Session Speaker

Proteasome Inhibition Therapies in the Management of Patients with Multiple Myeloma
Evangelos Terpos and Meletios A. Dimopoulos
Greece

Multiple myeloma (MM), a clonal neoplastic proliferation of plasma cells, is the second most common hematologic malignancy and is responsible for approximately 11,000 deaths per year in the United States and more than 19,000 deaths per year in Europe. The ubiquitin-proteasome system has become a promising novel molecular target in cancer due to its critical role in cellular protein degradation, its interaction with important pathways of cell cycle and apoptosis regulation and thus its unique mechanism of action. Bortezomib as first-in-class proteasome inhibitor has proven to be a highly effective compound in some hematological malignancies, overcoming conventional chemoresistance, directly inducing cell cycle arrest and apoptosis, and targeting the tumor microenvironment. It has been granted approval for relapsed MM and for newly diagnosed MM patients who are not eligible for autologous transplantation. Further combinations with conventional chemotherapeutic agents and immunomodulatory drugs have been developed providing high remission rates, better remission quality and prolonged survival. Bortezomib is also very effective in some of the complications of MM, such as in lytic bone disease and in renal impairment. It induces bone formation and is able to reverse renal dysfunction in a significant proportion of patients. Novel proteasome inhibitors, e.g. carfilzomib and NPI-0052, have been developed and have been already entered in phase 2 and 3 studies for MM. Carfilzomib is more selective for the chymotrypsin-like protease activity of the proteasome than bortezomib. Phase 2 studies in patients with refractory and relapsed MM showed that carfilzomib was active in patients with bortezomib-naïve disease, inducing partial response or better in at least 50% of patients as well as in patients who had been previously exposed to bortezomib, inducing minor response or better in at least 25% of patients. NPI-0052, also known as salinosporamide A, is related to one of the first proteasome inhibitors identified in nature, lactacystin. This agent has also shown encouraging results in the relapsed/refractory MM. In conclusion, proteasome inhibitors seem to have major role in the management of patients with MM but also with other malignancies, such as mantle cell lymphoma and solid tumors. Combinations with other anti-myeloma agents are expected to become the standard of care for several subsets of MM patients.