Polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome is a rare cause of mixed demyelinating-axonal polyneuropathy associated with multiorgan involvement and monoclonal plasma-cell dyscrasia.1^–4 The pathogenesis of POEMS syndrome is not well understood, but overproduction of vascular endothelial growth factor (VEGF)—probably secreted by plasmacytoma—is considered to be responsible for the characteristic symptoms.5 6 Therefore, the target of treatment in POEMS syndrome is plasmacytoma. Effective treatments are necessary because POEMS syndrome is a potentially fatal disorder, and patients’ quality of life frequently deteriorates because of progressive neuropathy, massive pleural effusion/ascites or thromboembolic event.2^–4

Because of the rarity of the disorder, there is no established treatment regimen. For patients with solitary plasmacytoma (usually osteosclerotic lesion), irradiation or surgical resection has usually been proposed.7 If patients have multiple osteosclerotic lesions or no detectable bone lesion, systemic chemotherapy is recommended.7 Previous case series and case reports have shown that high-dose chemotherapy with autologous peripheral blood stem-cell transplantation is an efficacious treatment for POEMS syndrome,8^–10 although the long-term outcome has not yet been elucidated. This treatment leads to obvious improvement in peripheral neuropathy as well as other symptoms, and a significant decrease in serum VEGF levels.10 However, transplantation is not indicated for elderly patients and patients with significant organ involvement such as renal failure.

Thalidomide has anti-angiogenic, anti-inflammatory and immunomodulating action, and has been successfully used in the treatment of plasma-cell proliferative disorders, such as multiple myeloma.11 We therefore conducted an open trial with thalidomide in patients for whom transplantation is not indicated, with monitoring of serum VEGF levels and nerve conduction studies.

METHODS

Patients

Between 2003 and 2007, 20 patients with POEMS syndrome were seen at Chiba University Hospital. Of these, 11 were treated with high-dose melphalan chemotherapy with peripheral blood stem-cell transplantation; the remaining nine could not receive transplantation due to being elderly (>65 years; n = 5), renal dysfunction (n = 1), failure to harvest blood stem cells (n = 2), or refusal of transplantation therapy (n = 1). These nine patients (7 men and 2 women) were treated with thalidomide (table 1). Their age at entry ranged from 42 years to 85 years (median, 65 years). Their condition fulfilled published diagnostic criteria;7 the nine patients had almost of all the “POEMS” features, as well as peripheral oedema, pleural effusion and ascites. All had motor-sensory polyneuropathy, predominantly affecting the lower limbs. At entry, four of the patients were unable to walk independently due to severe motor weakness and one was a wheelchair user. They had elevated serum VEGF levels (median: 2130 pg/ml; range, 751–9540 pg/ml; normal <680 pg/ml). IgG-λ or IgA-λ M-protein was detected in all of the nine patients. Thalidomide treatment was an initial therapy in six patients (numbers 2–7), whereas the remaining three had prior oral melphalan chemotherapy and subsequent relapse.

Thalidomide treatment and assessment

Thalidomide treatment was initiated with 100 mg daily with dexamethasone (20 mg/m² on day 1–4 monthly), and subsequently the thalidomide dose was increased up to 200 or 300 mg. Clinical and laboratory assessments were prospectively performed; neurological disability was evaluated with Hughes functional grading scale (0, normal; 1, able to run; 2, able to walk independently; 3, able to walk with aids; 4, chair-bound). Serum VEGF levels were measured every month by an enzyme-linked immunosorbent assay, as described elsewhere.10 CT of the chest and abdomen was performed every 3 months to examine pericardial/pleural effusion and ascites, and nerve conduction studies were conducted every 4 months. Nerve conduction parameters were analysed only in the median and ulnar nerves, because compound muscle action potentials were absent in lower limb studies in eight of the nine patients. All the patients gave written informed consent, and the treatment protocol was approved by the Institutional Review Board of Chiba University Hospital.

RESULTS

Clinical findings

Thalidomide therapy was continued for 8–23 months (mean 15 months). At the end of follow-up, the maintenance dose varied from 100 to 300 mg (table 1), because the dose was reduced in patients with good response (n = 4; numbers 1, 2, 4 and 9) or development of drug-induced skin eruption (n = 3, numbers 6, 7 and 8). The non-neurological symptoms of peripheral oedema, pleural effusion and ascites began to improve within 2 months after initiation of treatment. Improvement of neuropathy was rapid in three patients (numbers 1, 3 and 8), beginning 3 months later; these three could not walk without assistance before treatment, but gained independent locomotion 6 months after the start of treatment. The remaining six showed gradual improvement in neuropathic symptoms/signs until the end of the follow-up (n = 4) or stabilisation of neuropathic symptoms (n = 2; numbers 5 and 7). Patient 5 showed improvement in oedema and pleural effusuin/ascites, but his neuropathic condition was unchanged, and he remained confined to a wheelchair 15 months after the initiation of thalidomide treatment. At the end of the follow-up period, M-protein was still present in eight patients, and disappeared in one (patient 7).

Laboratory findings

Figure 1 shows sequential findings in nerve conduction studies and serum VEGF levels. Motor nerve conduction studies performed in the median and ulnar nerves showed gradual increases in the nerve conduction velocities in seven patients, whereas compound muscle action potentials were not recordable before and after treatment in one patient (Patient 5). Amplitudes of the compound muscle action potentials in the median nerve were increased by 50% in two patients (numbers 3 and 4). Serum VEGF levels decreased in all the nine after the initiation of treatment, and were normalised in five (patients 1–4, and 9) at the end of follow-up.

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Figure 1 Serial changes in median motor nerve conduction velocities (A), and serum levels of vascular endothelial growth factor (VEGF; B) after the start of thalidomide treatment. Dotted lines indicate the normal limits.

Adverse effects

Drug-induced skin eruption developed in three of the nine patients (numbers 6–8), when the thalidomide dose was increased to 200 or 300 mg daily, and therefore the dose was decreased. There were no other serious adverse effects, whereas constipation was noted in four patients, and three patients complained of mild drowsiness in the daytime. Worsening of neuropathic symptoms caused by thalidomide toxicity was not observed in any of the patients. At the last visit, the cumulative dose of thalidomide ranged from 14 g to 88 g.

DISCUSSION

Although this is an open trial including a small number of patients, our data suggest that thalidomide therapy is an effective treatment for POEMS syndrome. So far, two POEMS syndrome cases treated with thalidomide have demonstrated clinical improvement,12 13 but serial changes in neuropathy scale, serum VEGF levels and nerve conduction studies were not examined. In the present study, the short-term effects of thalidomide treatment appeared to be significant, leading to a lessening of the neuropathy and other symptoms within 3 months associated with increased nerve conduction velocities and substantial reduction of serum VEGF levels. These findings are consistent with a view that overproduction of VEGF leads to abnormally increased vascular permeability and neovasculisation, and therefore is responsible for symptoms in POEMS syndrome.6 Rapid reduction in VEGF levels in our patients suggest that thalidomide could have direct effects on VEGF production, secretion or action.

Because peripheral neuropathy is a major and disabling factor in patients with POEMS syndrome, thalidomide-induced neuropathy should be considered carefully. However, we showed that during the follow-up period up to 23 months, neuropathic symptoms, as well as nerve conduction velocities, continuously improved, and none of the patients showed worsening of neuropathic symptoms/signs. Previous studies suggest that a cumulative dose of thalidomide greater than 20 g increases a risk for development of neuropathy.14 However, most of our patients had a cumulative dose of more than 20 g (table 1), but did not appear to develop thalidomide neuropathy. We agree that the lowest effective dose of thalidomide should be used but, based on these data, we think that the benefit of thalidomide exceeds the risk of its potential neurotoxicity. A recent case report has shown benefits of lenalidomide, an analogue of thalidomide in a single patient with POEMS syndrome.15 This drug has a much lower risk for neuropathy (reported as only 1.7% of patients)16 and would better be used for treatment of POEMS syndrome, and should be considered in future studies, but it is available only in restricted countries at present. In clinical practice, thalidomide is an easily available, safe, less expensive and efficacious treatment for POEMS syndrome. This treatment should be considered as a treatment option, especially for elderly patients and patients with renal failure, who are not indicated for high-dose chemotherapy with peripheral blood stem-cell transplantation.