Current status of bortezomib in the treatment of multiple myeloma.

Bortezomib (formerly PS-341) has been the first proteasome inhibitor to enter clinical trials in cancer patients. Preclinical studies showing that this novel agent directly inhibits the proliferation of myeloma cells, induces their apoptosis, and abrogates paracrine tumor growth through alteration of interactions of myeloma and stromal cells and through nuclear factor kappaB-dependent cytokine secretion prompted the design of large phase II and III studies of bortezomib in patients with advanced relapsed and/or refractory multiple myeloma. Favorable results of these studies led to accelerated approval for use of bortezomib in patients with multiple myeloma who have progressed after at least their second therapy and, more recently, to expanded approval for second-line use in patients in whom one prior therapy has failed. Combination studies of bortezomib with various agents, including dexamethasone, DNA-damaging drugs (such as melphalan, cyclophosphamide, and doxorubicin), thalidomide, and lenalidomide, are currently ongoing in patients with both relapsed/refractory and newly diagnosed disease. Bortezomib may be the "backbone" for the development of more effective treatment strategies to improve patient outcome in multiple myeloma.