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Proteasome inhibitor therapy in multiple myeloma

The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusettes

Requests for reprints: Kenneth C. Anderson, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Fax: 617-632-2140. E-mail: kenneth_anderson{at}dfci.harvard.edu

Multiple myeloma remains incurable despite available therapies, and novel therapies that target both tumor cell and bone marrow microenvironment are urgently needed. Preclinical in vitro and in vivo studies show remarkable anti–multiple myeloma activity of the proteasome inhibitor bortezomib/PS-341 even in multiple myeloma cells refractory to multiple prior therapies, including dexamethasone, melphalan, and thalidomide. Based on these findings, the U.S. Food and Drug Administration recently approved the first proteasome inhibitor bortezomib (Velcade), formerly known as PS-341, for the treatment of relapsed/refractory multiple myeloma. Bortezomib therapy has set an outstanding example of translational research in the field of oncology. Genomics and proteomic studies further provide rationale for combining bortezomib with conventional and novel agents to inhibit multiple myeloma growth, overcome drug resistance, reduce attendant toxicity, and improve patient outcome in multiple myeloma.

Key Words: Proteasomes • Multiple Myeloma • growth • apoptosis • drug resistance

Grant support: NIH grants 50947 and CA 78373 (K.C. Anderson), Specialized Programs of Research Excellence grants P50 CA100707-01 and P01 CA078378-06 (K.C. Anderson), Doris Duke Distinguished Clinical Research Scientist Award (K.C. Anderson), Multiple Myeloma Research Foundation senior research award (D. Chauhan, T. Hideshima, and C. Mitsiades), Myeloma Research Fund, and Cure Myeloma Fund.

Received 12/17/04; revised 2/ 4/05; accepted 2/15/05.