular bone volume, decreased bone 
resorption and enhanced bone formation in non-tumor bearing mice. Finally, in 
mouse models of disseminated MM, the epoxyketone-based PIs decreased murine 
5TGM1 and human RPMI-8226 tumor burden and prevented bone loss. These data 
demonstrate that, in addition to anti-myeloma properties, carfilzomib and 
oprozomib effectively shift the bone microenvironment from a catabolic to an 
anabolic state and, similar to bortezomib, may decrease skeletal complications 
of MM.