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CME INFORMATION
CME Information: POEMS Syndrome: update on diagnosis,
risk-stratification, and management
CME Editor: Ayalew Tefferi, M.D.
Author: Angela Dispenzieri, M.D.
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䊏 Educational Objectives
Upon completion of this educational activity, participants will be better able to:
1. Recognize and make diagnosis of POEMS syndrome
2. Understand best therapies for POEMS syndrome
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CME Editor: Ayalew Tefferi, M.D. has no relevant financial relationships to disclose.
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C 2015 Wiley Periodicals, Inc.
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ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
AJH Educational Material
A JH
POEMS syndrome: Update on diagnosis, risk-stratification,
and management
Angela Dispenzieri*
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 three 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 3–6 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. 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. The benefit of anti-VEGF antibodies
is conflicting. Prompt recognition and institution of both supportive care measures and therapy directed
against the plasma cell result in the best outcomes.
C 2015 Wiley Periodicals, Inc.
Am. J. Hematol. 90:952–962, 2015. V
䊏 Disease Overview
POEMS syndrome is a rare paraneoplastic syndrome due to an underlying plasma cell disorder. The 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 toward
thrombosis, and abnormal pulmonary function tests; and (3) there is a Castleman disease variant of POEMS syndrome that may be 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 descent 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 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 are typically neuropathy, endocrine dysfunction,
and volume overload; (2) dominant symptoms have little to nothing to do with bone pain, extremes of bone marrow infiltration by plasma cells,
or renal failure; (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].
Professor of Medicine and Laboratory Medicine, Rochester, MN 55905
*Correspondence to: Angela Dispenzieri, Professor of Medicine and Laboratory Medicine, Rochester, MN. E-mail: [email protected]
Contract grant sponsor: Robert A. Kyle Hematologic Malignancies Fund; the Predolin Foundation; JABBS Foundation; Andrew & Lillian A. Posey Foundation;
Celgene; Millenium; Pfizer; Jannsen.
Received for publication: 11 August 2015; Accepted: 11 August 2015
Am. J. Hematol. 90:952–962, 2015.
Published online: in Wiley Online Library (wileyonlinelibrary.com).
DOI: 10.1002/ajh.24171
C 2015 Wiley Periodicals, Inc.
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ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
TABLE I. Criteria for the Diagnosis of POEMS Syndromea
Mandatory major
criteria
Other major criteria
(one required)
Minor criteria
Other symptoms
and signs
1. Polyneuropathy (typically
demyelinating)
2. Monoclonal plasma cell-proliferative
disorder (almost always k)
3. Castleman diseasea
4. Sclerotic bone lesions
5. Vascular endothelial growth factor
elevation
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
Clubbing, weight loss, hyperhidrosis,
pulmonary hypertension/restrictive
lung disease, thrombotic diatheses,
diarrhea, low vitamin B12 values
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.
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
[21–28]. 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 [29] (including plasma cells) [30,31], and megakaryocytes/platelets [32]. Both IL-1b and IL-6 have been shown to
stimulate VEGF production [29]. IL-12 has also been shown to correlate with disease activity [33]. 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) [34–36]. Translocations and deletion of chromosome 13 have been described, but hyperdiploidy is not
seen [37,38].
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 indepth search for POEMS syndrome: monoclonal protein (especially lambda light chain), thrombocytosis, anasarca,
or papilledema. Any patient who carries a diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) that is not responding
to standard CIDP therapy should be considered as a possible POEMS
syndrome patient, and additional testing should be done to rule in or
rule out the diagnosis of POEMS syndrome. The requirements set forth
doi:10.1002/ajh.24171
POEMS syndrome
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
[40–42] measurement of VEGF [13,17,20,43,44], and careful analysis of
a bone marrow biopsy [39]—can differentiate this syndrome from
other conditions like CIDP, monoclonal gammopathy of undetermined
significance (MGUS) neuropathy, and immunoglobulin light chain
amyloid neuropathy. A high platelet count is seen in 54% of POEMS
patients as compared to 1.5% of patients with CIDP [45]. Helpful cutoffs for plasma and serum VEGF levels to diagnosis POEMS syndrome
are 200 pg mL21 (specificity 95%; sensitivity 68%) [20] and 1,920
pg mL21 (specificity 98%; sensitivity 73%) [46], respectively. Wang
et al. have identified N-terminal propeptide of type I collagen as a
novel marker for the diagnosis of patients with POEMS [46]. They
found the best cut-off of N-terminal propeptide of type I collagen to
diagnose POEMS syndrome is 70 ng mL21 with a specificity of 91.5%
and a sensitivity of 80%. 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 [47].
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 incorrectly
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).
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 local practices, and promptness of diagnosis,
rather than ethnic differences [2,3,5,7,48]. 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 [50]; in our experience, pain may be
a dominant feature in about 10–15% of patients, and in one report as
many as 76% of patients had hyperesthesia [9,51]. 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 10year period, 67% had ocular signs and symptoms, the most common
of which was papilledema in 52% of those examined [52]. The most
common ocular symptoms reported were blurred vision in 15, diplopia
in 5, and ocular pain in 3. In another series of 94 patients, papilledema, which was found in 50% of patients, was an adverse prognostic feature for overall survival [53].
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 [2,4–8,54,55] Rarely calciphylaxis is also seen [56,57]. 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 [58].
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ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
TABLE II. Recommended Minimum Testing
Test
Neurologic
Detailed neurologic history (numbness, pain, weakness, balance, orthostasis) and
examination (including funduscopic exam)
Electrophysiologic study (nerve conduction studies)
Sural nerve biopsy
Organomegaly/lymphadenopathy/extravascular volume overload
Physical exam and CT scanc documenting lymphadenopathy, organomegaly, ascites,
pleural effusions, and edema
Endocrinopathy
History regarding menstrual and sexual function
Testosterone, estradiol, fasting glucose, glycosylated hemoglobin, thyroid stimulating
hormone, parathyroid hormone, prolactin, serum cortisol, luteinizing hormone,
follicle stimulating hormone, adrenocorticotropin hormone, Cortrosyn stimulation test
Hematologic
Serum protein electrophoresis AND immunofixation
Affected quantitative immunoglobulin
Complete blood count (hemoglobin, platelet)
24-hr urine total protein, electrophoresis, and immunofixation
Vascular endothelial growth factor
Bone marrow aspirate and biopsy (test for kappa/lambda by IHC)
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
Sclerotic bone lesions
Skeletal radiographs and/or PET/CTc
Pulmonary function
Pulmonary function tests
Echocardiography to assess right ventricular systolic and pulmonary artery pressures
Baseline
Every 3
months
Yearly
X
Xa
X
X
Xb
Xa
X
X
Xd
Xd
X
X
X
Xd
X
Xd
Xb
Xd
Xd
X
X
X
X
X
X
X
Xb
X
X
X
X
X
X
X
X
X
X
Xb
X
X
X
X
Xd
Xd
Xd
Xd
a
At 6 months and then yearly.
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.
b
Patients are at increased risk for arterial and/or venous thromboses
during their course, with nearly 20% of patients experiencing one of
these complications [10,59]. Ten percent of patients present with a
cerebrovascular event, most commonly embolic or vessel dissection
and stenosis [60]. 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 [61]. 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 non-bulky 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% [3,58]
Laboratory findings are notable for an absence of cytopenias. In
fact, nearly half of patients will have thrombocytosis or erythrocytosis
[48]. In the series of Li et al., 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
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American Journal of Hematology, Vol. 90, No. 10, October 2015
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 <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 [11,20,29,62] and correlate with the activity of
the disease [13,17,20,29]. 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 [63] and the cerebrospinal fluid [17]. IL-1b, TNF-a, and IL-6 levels are often also
increased. Serum VEGF levels are 10–50 times higher plasma levels
of VEGF [64] making it unclear which test is preferred. In patients
with POEMS, VEGF is found in both plasma cells [30,31] and platelets [62]. The higher level observed in serum is attributable to the
doi:10.1002/ajh.24171
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
TABLE III. Summary of Frequencies of POEMS Syndrome Findings Based
on Large Retrospective Series [2,3,5,7,48,49]
Characteristic
Polyneuropathy
Organomegaly
HepatomegalyHepatomegaly
SplenomegalySplenomegaly
LymphadenopathyLymphadenopathy
Castleman diseaseCastleman disease
Endocrinopathy
Gonadal axis abnormalityGonadal axis abnormality
Adrenal axis abnormalityAdrenal axis abnormality
Increased prolactin valueIncreased prolactin value
Gynecomastia or galactorrhea
Diabetes mellitusDiabetes mellitus
HypothyroidismHypothyroidism
Monoclonal plasma cell dyscrasiab
M protein on serum protein electrophoresis
Skin changes
HyperpigmentationHyperpigmentation
Acrocyanosis and plethoraAcrocyanosis and plethora
Hemangioma/telangiectasiaHemagioma/telangectasia
HypertrichosisHypertrichosis
ThickeningThickening
Papilledema
Extravascular volume overload
Peripheral edemaPeripheral edema
AscitesAscites
Pleural effusionPleural effusion
Pericardial effusion
Bone lesions
Thrombocytosis
Polycythemia
Clubbing
Decreased DLCO
Pulmonary hypertension
Weight loss > 10 lbWeight loss > 10 lb
FatigueFatigue
%
Affecteda
100
45–85
24–78
22–70
26–74
11–25
67–84
55–89
16–33
5–20
12–18
3–36
9–67
100
24–54
68–89
46–93
19
9–35
26–74
5–43
29–64
29–87
24–89
7–54
3–43
1–64
27–97
54–88
12–19
5–49
>15
36
37
31
a
Percentages are based on the total number of patients in the series.
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. Because these are among the earliest series describing
the syndrome, they are included.
b
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 [64].
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 mL21 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].
Extravascular overload most commonly manifests as peripheral
edema, but pleural effusion, ascites, and pericardial effusions are also
common. The composition of the ascites was studied in 42 patients
with POEMS syndrome. The ascitic fluid had low serum ascites albumin gradients consistent with an exudative rather than a portal
hypertension process in 74% of cases [65].
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
doi:10.1002/ajh.24171
POEMS syndrome
the lower than upper limbs [9,66–69]. In contrast to CIDP, conduction block is rare [9,67,69]. 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 [69]. 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
[70–73]. In one report, the presence of hyperalgesia was closely
related with a reduction in the myelinated, but not unmyelinated,
fiber population [74]. 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 [75]. 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 [61]. Scarlato et al. 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 [49], 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, non-ossifying
fibromas, and fibrous dysplasia [3,48,76,77] 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 FDGuptake, which can be variable [41,42]. FDG-uptake occurs in those
lesions which have a lytic component [78]. The advantage of whole
body CT—even low dose like what is quickly becoming the standard
in multiple myeloma—is that other features of the disease are also
seen: effusions, ascites, adenopathy, and hepatosplenomegaly.
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 [58,79]. In a series of 20 patients
with POEMS, followed over a 10-year period, 25% manifested pulmonary hypertension [79]. 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 [58]. Pulmonary hypertension has
been reported to occur in 27% of unselected patients with POEMS
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Dispenzieri
Figure 1. Spectrum of disease: osteosclerotic myeloma (OSM) to POEMS
to Castleman disease (CD). Taken with permission from Blood Reviews.
2007;21:285–299.
syndrome [80]. It is more likely to occur in patients with extravascular overload. Whether the digital clubbing seen in POEMS is a reflection of underlying pulmonary hypertension and/or parenchymal
disease is yet to be determined. Impaired DLCO has been shown to
be an adverse prognostic factor in another series [53].
The histologic findings of the dermis have been reported to range
from non-specific to glomeruloid hemangiomata to vascular abnormalities in apparently normal dermis [81–83]. Biopsies of normal
appearing skin demonstrated an extremely complex subpapillary vascular network with largely dilated and frequently anastomotic vessels
[84]. 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 [85]. 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 1.5 mg dL21. Four percent of patients developed
renal failure as preterminal events [48]. In another series from China,
37% of patients had a creatinine clearance (CrCl) of <60
mL min21 m22, and 9% had a CrCl of <30 mL min21 and 15% had
microhematuria [7]. The estimate of CrCl <60 mL min21 m22 has
recently been revised to 22% of patients by the same group from
China [86]. In our experience, renal disease is more likely to occur in
patients who have co-existing Castleman disease. In POEMS syndrome, the renal histologic findings are diverse with membranoproliferative features and evidence of endothelial injury being most
common [87]. On both light and electron microscopy, mesangial
expansion, narrowing of capillary lumina, basement membrane thickening, subendothelial deposits, widening of the sub-endothelial space,
swelling and vacuolization of endothelial cells, and mesangiolysis predominate [88–94]. Standard immunofluorescence is negative [89,95],
which differentiates it from primary membranoproliferative glomerulitis [87]. Rarely, infiltration by plasma cell nests or Castleman-like
lymphoma can be seen [94].
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) [3,5,48,96–129]. Several published cases of
“interesting features” associated with Castleman disease are likely
cases of POEMS syndrome [130–133]. 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 [134]. Those patients with peripheral neuropathy are
more likely to have edema and impaired peripheral circulation
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[131,135–140], and they are also more likely to have a monoclonal
lambda protein in their serum and/or urine [141].
Between 11 and 30% of POEMS patients who have a documented
clonal plasma cell disorder also have documented Castleman disease
or Castleman-like histology [1,3,5,7,48]. 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 neuropathy and a plasma cell clone should be 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 tend 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 [139], and abnormal capillary proliferation, similar to what is seen in the affected lymph nodes, has been described
[139]. 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 [48,58] Only fingernail clubbing, extravascular volume overload—i.e., effusions, edema, and ascites [48], respiratory symptoms
[58], pulmonary hypertension [80] impaired DLCO, and papilledema
[52] 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) [48]. In our experience and in a report by Li et al.,
patients with co-existing 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 of all 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 [60].
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 antiVEGF 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.
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
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ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
POEMS syndrome
Figure 2. Manifestations of POEMS syndrome. A. Skin changes including white nails and cyanosis. B. Optic disc edema. C–E. Mixed lytic osteosclerotic bone
lesions on plain radiograph (C) and CT scan (D and E). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Figure 3. Algorithm for the treatment of POEMS syndrome.
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. In a series of 35 patients with POEMS syndrome treated at
doi:10.1002/ajh.24171
the Mayo clinic, radiation was used as primary therapy [142]. This
resulted in a 4-year overall survival of 97% and a 4-year failure free
survival of 52%. More than half the “failures” occurred within 12
American Journal of Hematology, Vol. 90, No. 10, October 2015
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ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
Dispenzieri
TABLE IV. Activity of Therapy for the Treatment of POEMS Syndrome
Regimen
Radiation
Melphalan-Dexamethasone
Corticosteroids
Cyclophosphamide-Dexamethasone
ASCT
Thalidomide-Dexamethasone
Lenalidomide-Dexamethasone
Bortezomib
Bevacizumab
Outcome
50–70% of patients have significant clinical improvement [48,142,144–147]
81% hematologic response rate; 100% with some neurologic improvement
50% of patients have significant clinical improvement [3,48,71,90,148]
At least 50% of patients have significant improvement [177]
100% of surviving patients have significant clinical improvement [87,140,149–163]
Reported responses in 12 patients, but not recommended as first line due to risk of neuropathy
[25,164–166]
Reported responses in majority of patients (more than 60 patients reported) [167–170]
Used as single agent (n 5 1), with dexamethasone (n 5 2), with cyclophosphamide and dexamethasone (n 5 1), and with doxorubicin and dexamethasone (n 5 1). Reported responses in all
[171–175]
Two out of three using it as single agent died within weeks; one improved. Two other patients
using it as “salvage” improved, but relapsed and died despite continued therapy, normal VEGF
at 3.5 and 5.5 years. Six other cases of use with or after other alkylator based therapy yielded
one death and 4 patients with improvement [22–27,176]
months of radiation. Whether these were true failures or whether
they were driven by patient and physician anxiety over slow response
is unclear in this retrospective series. In a recent review of radiation
therapy in management of POEMS syndrome from South Korea, six
patients had radiotherapy as primary therapy—two of whom had
multiple lesions, but were deemed too sick for chemotherapy—and
seven patients received consolidative radiotherapy for persistent Mspike and/or persistent clinical symptoms [143]. The response rates in
this series for radiation alone were comparable to that of the Mayo
series, but in the Korean series both OS and PFS were inferior among
those patients who received radiation therapy alone, largely due to
the fact that these patients were sicker at time of treatment.
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 completing chemotherapy. It is
important to remember that 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.
Because there are no published randomized clinical trials among
patients with POEMS syndrome, treatment recommendations are
largely 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. The first prospective clinical trial to treat POEMS syndrome included 31 patients
who were treated with 12 cycles of melphalan and dexamethasone
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American Journal of Hematology, Vol. 90, No. 10, October 2015
[177]. The authors 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 was only 21 months; so long term outcomes are not yet
available. Personal experience and retrospective reports of the use of
cyclophosphamide-based therapy are also promising.
The French have reported in abstract form their results of a Phase
2 study of lenalidomide and dexamethasone for two cycles as neoadjuvant therapy preceding radiation or high dose therapy or as primary therapy as 9 cycles followed by 12 cycles of single agent
lenalidomide [167]. They have treated 27 patients: 10 preradiation
therapy, 8 pre-ASCT, and 9 as primary therapy. Although follow-up
is short, the authors report that several patients had rapid neurological response, no patient has died, and one patient has progressed.
These results are similar to previous case reports and case series
[168,169,178] though relapses have been reported. In the largest case
series of 20 patients [169], all patients responded, but 4 patients
relapsed 3–10 months after the end of treatment. Three of these treatment failures responded to further therapy, including one who
responded to reintroduction of the lenalidomide-dexamethasone combination. A systematic review of lenalidomide use in patients with
POEMS has been published [170]. Given the intrinsic risk patients
with POEMS syndrome have for thrombosis, it is imperative that at
least an aspirin be used for prophylaxis. The use of low molecular
weight heparin or warfarin should be balanced against fall risk.
Thalidomide in combination with dexamethasone has also shown
to produce responses in terms of VEGF, peripheral neuropathy, and
extravascular volume overload, but hematologic responses have not
been reported [164–166,179]. Enthusiasm for this therapy should be
tempered by the risk of peripheral neuropathy induced by this drug.
The Japanese reaccruing to a randomized trial of thalidomide plus
dexamethasone versus dexamethasone alone [180].
Like lenalidomide and thalidomide, bortezomib also has antiVEGF and anti-TNF effects. Bortezomib use has been reported in five
patients [171–175]. 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 other reports as single agent, with dexamethasone, or with
dexamethasone and cyclophosphamide all showed remarkable
improvements in patients without any worsening of the peripheral
neuropathy. Dramatic improvement in ascites was seen in more than
one instance. Enthusiasm for the bortezomib and/or thalidomide
should be tempered by their risk of drug-induced peripheral
neuropathy.
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ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
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 [18,54,87,140,149–156,181–185]. Doses of melphalan ranging from 140 to 200 mg m22 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 [157]. Anecdotally,
responses are durable, but relapses have been reported [27,186]. Of the
59 patients with POEMS syndrome treated at the Mayo Clinic Rochester, progression-free survival was 98, 94, and 75% at 1, 2, and 5 years,
respectively [184]. Symptomatic progressions were rare, whereas radiographic and VEGF progressions were most common. Treatmentrelated morbidity and mortality can be minimized by recognizing and
treating an engraftment-type syndrome characterized by fevers, rash,
diarrhea, weight gain, and respiratory symptoms and signs that occur
anytime between days 7 and 15 post-stem cell infusion [154]. A starting dose of prednisone ranging between 20 and 1,500 mg day21 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 kg21 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 and 19.5 days, respectively.
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 [24–26,187], including three who had improvement, but was then consolidated with high-dose chemotherapy with
autologous stem cell transplant [25,187]. 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 [188]. 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
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䊏 Concluding Remarks
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