Multiple Myeloma

MULTIPLE MYELOMA

This plasma cell malignancy is one of the models of neoplastic disease in humans as it arises from a single tumor stem cell. Moreover, the tumor cells produce a marker protein (myeloma immunoglobulin) that allows the total body burden of tumor cells to be quantified. Multiple myeloma principally involves the bone marrow and bone, causing bone pain, lytic lesions, bone fractures, and anemia as well as an increased susceptibility to infection.

Most patients with multiple myeloma are symptomatic at the time of initial diagnosis and require treatment with cytotoxic che-motherapy. Treatment with the combination of the alkylating agent melphalan and prednisone (MP protocol) has been a stan-dard regimen for nearly 30 years. About 40% of patients respond to the MP combination, and the median remission is on the order of 2–2.5 years. Recently, combination regimens incorporating lenalidomide plus dexamethasone or the proteosome inhibitor bortezomib plus melphalan and prednisone have been shown tobe more effective as first-line therapy.

In patients who are considered candidates for high-dose therapy with stem cell transplantation, melphalan and other alkylating agents are to be avoided, as they can affect the success of stem cell harvesting.

Thalidomide is a well-established agent for treating refractory or relapsed disease, and about 30% of patients will achieve a response to this therapy. More recently, thalidomide has been used in combi-nation with dexamethasone, and response rates on the order of 65% have been observed. Studies are now under way to directly compare the combination of vincristine, doxorubicin, and dexamethasone (VAD protocol) with the combination of thalidomide and dexa-methasone. In some patients, especially those with poor performance status, single-agent pulse dexamethasone administered on a weekly basis can be effective in palliating symptoms. Bortezomib was first approved for use in relapsing or refractory multiple myeloma and is now widely used in the first-line treatment of multiple myeloma. This agent is thought to exert its main cytotoxic effects through inhibition of the 26 S proteosome, which results in down-regulation of the nuclear factor kappa B (NF-κB) signaling pathway. Of note, inhibition of NF-κB has been shown to restore chemosensitivity. Based on this site of action, further efforts are focused on developing bortezomib in various combination regimens.