Abstract
The development of the proteasome inhibitor bortezomib is a prime example of successful bench-to-bedside research. NF-κB is implicated in the pathogenesis of multiple myeloma (MM), and bortezomib blocks NF-κB activation and its sequelae. Additional bortezomib mechanisms include interactions at the MM cell surface and mitochondrial level and in downstream apoptotic signaling. In the pivotal bortezomib study, the response rate was 35%; time to progression (TTP), 7 months; and median duration of response, 14.3 months. Responses were associated with improvements in quality of life, increases in laboratory parameters, and decreased transfusions. Bortezomib is thus indicated in the US for patients with relapsed, progressive MM and recommended for approval in Europe. The confirmatory phase III trial has been stopped early due to a significant improvement in TTP with bortezomib. The success of bortezomib in MM demonstrates the utility of targeting the tumour:host interaction and BM milieu, in addition to the tumour itself.
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