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Multiple myeloma (MM) is a malignancy of plasma cells within the bone marrow characterized by bone loss, renal disease, and immunodeficiency. Recent advances in the understanding of MM pathogenesis have improved established conventional cytotoxic therapy as well as transplantation regimens. Despite these advances, median overall survival is only 3–5 years. Therefore new therapies are urgently needed. Besides thalidomide, whose antimyeloma activity has only recently been defined, a plethora of novel agents, including the thalidomide-derived immunomodulatory drugs and bortezomib, have been identified to directly target the tumor cell or its microenvironment, and thereby inhibit MM cell growth and survival, and to overcome drug resistance. After validation of their preclinical anti-MM activity, several clinical trials are now ongoing to test the efficacy of these novel therapeutics, administered alone or in combination with conventional or other novel therapeutics and bone marrow transplantation. This article reviews the development of MM therapy, from its initial description approximately 150 years ago to the novel therapy regimens of recent years, highlighting that MM may soon become a chronic disease. [ABSTRACT FROM AUTHOR]

Proteasome inhibition is a new approach under investigation for cancer therapy. Protein degradation by the proteasome is a fundamental metabolic process. Inhibition of the proteasome has been shown to result in cell-cycle arrest and programmed cell death. Bortezomib (Velcade®; formerly PS-341, Millennium Pharmaceuticals, Inc, Cambridge, Massachusetts) is the first proteasome inhibitor to enter clinical trials and is approved for the treatment of multiple myeloma in patients who have received at least two prior therapies and progressed on their last therapy. It is also being investigated for the treatment of a range of other cancers, both solid and hematologic. In preclinical studies, bortezomib causes apoptosis in cancer cells and seems to enhance the cytotoxicity of other conventional tumoricidal agents in human tumor cell lines, murine tumor models, and human xenograft models. In addition to targeting cancer cells directly, there is growing evidence that proteasome inhibition interferes with protective interactions between cancer cells and the bone marrow and may also act to prevent tumor-associated angiogenesis. Preliminary data suggest that bortezomib inhibits proteasome activity in a dose-dependent and reversible manner, and has manageable toxicities. A phase II trial in relapsed and refractory multiple myeloma patients indicated that patients experienced substantial anticancer activity when treated with bortezomib monotherapy. [ABSTRACT FROM AUTHOR]