POEMS syndrome: Update on diagnosis, risk-stratification, and management

Abstract

Disease overview: POEMS syndrome is a paraneoplastic syndrome due to an underlying plasma cell neoplasm. The major criteria for the syndrome are polyradiculoneuropathy, clonal plasma cell disorder (PCD), sclerotic bone lesions, elevated vascular endothelial growth factor, and the presence of Castleman disease. Minor features include organomegaly, endocrinopathy, characteristic skin changes, papilledema, extravascular volume overload, and thrombocytosis. Diagnoses are often delayed because the syndrome is rare and can be mistaken for other neurologic disorders, most commonly chronic inflammatory demyelinating polyradiculoneuropathy. POEMS syndrome should be distinguished from the Castleman disease variant of POEMS syndrome, which has no clonal PCD and typically little to no peripheral neuropathy but has several of the minor diagnostic criteria for POEMS syndrome.

Diagnosis: The diagnosis of POEMS syndrome is made with 3 of the major criteria, two of which must include polyradiculoneuropathy and clonal plasma cell disorder, and at least one of the minor criteria.

Risk stratification: Because the pathogenesis of the syndrome is not well understood, risk stratification is limited to clinical phenotype rather than specific molecular markers. The number of clinical criteria is not prognostic, but the extent of the plasma cell disorder is. Those patients with an iliac crest bone marrow biopsy that does not reveal a plasma cell clone are candidates for local radiation therapy; those with a more extensive or disseminated clone will be candidates for systemic therapy.

Risk-adapted therapy: For those patients with a dominant sclerotic plasmacytoma, first line therapy is irradiation. Patients with diffuse sclerotic lesions or disseminated bone marrow involvement and for those who have progression of their disease 3 to 6 months after completing radiation therapy should receive systemic therapy. Corticosteroids are temporizing, but alkylators are the mainstay of treatment, either in the form of low dose conventional therapy or high dose with stem cell transplantation. The benefit of anti-VEGF antibodies is conflicting. Lenalidomide shows promise with manageable toxicity. Thalidomide and bortezomib also have activity, but their benefit needs to be weighed against their risk of exacerbating the peripheral neuropathy. Prompt recognition and institution of both supportive care measures and therapy directed against the plasma cell result in the best outcomes. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc.

Introduction

POEMS syndrome is a rare paraneoplastic syndrome due to an underlying plasma cell disorder. There acronym, which was coined by Bardwick in 1980 [1], refers to several, but not all, of the features of the syndrome: polyradiculoneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes. There are three important points that relate to this memorable acronym: (1) not all of the features within the acronym are required to make the diagnosis; (2) there are other important features not included in the POEMS acronym, including papilledema, extravascular volume overload, sclerotic bone lesions, thrombocytosis/erythrocytosis (P.E.S.T.), elevated VEGF levels, a predisposition towards thrombosis, and abnormal pulmonary function tests; and (3) there is a Castleman disease variant of POEMS syndrome may is associated with a clonal plasma cell disorder. Other names of the POEMS syndrome that are less frequently used are osteosclerotic myeloma, Takatsuki syndrome or Crow-Fukase syndrome [2, 3]. The disease was initially thought to be more common in patients of Japanese decent given the largest initial reports from Japan [2, 3]. However, over the years, large series have also been reported from France, the United States, China, and India [4–8]. A national survey conducted in Japan in 2003 showed a prevalence of approximately 0.3 per 100,000 [9].

The pathogenesis of the syndrome is not well understood. Distinctive presenting characteristics of the syndrome that differentiate POEMS syndrome from standard multiple myeloma (MM) include the following: (1) dominant symptoms have little to nothing to do with bone pain, extremes of bone marrow infiltration by plasma cells, or renal failure; (2) dominant symptoms are typically neuropathy, endocrine dysfunction, and volume overload; (3) vascular endothelial growth factor (VEGF) levels are high; (4) sclerotic bone lesions are present in the majority of cases; (5) overall survival is typically superior; and (6) lambda clones predominate [10].

To date, VEGF is the cytokine that correlates best with disease activity [11–20], although it may not be the driving force of the disease based on the mixed results seen with anti-VEGF therapy [21−27], VEGF is known to target endothelial cells, induce a rapid and reversible increase in vascular permeability, and be important in angiogenesis. It is expressed by osteoblasts, in bone tissue, macrophages, tumor cells [28] (including plasma cells) [29, 30], and megakaryocytes/platelets [31]. Both IL-1β and IL-6 have been shown to stimulate VEGF production [28]. Little is known about the plasma cells in POEMS syndrome except that more than 95% of the time they are lambda light chain restricted with restricted immunoglobulin light chain variable gene usage (IGLV1) [32–34]. Aneuploidy and deletion of chromosome 13 have been described, but hyperdiploidy is not seen [35].

Diagnosis

The diagnosis is made based on a composite of clinical and laboratory features (Table I), and the diagnosis will be missed if it is not considered. Most notably, the constellation of neuropathy and any of the following should elicit an in depth search for POEMS syndrome: monoclonal protein (especially lambda light chain); thrombocytosis; anasarca; or papilledema. The requirements set forth in Table I are designed to retain both sensitivity and specificity, potentially erring on the side of specificity. Making the diagnosis can be a challenge, but a good history and physical examination followed by appropriate testing—most notably radiographic assessment of bones [36], measurement of VEGF [13, 17, 20, 37, 38], and careful analysis of a bone marrow biopsy [39]—can differentiate this syndrome from other conditions like chronic inflammatory polyradiculoneuropathy (CIDP), monoclonal gammopathy of undetermined significance (MGUS) neuropathy and immunoglobulin light chain amyloid neuropathy. As will be discussed, there is a Castleman's variant of POEMS syndrome that does not have a clonal plasma cell proliferative disorder underlying, but have many of the other paraneoplastic features [40].

Table I. Criteria for the Diagnosis of POEMS Syndromea

Mandatory major criteria	1. Polyneuropathy (typically demyelinating)
POEMS, polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes. The diagnosis of POEMS syndrome is confirmed when both of the mandatory major criteria, one of the three other major criteria, and one of the six minor criteria are present. a There is a Castleman disease variant of POEMS syndrome that occurs without evidence of a clonal plasma cell disorder that is not accounted for in this table. This entity should be considered separately. b Because of the high prevalence of diabetes mellitus and thyroid abnormalities, this diagnosis alone is not sufficient to meet this minor criterion. c Approximately 50% of patients will have bone marrow changes that distinguish it from a typical MGUS or myeloma bone marrow. [39] Anemia and/or thrombocytopenia are distinctively unusual in this syndrome unless Castleman disease is present.
	2. Monoclonal plasma cell-proliferative disorder (almost always λ)
Other major criteria	3. Castleman disease*
(one required)	4. Sclerotic bone lesions
	5. Vascular endothelial growth factor elevation
Minor criteria	6. Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy)
	7. Extravascular volume overload (edema, pleural effusion, or ascites)
	8. Endocrinopathy (adrenal, thyroid,b pituitary, gonadal, parathyroid, pancreaticb)
	9. Skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, plethora, acrocyanosis, flushing, white nails)
	10. Papilledema
	11. Thrombocytosis/polycythemiac
Other symptoms and signs	Clubbing, weight loss, hyperhidrosis, pulmonary hypertension/restrictive lung disease, thrombotic diatheses, diarrhea, low vitamin B12 values

Distinguishing POEMS syndrome from a MGUS, smoldering MM (SMM), MM, or solitary plasmacytoma is important since the treatment, supportive care, and the expected treatment-related toxicities are quite different. If a patient with POEMS syndrome is deemed to have a MGUS or SMM, then no treatment directed at the clone will be recommended, existing symptoms will worsen, and the patient will accumulate additional elements of the paraneoplastic syndrome. If the patient is diagnosed with MM or plasmacytoma, and standard therapies for these disorders are administered, the likelihood is high that there will be increased treatment-related morbidity and inadequate supportive care. Therefore, a patient with POEMS syndrome should be thoroughly evaluated to define a baseline that can be used for future assessments (Table II).

Table II. Recommended Minimum Testing

Test	Baseline	Every 3 months	Yearly
a At 6 months and then yearly. b As clinically indicated. c CT bone windows are very helpful in detecting bone lesions as well as lymph nodes and organomegaly. d Only if affected.
Neurologic
Detailed neurologic history (numbness, pain, weakness, balance, orthostasis) and examination (including funduscopic exam)	X	Xa	X
Electrophysiologic study (nerve conduction studies)	X	Xa	X
Sural nerve biopsy	Xb
Organomegaly/ Lymphadenopathy/ Extravascular volume overload
Physical exam and CT scanc documenting lymphadenopathy, organomegaly, ascites, pleural effusions, and edema	X	Xd	Xd
Endocrinopathy
History regarding menstrual and sexual function	X	X	X
Testosterone, estradiol, fasting glucose, glycosylated hemoglobin, thyroid stimulating hormone, parathyroid hormone, prolactin, serum cortisol	X	Xd	Xd
Luteinizing hormone, follicle stimulating hormone, adrenocorticotropin hormone, Cortrosyn stimulation test	Xb	Xd	Xd
Hematologic
Serum protein electrophoresis AND immunofixation	X	X	X
Affected quantitative immunoglobulin	X	Xb	X
Complete blood count (Hemoglobin, platelet)	X	X	X
24 hour urine total protein, electrophoresis, and immunofixation	X		X
Bone marrow aspirate and biopsy (test for kappa/lambda by IHC)	X	X
Vascular endothelial growth factor	X	X	X
Skin
History and physical with attention to skin pigment, thickening and texture, body hair quantity and texture, color of distal extremities, and development of cherry angiomata	X	X	X
Sclerotic bone lesions
Skeletal radiographs and/or PET/CT^‡	X		Xb
Pulmonary Function
Pulmonary function tests	X	Xd	Xd
Echocardiography to assess right ventricular systolic and pulmonary artery pressures	X	Xd	Xd

A thorough review of systems and physical examination are required. Estimated frequencies of findings are shown in Table III. The variability between series is most likely a function retrospective reporting—i.e., if a physician does not order a test or chart a finding, it will not be captured—and promptness of diagnosis, rather than ethnic differences [2, 3, 5, 7, 41]. The neuropathy is the dominant characteristic. The quality and extent of the neuropathy, which is peripheral, ascending, symmetrical, and affecting both sensation and motor function should be elicited [42]; in our experience, pain may be a dominant feature in about 10-15 percent of patients, and in one report as many as 76% of patients had hyperesthesia [9, 43]. Papilledema is present in at least one-third of patients. Of the 33 patients at our institution referred for a formal ophthalmologic examination during a 10-year period, 67% had ocular signs and symptoms, the most common of which was papilledema in 52% of those examined [44]. The most common ocular symptoms reported were blurred vision in 15, diplopia in 5, and ocular pain in 3.

Table III. Summary of Frequencies of POEMS Syndrome Findings Based on Large Retrospective Series [2, 3, 5, 7, 41, 66]

Characteristic	% Affecteda
a Percentages are based on the total number of patients in the series b In both the Takasuki and Nakanishi series, only 75% of patients had a documented plasma cell disorder, which defies the current definition for POEMS syndrome. Since these are among the earliest series describing the syndrome, they are included.
Polyneuropathy	100
Organomegaly	45–85
Hepatomegaly	24–78
Splenomegaly	22–70
Lymphadenopathy	26–74
Castleman disease	11–25
Endocrinopathy	67–84
Gonadal axis abnormality	55–89
Adrenal axis abnormality	16–33
Increased prolactin value	5–20
Gynecomastia or galactorrhea	12–18
Diabetes mellitus	3–36
Hypothyroidism	9–67
Monoclonal plasma cell dyscrasiab	100
M protein on serum protein electrophoresis	24–54
Skin changes	68–89
Hyperpigmentation	46–93
Acrocyanosis and plethora	19
Hemangioma/telangiectasia	9–35
Hypertrichosis	26–74
Thickening	5–43
Papilledema	29–64
Extravascular volume overload	29–87
Peripheral edema	24–89
Ascites	7–54
Pleural effusion	3–43
Pericardial effusion	1–64
Bone lesions	27–97
Thrombocytosis	54–88
Polycythemia	12–19
Clubbing	5–49
Decreased DLCO	>15
Pulmonary hypertension	36
Weight loss > 10 lb	37
Fatigue	31

A whole skin examination should be performed looking for hyperpigmentation, a recent out-cropping of hemangioma, hypertrichosis, dependent rubor and acrocyanosis, white nails, sclerodermoid changes, facial atrophy, flushing, or clubbing [2, 4–8, 45, 46]. Rarely calciphylaxis is also seen [47, 48]. Respiratory complaints are usually limited given patients' neurologic status impairing their ability to induce cardiovascular challenges. In a series of 137 POEMS syndrome patients seen at our institution between 1975 and 2003, at presentation the frequency with which patients reported dyspnea, chest pain, cough, and orthopnea, were 20, 10, 8, and 7%, respectively [49].

Patients are at increased risk for arterial and/or venous thromboses during their course, with nearly 20% of patients experiencing one of these complications [10, 50]. Ten percent of patients present with a cerebrovascular event, most commonly embolic or vessel dissection and stenosis [51]. The median time between peripheral neuropathy symptom onset and the cerebrovascular event was 23 months (range, 0.5–64 months). Risk factors for cerebral events included thrombocytosis and bone marrow plasmacytosis. Aberrations in the coagulation cascade have been implicated in POEMS syndrome [52]. In one report, circulating coagulation factors like fibrinopeptide A, thrombin-antithrombin complex are increased during the active phase of illness, but other factors relating to fibrinolysis, plasminogen, a2 plasmin inhibitor plasmin complex, and FDP did not increase.

On physical examination, objective evidence of the symptoms described above can be found in addition to nonbulky adenopathy, gynecomastia, darkened areolae, diminished breath sounds, hepatosplenomegaly, areflexia, and a steppage gait, commonly with a positive Romberg sign. In our experience, finger-nail clubbing is seen in about 4% of cases, but others have reported rates as high as 49% [3, 49].

Laboratory findings are notable for an absence of cytopenias. In fact, nearly half of patients will have thrombocytosis or erythrocytosis [41]. In the series of Li and colleagues, 26% of patients had anemia, which the authors attributed to impaired renal function [7]. Their series was enriched with Castleman disease cases (25%), which may have also contributed to this unprecedentedly high rate of anemia.

The bone marrow biopsy reveals megakaryocyte hyperplasia and megakaryocyte clustering in 54% and 93% of cases, respectively [39]. These megakaryocyte findings are reminiscent of a myeloproliferative disorder, but JAK2V617F mutation is uniformly absent. One-third of patients do not have clonal plasma cells on their iliac crest biopsy. These are the patients who present at with a solitary or “multiple solitary plasmacytomas.” The other two thirds of patients have clonal plasma cells in their bone marrow, and 91% of these cases are clonal lambda. The median percent of plasma cells observed is less than 5%. Immunohistochemical staining is more sensitive than is 6-color flow since the former provides information on bone marrow architecture, which is key in making the diagnosis in nearly half of cases. In our study of 67 pretreatment bone marrows biopsies from patients with POEMS syndrome, lymphoid aggregates were found in 49% of cases. Of these, there was plasma cell rimming in all but one, and in 75% and 4% the rimming was clonal lambda and kappa, respectively. This finding was not seen in bone marrows from normal controls or from patients with MGUS, multiple myeloma, or amyloidosis. The only other disease that this clonal rimming was seen was in patients with lymphoplasmacytic lymphoma. Overall, only 8/67 (12%) of POEMS cases had normal iliac crest bone marrow biopsies, i.e. no detectable clonal plasma cells, no plasma cell rimmed lymphoid aggregates, and no megakaryocyte hyperplasia.

Plasma and serum levels of VEGF are markedly elevated in patients with POEMS [11, 20, 28, 53] and correlate with the activity of the disease [13, 17, 20, 28]. The principal isoform of VEGF expressed is VEGF165 [13]. VEGF levels are independent of M-protein size [13]. Increased VEGF has been found in ascitic fluid [54] and the cerebrospinal fluid [17]. IL-1β, TNF-α and IL-6 levels are often also increased. Serum VEGF levels are 10–50 times higher plasma levels of VEGF [55], making it unclear which test is preferred. In patients with POEMS, VEGF is found in both plasma cells [29, 30] and platelets [53]. The higher level observed in serum is attributable to the release of VEGF from platelets in vitro during serum processing. Because plasma is a product of an anticoagulated sample, there is less platelet activation and therefore less platelet VEGF contributing to the plasma measurement than the serum sample. Tokashiki et al. argue that serum VEGF is the better test because it reflects the VEGF contribution from both the serous and platelet compartments [55]. However, the counter-argument is that the amount VEGF release by platelets may vary due to collection and processing technique, making serum measurements of VEGF less reliable. Our group has recently demonstrated that a plasma VEGF level of 200 pg/mL had a specificity of 95% with a sensitivity of 68% in support of a diagnosis of POEMS syndrome. Other diseases with high VEGF include connective tissue disease and vasculitis [20].

Nerve conduction studies in patients with POEMS syndrome show slowing of nerve conduction that is more predominant in the intermediate than distal nerve segments as compared to CIDP, and there is more severe attenuation of compound muscle action potentials in the lower than upper limbs [9, 56–59]. In contrast to CIDP, conduction block is rare [9, 57, 59]. The conduction findings could suggest that demyelination is predominant in the nerve trunk rather than the distal nerve terminals and axonal loss is predominant in the lower limb nerves [9]. Axonal loss is greater in POEMS syndrome than it is in CIDP [59]. The nerve biopsy shows typical features of uncompacted myelin lamellae. At ultrastructural examination there are no features of macrophage-associated demyelination, which are seen in some cases of chronic inflammatory demyelinating polyneuropathy [60–63]. In one report, the presence of hyperalgesia was closely related with a reduction in the myelinated, but not unmyelinated, fiber population [64]. In another study, ultrastructural analysis of POEMS nerves revealed endothelial cytoplasmic enlargement, opening of the tight junctions between endothelial cells and presence of many pinocytic vesicles adjacent to the cell membranes, all consistent with an alteration of the permeability of endoneurial vessels [17]. Arimura et al. studied the direct effects of VEGF on blood nerve barrier function using an animal model and found that VEGF increased the microvascular permeability inducing endoneurial edema [65]. The authors postulate that this increased permeability could allow serum components toxic to nerves, like complement and thrombin, to induce further damage. In one study of human nerve biopsies of POEMS patients, more than 50% of endoneurial blood vessels had narrowed or closed lumina with thick basement membranes, strong polyclonal immunoglobulin staining in the endoneurium (consistent with blood-nerve barrier opening), and thrombin-antithrombin complexes immunohistochemically [52]. Scarlato and colleagues have proposed that the mechanism of peripheral neuropathy in POEMS syndrome is due to endothelial injury, indirectly or directly caused by an abnormal activation of endothelial cells by VEGF, which is overexpressed in the nerves of patients with POEMS syndrome [17]. According to these authors there may be hypertrophy and proliferation of endothelial cells with a secondary microangiopathy, which fuels the destructive feedback loop of reduced oxygen supply, expression of HIF-1a, with a secondary increase in local VEGF expression.

Endocrinopathy is a central but poorly understood feature of POEMS. In a recent series [66], ∼84% of patients had a recognized endocrinopathy, with hypogonadism as the most common endocrine abnormality, followed by thyroid abnormalities, glucose metabolism abnormalities, and lastly by adrenal insufficiency. The majority of patients have evidence of multiple endocrinopathies in the four major endocrine axes (gonadal, thyroid, glucose, and adrenal).

Osteosclerotic lesions occur in ∼95% of patients, and can be confused with benign bone islands, aneurysmal bone cysts, nonossifying fibromas, and fibrous dysplasia [3, 41, 67, 68]. Some lesions are densely sclerotic, while others are lytic with a sclerotic rim, while still others have a mixed soap-bubble appearance. Bone windows of CT body images are often very informative, often even more so than FDG-uptake, which can be variable.

The pulmonary manifestations are protean, including pulmonary hypertension, restrictive lung disease, impaired neuromuscular respiratory function, and impaired diffusion capacity of carbon monoxide, but improve with effective therapy [49, 69]. In a series of 20 patients with POEMS, followed over a 10-year period, 25% manifested pulmonary hypertension [69]. In a larger series of 137 patients who were not uniformly tested, nearly 10% of patients had restrictive lung disease, reduced diffusing capacity of the lung for carbon dioxide (DLCO), and/or pulmonary hypertension. Nearly 25% had significant chest roentgenogram abnormalities [49]. Li et al. found that 36% of their patients had pulmonary systolic pressures over 40 mmHg, [7] and 15% had reduced DLCO. Whether the digital clubbing seen in POEMS is a reflection of underlying pulmonary hypertension and/or parenchymal disease is yet to be determined.

The histologic findings of the dermis have been reported to range from nonspecific to glomeruloid hemangiomata to vascular abnormalities in apparently normal dermis [70–72]. Biopsies of normal appearing skin demonstrated an extremely complex subpapillary vascular network with largely dilated and frequently anastomotic vessels [73]. Capillary loops appeared more complex than normal, and most of them were probably clotted.

Serum creatinine levels are normal in most cases, but serum cystatin C, which is a surrogate marker for renal function, is high in 71% of patients [74]. In our experience, at presentation, fewer than 10% of patients have proteinuria exceeding 0.5 g/24 hr, and only 6% have a serum creatinine greater than or equal to 1.5 mg/dL. Four percent of patients developed renal failure as preterminal events [41]. In another series from China, 37% of patients had a creatinine clearance (CrCl) of less than 60 mL/min, and 9% had a CrCl of less than 30 mL/min and 15% had microhematuria. In our experience, renal disease is more likely to occur in patients who have coexisting Castleman Disease. In POEMS syndrome, the renal histologic findings are diverse with membranoproliferative features and evidence of endothelial injury being most common [75]. On both light and electron microscopy, mesangial expansion, narrowing of capillary lumina, basement membrane thickening, subendothelial deposits, widening of the subendothelial space, swelling and vacuolization of endothelial cells, and mesangiolysis predominate [76–82]. Standard immunofluorescence is negative [77, 83], which differentiates it from primary membranoproliferative glomerulitis [75]. Rarely infiltration by plasma cells nests or Castleman-like lymphoma can be seen [82].

Relationship to Castleman Disease and Castleman Disease Variant of POEMS

Castleman Disease (or angiofollicular lymph node hyperplasia) is a rare lymphoproliferative disorder which has many presentations, ranging from an asymptomatic unifocal mass to multifocal masses with a multitude of symptoms. The symptoms can range from simple B-symptoms to various autoimmune phenomenon to a frank POEMS syndrome (Fig. 1) [3, 5, 41, 84–117]. Several published cases of “interesting features” associated with Castleman disease are likely cases of POEMS syndrome [118–121]. Multicentric Castleman disease with and without peripheral neuropathy tend to be different; it has even been proposed that the presence or absence of peripheral neuropathy should be part of the multicentric Castleman disease classification system [122]. Those patients with peripheral neuropathy are more likely to have edema and impaired peripheral circulation [123–130], and they are also more likely to have a monoclonal lambda protein in their serum and/or urine [131].

Figure 1. Spectrum of disease: osteosclerotic myeloma (OSM) to POEMS to Castleman disease (CD). Taken with permission from Blood Reviews 2007; 21:285–99.

Between 11 and 30% of POEMS patients who have a documented clonal plasma cell disorder also have documented Castleman disease or Castleman-like histology [1, 3, 5, 7, 41]. In 30 patients with POEMS syndrome, 19 of 32 biopsied lymph nodes showed angiofollicular hyperplasia typical of Castleman disease [3]. In another series, 25 of 43 biopsied lymph nodes were diagnostic of Castleman disease and 84% of these had hyaline vascular type [7]. Only those with peripheral neuropath AND a plasma cell clone should classified as standard POEMS syndrome. Without both of these characteristics, patients can be classified as Castleman disease variant of POEMS if they have other POEMS features.

The neuropathy in Castleman disease patients tends to be more subtle than that of POEMS patients with osteosclerotic myeloma and is more often sensory. At its worst, however, it is a mixture of demyelination and axonal degeneration with normal myelin spacing on electron microscopy [124, 129], and abnormal capillary proliferation, similar to what is seen in the affected lymph nodes, has been described [132]. In contrast to the osteosclerotic myeloma variant of POEMS in which VEGF is the most consistently elevated cytokine, in Castleman disease IL-6 is the dominant aberrantly overexpressed cytokine. Castleman disease patients often have a brisk polyclonal hypergammaglobulinemia.

Risk Stratification

To date, there are no known molecular or genetic risk factors that predict for overall survival. The course of POEMS syndrome is usually chronic with modern estimated median survivals of nearly 14 years [41, 49]. Only fingernail clubbing, extravascular volume overload, i.e., effusions, edema, and ascites [41], and respiratory symptoms [49] have been associated with a significantly shorter overall survival. The number of POEMS features does not affect survival [5, 10]. Patients who are candidates for radiation therapy have a better overall survival (Fig. 2) [41]. In our experience and in a recent report by Li and colleagues, patients with coexisting Castleman disease may have an inferior overall survival as compared to patients without [7]. In a series of 11 patients, lower VEGF levels predicted for better response to therapy, with resolution of the skin changes, improvement of the neuropathic disturbances and reduction all of the features assumed to be related to increased permeability, like papilledema and organomegaly [17]. Thrombocytosis and increased bone marrow infiltration are associated with risk for cerebrovascular accidents [51].

Figure 2. Survival on the basis of treatment with radiation. P < 0.04 for comparison of the two groups. Taken with permission from Dispenzieri et al, Blood 2003;101:2496–2506.

Therapy Overview

Despite the relationship between disease response and dropping levels of VEGF, the most experience with successful outcomes has been associated with directing therapy at the underlying clonal plasma cell disorder rather than solely targeting VEGF with anti-VEGF antibodies. The treatment algorithm is based on the extent of the plasma cell infiltration (Fig. 3). There are those patients who do not have bone marrow involvement as determined by blind iliac crest sampling and those who do have disseminated disease, i.e. either bone diffuse marrow involvement and/or more than three skeletal lesions, and the approach to these two groups of patients differs.

Figure 3. Algorithm for the treatment of POEMS Syndrome.

Management of POEMS Syndrome without Disseminated Bone Marrow Involvement

In the case of patients with an isolated bone lesion without clonal plasma cells found on iliac crest biopsy, radiation is the recommended therapy as it is in the case of a more straightforward solitary plasmacytoma of bone. Not only does radiation to an isolated (or even two or three isolated) lesion(s) improve the symptoms of POEMS syndrome over the course of 3–36 months, but it can be curative.

Management of POEMS Syndrome with Disseminated Bone Marrow Involvement

Once there is disseminated bone marrow involvement, albeit even with a low plasma cell percentage, radiation is not expected to be curative. If the bone lesion (i.e., plasmacytoma) is reasonably large, radiation can be considered as primary therapy despite a positive iliac crest biopsy. One approach in this type of case is to follow symptoms, serum M-protein and blood VEGF levels over the course of 6–12 months after completing radiation, and then decide upon whether systemic therapy should be added. More commonly, once there is disseminated disease identified, systemic therapy is recommended with the caveat that large bony lesions with a significant lytic component may require adjuvant radiation therapy. Decisions about adjuvant radiation should be made on a case by case basis, and typically not until a minimal of 6 months after completely chemotherapy. It is important to remember that the there is a lag between completion of successful therapy and neurologic response, often with no discernible improvement until 6 months after completion of therapy. Maximal response is not seen until 2–3 years hence. Other features like anasarca, papilledema, and even skin changes may improve sooner. Optimal FDG-PET response may also lag by 6–12 months.

Since there are no randomized clinical trials among patients with POEMS syndrome, treatment recommendations are based on case series and anecdote. The treatment armamentarium is borrowed from other plasma cell disorders, most notably multiple myeloma and light chain amyloidosis. Table IV demonstrates a summary of observed outcomes. Corticosteroids may provide symptomatic improvement, but response duration is limited. The most experience has been with alkylator based therapy, either low dose or high dose with peripheral blood stem cell transplant. Recently, a group from China has reported on the first prospective clinical trial to treat POEMS syndrome [133]. They treated 31 patients with 12 cycles of melphalan and dexamethasone and found that 81% of patients had hematologic response, 100% had VEGF response, and 100% with at least some improvement in neurologic status. A limitation of this study is that follow-up is only 21 months, and so long-term outcomes are not yet available. Personal experience and retrospective reports of the use of cyclophosphamide based therapy are also promising.

Table IV. Activity of Therapy for the Treatment of POEMS Syndrome

Regimen
HCR, hematological complete response; PN, polyneuropathy; PS, performance status; Bortez, bortezomib; CS, corticosteroids; CTX, cyclophosphamide; Dex, dexamethasone; HTN, hypertension; Len, lenalidomide; Mel, melphalan; PS, performance status; VAD, vincristine, doxorubicin, dexamethasone; VEGF, vascular endothelial growth factor. a Castleman's variant of POEMS syndrome
Radiation [41, 157–160]	≥ 50% of patients have significant clinical improvement
Melphalan-Dexamethasone	81% hematologic response rate; 100% with some neurologic improvement
Corticosteroids [3, 41, 61, 78, 161]	≥ 15% of patients have significant clinical improvement
High-dose chemotherapy with PBSCT [75, 130, 137–145, 162−167]	100% of surviving patients have significant clinical improvement
Thal after MP [168]	No hematological response but improved ascites; stabilized PN, splenomegaly, pulmonary hypertension
Thal + Dex after CAD [169]	CD/POEMS: improved ascites, effusions, pulmonary hypertension, PN, renal function, IL-6 level
Thal + Dex [170]	N = 9; VEGF improved in all; PN improved in 66%; stable in 33%; improved edema; no HCR
Thal after VAD, CTX, bevacizumab [25]	Improved cardiopulmonary status, but no improved PN and rising VEGF
Lenalidomide + Dex [148]	Improved ascites, PS, PN, VEGF, testosterone, pulmonary function tests
Lenalidomide+ Dex [149]	N = 9; all had hematologic response; clinical responses in all evaluable patients including PS, neurological syndrome, edema, and VEGF.
Bortez+AD after VAD, CMP, and AD [150]	Improved M-protein, VEGF, paresthesias, splenomegaly, effusions, muscle strength, gynecomastia, and skin changes
Bortez + Dex [151]	Improved M-protein, polyneuropathy, hepatomegaly, testosterone; no change in electromyelography
Bortez × 5 cycles + thalidomide added at cycle 6 (prior Dex and MP) [171]	Improvement of anasarca, peripheral neuropathy, VEGF, and PET scan with Bortez alone, but thalidomide added because of persistent edema, M-protein, peripheral neuropathy, and barely elevated VEGF. With thalidomide, disappearance of pleural effusion, ascites, and M-protein and normalization of VEGF
Bortezomib dexamethasonea [172]	Improvement by 3 cycles, but continued for 6, and complete remission 4 years after completing therapy. Marked improvement in adenopathy, pleural effusion and ascites, hepatosplenomegaly, and IL-6
Bortez, CTX, Dex [173]	Clinical response of anasarca within 6 weeks and tolerated therapy for 18 months achieving a nCR and a VEGF response. PN, hyperpigmentation, pulmonary hypertension improved significantly
Bevacizumab alone [21]	Death within 6 weeks
Bevacizumab alone [22]	Worsening PN, anasarca, multiorgan failure; died of pneumonia 5 weeks after therapy
Bevacizumab alone [23]	Improved pain, breathing, walking
Bevacizumab + Mel-Dex [24]	Improved effusions/ascites
Prior VAD/CTX [25]	Improved edema, pain, weakness, VEGF
Bevacizumab + CTX-Dex[26]	Initial worsening; repeat with bevacizumab → improved pulmonary HTN, anasarca, skin changes
Bevacizumab + CTX-CS[27]	Initial improvement, but multiorgan failure and death
Bev + CTX-radiation[152]	Two patients. First patient treated with radiation and CTX and then Bev. Clinical improvement started before Bev. At radiological relapse, Bev no use, so lenalidomide plus Dex used with benefit. Second patient treated with same sequence, but course complicated by sepsis. Biochemical and early neurologic response before Bev started.
Bev +CTX [20]	Clinical and biochemical relapse. No response to CTX, so bevacizumab added. Death.

High-dose chemotherapy with peripheral blood stem cell transplant can also be quite effective, but selection basis may confound these reports. Case series suggest 100% of patients achieve at least some neurologic improvement [18, 45, 75, 130, 134–144]. Doses of melphalan ranging from 140 mg/m² to 200 mg/m² have been used, with the lower doses used for sicker patients. In addition, tandem transplant has been applied in one patient, but again, no information is available regarding any added value of the second transplant [145]. Anecdotally, responses are durable, but relapses have been reported [27, 146]. Of the 59 patients with POEMS syndrome treated a the Mayo Clinic Rochester, progression free survival was 98%, 94%, and 75% at 1, 2, and 5 years, respectively [147]. Symptomatic progressions were rare, whereas radiographic and VEGF progressions were most common. Treatment-related morbidity and mortality can minimized by recognizing and treating an engraftment-type syndrome characterized by fevers, rash, diarrhea, weight gain, and respiratory symptoms and signs that occurs anytime between days 7 and 15 poststem cell infusion [142]. A starting dose of prednisone ranging between 20 and 1,500 mg/day has been used. No evidence-based recommendation can be given as to the appropriate dose, but personal experience would place the daily starting anywhere between 1 and 2 mg/kg to 500 mg. The taper can typically start within 2 days, and can be completed no sooner than 10 days. Splenomegaly was the baseline factor that best predicted for a complicated peri-transplant course. Patients had a higher than expected transfusion need with median numbers of platelet and erythrocyte transfusions being 5 apheresis units and 6 units, respectively. They also had delayed engraftment with a median time to neutrophil engraftment of 16 days, with only 10% engrafting by Day 13. Their times to platelets 20 x 10⁹/L and 50 x 10⁹/L were 14.5 days and 19.5 days, respectively.

Other promising treatments include lenalidomide, thalidomide, and bortezomib, drugs all of which can have anti-VEGF and anti-TNF effects. Enthusiasm for the latter two therapies should be tempered by the high rate of peripheral neuropathy induced by these drugs. We have observed dramatic improvements in one patient treated with this drug [148]. In France, nine patients, one of whom was newly diagnosed, were treated with lenalidomide and dexamethasone [149]. Serious side effects were noted in three patients with two hematologic toxicities and a cutaneous allergy. All evaluable for hematologic response had at least a partial hematologic response, and clinical responses, including improvement in performance status and neurologic symptoms, were documented among the 8 who had sufficient follow-up. One patient relapsed 5 months after discontinuing therapy, but responded to reintroduction of the drug. Bortezomib use has been reported in two patients [150, 151]. The first report is difficult to interpret since the patient had a number of chemotherapies prior to receiving a bortezomib, doxorubicin, and dexamethasone combination. There was early evidence of improvement even before starting the bortezomib regimen. The second report is more convincing that seven cycles of bortezomib and dexamethasone resulted in patient improvement. Although an anti-VEGF strategy is appealing, the results with bevacizumab have been mixed [22–27]. Five patients who had also received either radiation or alkylator during and/or predating the bevacizumab had benefit [24–26, 152], including three who had improvement, but was then consolidated with high-dose chemotherapy with autologous stem cell transplant [25, 152]. Three patients receiving bevacizumab died [21, 22, 27].

Both our experience and the literature would support that single agent IV IG or plasmapheresis is not helpful. A recent report, however, describes reduction in serum VEGF and clinical improvement with single agent IV IG. The response was not durable, which prompted another course of IV IG with radiation to a solitary plasmacytoma [153]. Other treatments like interferon-alpha, tamoxifen, trans-retinoic acid, ticlopidine, argatroban, and strontium-89 have been reported as having activity mostly as single case reports [10].

Managing Symptoms of Disease

Attention to supportive care is imperative. Orthotics, physical therapy, and CPAP all play an important role in patients' recovery. Ankle foot orthotics can increase mobility and reduce falls. Physical therapy reduces the risk for permanent contractures and leads to improved function both in the long and short term. For those with severe neuromuscular weakness, CPAP and/or biBAP provides better oxygenation and potentially reduces the risk complications associated with hypoventilation like pulmonary infection and pulmonary hypertension.

Monitoring Response

Patients must be followed carefully on a quarterly basis tracking the status of deficits comparing these to baseline (Table II) [147]. VEGF responses may occur as soon as 3 months [143], but they can be delayed. VEGF is an imperfect marker since discordance between disease activity and response have been reported [154], so trends rather than absolute values should direct therapeutic decisions. Serum M-protein responses by protein electrophoresis, immunofixation electrophoresis, or serum immunoglobulin free light chains also pose a challenge. The size of the M-protein is typically small making standard multiple myeloma response criteria inapplicable in most cases. In addition, patients can derive very significant clinical benefit in the absence of and M-protein response [142, 155]. Finally, despite the fact that the immunoglobulin free light chains are elevated in 90% of POEMS patients, the ratio is normal in all but 18% [74], making the test of limited value for patients with POEMS syndrome.

Recommendations about how to approach organ response have recently been suggested for the purposes of clinical trials since there are more than 2-dozen parameters that can be assessed in a given patient with POEMS syndrome given the multisystem nature of the disease [147, 156]. Alternatively, response criteria for POEMS syndrome could be abridged as follows: 1) hematologic response using a modified amyloid response criteria; 2) VEGF response; 3) and a simplified organ response, which is limited to those systems causing the most morbidity, like peripheral neuropathy assessment, pulmonary function testing (diffusion capacity of carbon monoxide), and extravascular overload (grading ascites and pleural effusion as absent, mild, moderate, or severe).

Concluding Remarks

In summary, POEMS syndrome is an important paraneoplastic syndrome associated with a clonal plasma cell neoplasm. Making the diagnosis can be a challenge, but a good history and physical examination followed by appropriate testing—most notably radiographic assessment of bones, measurement of VEGF, and careful analysis of a bone marrow biopsy—can differentiate this syndrome from other conditions like CIDP, immunoglobulin light chain amyloidosis, and MGUS neuropathy. Once the diagnosis is made, attention to supportive care and treatments that are active in MM are essential; however, application of neurotoxic MM therapies should be used in the context of a clinical trial or at the time of relapsed or resistant disease.