POEMS syndrome is a rare and disabling autoinflammatory condition characterised by a typical peripheral neuropathy and the presence of a monoclonal plasma cell disorder. The acronym ‘POEMS’ represents the complex and multisystem features of the disease, including polyneuropathy, organomegaly, endocrinopathy, a monoclonal plasma cell disorder and skin disease. The diagnosis of POEMS is a significant challenge because of the heterogeneity of clinical presentations and variation of POEMS features. Patients are often misdiagnosed with another cause of inflammatory neuropathy and receive one or more ineffective immunomodulatory medications, resulting in delayed diagnosis and further clinical deterioration before a diagnosis is made. University College London Hospitals sees one of the largest reported POEMS cohorts in Europe, and runs a multispecialist clinic to assist with diagnosis, treatment and ongoing support. This review draws upon our experience to present the typical features of POEMS syndrome and highlight diagnostic conundrums commonly experienced, supplemented with clinical cases. We provide an investigative guide for clinicians when considering POEMS as the diagnosis, and propose a treatment algorithm that centres on the site and degree of monoclonal cell proliferation.
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POEMS syndrome, an acronym first coined by Bardwick in 1980, describes the clinical phenotype of a rare and disabling multisystem, autoinflammatory condition featuring polyneuropathy, organomegaly, endocrinopathy, the presence of a monoclonal plasma cell disorder and skin disease.1 Larger cohort studies have identified several other characteristic findings, including papilloedema, extravascular volume overload, sclerotic bone lesions and thrombocytosis (abbreviated to ‘PEST’ as a supplementary aide-memoire2). The pathogenesis of POEMS syndrome is not understood, but probably relates to the monoclonal plasma cell proliferative disorder and the impact this has on inducing a cytokine-driven inflammatory response.3–7 Vascular endothelial growth factor (VEGF), a potent angiogenic cytokine, may be markedly raised in the serum of patients with POEMS.8 Reported treatment trials blocking VEGF with bevacizumab resulted in worsening of neuropathy and some deaths.9 10 VEGF is therefore a useful biomarker for disease detection and monitoring,3 4 8 11 but its role in pathogenesis is poorly understood.
Dispenzieri et al2 proposed widely accepted diagnostic criteria in 2003 in an attempt to standardise the various features and investigation findings necessary to make a diagnosis of POEMS syndrome (see table 1). Polyneuropathy and a monoclonal plasma cell disorder are hallmarks of the clinical disease, and therefore mandatory criteria for diagnosis. As is typical in medicine, textbook definitions rarely reflect what is seen in clinical practice. Although there are clear diagnostic criteria, POEMS syndrome remains notoriously difficult to diagnose. Although 95% of cases have a monoclonal lambda light chain plasma cell dyscrasia12 coupled with the highly sensitive biomarker VEGF,4 misdiagnosis remains likely. The heterogeneity of clinical presentations, with patients commonly presenting with only a limited number of the features described, contributes to the diagnostic difficulties. The subtlety or lack of bone marrow abnormality provides false reassurance of the absence of a monoclonal plasma cell disorder. The typically inflammatory neuropathy mimics that of the much more familiar chronic inflammatory demyelinating polyradiculoneuropathy (CIDP); over 60% of patients are initially diagnosed with CIDP,13 resulting in treatment with ineffective immunomodulatory therapy and subsequent clinical deterioration due to delayed diagnosis by a median of 12 months.13 Features such as endocrinopathy, papilloedema and skin conditions are non-specific, and may not typically be attributed to a neurological syndrome. Furthermore, subtle investigation findings may be misinterpreted or downplayed, resulting in reports that may not synthesise the whole picture. With all the diagnostic uncertainty and misleading information in such a complex disease, it is little wonder clinicians fail to consider the diagnosis.
Once the diagnosis is made, there are still uncertainties regarding treatment. Treatment is directed at the underlying clonal plasma cell disorder and depends on the distribution of the disease and extent of bone marrow involvement. Novel chemotherapeutic agents and autologous stem cell transplantation allow for significant improvement of disease-free survival. Treatment selection, assessing response, monitoring disease and identifying relapses are complex and require multiple investigational modalities. Indeed, the multisystem nature of POEMS and its compounding disabilities requires multidisciplinary support and assistance.
This review aims to guide clinicians through the diagnostic process towards making a diagnosis of POEMS syndrome. We describe the ‘typically atypical’ patient with POEMS and illustrate some of the diagnostic conundrums of POEMS using case examples. We provide recommendations for the thorough investigative workup required to diagnose POEMS syndrome and the commonly misreported findings to look out for. We propose a treatment guideline and provide recommendations for monitoring patients and identifying relapses.
The typically atypical presentation of POEMS syndrome
Table 1 shows the diagnostic criteria for POEMS syndrome. The presence of polyneuropathy and a monoclonal plasma cell disorder is fundamental to the diagnosis. The polyneuropathy in POEMS syndrome shares many characteristics of CIDP, with the development of a subacute, progressive motor-predominant polyradiculoneuropathy. Both conditions show cerebrospinal fluid (CSF) albuminocytological dissociation and electrophysiological evidence of demyelination, with f-wave prolongation, slowed conduction velocity and temporal dispersion. However, the neuropathies are very different. Table 2 details the clues in the history, examination and neurophysiological findings that help to distinguish POEMS neuropathy from CIDP. In practice, neurophysiology results may be misinterpreted and reported as fitting diagnostic criteria for CIDP,14 and for this reason we recommend all patients presenting with an inflammatory neuropathy should have appropriate investigations for the presence of a monoclonal plasma cell proliferative disorder (serum and urine protein electrophoresis, immunofixation and serum free light chain assay), and consideration of VEGF included at the outset, and certainly so if there is a lambda light chain paraprotein. The finding of a lambda light chain and/or a raised VEGF should prompt further thorough investigation, detailed below. The neurohistopathology of POEMS nerves is of axonal and demyelinating lesions with uncompacted myelin lamellae.15 16 Uncompacted myelin is non-specific; there are much more sensitive biomarkers such as a monoclonal proliferative disorder with lambda light chains and raised VEGF,3 4 and so we do not recommend nerve biopsy to distinguish POEMS from CIDP. However nerve biopsy may be indicated to rule out suspected vasculitis, amyloid or an infiltrative disorder, all of which may cause a painful or non-steroid or intravenous immunoglobulin-responsive neuropathy such as POEMS.
Monoclonal plasma cell disorder
Having considered POEMS syndrome, it is important to prove the presence of a monoclonal plasma cell disorder to make the diagnosis. This requires detection of monoclonal proteins (paraproteins) formed by a single heavy chain (M, G or A) and a light chain (kappa or lambda), which is usually but not always secreted. Around 10% of patients with polyneuropathy of otherwise unknown cause have a monoclonal gammopathy.17 A low-level stable paraprotein is occasionally discovered in older persons, and often this is attributed to an insignificant monoclonal gammopathy of unknown significance (MGUS). Interestingly, most monoclonal gammopathies in association with neuropathy are IgM (78%) and kappa (88%).18 For reasons unknown, gammopathies in POEMS syndrome are characteristically IgA (52%) and IgG (47%), and almost never IgM.2 Lambda light chain predominates and occurs in 95% of POEMS cases.2 Although in cases of MGUS there can be IgA or IgG lambda monoclonal proliferation, this peculiar pattern of heavy and light chain combination should serve as a ‘red flag’, strongly alerting clinicians to consider the diagnosis of POEMS or light chain amyloidosis.
A monoclonal plasma cell disorder can be demonstrated through testing serum, urine or bone marrow, or through histopathology of a biopsy specimen. Serum protein electrophoresis, immunofixation and serum free light chain analysis must all be performed to detect a subtle plasma cell disorder with appropriate sensitivity. Many haematology laboratories do not provide immunofixation and serum free light chain analysis if preliminary investigations are unrevealing, and therefore neurologists must work with their laboratories to enable such testing as routine for all suspected POEMS cases. Below is an example of this in clinical practice.
Case example 1: the importance of thorough haematological investigations
A 56-year-old man with a background history of treated Castleman’s disease presented in 2004 with lower limb neuropathic sounding pain. This progressed over 3 years to involve oedema and weakness with bilateral foot drop. Neurophysiology showed a severe sensorimotor neuropathy, with axonal loss on electromyography. Six serum protein electrophoresis examinations over 3 years were all negative. In 2007, the first immunofixation test showed a low-concentration IgA lambda paraprotein not visible on serum protein electrophoresis. This demonstrates the usefulness of immunofixation. If immunofixation and serum free light chain analysis are not performed, a monoclonal paraprotein will be missed in about 30% of POEMS cases.2
Urine protein electrophoresis, immunofixation and light chain analysis are performed through urine collection, but for practical reasons are often not sent. However, a random (as opposed to 24-hour collection) urine sample is all that is required to detect monoclonal proteins. The natural homeostatic ultrafiltration of urine is a serum free light chain concentrator and can result in patients who are serum-negative having positive urine results.
Case example 2: the importance of testing the urine
A 38-year-old woman presented with a demyelinating neuropathy diagnosed as probable CIDP. She had undergone at least three serum protein electrophoresis, immunofixation and serum free light chain assessments over 2 years, which were all normal. Her urinary Bence Jones protein was positive, with free lambda light chains detected by immunofixation. By the time of detection, she had received prednisolone, two courses of intravenous immunoglobulin, methotrexate and plasma exchange without any improvement. We use this example to stress the importance of sending all tests, including urine as part of the full investigative workup, where Bence Jones protein or urinary light chains may be the only evidence of a monoclonal plasma cell disorder.
Bone marrow aspiration and trephine should be performed for immunophenotypic evaluation once a monoclonal plasma cell disorder is detected serologically or in the urine. Examination of the bone marrow provides an invaluable tool in the diagnosis and classification of plasma cell dyscrasias and to ascertain extent of disease.19 Two-thirds of bone marrow biopsies in POEMS show a plasma cell malignant clone20 typically at a low level of around 5%–10%, often with a very high proportion of abnormal cells restricted to expressing lambda light chains (≈90%). The presence of bone marrow lymphoid aggregates rimmed by monotypic or polytypic plasma cells should lead haematopathologists to raise the possibility of POEMS syndrome20 (see figure 1). Megakaryocyte hyperplasia and clustering also occur in POEMS syndrome bone marrow histology, and can therefore lead to the misinterpretation of a myeloproliferative disorder. However, one-third of bone marrow biopsies do not show evidence of a plasma cell clone. This is because the monoclonal plasma cell disorder is limited to multifocal or solitary plasmacytomas (a discrete solitary mass of neoplastic monoclonal plasma cells in soft tissue or bone).2 20 21 For this reason, a non-diagnostic bone marrow result necessitates further investigation for plasmacytomas through whole body imaging such as positron emission tomography (PET)-CT. The CT modality enables sclerotic and lytic lesions to be identified and fluorodeoxyglucose (FDG)-PET provides pointers to glucose-avid plasmacytomas. The most FDG-avid, accessible bone lesion should be biopsied to obtain histological confirmation of the diagnosis. The extent and location of monoclonal plasma cell disorder influence treatment decisions and are discussed further.
Table 1 shows the wide-ranging multisystem features of POEMS. Endocrine disturbance occurs in 65% of our UK POEMS cohort, with a high incidence of hypogonadism and hypopituitarism. Hypogonadism and hypopituitarism most frequently manifest as erectile dysfunction and gynaecomastia in men, and as early menopausal symptoms in women. The baseline prevalence of diabetes mellitus and thyroid disease is too high to include as diagnostic criteria for POEMS syndrome, unless there is a distinct temporal relationship with symptom onset. Organomegaly of the spleen, liver or lymph nodes occurs in around half of our cohort. Red flags that should alert neurologists to the diagnosis of POEMS syndrome include ‘glomeruloid haemangiomata’, dome-shaped red-brown papular (sometimes pedunculated) nodules on the trunk or proximal extremities that probably arise due to overexpression of VEGF (see figure 2). Papilloedema is rare in inflammatory neuropathy,22 so when discovered should trigger investigation for POEMS syndrome (prevalence around 40%).2 If it is severe enough to be haemorrhagic, the haemorrhage is subretinal and very striking (see figure 2). Neuropathy in a young patient with unexplained peripheral oedema and skin changes suggesting capillary leak does not occur in CIDP and are further clinical clues to POEMS syndrome. Severely affected patients may also develop capillary leakage in the lungs, abdomen and heart, resulting in poor gas transfer, ascites and pericardial effusions.
Patients rarely present with the perfect cluster of symptoms described in the POEMS acronym. We have seen a variety of patients with POEMS variants and present two examples below.
Case example 3: POEMS without the ‘P’
A 45-year-old man presented with a 2-year history of pain in the right lower limb on walking. Investigations showed compression of the right femoral artery with lymphadenopathy, reported on biopsy as ‘reactive changes’. He was suspected of having Castleman’s disease, but a repeat biopsy of another node to look for evidence for this was reported as reactive, with no evidence of typical Castleman’s histology. An IgA lambda paraprotein was found on serum protein electrophoresis/immunofixation, in association with an endocrinopathy with low testosterone. Serum VEGF was more than 5000 pg/mL (reference range 5–77). PET imaging showed osteosclerotic lesions throughout the spine. A bone marrow trephine contained more than 15% plasma cells. Clinical examination identified several glomerular haemangiomas on the trunk. Apart from pain in the lower right leg, which was probably vascular in origin, there were no neuropathic symptoms in the limbs. Clinical examination and neurophysiology showed no evidence of a neuromuscular disorder. He was diagnosed with POEMS syndrome based on the multitude of findings, but strictly did not fit the diagnostic criteria due to absence of polyneuropathy. He is awaiting an autologous stem cell transplant as first-line therapy.
Case example 4: ‘*O*MS’
A patient presented following a seizure and was found to have had a left occipital stroke. During the investigation, the patient was noted to have both thrombocytosis and a raised haematocrit, with negative myeloproliferative genetic tests (Jak2 and Cal-R mutations). Serum protein electrophoresis identified an IgG lambda paraprotein. Bone marrow biopsy found a 15% lambda-restricted plasma cell clone. Imaging showed multiple lymph nodes and an L4 vertebra sclerotic lesion. On examination, there was peripheral acrocyanosis but no evidence of endocrinopathy. The serum VEGF was markedly elevated at 11 000 pg/mL (reference range 5–771). There was no clinical or electrophysiological evidence of neuropathy. Lymph node biopsy showed angiofollicular lymph node hyperplasia, consistent with Castleman’s disease. The patient completed five cycles of treatment with lenalidomide, cyclophosphamide and dexamethasone, to be followed by autologous stem cell transplantation. A recent PET scan showed resolution of lymph nodal disease and serum VEGF of 1074 pg/mL after cycles of lenalidomide and dexamethasone.
Castleman’s disease is a lymphoproliferative disorder that can be limited to a single group of lymph nodes (unicentric) or multiple lymph nodes, and organs such as the spleen and thymus (multicentric). Lymph node biopsy can show evidence of Castleman’s disease in up to 30% of POEMS cases.23 Patients with POEMS with Castleman’s disease appear to have a less severe neuropathy, which may explain why there can be such heterogeneity. There are other cases of atypical POEMS in the literature with an argument to redefine the diagnostic criteria and include the entity of Castleman’s disease variant of POEMS.24 An atypical presentation of POEMS with a positive VEGF is probably more likely to be POEMS than another disease, and therefore VEGF is a useful test when faced with an atypical presentation. Specialist clinics can provide guidance on interpreting results such as this.
Investigating POEMS syndrome
Patients require extensive investigations to confirm the presence or absence of a multitude of systemic features at diagnosis, during monitoring and following treatment. Table 3 sets out our proposed investigative guideline. Skeletal surveys and CT chest, abdomen and pelvis can help to identify mixed sclerotic and lytic bone lesions but involve significant irradiation. Whole body MRI is often used as a screening tool and PET-CT is the most useful imaging modality to identify FDG-avid plasmacytomas or lymph nodes for biopsy.
The role of VEGF
VEGF has been proven to be a highly accurate surrogate biomarker of disease detection and activity in POEMS. Plasma and serum concentrations are markedly elevated compared with those in patients with other plasma cell dyscrasias (P<0.001), peripheral neuropathy (P<0.001) and connective tissue disease/vasculitis (P<0.009).25 26 Hypoxia, anaemia and low iron can lead to false-positive results, but rarely as high as POEMS positive samples, which are two to three times the upper limit of normal.26 Patients treated within the last month with corticosteroids can have false-negative results, and results from such cases should be interpreted with caution.6 10 Serum VEGF concentrations are 10–50 times higher than that of plasma in both health and disease, as serum contains VEGF released by ex vivo platelet activation during the clotting process, as well as the serum.4 Both tests are similarly useful in the diagnosis and monitoring of POEMS, but for clarity we advise using either the serum or the plasma for each patient, and not both. The VEGF concentrations given in this paper all relate to serum VEGF.
Case example 5: anaemia and low iron induce VEGF production
A 20-year-old male mechanic presented with acute global weakness following a sore throat, diagnosed as Guillain-Barré syndrome. He improved following intravenous immunoglobulin and could return to work. In the following year he experienced relapses on a 2 monthly basis. Each episode responded to corticosteroids, intravenous immunoglobulin or plasma exchange. Neurophysiology showed a demyelinating polyradiculoneuropathy and CSF showed albuminocytological dissociation. MR scanning revealed thickened nerve roots. There was no monoclonal paraprotein on serum protein electrophoresis, immunofixation or serum free light chain analysis. PET scanning was normal and there were no bone lesions on imaging. Clinically there was no evidence of POEMS features other than neuropathy. We made a diagnosis of CIDP. His serum VEGF was significantly raised at 1627 pg/mL, and 5 months later was 2615 pg/mL. Bone marrow biopsy was normal. He had persistent iron deficiency anaemia despite oral supplementation. We suspected that iron deficiency was driving his high serum VEGF, and therefore we treated him more aggressively with intravenous iron, following normal endoscopy and colonoscopy. Subsequently, after 4 months the serum VEGF concentration dropped to 800 pg/mL; he will undergo further testing in due course.
Case example 6: hypoxia induces VEGF production
A 55-year-old woman gave a 10-month history of progressive weakness, numbness and pain in the distal lower limbs. She was diagnosed with POEMS following bone marrow biopsy and a serum VEGF of 5657 pg/mL. We selected lenalidomide and dexamethasone as initial treatment with co-trimoxazole prophylactic cover. Within 1 month, her serum VEGF fell from 5657 to 599 pg/mL. She developed a rash, and so we stopped the co-trimoxazole and started dapsone. Subsequently she developed methaemoglobinaemia secondary to dapsone, inducing hypoxia. Her serum VEGF increased at this time to 1303 pg/mL. We stopped the dapsone and the serum VEGF rapidly normalised (see figure 3 for details).
Both cases illustrate that despite VEGF being highly sensitive and specific for POEMS syndrome, iron deficiency and hypoxia induce VEGF production, so should be considered as a possible contributing factor when one is faced with abnormal values close to the upper limit of normal (reference range 5–771 pg/mL). There have been other cases of patients with high falsely positive VEGF results, such as in connective tissue disease and vasculitis.6 For this reason, the VEGF concentration should be interpreted in the context of a typical POEMS neuropathy and a lambda light chain plasma cell dyscrasia to diagnose POEMS.
Treating POEMS syndrome
Despite VEGF being a sensitive biomarker of POEMS syndrome, trials of the anti-VEGF monoclonal, bevacizumab, have yielded ineffective, if not detrimental results.9 10 The mainstay of treating POEMS syndrome is therefore through suppression of the monoclonal plasma cell proliferation. This can be done in several ways, depending on the extent of disease, comorbidities and patient fitness.
As mentioned before, the monoclonal plasma cell disorder can comprise diffuse bone marrow infiltration and/or solitary/multifocal plasmacytomas. Patients with bone marrow involvement on bone marrow biopsy, or three or more plasmacytomas, are considered to have systemic disease; two or fewer plasmacytomas is considered as focal disease. Figure 4 provides a treatment algorithm that depends on the extent of disease.27
Focal disease (one or two plasmacytomas)
Radiotherapy to two or fewer plasmacytoma lesions is first-line treatment in focal disease. The objective is to obtain complete remission with minimal side effects while avoiding protracted treatment when compared with systemic therapies. From 67 patients with POEMS in our service, 22 have received radiotherapy as first line. Eleven went on to have second-line systemic therapy due to clinical or biochemical relapse, after an average of 22 months (median 13 months). Eleven patients have remained clinically stable, with our longest surviving patient at 19 years following radiotherapy.
Case example 7: how to treat focal lesions
A 73-year-old man with a background of ischaemic heart disease presented in 2011 with generalised lower limb weakness and bilateral foot drop. After 6 months, he has become a wheelchair user with little hand movement. He was totally dependent on his family for his daily needs. On examination, there was fluid overload, but no evidence of skin lesions, organomegaly or papilloedema. Investigations showed a severe length-dependent sensorimotor demyelinating neuropathy. Blood tests showed subclinical hypothyroidism and an IgG lambda paraprotein of 3 g/L. CSF protein was significantly elevated at 2.8 g/L, with no cells. For this reason, a serum VEGF was measured (11 000 pg/mL, normal 5–771). A skeletal survey and follow-up PET-CT showed a solitary ‘soap-bubble’ lesion of the proximal left femur (figure 5). A soap-bubble appearance is an expansile, often eccentric, vaguely trabeculated space with a thin sclerotic sharply defined margin, and usually signifies osteoclastomas/giant cell tumours of the bone.28 Bone marrow aspirate and trephine histology were normal. A biopsy of the femoral lesion identified a CD138 plasma cell infiltrate. We gave him intravenous methylprednisolone for 3 days to stabilise his condition; this resulted in an acute coronary syndrome for which he received coronary stents. Due to the poor stability of the femoral lesion, an intramedullary nail was inserted, and 25 fractions (total 50 Gy) of radiotherapy were directed at the lesion. The serum VEGF 3 months later had fallen to 506 pg/mL and he noticed improved power in the lower limbs. He continues to improve. Five years after radiotherapy the serum VEGF remains normal, repeat imaging of the femoral lesion is stable, and he can now walk 200 yards with orthotics and is independent in activities of daily living.
Generalised disease (three or more plasmacytomas or positive bone marrow histology)
Patients with generalised disease require systemic treatment. Melphalan-conditioned autologous stem cell transplantation is the gold standard, with chemotherapy used for patients deemed unfit for transplantation.
Due to small patient numbers, treatment algorithms for POEMS syndrome have been adopted from multiple myeloma or light chain amyloidosis. High-dose chemotherapy plus autologous stem cell transplantation is the current gold standard treatment for POEMS syndrome, with good haematological control, with progression-free survival of 98%, 94% and 75% at 1, 2 and 5 years,27 29 30 and good organ-specific response levels, with 100% patients achieving ‘a degree of neurological recovery’.31 32 The first autologous stem cell transplantation for POEMS syndrome at University College London was performed in 199933 on a 56-year-old man who remains in remission, fully ambulant and with a most recent serum VEGF of 276 pg/mL. We have subsequently performed 36, and only 3 have required further treatment with systemic chemotherapy. Age, comorbidities and physiological fitness should be considered before autologous stem cell transplantation. We quote a 5%–10% risk of the need for intensive care treatment, and 3%–5% risk of death, depending on performance status.30 34 Engraftment syndrome probably occurs in around 20%–50% of patients,30 although we have not seen this in our cohort of 36 treated patients. Patients can relapse, and in such cases low-dose long-term chemotherapy is an option, or a second autologous stem cell transplantation, but there is no evidence for this.
Patients deemed unfit for autologous stem cell transplantation can be treated with chemotherapeutic agents as pretransplant induction therapy, enabling transplantation at a later date, or long term if stem cell transplantation is not an option. Broadly speaking, chemotherapy used to be based on an alkylating agent (such as melphalan or cyclophosphamide) and dexamethasone.27 35 Thalidomide and lenalidomide, potent inhibitors of tumour secreting cytokines such as interleukin 6, tumour necrosis factor and VEGF, are emerging as treatments for POEMS syndrome. We are now often using lenalidomide as first line. A systematic review of lenalidomide in POEMS reported neuropathy improvement in 90% of cases and a progression-free survival estimate at 12 months of 93%.36 Using lenalidomide and dexamethasone, we have seen remarkable and rapid improvement in clinical status, particularly in fluid overload, VEGF and haematological response. The risks of peripheral neuropathy with thalidomide, and of thrombosis with both thalidomide and lenalidomide, require careful monitoring and the need for prophylactic low molecular weight heparin. Bortezomib as a single agent, or combined with cyclophosphamide, has shown promising results in 25 patients, but can also cause or worsen peripheral neuropathy.37
Case example 8: choosing the correct treatment
A 69-year-old man was suspected of having POEMS syndrome on the basis of demyelinating polyneuropathy, fluid overload, skin changes (acrocyanosis and hypertrichosis) and papilloedema. Investigations showed an IgG lambda paraprotein of 9 g/L, serum VEGF of 2843 pg/dL and a solitary plasmacytoma of the left ilium with plasma cell infiltration. Bone marrow biopsy of the right ilium was normal. He received 19 fractions of local radiotherapy. Three months later he had developed weight loss and worsening neuropathy, and his serum VEGF had doubled to 4865 pg/mL. Disease reassessment included a repeat PET-CT scan that showed evidence of multifocal skeletal lesions with persistent avidity in the index lesion. Retrospective analysis of the original PET scan identified bone lesions not previously noted. Due to the presence of systemic disease, we started lenalidomide and dexamethasone, with prior stem cell harvesting with a view to autologous stem cell therapy. We used systemic induction immunomodulatory therapy before transplant in an attempt to limit the collective volume of multifocal skeletal plasmacytomas.
Multidisciplinary input is essential when caring for patients with POEMS syndrome. Disability management through the use of orthotics, walking aids and home adaptations should be provided through physiotherapy and occupational therapy services, preferably in a multidisciplinary environment. Neuropathy in POEMS classically takes around 2–3 years post-treatment before significant improvement begins. A retrospective review of 60 patients with POEMS following autologous stem cell transplantation showed a median improvement in the neuropathy impairment score of 18 points (66–48 points) in 12 months and 30 points at a median follow-up of 60 months.31 We typically refer patients for neurorehabilitation both early in the disease and once neuropathy starts to improve. Patients can receive educational and emotional support through specialist nurses and psychologists, and we refer patients to the POEMS Facebook group (search ‘POEMS syndrome’ on Facebook for the page).
Assessing response to treatment and monitoring is complex and requires thorough investigation and clinical assessment to determine response. Broadly, we use the following categories to assess response:
Haematological response: This is defined by the clearance of monoclonal proteins from the blood, and clearance of plasma cells from the bone marrow. This can be misleading, as the monoclonal component in POEMS tends to be very subtle, and patients can improve significantly despite the absence of a monoclonal protein response.27
VEGF: VEGF tends to correlate with disease activity and should normalise (serum concentration <771 pg/mL) over 6 months, but again this may not correlate with the treatment response.
PET-CT imaging: This can help to show reduction in standardised uptake values (SUVmax) of previously avid lesions; such reductions take many months (often more than 12).
Organ response: Organ response can be difficult to quantify, but the following markers would indicate improvement:
reduction in weight secondary to resolution of fluid overload
shrinkage of enlarged organs or lymph nodes
shrinkage or disappearance of glomeruloid haemangiomas
improvement in pulmonary and cardiac function
improvement in neuropathy severity scores such as Rasch-built Overall Disablilty Score (R-ODS)-CIDP or Medical Research Council (MRC) muscle sum scores.
Collating all the above provides an overall picture of the patient’s disease status. Any worsening of clinical, radiological or haematological indicators should prompt further investigation with the tests highlighted in table 3, ultimately with consideration of a bone marrow biopsy where appropriate.
Case example 9: assessing and monitoring response to treatment
A 72-year-old male farmer was diagnosed with POEMS syndrome in 2012 on the basis of a demyelinating peripheral neuropathy, organomegaly, IgG lambda paraprotein of 6 g/dL and a solitary FDG-avid pubic bone lesion on PET-CT imaging. Bone marrow biopsy also found 10% plasma cell infiltration. His serum VEGF concentration was 3917 pg/mL. At the time of diagnosis, he could not stand. We started systemic therapy with melphalan and dexamethasone, and delivered focal radiotherapy to the pubic bone lesion as 30 Gy in 10 fractions, completed in February 2013. Repeat PET-CT imaging 4 months following treatment found no change to the pubic bone lesion, but more reassuringly the serum VEGF had fallen to 550 pg/mL, and the paraprotein concentration had halved to 3 g/dL. At this stage, repeat bone marrow biopsy was indicated to ascertain the degree of residual disease burden. This showed 1% plasma cell infiltration, and at 6 months his neuropathy started to show signs of improvement, with reduced pain and increased mobility. We therefore decided to continue monitoring at this stage. A persistently abnormal bone marrow together with an unchanged appearance of the pubic bone lesion would indicate ongoing disease, requiring consideration of systemic/immunomodulatory therapy. Repeat PET imaging 1 year following treatment in February 2014 showed reduced avidity of the lesion from SUVmax of 14.1 to 4.9. The serum VEGF remained low at 350 pg/mL and the paraprotein undetectable. This case shows that PET-avid lesions can persist despite there being a response to treatment, and shows the importance of considering multiple factors when assessing response to therapy. The patient remains well, and demonstrated this by jogging into the clinic room on his last visit.
POEMS syndrome is a devastating condition for many patients, unless prompt diagnosis and effective treatment can prevent significant disability and the multitude of associated features. The key to making the diagnosis is to identify a demyelinating peripheral neuropathy, a lambda light chain monoclonal plasma cell disorder and a raised serum VEGF. Investigations distinguish focal from systemic disease, which guides subsequently highly effective treatment in the form of radiotherapy, chemotherapy or autologous peripheral stem cell transplantation.
Not all patients with POEMS syndrome present with the classic features described in the acronym.
All patients presenting with an inflammatory neuropathy should be investigated for a monoclonal plasma cell proliferative disorder; if abnormal, they should be considered for serum VEGF.
The combination of a demyelinating neuropathy, a lambda light chain paraprotein and raised VEGF is very likely to confirm POEMS syndrome and should prompt further investigations such as bone marrow biopsy and PET scan to ascertain the degree of monoclonal involvement.
Patients are deemed to have focal or systemic disease based on the extent of monoclonal plasma cell dyscrasia, and this guides subsequent treatment options.
Significant improvements in the neuropathy of POEMS syndrome can take up to 3 years following treatment.
Contributors SK and MPTL were responsible for the conception and design of the work. SK collated cases and drafted the paper. All other authors were responsible for interpretation of data, and revisions and edits. All authors agree to be accountable for the work and provide final approval.
Funding SK is funded by an ABN/Guarantors of Brain Clinical Training Research Fellowship [Grant number 541665]. MPTL is supported by the National Institute of Health Research, University College London Hospitals, Biomedical Research Centre.
Competing interests None declared.
Patient consent Obtained.
Ethics approval All patients signed consent forms to allow for their case histories and clinical images to be published.
Provenance and peer review Commissioned; externally peer reviewed. This paper was reviewed by Robert Hadden, London, UK, and Gareth Llewelyn, Cardiff, UK.
Data sharing statement No unpublished data.
Author note VEGF testing is performed currently at the Department of Neuroimmunology at the National Hospital for Neurology and Neurosurgery, London, UK, and has a turnaround time of around 2 weeks.
Correction notice This article has been corrected since it published Online First. A second sentence has been added to the Funding statement.