The proteasome has emerged as an important target for cancer therapy with the 
approval of bortezomib, a first-in-class, reversible proteasome inhibitor, for 
relapsed/refractory multiple myeloma (MM). However, many patients have disease 
that does not respond to bortezomib, whereas others develop resistance, 
suggesting the need for other inhibitors with enhanced activity. We therefore 
evaluated a novel, irreversible, epoxomicin-related proteasome inhibitor, 
carfilzomib. In models of MM, this agent potently bound and specifically 
inhibited the chymotrypsin-like proteasome and immunoproteasome activities, 
resulting in accumulation of ubiquitinated substrates. Carfilzomib induced a 
dose- and time-dependent inhibition of proliferation, ultimately leading to 
apoptosis. Programmed cell death was associated with activation of 
c-Jun-N-terminal kinase, mitochondrial membrane depolarization, release of 
cytochrome c, and activation of both intrinsic and extrinsic caspase pathways. 
This agent also inhibited proliferation and activated apoptosis in 
patient-derived MM cells and neoplastic cells from patients with other 
hematologic malignancies. Importantly, carfilzomib showed increased efficacy 
compared with bortezomib and was active against bortezomib-resistant MM cell 
lines and samples from patients with clinical bortezomib resistance. Carfilzomib 
also overcame resistance to other conventional agents and acted synergistically 
with dexamethasone to enhance cell death. Taken together, these data provide a 
rationale for the clinical evaluation of carfilzomib in MM.