Thalidomide [Thalomid, α-(N-phthalimido)-glutarimide] is a glutamic acid derivative that was used in the late 1950s as a sedative and as a therapy for pregnancy-related morning sickness. It was available in over 40 countries, including Germany, Canada, and Australia. Its use in the United States during this period was restricted to clinical trials since the Food and Drug Administration (FDA) did not approve the drug, citing lack of safety data [1
]. In 1961, the teratogenicity of thalidomide was recognized, and the drug was quickly taken off the market worldwide [3
]. Over the past 5 years, thalidomide has reemerged as an anticancer agent with anti - angiogenic and immunomodulatory properties.
Although the resurgence of thalidomide into clinical practice occurred only recently, the drug never fully disappeared from clinical use since the 1960s. Shortly after its withdrawal from the market, it was found to be effective in the treatment of erythema nodosum leprosum (ENL) [6
]. In the early 1990s it showed promise in the treatment of HIV wasting syndrome, graft-versus-host disease [7
], and Behçet’s disease. In 1998, thalidomide was approved by the FDA for the treatment of ENL with certain safety requirements. Prescription of thalidomide in the United States requires participation of physicians, pharmacists, and patients with the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.®
) program to prevent teratogenicity [8
Thalidomide is now commonly used in clinical practice “off label” in the treatment of multiple myeloma [9
]. Its use in myeloma is based on several reports showing significant activity in relapsed and refractory disease [12
]. More recently, the combination of thalidomide with dexamethasone has shown promise as initial therapy for newly diagnosed myeloma [16
]. Currently, two phase III studies are evaluating the combination of thalidomide with dexamethasone versus dexamethasone alone in newly diagnosed myeloma.
Thalidomide has also shown some activity against renal cell carcinoma, Kaposi’s sarcoma, agnogenic myeloid metaplasia, Waldenström’s macroglobulinemia, and myelodysplastic syndrome [18
]. However, there are still only limited efficacy data in these conditions compared to myeloma, and its use in these settings is investigational. Studies are ongoing in several other malignant and nonmalignant disorders.
Given the increasing clinical use of thalidomide, it becomes important to study the adverse effects of this agent. Besides teratogenicity, thalidomide has certain unique and frequent toxicities, such as constipation, sedation, fatigue, and neuropathy. This review summarizes the incidence, nature, and management of the adverse effects associated with thalidomide therapy. The frequencies of adverse events described in this paper ( and ) are approximate estimates based on clinical trials in myeloma as well as other malignant and nonmalignant disorders. Further, the recommendations for prevention and treatment of adverse events () are just guidelines and are most applicable in the treatment of relapsed refractory myeloma and similar serious malignancies. They need to be adapted according to the clinical condition of the patient and the disease being treated.
Common Toxicities of Thalidomide
Less Common Toxicities of Thalidomide
Prevention and Management of Thalidomide Complications