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Bortezomib for multiple myeloma

The ubquitin–proteasome pathway is a key regulator of homeostasis within cells, degrading misfolded or redundant proteins, and also those involved in mediating transcription, cell-cycle progression and apoptosis. Inhibition of the 26S proteasome results in accumulation of such proteins and ultimately leads to cell death. Malignant cells are more susceptible to proteasome inhibition due to their higher proliferation rates, protein production and their dependence on anti-apoptotic molecules for cell survival. Bortezomib has recently gained European Commission approval for the treatment of relapsed multiple myeloma on the basis of clinical trials demonstrating its efficacy, tolerability and superiority to high-dose dexamethasone. Preclinical data demonstrates the ability to synergise with other chemotherapeutic agents and overcome drug resistance, and hence combination studies are underway. This review describes the pharmacology, toxicity, preclinical and clinical activity of bortezomib, predominantly in the setting of multiple myeloma.