Safety and efficacy of thalidomide in patients with POEMS syndrome: a multicentre, randomised, double-blind, placebo-controlled trial

Sonoko Misawa, Yasunori Sato, Kanako Katayama, Kengo Nagashima, Reiko Aoyagi, Yukari Sekiguchi, Gen Sobue, Haruki Koike, Ichiro Yabe, Hidenao Sasaki, Osamu Watanabe, Hiroshi Takashima, Masatoyo Nishizawa, Izumi Kawachi, Susumu Kusunoki, Yoshiyuki Mitsui, Seiji Kikuchi, Ichiro Nakashima, Shu ichi Ikeda, Nobuo KoharaTakashi Kanda, Jun ichi Kira, Hideki Hanaoka, Satoshi Kuwabara

Research output: Contribution to journalArticle

27 Citations (Scopus)

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. Findings 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. Interpretation 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. Funding Japanese Ministry of Health, Labour, and Welfare, and Fujimoto Pharmaceuticals.

Original languageEnglish
Pages (from-to)1129-1137
Number of pages9
JournalThe Lancet Neurology
Volume15
Issue number11
DOIs
Publication statusPublished - 2016 Oct 1
Externally publishedYes

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POEMS Syndrome
Thalidomide
Placebos
Safety
Vascular Endothelial Growth Factor A
Bradycardia
Stem Cell Transplantation
Therapeutics
Paraproteinemias
Intention to Treat Analysis
Ileus
Autologous Transplantation
Constipation
Plasma Cells
Heart Arrest
Serum
Dehydration
Dexamethasone
Registries
Disease Progression

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Safety and efficacy of thalidomide in patients with POEMS syndrome : a multicentre, randomised, double-blind, placebo-controlled trial. / Misawa, Sonoko; Sato, Yasunori; Katayama, Kanako; Nagashima, Kengo; Aoyagi, Reiko; Sekiguchi, Yukari; Sobue, Gen; Koike, Haruki; Yabe, Ichiro; Sasaki, Hidenao; Watanabe, Osamu; Takashima, Hiroshi; Nishizawa, Masatoyo; Kawachi, Izumi; Kusunoki, Susumu; Mitsui, Yoshiyuki; Kikuchi, Seiji; Nakashima, Ichiro; Ikeda, Shu ichi; Kohara, Nobuo; Kanda, Takashi; Kira, Jun ichi; Hanaoka, Hideki; Kuwabara, Satoshi.

In: The Lancet Neurology, Vol. 15, No. 11, 01.10.2016, p. 1129-1137.

Research output: Contribution to journalArticle

Misawa, S, Sato, Y, Katayama, K, Nagashima, K, Aoyagi, R, Sekiguchi, Y, Sobue, G, Koike, H, Yabe, I, Sasaki, H, Watanabe, O, Takashima, H, Nishizawa, M, Kawachi, I, Kusunoki, S, Mitsui, Y, Kikuchi, S, Nakashima, I, Ikeda, SI, Kohara, N, Kanda, T, Kira, JI, Hanaoka, H & Kuwabara, S 2016, 'Safety and efficacy of thalidomide in patients with POEMS syndrome: a multicentre, randomised, double-blind, placebo-controlled trial', The Lancet Neurology, vol. 15, no. 11, pp. 1129-1137. https://doi.org/10.1016/S1474-4422(16)30157-0
Misawa, Sonoko ; Sato, Yasunori ; Katayama, Kanako ; Nagashima, Kengo ; Aoyagi, Reiko ; Sekiguchi, Yukari ; Sobue, Gen ; Koike, Haruki ; Yabe, Ichiro ; Sasaki, Hidenao ; Watanabe, Osamu ; Takashima, Hiroshi ; Nishizawa, Masatoyo ; Kawachi, Izumi ; Kusunoki, Susumu ; Mitsui, Yoshiyuki ; Kikuchi, Seiji ; Nakashima, Ichiro ; Ikeda, Shu ichi ; Kohara, Nobuo ; Kanda, Takashi ; Kira, Jun ichi ; Hanaoka, Hideki ; Kuwabara, Satoshi. / Safety and efficacy of thalidomide in patients with POEMS syndrome : a multicentre, randomised, double-blind, placebo-controlled trial. In: The Lancet Neurology. 2016 ; Vol. 15, No. 11. pp. 1129-1137.
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TY - JOUR

T1 - Safety and efficacy of thalidomide in patients with POEMS syndrome

T2 - a multicentre, randomised, double-blind, placebo-controlled trial

AU - Misawa, Sonoko

AU - Sato, Yasunori

AU - Katayama, Kanako

AU - Nagashima, Kengo

AU - Aoyagi, Reiko

AU - Sekiguchi, Yukari

AU - Sobue, Gen

AU - Koike, Haruki

AU - Yabe, Ichiro

AU - Sasaki, Hidenao

AU - Watanabe, Osamu

AU - Takashima, Hiroshi

AU - Nishizawa, Masatoyo

AU - Kawachi, Izumi

AU - Kusunoki, Susumu

AU - Mitsui, Yoshiyuki

AU - Kikuchi, Seiji

AU - Nakashima, Ichiro

AU - Ikeda, Shu ichi

AU - Kohara, Nobuo

AU - Kanda, Takashi

AU - Kira, Jun ichi

AU - Hanaoka, Hideki

AU - Kuwabara, Satoshi

PY - 2016/10/1

Y1 - 2016/10/1

N2 - 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. Findings 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. Interpretation 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. Funding Japanese Ministry of Health, Labour, and Welfare, and Fujimoto Pharmaceuticals.

AB - 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. Findings 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. Interpretation 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. Funding Japanese Ministry of Health, Labour, and Welfare, and Fujimoto Pharmaceuticals.

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