Thalidomide and Its Derivatives: New Promise for Multiple Myeloma

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Abstract
The combination of melphalan and prednisone has been accepted as standard treatment for multiple myeloma (MM) because most studies demonstrate only minimal survival benefit of combination chemotherapy regimens when compared with melphalan and prednisone. Despite modest gains with more intensive myeloablative regimens for certain subgroups, myeloma remains incurable. In 1999, investigators at the University of Arkansas reported the promising results of a phase II study of thalidomide in patients with resistant MM. Since then various trials of thalidomide alone, and in combination, have been tested in patients with resistant, and more recently, untreated MM. In addition, preliminary results of phase I studies of the immunomodulatory derivatives (IMiDs) of thalidomide have recently been reported. The author reviewed and reports the results of clinical trials of thalidomide and the IMiDs, as well as the pharmacology, mechanism of action, and toxicity of these agents. Thalidomide has demonstrated significant activity in both resistant and previously untreated multiple myeloma. Combination therapy with dexamethasone increases response rate, even in patients previously resistant to both drugs given as single agents, indicating probable synergy. More recent studies of thalidomide-dexamethasone in previously untreated patients are encouraging. IMiD-3 is active in resistant myeloma and has a toxicity profile different from that of thalidomide. Many studies have confirmed the activity of thalidomide in MM, as well as more responses with dexamethasone. Newer thalidomide derivatives with reduced toxicity are promising. Thalidomide-dexamethasone may now represent the treatment of choice for previously untreated patients. Further studies with these and other novel agents early in the course of myeloma, followed by rational programs of dose intensification, may improve complete remission rates and the frequency of long-term control.