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Lancet Neurol. 2016 Oct;15(11):1129-37. doi: 10.1016/S1474-4422(16)30157-0. Epub 2016 Aug 3.

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

Author information

1
Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan.
2
Clinical Research Centre, Chiba University Hospital, Chiba, Japan.
3
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
4
Department of Neurology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
5
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
6
Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.
7
Department of Neurology, Faculty of Medicine, Kindai University, Osaka, Japan.
8
Department of Neurology, National Hospital Organization Hokkaido Medical Centre, Sapporo, Japan.
9
Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan.
10
Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan.
11
Department of Neurology, Kobe City Medical Centre General Hospital, Kobe, Japan.
12
Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan.
13
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
14
Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan. Electronic address: kuwabara-s@faculty.chiba-u.jp.

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.

PMID:
27496680
DOI:
10.1016/S1474-4422(16)30157-0
[Indexed for MEDLINE]

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