title: A pharmacokinetic study evaluating the relationship between treatment efficacy and incidence of adverse events with thalidomide plasma concentrations in patients with refractory multiple myeloma.
abstract: BACKGROUND
  Multiple myeloma (MM) is a clonal disorder of plasma cells, accounting for 10% of hematologic malignancies. Relapsed or refractory MM has a poor prsognosis. Thalidomide has been reported to be effective for these patients; however, high-dose thalidomide has induced many adverse events, including in the nervous, gastrointestinal, and hematopoietic systems in approximately 20%-50% of patients. Recently, low-dose thalidomide therapy has been used in many countries in order to reduce these adverse events. The objective of this study was to determine whether plasma concentration of thalidomide is related to the efficacy and the development of adverse events in patients with refractory MM treated with low-dose thalidomide plus low-dose dexamethasone.
  
  
  METHODS
  A total of 66 patients (age range, 40-74 years) presenting with progressive disease after previous treatments were treated with low-dose thalidomide and low-dose dexamethasone. Thalidomide was administered orally at 100 mg/day for the first week. When severe adverse events did not develop, the dose was increased to 200 mg/day in the second week and was continued until progression. Dexamethasone was administered at a dose of 4 mg/day for the first 4 weeks, then decreased by 1 mg every week, and finally maintained at 1 mg/day. Plasma trough concentration of thalidomide 3 days after thalidomide treatment was analyzed by high-performance liquid chromatography in 45 patients (age range, 42-74 years) who agreed to participate in this study of thalidomide concentration analysis.
  
  
  RESULTS
  The mean concentrations at 100 mg/day and 200 mg/day were 0.343 microg/mL (range, 0.05-1.45 microg/mL) and 0.875 microg/mL (range, 0.19-2.09 microg/mL), respectively. The overall response rate (near-complete response + partial response + minimal response) of this treatment was 73%. Five had stable disease, and 3 patients experienced progressive disease. There was no relationship between the concentration of thalidomide in the plasma and the efficacy (P > .8). Severe adverse events, including grade > 2 nonhematologic and grade > 3 hematologic adverse events, were observed in 21 patients (46.6%). There was no significant difference in the concentration of thalidomide between the patients with and without severe adverse events (P > .843).
  
  
  CONCLUSIONS
  The thalidomide concentration in the plasma does not predict treatment efficacy and the development of adverse events.
authors.affiliation: Faculty of Medicine, School of Health Sciences, Gunma University, Maebashi, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kodama
authors.forename: Masahiro
authors.initials: M
authors.lastname: Abe
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Iida
authors.forename: Shuji
authors.initials: S
authors.lastname: Ozaki
authors.forename: Akira
authors.initials: A
authors.lastname: Sakai
authors.forename: Morio
authors.initials: M
authors.lastname: Sawamura
authors.forename: Chihiro
authors.initials: C
authors.lastname: Shimazaki
authors.forename: Akira
authors.initials: A
authors.lastname: Miyata
authors.forename: Toshio
authors.initials: T
authors.lastname: Wakayama
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Murakami
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D003907:Dexamethasone / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000097:blood* / Q000188:drug therapy*; D013792:Thalidomide / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood*
chemical_list: D013792:Thalidomide; D003907:Dexamethasone