POEMS Syndrome: Still an Enigma?

December 15, 2013
Olivier Hermine, MD, PhD
Olivier Hermine, MD, PhD

,
Laurent Frenzel, MD, PhD
Laurent Frenzel, MD, PhD

,
Arnaud Jaccard, MD, PhD
Arnaud Jaccard, MD, PhD

Volume 27, Issue 12

Because of challenges in making the correct diagnosis and the physician’s reluctance to administer chemotherapy for a disease characterized by such a low tumoral mass, patients may experience a delay in the initiation of appropriate treatment.

In this issue of ONCOLOGY, Drs. Angela Dispenzieri and Francis Buadi offer an excellent review of the clinical, radiological, and biological features of POEMS syndrome, and provide precise guidelines for its diagnosis and treatment.[1]

POEMS syndrome (polyradiculoneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes) is a very rare disease with protean clinical manifestations resulting from a small “dangerous” B-cell clone. These diverse manifestations lead the patient on a diagnostic odyssey between various specialists (neurologists; cardiologists; dermatologists; internal medicine specialists; eye, ear, nose, and throat specialists; and nephrologists), who frequently seek advice and guidance from hematologists because of the presence of a monoclonal gammopathy. Unfortunately, as there often is no apparent malignant proliferation, the hematologists may send the patient back to the referring physician.

Because of challenges in making the correct diagnosis and the physician’s reluctance to administer chemotherapy for a disease characterized by such a low tumoral mass, patients may experience a delay in the initiation of appropriate treatment. Organ damage may occur as a consequence, which may eventually reduce overall survival. It is likely that the information provided by Drs. Dispenzieri and Buadi in their article will facilitate earlier diagnosis of POEMS syndrome, to ensure better and earlier treatment.

This association of rarity and wide-ranging clinical manifestations is a hallmark of the diseases associated with toxic monoclonal gammopathies in the absence of a high tumor burden. The diagnosis of such diseases raises several questions about the mechanism of toxicity of the gammopathy, as well as the type of underlying B-cell lymphoproliferation and its treatment.

The mechanism of toxicity can be aggregation and/or deposit (light-chain amyloidosis, monoclonal immunoglobulin deposition disease, crystal-storing histiocytosis, and type I cryoglobulinemia) or auto-antibody activity (chronic cold agglutinin disease, mixed cryoglobulinemia, xanthomatosis, and demyelinating peripheral neuropathies). In some diseases, however, the relationship between a monoclonal gammopathy and severe clinical manifestations is not well understood, as in Schnitzler syndrome (urticaria, bone lesions, periodic fever), capillary leak syndrome, or hyperparathyroidism.

Although very important advances have been made in the diagnosis and management of POEMS syndrome, its physiopathology remains a mystery. POEMS syndrome is usually associated with a monoclonal plasmacytic proliferation that may present as osteosclerotic lesions or moderate bone marrow infiltration. The syndrome also can be associated with a lymphoplasmacytic clone with an immunoglobulin M (IgM) gammopathy or with several other types of B monoclonal proliferation, including monoclonal gammopathy of unknown significance (MGUS). It is the monoclonal light chain immunoglobulin that is of particular importance in POEMS-in the vast majority of cases, a lambda light chain derived from two variable (V)-region germline genes, IGLV1-44*01 and IGLV1-40*01.[3,4] It is well established that overproduction of vascular endothelial growth factor (VEGF) plays a key role in the symptoms of POEMS syndrome-particularly neuropathy, edema, and hemangioma. Therefore, it is tempting to assume that the monoclonal lambda light chain induces VEGF production by a yet unresolved mechanism. Thus, POEMS syndrome will occur when the monoclonal lambda light chain immunoglobulin is secreted following activation of one of the two aforementioned germline genes, whatever the underlying monoclonal B-cell proliferation.

The existence of asymptomatic bone lesions in some patients several years before the emergence of clinical symptoms of POEMS syndrome could be explained by the initial absence of monoclonal circulating light chains, with symptoms starting to occur when the light chains begin to circulate, triggering VEGF overproduction. The overproduction of VEGF and probably of other interfering cytokines may play a role in the particular behavior of the monoclonal proliferation that presents as osteosclerotic plasmacytoma of low proliferative index, and also in the onset of the frequently associated POEMS syndrome variant, Castleman disease.

The treatment of disease related to toxic monoclonal gammopathies has several aims. First, symptomatic treatments are always critical and may prevent life-threatening complications. Second, in most cases, control of the underlying B-cell lymphoproliferation may improve symptoms of the disease. Third, treatment to address specific complications may be beneficial.

As an example, in Schnitzler syndrome, treatment with the interleukin-1 (IL-1) antagonist anakinra seems to be sufficient to fully abrogate the symptoms of the disease, without any treatment directed against the monoclonal clone.[5] In POEMS syndrome, however, use of anti-VEGF antibodies without any chemotherapy may result in death.[1] Therefore, as in most other gammopathies associated with toxicity, the treatment of POEMS must be directed against the secreting clone.

The POEMS syndrome treatment guidelines proposed by Drs. Dispenzieri and Buadi, based on the number of osteosclerotic bone lesions and the presence or absence of bone marrow infiltration, are very easy to use. Examination of the bone marrow is critical to determine whether infiltration of bone has occurred, given that irradiation is essential if a bone lesion is found. In the case of localized disease, irradiation may induce resolution of symptoms and, eventually, cure. In contrast, when irradiation is not possible, high-dose chemotherapy with stem cell support is the treatment of choice in fit patients, and achieves a nearly 100% response. Alternatively, drugs developed for the treatment of plasmacytic proliferation may be used. Lenalidomide seems to be the more promising therapy, because of its anti-proliferative and anti-angiogenic effects and lack of major neurotoxicity. In small series, a significant proportion of patients have responded to this treatment.[6]

This comprehensive review by Drs. Dispenzieri and Buadi is well placed among the major articles on all aspects of POEMS syndrome currently available in the medical literature. It will be very helpful not only to oncologists, but also to a variety of physician specialists.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Dispenzieri A, Buadi F. A review of POEMS syndrome. Oncology (Williston Park). 2013;27:1242-50.

2. Merlini G, Stone MJ. Dangerous small B-cell clones. Blood. 2006;108:2520-30.

3. Soubrier M, Labauge P, Jouanel P, et al. Restricted use of vλ genes in poems syndrome. Haematologica. 2004;89:e4-e5.

4. Abe D, Nakaseko C, Takeuchi M, et al. Restrictive usage of monoclonal immunoglobulin lambda light chain germline in POEMS syndrome. Blood. 2008;112:836-9.

5. Simon A, Asli B, Braun-Falco M, et al. Schnitzler’s syndrome: diagnosis, treatment, and follow-up. Allergy. 2013;68:562-8.

6. Royer B, Merlusca L, Abraham J, et al. Efficacy of lenalidomide in POEMS syndrome: a retrospective study of 20 patients. Am J Hematol. 2013;88:207-12.