Received: 11 May 2021 Accepted: 14 May 2021

DOI: 10.1002/ajh.26240

ANNUAL CLINICAL UPDATES IN

HEMATOLOGICAL MALIGNANCIES

POEMS syndrome: 2021 Update on diagnosis,

risk-stratification, and management

Angela Dispenzieri

Division of Hematology, Department of

Medicine, Mayo Clinic, Rochester,
Minnesota, USA
Correspondence
Angela Dispenzieri, Division of Hematology,
Department of Medicine, Mayo Clinic,
Rochester, MN, USA.
Email: dispenzieri.angela@mayo.edu
Abstract
Disease overview: POEMS syndrome is a paraneoplastic syndrome due to an under-
lying plasma cell neoplasm. The major criteria for the syndrome are poly-
radiculoneuropathy, 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.
Diagnosis: The diagnosis of POEMS syndrome is made with three of the major
criteria, two of which must include polyradiculoneuropathy and clonal plasma cell dis-
order, 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. Risk factors include low serum albumin, age, pleural effusion, pulmonary
hypertension, and reduced eGFR.
Risk-adapted therapy: For those patients with a dominant 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 exacer-
bating the peripheral neuropathy. Prompt recognition and institution of both sup-
portive care measures and therapy directed against the plasma cell result in the best
outcomes.

1 | D I S E A S E OV E R V I E W Bardwick in 1980,1 refers to several, but not all, of the features of the
syndrome: polyradiculoneuropathy, organomegaly, endocrinopathy,
The POEMS syndrome is a rare paraneoplastic syndrome due to an monoclonal plasma cell disorder, and skin changes. There are three
underlying plasma cell disorder. The acronym, which was coined by important points that relate to this memorable acronym: (1) not all of
the features within the acronym are required to make the diagnosis;
Expert OPINIONS (2) there are other important features not included in the POEMS
A.D. and this work are supported in part by the Robert A. Kyle Hematologic Malignancies
acronym, including papilledema, extravascular volume overload, scle-
Fund, the Predolin Foundation the JABBS Foundation and the Andrew & Lillian A. Posey
Foundation. rotic bone lesions, thrombocytosis/ erythrocytosis (P.E.S.T.), elevated

872 © 2021 Wiley Periodicals LLC. wileyonlinelibrary.com/journal/ajh Am J Hematol. 2021;96:872–888.


DISPENZIERI
VEGF levels, a predisposition towards thrombosis, and abnormal pul-
monary 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 syn-
drome.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
approximately 0.3 per 100 000.9
The pathogenesis of the syndrome is not well understood. Dis-
tinctive 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
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
Also, VEGF is known to target endothelial cells, induce a rapid and
reversible increase in vascular permeability, and be important in angio-
genesis. It is expressed by osteoblasts, in bone tissue, macrophages,
tumor cells29 (including plasma cells),30,31 and megakaryocytes/plate-
lets.32 Wang and colleagues have demonstrated the bone marrow
plasma cells of patients with POEMS syndrome had higher levels of
VEGF mRNA expression than did their CD138-negative cells.33 A
remarkable observation was that both polyclonal plasma cells and
clonal plasma cells had equally high levels of intracellular VEGF
though monoclonal PCs had higher levels of intracellular IL-6 expres-
sion. Both IL-1β and IL-6 have been shown to stimulate VEGF produc-
tion.29 Plus, IL-12 has also been shown to correlate with disease
activity.34 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).35–38 Translocations and deletion of chromosome
13 have been described.39,40 There are emerging but inconsistent
findings on the genetic profiles of patients with
41,42
syndrome.
2 | D I A G NO S I S
The diagnosis is made based on a composite of clinical and laboratory
features (Table 1), and the diagnosis will be missed if it is not consid-
ered. 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. Historically, it was recommended that any
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873
TABLE 1 Criteria for the diagnosis of POEMS syndromea
Mandatory major 1. Polyneuropathy (typically demyelinating)
criteria 2. Monoclonal plasma cell-proliferative
disorder (almost always λ)
Other major criteria 3. Castleman diseasea
(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 Clubbing, weight loss, hyperhidrosis,
and signs pulmonary hypertension/restrictive lung
disease, thrombotic diatheses, diarrhea,
low vitamin B12 values
Note: 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.
Abbreviations: POEMS, polyneuropathy, organomegaly, endocrinopathy,
M protein, skin changes.
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.48 Anemia
and/or thrombocytopenia are distinctively unusual in this syndrome unless
Castleman disease is present.
patient who carries a diagnosis of chronic inflammatory demyelinating
polyneuropathy (CIDP) that is not responding to standard CIDP ther-
apy should be considered as a possible POEMS syndrome patient, and
POEMS additional testing should be done to rule in or rule out the diagnosis
of POEMS syndrome. An important model-based cost-effectiveness
analysis was recently performed that suggests this strategy is too little
too late.43 They compared initial VEGF testing for all patients with an
acquired demyelinating neuropathy vs performing VEGF testing only
after CIDP therapy had failed. The authors found that treatment asso-
ciated with an incorrect CIDP diagnosis led to total wasted healthcare
expenditures with an average cost-per-POEMS-patient misdiagnosed
of £14 701 to £20 214 and estimated that the introduction of manda-
tory VEGF testing for patients with acquired demyelinating neuropa-
thy would lead to annual cost-savings of £107 398 for the National
Health Service. Moreover, it would prevent misdiagnosis in 16 cases
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874 DISPENZIERI

per year, reducing morbidity and the cost associated with delayed
diagnosis.
The requirements set forth in Table 1 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 physi-
cal examination followed by appropriate testing—most notably radio-
44–46 13,17,20,47,48
graphic assessment of bones, measurement of VEGF,
and careful analysis of a bone marrow biopsy49—can differentiate this
syndrome from other conditions like CIDP, monoclonal gammopathy
of undetermined significance (MGUS) neuropathy and immunoglobu-
lin light chain amyloid neuropathy. A high platelet count is seen in
54% of POEMS patients as compared to 1.5% of patients with
CIDP.50 Helpful cut-offs for plasma and serum VEGF levels to diagno-
sis POEMS syndrome are 200 pg/ml (specificity 95%; sensitivity
68%)20 and 1920 pg/ml (specificity 98%; sensitivity 73%),51 respec-
tively. Wang and colleagues have identified the N-terminal propeptide
of type I collagen as a novel marker for the diagnosis of patients with
POEMS.51 They found the best cut-off of N-terminal propeptide of

TABLE 2 Recommended minimum testing

Test Base-line Every 3–6 Months Every 1–2 Years

History and review of systems
Detailed neurologic history (numbness, pain, X X
weakness, balance, orthostasis)
History regarding menstrual and sexual function X X
Skin pigment, thickening and texture, body hair X X
quantity and texture, color of distal extremities,
and development of cherry angiomata
Physical exam
Neurologic exam X X
Fundoscopy X X
Organomegaly, lymphadenopathy, extravascular X X
volume overload
Skin (see above) X X
Blood
Complete blood count (hemoglobin, platelet) X X
Serum protein electrophoresis, quantitative X X
immunoglobulin and immunofixation
Vascular endothelial growth factor X X
Testosterone, estradiol, fasting glucose, X Xa X
glycosylated hemoglobin, thyroid stimulating
hormone, prolactin
Follicle stimulating hormone, luteinizing hormone, Xa Xa
adrenocorticotropin hormone, cortrosyn
stimulation test, serum cortisol, parathyroid
hormone
Other studies
24-h urine total protein, electrophoresis, and X X
immunofixation
Bone marrow aspirate and biopsy (test for kappa/ X Xa
lambda by IHC)
Electrophysiologic study (nerve conduction X Xa
studies)
Sural nerve biopsy Xa
Echocardiography to assess right ventricular X Xb
systolic and pulmonary artery pressures
Pulmonary function tests including DLCO X Xb
a
Skeletal CT and/or PET/CT for bone lesions, X X
organomegaly, effusions

Abbreviations: DLCO, diffusion capacity of carbon monoxide; IHC, immunohistochemistry.

a
As clinically indicated.
b
Only if affected.
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DISPENZIERI 875

type I collagen to diagnosis POEMS syndrome is 70 ng/ml, with a T A B L E 3 Summary of frequencies of POEMS Syndrome findings
specificity of 91.5% and a sensitivity of 80%. As will be discussed, based on large retrospective series2,3,5,7,52,83

there is a Castleman's variant of POEMS syndrome that does not have Characteristic % Affecteda
a clonal plasma cell proliferative disorder underlying, but have many Polyneuropathy 100
of the other paraneoplastic features.52
Organomegaly 45–85
Distinguishing POEMS syndrome from a MGUS, smoldering MM
Hepatomegaly 24–78
(SMM), MM, or solitary plasmacytoma is important since the treat-
Splenomegaly 22–70
ment, supportive care, and the expected treatment related toxicities
Lymphadenopathy 26–74
are quite different. If a patient with POEMS syndrome is incorrectly
Castleman disease 11–25
deemed to have a MGUS or SMM, then no clone directed treatment
Endocrinopathy 67–84
will be recommended, existing symptoms will worsen, and the patient
will accumulate additional elements of the paraneoplastic syndrome. Gonadal axis abnormality 55–89

If the patient is diagnosed with MM or plasmacytoma, and standard Adrenal axis abnormality 16–33
therapies for these disorders are administered, the likelihood is high Increased prolactin value 5–20
that there will be increased treatment related morbidity and inade- Gynecomastia or galactorrhea 12–18
quate supportive care. Therefore, a patient with POEMS syndrome Diabetes mellitus 3–36
should be thoroughly evaluated to define a baseline that can be used Hypothyroidism 9–67
for future assessments (Table 2). Monoclonal plasma cell dyscrasiab 100
A thorough review of systems and physical examination are
M protein on serum protein electrophoresis 24–54
required. Estimated frequencies of findings are shown in Table 3. The
Skin changes 68–89
variability between series is most likely a function retrospective
Hyperpigmentation 46–93
reporting—that is if a physician does not order a test or chart a finding,
Acrocyanosis and plethora 19
it will not be captured—and local practices, and promptness of diagno-
Hemangioma/telangiectasia 9–35
sis, rather than ethnic differences.2,3,5,7,53 The neuropathy is the domi-
Hypertrichosis 26–74
nant characteristic. The quality and extent of the neuropathy, which is
peripheral, ascending, symmetrical, and affecting both sensation and Thickening 5–43
54 Papilledema 29–64
motor function should be elicited ; in our experience, pain may be a
dominant feature in about 10%–15% of patients, though in one report Extravascular volume overload 29–87
as many as 76% of patients had hyperesthesia.9,55 Papilledema is pre- Peripheral edema 24–89
sent in at least one-third of patients (Figure 1A). Of the 33 patients at Ascites 7–54
our institution referred for a formal ophthalmologic examination dur- Pleural effusion 3–43
ing a 10-year period, 67% had ocular signs and symptoms, the most Pericardial effusion 1–64
common of which was papilledema in 52% of those examined.56 The
Bone lesions 27–97
most common ocular symptoms reported were blurred vision in
Thrombocytosis 54–88
15, diplopia in five, and ocular pain in three. In a series of 41 patients
Polycythemia 12–19
from China, there was a positive correlation between serum VEGF
Clubbing 5–49
levels and the binocular mean retinal nerve fiber layer thickness.57 In
Decreased DLCO >15
another series of 94 patients, papilledema, which was found
Pulmonary hypertension 36
in approximately 50% of patients, was an adverse prognostic feature
58
for overall survival. Weight loss >10 lb 37

A whole skin examination should be performed looking for hyper- Fatigue 31

pigmentation, a recent out-cropping of hemangioma, hypertrichosis,
dependent rubor and acrocyanosis, white nails (Figure 1B), sclero-
dermoid changes, facial atrophy, flushing or clubbing.2,4–8,59,60 Rarely
calciphylaxis is seen.61,62 Respiratory complaints are usually limited
given patients' neurologic status impairing their ability to induce car-
diovascular 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.63
Patients are at increased risk for arterial and/or venous thrombo-
ses during their course, with as many as nearly 30% of patients
experiencing one of these complications.10,63,64 There are twice as
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.
many arterial events prior to instituting therapy as there are venous
events.65 Ten percent of patients present with a cerebrovascular
event, most commonly embolic or vessel dissection and stenosis.65
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
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876 DISPENZIERI

F I G U R E 1 Manifestations of POEMS syndrome. (A) Optic disc edema. (B) Skin changes including white nails and cyanosis. (C-E) Mixed lytic
osteosclerotic bone lesions on plain radiograph (C) and CT scan (D and E)

marrow plasmacytosis. Aberrations in the coagulation cascade have These megakaryocyte findings are reminiscent of a myeloproliferative
been implicated in POEMS syndrome.67 In one report, circulating disorder, but JAK2V617F mutation is uniformly absent. One-third of
coagulation factors like fibrinopeptide A, thrombin-antithrombin com- patients do not have clonal plasma cells on their iliac crest biopsy.
plex are increased during the active phase of illness, but other factors These are the patients who present at with a solitary or “multiple soli-
relating to fibrinolysis, plasminogen, a2 plasmin inhibitor plasmin com- tary plasmacytomas.” The other two thirds of patients have clonal
plex, and FDP did not increase. plasma cells in their bone marrow, and 91% of these cases are
On physical examination, objective evidence of the symptoms clonal lambda. The median percent of plasma cells observed is less
described above can be found in addition to non-bulky adenopathy, than 5%. Immunohistochemical staining is more sensitive than is six-
gynecomastia, darkened areolae, diminished breath sounds, color flow since the former provides information on bone marrow
hepatosplenomegaly, areflexia, and a steppage gait, commonly with a architecture, which is key in making the diagnosis in nearly half of
positive Romberg sign. In our experience, finger-nail clubbing is seen cases. This finding was validated in another study.33 In our study of
in about 4% of cases, but others have reported rates as high as 67 pretreatment bone marrow biopsies from patients with POEMS
49%.3,63 syndrome, lymphoid aggregates were found in 49% of cases.49 Of
Laboratory findings are notable for an absence of cytopenias. these, there was plasma cell rimming in all but one, and in 75% and
In fact, half of patients will have thrombocytosis or 4% the rimming was clonal lambda and kappa, respectively. This find-
53
erythrocytosis. In the series of Li and colleagues, 26% of patients ing was not seen in bone marrow samples from normal controls or
had anemia, which the authors attributed to impaired renal func- from patients with MGUS, multiple myeloma, or amyloidosis. The only
tion.7 Their series was enriched with Castleman disease cases other disease where this clonal rimming was seen was in patients with
(25%), which may have also contributed to this unprecedented rate lymphoplasmacytic lymphoma. Overall, only 8/67 (12%) of POEMS
of anemia. cases had normal iliac crest bone marrow biopsies, that is no detect-
The bone marrow biopsy reveals megakaryocyte hyperplasia and able clonal plasma cells, no plasma cell rimmed lymphoid aggregates,
megakaryocyte clustering in 54% and 93% of cases, respectively.49 and no megakaryocyte hyperplasia.

DISPENZIERI
Plasma and serum levels of VEGF are markedly elevated in patients
with POEMS11,20,29,68 and correlate with the activity of the dis-
13,17,20,28 13
ease. The principal isoform of VEGF expressed is VEGF165.
VEGF levels are independent of M-protein size.13 Increased VEGF has
been found in ascitic fluid69 and the cerebrospinal fluid.17 Note, IL-1β,
TNF-α and IL-6 levels are often also increased. Serum VEGF levels are
68
10–50 times higher plasma levels of VEGF, making it unclear which test
is preferred. In patients with POEMS, VEGF is found in both plasma
cells30,31,33 and platelets.68 The higher level observed in serum is attribut-
able 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 contrib-
uting to the plasma measurement than the serum sample. Tokashiki et al.
argue that serum VEGF is the better test because it reflects the VEGF
70
contribution from both the serous and platelet compartments. How-
ever, the counter-argument is that the amount VEGF release by platelets
may vary due to collection and processing technique, making serum mea-
surements of VEGF less reliable.
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 albu-
min gradients consistent with an exudative rather than a portal hyper-
tension process in 74% of cases.71
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 poten-
9,72–75
tials in the lower than upper limbs. In contrast to CIDP, conduc-
tion block is rare.9,73,75 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
9
nerves. Axonal loss is greater in POEMS syndrome than it is in
CIDP.75 The role high-resolution nerve ultrasound plays in differenti-
ating POEMS from CIDP is still a work in progress, since both display
increased cross sectional nerve area in the upper extremities.76 The
nerve biopsy shows demyelination, often with axonal loss, and typical
features of uncompacted myelin lamellae. Large onion bulbs are typi-
77
cally not seen unlike the case with CIDP. More inflammation is seen
in CIDP nerve biopsies. Moreover, when inflammation is observed in
POEMS nerve biopsies, it is mostly epineurial perivascular whereas
in CIDP the inflammation is endoneurial perivascular and epineurial
perivascular. Finally, more epineurial neovascularization is seen in
POEMS biopsies than in those of CIDP. In one report, the presence of
hyperalgesia was closely related with a reduction in the myelinated,
but not unmyelinated, fiber population.78
At ultrastructural examination there are no features of
macrophage-associated demyelination, which are seen in some cases
of chronic inflammatory demyelinating polyneuropathy79–82 In
another study, ultrastuctural analysis of POEMS nerves revealed
endothelial cytoplasmic enlargement, opening of the tight junctions
between endothelial cells and presence of many pinocytic vesicles
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877
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.83 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.67 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 over-
expressed in the nerves of patients with POEMS syndrome.17
According to these authors there may be hypertrophy and prolifera-
tion of endothelial cells with a secondary microangiopathy, which
fuels the destructive feedback loop of reduced oxygen supply, expres-
sion of HIF-1a, with a secondary increase in local VEGF expression.
Endocrinopathy is a central but poorly understood feature of
POEMS. In one series,84 approximately 84% of patients had a recog-
nized endocrinopathy, with hypogonadism as the most common endo-
crine 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 adre-
nal).85 It is important not to miss subclinical adrenal insufficiency,
because patients can develop adrenal crisis.
Osteosclerotic lesions occur in approximately 95% of patients,
and can be confused with benign bone islands, aneurysmal bone cysts,
non-ossifying fibromas, and fibrous dysplasia (Figure 1C-E).3,53,86,87
Some lesions are densely sclerotic, while others are lytic with a scle-
rotic 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.45,46 Note,
FDG-uptake occurs in those lesions which have a lytic component.88
The advantage of whole body CT—even low dose like what is used as
part of the PET examination or alone as is used routinely for multiple
myeloma—is that other features of the disease are also seen, that is
effusions, ascites, adenopathy, and hepatosplenomegaly.
The pulmonary manifestations are protean, including pulmonary
hypertension, restrictive lung disease, impaired neuromuscular respi-
ratory function, and impaired diffusion capacity of carbon monoxide,
but improve with effective therapy.63,89 In a series of 20 patients with
POEMS, followed over a 10-year period, 25% manifested pulmonary
hypertension.89 In a larger series of 137 patients who were not uni-
formly 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.63 Pulmonary hypertension has been
reported to occur in 27% of unselected patients with POEMS
 10968652, 2021, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.26240 by CochraneArgentina, Wiley Online Library on [28/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
878 DISPENZIERI

F I G U R E 2 Survival outcomes. (A) Long term overall survival of 291 patients with POEMS syndrome. Taken with permission from Kourelis,
T. V., et al. (2016). “Long-term outcome of patients with POEMS syndrome: An update of the Mayo Clinic experience.” Am J Hematol 91(6): 585–
589. (B) Progression free survival of 262 patients. (C) Progression free survival of 262 patients based on hematologic response. (D) Progression
free survival after first relapse (n = 62). (B-D) taken with permission from Kourelis, T. V., et al. (2016). “Risk factors for and outcomes of patients
with POEMS syndrome who experience progression after first-line treatment.” Leukemia 30(5): 1079–1085

F I G U R E 3 Algorithm for the

treatment of POEMS Syndrome.
Taken with permission from
Kourelis, T. V., et al. (2016). “Risk
factors for and outcomes of
patients with POEMS syndrome
who experience progression after
first-line treatment.” Leukemia
30(5): 1079–1085

syndrome.90 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 another series.58
The histologic findings of the dermis have been reported to range
from non-specific to glomeruloid hemangiomata to vascular abnormal-
ities in apparently normal dermis.91–93 Biopsies of normal appearing
skin demonstrated an extremely complex subpapillary vascular net-
work with largely dilated and frequently anastomotic vessels.94
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DISPENZIERI 879

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.95 In our experience, at presentation, fewer than
10% of patients have proteinuria exceeding 0.5 g/24 h, and only
6% have a serum creatinine greater than or equal
1.5 mg/dl. Four percent of patients developed renal failure as pre-
terminal events.53 In a series from China, 22% of patients had a cre-
atinine clearance (CrCl) of less than 60 ml/min/m2.7,96 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.97 On both
light and electron microscopy, mesangial expansion, narrowing of
capillary lumina, basement membrane thickening, sub-endothelial
deposits, widening of the sub-endothelial space, swelling and
vacuolization of endothelial cells, and mesangiolysis predomi-
98–104 99,105
nate. Standard immunofluorescence is negative,
differentiates it from primary membranoproliferative glomerulitis.
Rarely infiltration by plasma cells nests or Castleman-like lym-
phoma can be seen.104
3 | R E LA T I O N S H I P T O CA S TL E M A N
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 mul-
titude of symptoms. The symptoms can range from simple B-
symptoms to various autoimmune phenomenon to a frank POEMS
syndrome.3,5,53,105–139 Several published cases of “interesting fea-
tures” associated with Castleman disease are likely cases of POEMS
140–143
syndrome. Multicentric Castleman disease with and without
peripheral neuropathy tend to be different; it has even been proposed
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 demye-
lination and axonal degeneration with normal myelin spacing on
electron microscopy,149 and abnormal capillary proliferation, similar
to what is seen in the affected lymph nodes, has been described.149
to 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.
4 | RIS K ST RAT I FIC A TION
To date, there are no known molecular or genetic risk factors that pre-
dict for overall survival. Prior to the common use of high-dose chemo-
therapy with autologous stem cell support and the renaissance of
which myeloma therapies, the median survival was nearly 14 years.53,63
97
Overall survival has improved over time (Figure 2A); patients diag-
nosed before and after 2003 had 10-year survival rates of 55% and
79%, respectively.152 In a report from the Mayo Clinic, favorable prog-
nostic factors for overall survival included albumin greater than 3.2 g/
dl, attainment of a complete hematologic response and younger age.
Investigators from China have developed a risk nomogram that
includes age greater than 50, presence of a pleural effusion, an eGFR
<30 ml/min/1.73 m2, and pulmonary hypertension.153 Other risk fac-
tors predicting for shorter overall survival that have been previously
described include fingernail clubbing, extravascular volume overload—
that is, effusions, edema, and ascites,53 respiratory symptoms,63
TABLE 4 Activity of therapy for the treatment of POEMS
syndrome
Regimen Outcome
Radiation 50%–70% of patients have significant clinical
improvement

that the presence or absence of peripheral neuropathy should be part Melphalan- 81% hematologic response rate; 100% with
144 dexamethasone some neurologic improvement
of the multicentric Castleman disease classification system. Those
Corticosteroids 50% of patients have significant clinical
patients with peripheral neuropathy are more likely to have edema
141,145–150
improvement
and impaired peripheral circulation, and they are also more
Cyclophosphamide- At least 50% of patients have significant
likely to have a monoclonal lambda protein in their serum and/or
dexamethasone improvement
urine.151
ASCT 100% of surviving patients have significant
Between 11%–30% of POEMS patients who have a documented clinical improvement
clonal plasma cell disorder also have documented Castleman disease
Thalidomide- Reported responses, but not recommended
or Castleman-like histology.1,3,5,7,53 In 30 patients with POEMS syn- dexamethasone as first line due to risk of neuropathy
drome, 19 of 32 biopsied lymph nodes showed angiofollicular hyper- Lenalidomide- 75%–95% patients have significant clinical
plasia typical of Castleman disease.3 In another series, 25 of dexamethasone improvement and VEGF improvement
43 biopsied lymph nodes were diagnostic of Castleman disease and Bortezomib Nearly 100% in combination with
84% of these had hyaline vascular type.7 Only those with peripheral cyclophosphamide and dexamethasone.
neuropathy AND a plasma cell clone should classified as classic Caution regarding risk of worsening
neuropathy. Usually used after first line.
POEMS syndrome. Without both of these characteristics, patients can
Bevacizumab No consistent benefit
be classified as Castleman disease variant of POEMS.

880
pulmonary hypertension90 impaired DLCO, and papilledema.58 The
number of POEMS features does not affect survival.5,10,53 A recent
paper studying endocrine findings in patients with POEMS syndrome
suggested that patients with clinical hypothyroidism had lower infe-
rior progression free and overall survival rates.154 In our experience
and in a report by Li and colleagues, patients with co-existing
Castleman disease may have an inferior overall survival as compared
7
to patients without. 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.66
5 | T H E R A P Y OV E R V I E W
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 anti-
bodies. The treatment algorithm is based on the extent of the plasma
cell infiltration (Figure 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, that is either bone dif-
fuse marrow involvement and/or more than three skeletal lesions, and
the approach to these two groups of patients differs. In general
patients have good progression free survival with modern therapies,
with overall 6-year PFS of more than 50% (Figure 2B). The longest
PFS is observed for those patients who achieve a hematologic com-
plete response (5-year PFS 88%), but even those patients who do not
have CR, 5-year PFS is 50% (Figure 2C). Among those patients who
relapse, their subsequent PFS is 39 months (Figure 2D).
6 | M A N A G E M E N T O F P O E M S SY N D R O M E
W I T H O U T D I S S E M I N A T E D BO N E M A R R O W
INVOLVMENT
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 syn-
drome over the course of 3–36 months, but it can be curative. In a
series of 35 patients with POEMS syndrome treated at the Mayo
clinic, radiation was used as primary therapy.155 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 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 ret-
rospective series. An update of this series, which now included
10968652, 2021, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.26240 by CochraneArgentina, Wiley Online Library on [28/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
DISPENZIERI
91 patients receiving radiation therapy, the 10-year overall survival
was 70%152 and the 6-year progression free survival was 62%.156 In a
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 radiother-
apy for persistent M-spike and/or persistent clinical symptoms.157
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.
7 | M A N A G E M E N T O F P O E M S SY ND R O M E
WITH DISSEMINATED BONE MARROW
INVOLVMENT
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 (ie, plasmacytoma) is reasonably large, radi-
ation 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 dis-
seminated 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 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 ana-
sarca, papilledema, and even skin changes typically improve sooner.
Optimal FDG-PET response may also lag by 6–12 months.
Since there is a paucity published randomized clinical trials among
patients with POEMS syndrome, treatment recommendations are
based on limited trial data, case series and anecdote. Despite the rela-
tionship 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. Table 4 dem-
onstrates a summary of observed outcomes. The treatment armamen-
tarium is borrowed from other plasma cell disorders, most notably
multiple myeloma and light chain amyloidosis.
The most experience has been with alkylator based therapy,
either low dose or high dose with peripheral blood stem cell trans-
plant. The first prospective clinical trial to treat POEMS syndrome
included 31 patients who were treated with 12 cycles of melphalan
and dexamethasone.158 The authors found that 81% of patients
had hematologic response, 100% had VEGF response, and 100%
 10968652, 2021, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.26240 by CochraneArgentina, Wiley Online Library on [28/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
DISPENZIERI 881

TABLE 5 Response criteria for POEMS syndrome

Parameter Evaluable Complete response Improvement Progressiona

Plasma VEGF 2
ULN Normalb 50% reduction from baselineb 50% increase from lowest level
Hematologic M-spike 0.5 g/dlc, Negative serum & urine 50% reduction of M-spike from 25% increase from lowest level,
1.0 g/dld,e IFE & bone marrowb baselinef which must be >0.5 g/dl
PET/CT At least one lesion No FDG uptake 50% reduction in sum of 30% increase of sum of SUVmaxg
with FDG SUVmaxg SUVmaxg from lowest level, which must be
at least 4 SUVmaxg OR appearance
of new FDG avid lesion
mNIS +7POEMS All patients … # 15% change from baseline " 15% change from lowest value
(a minimum of 10 points) (a minimum of 10 points)
Ascites / Present Absent Improved by 1 CTCAE grade Worsened by 1 CTCAE grade from
effusion / from baseline lowest grade
edema
ECHO RVSP ≥40 mm Hg … <40 mm Hg
Papilledema Present Absent Worsening by 1 CTCAE grade
DLCO <70% predicted ≥70% predicted … Worsening by 1 CTCAE grade

Abbreviations: DLCO, diffusing capacity of carbon monoxide; ECHO RVSP, echocardiogram right ventricular systolic pressure; IFE, immunofixation.
a
Any progression event (VEGF, hematologic, or clinical) will be considered progression, assuming change is attributable to disease and not an adverse
event. .To document progression, option exists for repeating value. If confirmed, progression date is first date of suspected progression.
b
For VEGF and M-spike and IFE response documentation, blood values need to be repeated for verification.
c
For VGPR evaluable.
d
For PR evaluable.
e
Quantitative IgA is acceptable surrogate for M-spike for proteins migrating in the beta region.
f
VGPR is defined as no measurable monoclonal protein on serum or urine electrophoresis, but positive IFE.
g
By body weight.

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 retrospec-
tive reports of the use of cyclophosphamide-based therapies are
also promising.
High-dose chemotherapy with peripheral blood stem cell trans-
plant can also be quite effective, but selection basis may confound
these reports. Case series suggest 100% of patients achieve at least
18,59,97,150,159–171
some neurologic improvement. Doses of melphalan
2
ranging from 140 to 200 mg/m 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
172
any added value of the second transplant. Anecdotally, responses
are durable, but relapses have been reported.27,173,170 In our experi-
ence with 80 patients, the 6-year PFS was 72% and 10-year OS was
89%.152
Treatment-related morbidity and mortality can minimized by rec-
ognizing and treating an engraftment-type syndrome characterized by
fevers, rash, diarrhea, weight gain, and respiratory symptoms and
signs that occurs anytime between days 7 to 15 post-stem cell
167
infusion. A starting dose of prednisone ranging between
20–1500 mg/day has been used. No evidence based recommendation
can be given as to the appropriate dose, but of late we have been
using 1–2 mg/kg. The taper can typically start within 2 days and com-
pleted over 10–14 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 five apheresis units and
six 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
109/L and
50
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. Li and colleagues reported a phase II trial of 12 cycles of
lenalidomide and dexamethasone in 41 patients.174 The complete
hematologic response rate was 46%, the neurologic response rate
was 95%, and the VEGF response rate was 83%. After a median fol-
low up of 34 months, the estimated 3-year OS and PFS were 90%
and 75%, respectively. Nozza et al. have reported prospective data on
18 patients (13 previously treated and five newly diagnosed, but not
eligible for ASCT) treated with lenalidomide and dexamethasone.175
Patient responding after six cycles continued treatment until pro-
gression or toxicity. Endpoints were neurological or clinical improve-
ment. After six cycles of Rd, all but four had improvement in their
ONLS, and at 39 months of follow-up, all patients were alive with a
3-year progression-free survival of 59%. This is consistent with other
case series in which all patients respond, but relapses appear to
occur 3–10 months after the end of therapy.176–178 Given the intrin-
sic 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, warfarin, or a Xa inhibitor should
be balanced against fall risk. Some authors recommend baseline head
magnetic resonance angiography prior to starting lenalidomide and

882
dexamethasone due to their experience with lenalidomide-induced
ischemic cerebrovascular disease in a patient with POEMS
57
syndrome.
Zhao and colleagues have performed a retrospective review of
nearly 350 patients with POEMS syndrome receiving melphalan and
dexamethasone, ASCT, or lenalidomide and dexamethasone and con-
cluded that the highest response rates were seen with ASCT, followed
by lenalidomide and dexamethasone, and finally by melphalan and
dexamethasone. Patients receiving lenalidomide and dexamethasone
had the shortest PFS and a trend for a shorted OS. It should also be
noted that those patients undergoing ASCT had the lowest risk dis-
179
ease. In a similar vein, Bianco and colleagues in a much smaller
series (n = 15) systematically compared changes seen among patients
receiving ASCT or lenalidomide and dexamethasone found changes
neurologic changes and 1 and 2 years were comparable for the two
176–178,180–182
therapies. Thalidomide in combination with dexametha-
sone has also shown to produce responses in terms of VEGF, periph-
eral neuropathy, and extravascular volume overload, but hematologic
responses have not been reported.183–186 Enthusiasm for this therapy
should be tempered by the risk of peripheral neuropathy induced by
this drug. Misawa and colleagues have reported on a 25 patient
24-week randomized double blind trial of thalidomide plus dexameth-
asone versus dexamethasone alone for patients ineligible for autolo-
gous stem cell transplantation.187 The VEGF levels dropped faster in
patients treated with thalidomide, though there were no significant
differences in other endpoints between the two groups at 24 weeks.
During the 72-week open label extension study, nerve conduction
velocities increased as compared to baseline. Fifty-four percent of the
thalidomide patients had sinus bradycardia and two-thirds had consti-
pation. There is no mention of worsening neuropathy in the first
24 weeks, but 23% of patients had worsening of their sensory neu-
ropathy in the 48-week open extension portion. Enthusiasm for this
therapy should be tempered by the risk of peripheral neuropathy
induced by this drug.
Like lenalidomide and thalidomide, bortezomib also has anti-
VEGF and anti-TNF effects. Bortezomib use has been reported in
approximately 50 patients.188–194 The first report is difficult to inter-
pret since the patient had a number of chemotherapies prior to
receiving a bortezomib, doxorubicin, and dexamethasone combina-
tion. There was early evidence of improvement even before starting
the bortezomib regimen. The other reports as single agent, with dexa-
methasone, 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. Finally, the largest series was from Shanghai
Changzheng Hospital in which 20 patients with newly diagnosed
POEMS syndrome were treated with 3–6 cycles of cyclophospha-
mide, reduced dose bortezomib, and dexamethasone.187 The overall
hematologic response rate was 76% with seven patients achieving
complete hematologic response; 88% had VEGF response. Ninety-five
percent of patients had a reduction of the ONLS (overall neuropathy
limitation scale) by one or more. No neurologic worsening was
observed. Median follow-up was only 11 months, though one patient
10968652, 2021, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.26240 by CochraneArgentina, Wiley Online Library on [28/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
DISPENZIERI
switched to lenalidomide therapy after reaching only stable disease
after five cycles of bortezomib-based therapy.
There are three instances of using daratumumab combinations in
patients with POEMS syndrome195,196: two instances of
daratumumab with lenalidomide and dexamethasone and another
of daratumumab with lenalidomide, bortezomib, and dexamethasone.
In all three instances, hematologic, VEGF, and neurologic improve-
ments were seen. There is also a case of a patient being treated with
BCMA CAR-T who is in complete response at 10 months.197
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–,198 including three who had improve-
ment, but was then consolidated with high-dose chemotherapy with
autologous stem cell transplant.25,198 Three patients receiving
bevacizumab died.21,22,27
Both our experience and the literature would support that single
agent intravenous gammaglobulin (IVIG) or plasmapheresis is not help-
ful. One more recent report, however, described reduction in serum
VEGF and clinical improvement with single agent IVIG. The response
was not durable, which prompted another course of IVIG with radia-
tion to a solitary plasmacytoma.199 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
8 | MANAGING SYMPTOMS OF DISEASE
Attention to supportive care is imperative. Orthotics, physical therapy,
and continuous positive airway pressure (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 con-
tractures and leads to improved function both in the long and short
term. For those with severe neuromuscular weakness, CPAP and/or
bi-level positive airway pressure provide better oxygenation and
potentially reduces the risk complications associated with hypo-
ventilation like pulmonary infection and pulmonary hypertension.
Patients should also be screened for depression.200
9 | M O N I T O RI N G R E S P O N S E
Patients must be followed carefully on a quarterly basis tracking the
status of deficits comparing these to baseline (Table 2).170 The VEGF
responses may occur as soon as 3 months,168 but they can be delayed.
VEGF is an imperfect marker since discordance between disease
activity and response have been reported,201 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,

DISPENZIERI
patients can derive very significant clinical benefit in the absence of
and M-protein response.167,202 Finally, despite the fact that the immu-
noglobulin free light chains are elevated in 67%–90% of POEMS
patients, the ratio is normal in all but 13%–18%,95,203 making the test
of limited value for patients with POEMS syndrome.
Recommendations about how to approach organ response have
been suggested for the purposes of clinical trials since there are more
than two-dozen parameters that can be assessed in a given patient
with POEMS syndrome given the multisystem nature of the dis-
ease.170,204 Alternatively, response criteria for POEMS syndrome
could be abridged as follows: (1) hematologic response using a modi-
18
fied amyloid response criteria; (2) VEGF response; (3) FDG-PET
response; (4) and a simplified organ response, which is limited to those
systems causing the most morbidity, like peripheral neuropathy
assessment, pulmonary function testing, and extravascular overload
(Table 5).
10 | C O NC L U D I N G R E M A R K S
In summary, POEMS syndrome is an important paraneoplastic syn-
drome associated with a clonal plasma cell neoplasm. Making the diag-
nosis can be a challenge, but a good history and physical examination
followed by appropriate testing—most notably radiographic assess-
ment 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 neurop-
athy. 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.
CONF LICT OF IN TE RE ST
Research dollars from Celgene, Millenium, Pfizer, and Alnylam; Advi-
sory Board for Janssen.
DATA AVAI LAB ILITY S TATEMENT
This manuscript has no new data.
ORCID
Angela Dispenzieri https://orcid.org/0000-0001-8780-9512
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How to cite this article: Dispenzieri A. POEMS syndrome:
2021 Update on diagnosis, risk-stratification, and
management. Am J Hematol. 2021;96:872–888. https://doi.
org/10.1002/ajh.26240