Therapeutic Options in Multiple Myeloma: Focus on Bortezomib

Abstract

Myeloma is the most frequent malignancy to involve the bone. The bone microenvironment plays an important role in supporting tumor growth, bone destruction and resistance to chemotherapy. Until the advent of novel therapies such as bortezomib, the prognosis for patients with myeloma did not change significantly over 40 years. The median survival of patients until 1996 was approximately 30 months, and has now improved to almost 5 years. Bortezomib is the first-in-class proteasome antagonist approved for treatment of myeloma. It is active in newly diagnosed, relapsed and refractory patients and is now being used as a platform for combinations with other new agents for myeloma. Its major side effects include neuropathy and thrombocytopenia. In addition to its anti-myeloma effect, bortezomib also targets the bone microenvironment and can inhibit osteoclast formation, and stimulate osteoblast activity in patients with myeloma. Potentially, combination of bortezomib with other agents that stimulate bone formation or block bone resorption will further enhance the anti-myeloma effects of bortezomib and overcome the contribution of the tumor microenvironment to myeloma growth. Multiple myeloma (MM) is a primary plasma cell malignancy, which is the most frequent malignancy to involve the bone. Over 80% of patients with MM have bone involvement during the course of their disease. 1 The prognosis for patients with MM had not changed significantly over the last 40 years until the last 5 years. 2 The median survival of patients up to 1996 was approximately 30 months, and this has now improved to almost 5 years with the advent of newer therapies. The new therapies that have made a major impact on the survival and quality of life in MM patients have been the introduction of immunomodulatory drugs (IMiDs) and bortezomib, which is the first-in-class proteasome antagonist to come to the clinic. Both the IMiDs, thalidomide and lenalidomide, and bortezomib have been used alone and in combination with dexamethasone as well as with each other to treat MM patients. These agents have increased response rates and prolonged both progression free survival and overall survival of patients with relapsed and/or refractory MM from 12 months to 24 months and newly diagnosed MM from 30 months to 45 months. Further, these drugs also have effects on MM bone disease, either by suppressing osteoclast (OCL) activity or in the case of bortezomib enhancing osteoblast (OBL) activity. In this review, we will examine the mechanism of action of bortezomib and its capacity to target MM cells as well as the marrow microenvironment in patients with MM.