Thalidomide and thrombosis in multiple myeloma

Abstract

Multiple myeloma is a plasma cell tumor which accounts for about 10% of hematological cancers. It often presents with signs of compromised bone marrow functions, symptoms of bone destruction or spinal cord/nerve root compression, and signs of renal impairment. In recent years, some advances in the management of this malignancy have been achieved, although it remains largely an incurable disease. For many years treatment has been based on conventional dose alkylating agents (i.e. melphalan) in combination with standard prednisolone and/or other chemotherapeutic agents (i.e. adriamycin, vincristine, Bis-Chloronitrosourea (BCNU). Of particular importance have been: (i) the introduction of high dose dexamethasone combined to chemotherapy based upon non-containing alkylating agents [such as the vincristine, adriamycin, dexamethasone (VAD) regimen] and (ii) the possibility to use high-dose melphalan with the support of autologous peripheral blood stem cell (PBSC) transplantation. Nowadays, high-dose melphalan therapy with PBSC support is considered the primary strategy for newly diagnosed patients aged under 60 (or aged 60–70 years with a good performance status). It is given after initial cytoreduction with VAD-based regimens and PBSC mobilization and harvesting. In this setting of patients, this strategy has increased the rate of complete remission from 5 to 50% as compared to standard therapy, and has prolonged event-free and overall survival. In spite of this, patients still relapse and, in these cases few options are available. Very recently, the search for new active drugs prompted the use of thalidomide for treatment of advanced and refractory multiple myeloma, which gave an overall response rate of 32 to 37% in these patients [1,2]. Thalidomide is an old drug, withdrawn from clinical use in the 1960s because of its severe teratogenicity. It possesses a number of anticancer effects, including direct tumor growth inhibition, suppression of cytokine production by the bone marrow microenvironment, interference with tumor cell-stromal cell adhesion, antiangiogenetic and immunomodulating activities. Which mechanism(s) mediate its activity against myeloma is yet undefined. However the introduction of thalidomide has remarkably expanded the therapeutic armamentarium for the management of multiple myeloma. Because of the first encouraging results and the lack of myelosuppressive effect it has been considered ideal for use in combination with chemotherapy and is also being tested in clinical trials of front-line combination therapy for newly diagnosed patients [3]. The overall results of all trials available for salvage therapy show that the addition of dexamethasone to thalidomide increases the response rate beyond 50%, and the inclusion of cytotoxic chemotherapy raises the response to about 60%. Even more promising results may come from the use of thalidomide in previously untreated myeloma pa