title: Safety and efficacy of thalidomide in patients with POEMS syndrome: a multicentre, randomised, double-blind, placebo-controlled trial.
abstract: BACKGROUND
  Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare cause of demyelinating neuropathy, with multi-organ involvement characterised by plasma cell dyscrasia and VEGF overproduction. No treatments have been established for patients with POEMS syndrome who are not eligible for stem-cell transplantation. Thalidomide suppresses VEGF and plasma cell proliferation. We aimed to assess the safety and efficacy of thalidomide for the treatment of POEMS syndrome.
  
  
  METHODS
  We did a randomised, double-blind, placebo-controlled, phase 2/3 trial at 12 hospitals in Japan. Adults (age ≥20 years) with POEMS syndrome who were ineligible for autotransplantation were randomly assigned (1:1) by a minimisation method to treatment with oral dexamethasone (12 mg/m(2) per day on the first 4 days of every 28-day cycle) plus either oral thalidomide (200 mg daily) or placebo for six cycles. All study personnel and patients were masked to treatment allocation. The primary endpoint was the reduction rate of serum VEGF concentrations at 24 weeks. Analysis was by intention to treat. This study is registered with the UMIN Clinical Trials Registry, UMIN000004179.
  
  
  RESULTS
  Between Nov 11, 2010, and July 3, 2014, we randomly assigned 25 patients to receive either thalidomide (n=13) or placebo (n=12); one patient in the placebo group was excluded from analyses because of a protocol violation. The adjusted mean VEGF concentration reduction rate at 24 weeks was 0·39 (SD 0·34) in the thalidomide group compared with -0·02 (0·54) in the placebo group (adjusted mean difference 0·41, 95% CI 0·02-0·80; p=0·04). Mild sinus bradycardia was more frequent in the thalidomide group than in the placebo group (seven [54%] vs zero; p=0·006). Five patients had serious adverse events: three in the thalidomide group (transient cardiac arrest, heart failure, and dehydration) and two in the placebo group (ileus and fever). No deaths occurred during the randomised study. In the 48-week open-label study period (n=22), newly developed adverse events were sinus bradycardia (n=4), constipation (n=5), and mild sensory neuropathy (n=5). Two patients died in the open-label study; both patients were initially in the placebo group, and the cause of death was progression of the disease.
  
  
  CONCLUSIONS
  Thalidomide reduces serum VEGF concentrations and represents a new treatment for patients with POEMS syndrome who are not eligible for stem-cell transplantation. Thalidomide treatment poses a risk of bradycardia; however, the benefits are likely to exceed the risk.
  
  
  BACKGROUND
  Japanese Ministry of Health, Labour, and Welfare, and Fujimoto Pharmaceuticals.
authors: Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Sonoko
authors: S
authors: Misawa
authors: Clinical Research Centre, Chiba University Hospital, Chiba, Japan.
authors: Yasunori
authors: Y
authors: Sato
authors: Clinical Research Centre, Chiba University Hospital, Chiba, Japan.
authors: Kanako
authors: K
authors: Katayama
authors: Clinical Research Centre, Chiba University Hospital, Chiba, Japan.
authors: Kengo
authors: K
authors: Nagashima
authors: Clinical Research Centre, Chiba University Hospital, Chiba, Japan.
authors: Reiko
authors: R
authors: Aoyagi
authors: Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Yukari
authors: Y
authors: Sekiguchi
authors: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Gen
authors: G
authors: Sobue
authors: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Haruki
authors: H
authors: Koike
authors: Department of Neurology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors: Ichiro
authors: I
authors: Yabe
authors: Department of Neurology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors: Hidenao
authors: H
authors: Sasaki
authors: Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors: Osamu
authors: O
authors: Watanabe
authors: Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors: Hiroshi
authors: H
authors: Takashima
authors: Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.
authors: Masatoyo
authors: M
authors: Nishizawa
authors: Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.
authors: Izumi
authors: I
authors: Kawachi
authors: Department of Neurology, Faculty of Medicine, Kindai University, Osaka, Japan.
authors: Susumu
authors: S
authors: Kusunoki
authors: Department of Neurology, Faculty of Medicine, Kindai University, Osaka, Japan.
authors: Yoshiyuki
authors: Y
authors: Mitsui
authors: Department of Neurology, National Hospital Organization Hokkaido Medical Centre, Sapporo, Japan.
authors: Seiji
authors: S
authors: Kikuchi
authors: Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors: Ichiro
authors: I
authors: Nakashima
authors: Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan.
authors: Shu-Ichi
authors: S
authors: Ikeda
authors: Department of Neurology, Kobe City Medical Centre General Hospital, Kobe, Japan.
authors: Nobuo
authors: N
authors: Kohara
authors: Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors: Takashi
authors: T
authors: Kanda
authors: Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Jun-Ichi
authors: J
authors: Kira
authors: Clinical Research Centre, Chiba University Hospital, Chiba, Japan.
authors: Hideki
authors: H
authors: Hanaoka
authors: Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan. Electronic address: kuwabara-s@faculty.chiba-u.jp.
authors: Satoshi
authors: S
authors: Kuwabara
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D016878:POEMS Syndrome / Q000097:blood / Q000188:drug therapy*; D013792:Thalidomide / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000187:drug effects*
chemical_list: D020533:Angiogenesis Inhibitors; D000893:Anti-Inflammatory Agents; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D013792:Thalidomide; D003907:Dexamethasone