POEMS Syndrome: What's in a Name?

Drs. Dispenzieri and Buadi provide a thorough review of POEMS syndrome, describing its diagnosis, evaluation, and treatment. This rare entity poses many challenges to clinicians, from arriving at the correct diagnosis to identifying evidence-based treatment options. While the name POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) provides a nice acronym for a collection of seemingly disparate features, the diagnosis does not require that all these elements be present, and many other features are not included. The collection of findings-both clinical and laboratory-in this multisystem disease may be very diverse and the clinician must have a very high level of suspicion in order not to miss or delay a diagnosis of POEMS syndrome.

Diagnosis uniformly requires only two features: polyneuropathy and a monoclonal plasma cell disorder. The former may lead a patient to seek the attention of a neurologist, and care must be taken to distinguish
POEMS from chronic inflammatory demyelinating polyneuropathy (CIDP), for the patient may be started on therapy that will prove ineffective while the symptoms worsen. In a similar way for the latter, given the commonly low disease burden in POEMS, a patient found to have an M-spike may be diagnosed with monoclonal gammopathy of undetermined significance (MGUS) and forgo treatment altogether in favor of observation while the disease progresses unchecked. Even patients who present with many of the noted features may experience a diagnostic delay until the many organ systems involved are unified under one diagnosis. Radiological findings may also pose a challenge, since the osteosclerotic lesions are often misinterpreted as being benign entities.

POEMS syndrome is a unique plasma cell disorder, in that it is characterized by a low disease burden, as reflected by the level of plasmacytosis in the bone marrow and the level of monoclonal-spike, making the monoclonal protein (M-protein) a poor tumor marker for the disease. Vascular endothelial growth factor (VEGF) has been identified as a much better marker, and elevated levels are usually associated with disease activity. However, VEGF assessment is not without its limitations, since VEGF levels may fluctuate and may not reflect clinical response to therapy. It is a useful tool for making the diagnosis and for distinguishing POEMS syndrome from other neuropathies; however, VEGF elevations are not the only abnormality driving the disease. This has been most clearly demonstrated with the use of therapies against VEGF. The introduction of the VEGF-targeting monoclonal antibody bevacizumab generated great enthusiasm in the field of POEMS management, but the results have not been as promising as expected. Patients treated with single-agent bevacizumab do show a marked decrease in VEGF levels, but this is rarely accompanied by clinical improvement.[1-3]

Other studies have incorporated this agent in combination with cytotoxic drugs and even autologous transplantation. Here, clinical responses were seen, but the contribution of decreased VEGF is still unclear.[4,5] The delay in clinical responses does not correlate with the rapid decrease in VEGF levels noted. As Drs. Dispenzieri and Buadi indicate, therapy should be driven by the extent of plasma cells and targeted against them. Novel agents successfully used in the treatment of other plasma cell dyscrasias have been shown to have anti-angiogenic effects and to target VEGF as well as other entities in the microenvironment. Effective agents have been shown to have complex mechanisms of action that interfere with various aspects of oncogenesis, such as proliferation, apoptosis, angiogenesis, and cell-cell interactions.

While VEGF has been most consistently associated with disease activity, many cytokines have been evaluated, and the pathogenesis of POEMS syndrome is likely due to a more complex microenvironment. Keyzner and colleagues identified several differences in the cytokine milieu among patients with plasma cell dyscrasias, including POEMS, myeloma, and amyloidosis.[6] POEMS patients showed relative elevations in interleukin (IL)-4, IL-10, IL-13, interferon (IFN)-alpha, and epidermal growth factor. Levels of IL-1 receptor antagonist (IL-1RA) were predictive of engraftment syndrome, which complicates autologous stem cell transplantation (ASCT) in patients with POEMS. Patients with the Castleman disease variant of POEMS offer another source of insight. These patients are more likely to demonstrate a rise in IL-6 than a rise in VEGF. Their clinical course is marked by less neuropathy and more anemia than their counterparts, but the link to differences in pathogenesis has yet to be established.

Data in POEMS syndrome are limited by the small number of patients with this disorder; however, our understanding is growing as we gain insight into all plasma cell dyscrasias. Important differences must be identified in order to best serve our patients. For instance, while ASCT is an effective treatment option in POEMS syndrome, patients tend to have higher rates of engraftment syndrome and higher transfusion requirements.[7] This illustrates the importance of tailored supportive care in POEMS therapy. Patients with POEMS syndrome have cytogenetic abnormalities similar to those in patients with multiple myeloma, including frequent IgH translocations, but in a different distribution. Whether the difference in the distribution of the abnormalities contributes to a different clinical course remains to be seen, as no correlation with outcomes has been noted other than an increased frequency of papilledema in patients with 14q32 translocations.[8]

POEMS syndrome is a multisystem disorder and may consist of various combinations of dozens of laboratory or clinical findings. Early identification of the diagnosis followed by early intervention is key to improving patient outcomes. The last decade has seen great progress in the understanding of plasma cell dyscrasias and the introduction of novel therapies. The importance of the microenvironment is increasingly recognized, and provides targets for therapeutic interventions. The pathogenesis of POEMS syndrome may be elucidated as our understanding of the interactions between plasma cells and their microenvironment deepens.

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

References:

1. Straume O, Bergheim J, Ernst P. Bevacizumab therapy for POEMS syndrome. Blood. 2006;107:4972-73.

2. Kanai K, Kuwabara S, Misawa S, Hattori T. Failure of treatment with anti-VEGF monoclonal antibody for long-standing POEMS syndrome. Intern Med. 2007;46:311-13.

3. Dietrich PY, Duchosal MA. Bevacizumab therapy before autologous stem cell transplantation for POEMS syndrome. Ann Oncol. 2008;19:595.

4. Badros A, Porter N, Zimrin A. Bevacizumab therapy for POEMS syndrome. Blood. 2005;106:1135.

5. Ohwada C, Nakaseko C, Sakai S, et al. Successful combination treatment with bevacizumab, thalidomide, and autologous PBSC for severe POEMS syndrome. Bone Marrow Transplant. 2009;43:739-40.

6. Keyzner A, D’Souza A, Lacy M, et al. Low levels of interleukin-1 receptor antagonist (IL-1RA) predict engraftment syndrome after autologous stem cell transplantation in POEMS syndrome and other plasma cell neoplasms. Biol Blood Marrow Transplant. 2013;19:1395-8.

7. Dispenzieri A, Lacy MQ, Hayman SR, et al. Peripheral blood stem cell transplant for POEMS syndrome is associated with high rates of engraftment syndrome. Eur J Haematol. 2008;80:397-406.

8. Kang WY, Shen KN, Duan MH, et al. 14q32 translocations and 13q14 deletions are common cytogenetic abnormalities in POEMS syndrome. Eur J Haematol. 2013;91:490-6.