Thalidomide

Thalidomide is unique in that it is the only anticancer agent in the treatment of MM that maintains the same high response rate in newly diagnosed as well as in the relapsed and refractory MM patients.33,34 Thalidomide, also known as alpha-(N-phthalimido) glutarimide, consists of a two-ringed structure with an asymmetric carbon in the glutarimide ring that exists as an equal mixture of S- (—) and R- (+) enantiomers that inter-convert rapidly under physiologic conditions. This makes attempts at isolation of the dextro form, in an effort to eliminate teratogenicity, unsuccessful. As it is sparingly soluble in water and ethanol, there is no intravenous formulation.35 Thalidomide undergoes rapid pH-dependent hydrolysis in aqueous solution. Mean terminal half-lives for a 200-mg dose range from 4 to 9 h, whereas higher doses of 800 mg have a substantially longer terminal half-life of approximately 8 h.36 Pharmacokinetics in renal and hepatic dysfunction is not well established; in patients with renal failure secondary to MM, however, similar dose levels to those for patients with non-impaired renal function are used.

Thalidomide inhibits angiogenesis and induces apoptosis of established neovasculature in experimental models.3738 The bone marrows of MM patients show prominent vascularization, which correlates positively with high plasma cell labeling index disease activity and independently confers a poor progno-sis.39-42 Moreover, the plasma levels of various angio-genic cytokines, such as basic fibroblast growth factor and vascular endothelial growth factor (VEGF), are elevated in patients with active myeloma.40-42

The first study of thalidomide in MM by Singhal et al.43 consisted of 84 previously treated patients with refractory myeloma, 76 of whom had relapsed after high-dose chemotherapy. Oral thalidomide was administered as a single agent for a median of 80 days (range 2-465). The starting dose was 200 mg daily, and this was increased by 200 mg every 2 weeks to a maximum of 800 mg/day. The response was assessed based on a reduction of myeloma protein in serum or urine that lasted for at least 6 weeks. The serum or urine levels of paraprotein were reduced by at least 90% in eight patients, two had a complete remission (CR), six patients had a 75% reduction of paraprotein, seven patients had a 50% reduction, while six had a 25% reduction, accounting for a total rate of response of 32%. Reductions in the paraprotein levels were apparent within 2 months in 78% of the patients who responded to therapy. This was associated with increased hemoglobin levels and decreased numbers of plasma cells in the bone marrow. The microvascular density of bone marrow, however, did not significantly change in responding patients. After 12 months of follow-up, Kaplan-Meier estimates of the mean (±SE) rates of event-free survival and overall survival for all patients were 22 ± 5% and 58 ± 5%, respectively.43 A more recent follow-up included 169 patients with advanced myeloma, in whom 67% had abnormal cytogenetics (CG) and 76% a prior autotransplant.44 A 25% reduction in the M protein was noted in 37% of

Table 87.1 Thalidomide in relapsed/refractory

multiple myeloma

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