POEMS syndrome

Author
S Vincent Rajkumar, MD
Section Editor
Robert A Kyle, MD
Deputy Editor
Rebecca F Connor, MD
Disclosures
All topics are updated as new evidence becomes available and our peer review process
is complete.
Literature review current through: May 2013. | This topic last updated: Mai 7, 2013.

INTRODUCTION POEMS syndrome (Polyneuropathy, Organomegaly,

Endocrinopathy, Monoclonal protein, Skin changes) is characterized by the presence of
a monoclonal plasma cell disorder, peripheral neuropathy, and one or more of the
following features: osteosclerotic myeloma, Castleman's disease, increased levels of
serum vascular endothelial growth factor (VEGF), organomegaly, endocrinopathy,
edema, typical skin changes, and papilledema [1].

The clinical features, diagnosis, and treatment of POEMS syndrome will be discussed
here. A discussion of Castleman's disease is presented separately. (See "Castleman's
disease".)

HISTORICAL BACKGROUND In 1938, a patient was described with sensorimotor

peripheral neuropathy, hyperpigmentation, elevated cerebrospinal fluid protein, and a
solitary plasmacytoma [2]. Eighteen years later, two patients were reported with
peripheral neuropathy, hyperpigmentation, elevation of cerebrospinal fluid protein, and
plasmacytomas with new bone formation [3]. In 1980 the acronym "POEMS" was
suggested for this disorder, representing the following constellation of findings [4]:

Polyneuropathy

Organomegaly

Endocrinopathy

Monoclonal protein

Skin changes

Additional features described in this syndrome include sclerotic bone lesions,

Castleman's disease, papilledema, pleural effusion, edema, ascites, erythrocytosis, and
thrombocytosis. This disorder has also been called osteosclerotic myeloma, Crow-
Fukase syndrome, PEP syndrome (plasma cell dyscrasia, endocrinopathy,
polyneuropathy), or Takatsuki syndrome. The complex interrelationships among
POEMS syndrome, osteosclerotic myeloma, and Castleman's disease are still being
investigated.
PATHOPHYSIOLOGY The cause of POEMS syndrome is unknown, although
chronic overproduction of pro-inflammatory and other cytokines (eg, vascular
endothelial growth factor) appears to be a major feature of this disorder, with
microangiopathy, edema, effusions, and increased vascular permeability,
neovascularization, polyneuropathy, pulmonary hypertension, leukocytosis, and
thrombocytosis as possible examples of their effect [5-7].

Patients frequently have higher levels of interleukin-1 (IL-1), tumor necrosis factor
alpha (TNF-alpha), and interleukin-6 (IL-6) than patients with multiple myeloma [5]. It
has been postulated that manifestations of POEMS syndrome might be regarded as the
result of a marked activation of these cytokines associated with a weak or decreased
TGF-1 antagonistic reaction [5]. Serum IL-6 levels in six patients with active POEMS
syndrome were higher than those with stable POEMS; elevated levels of serum IL-6
increased before each exacerbation of clinical symptoms [8]. Elevated levels of IL-6
have also been reported in pericardial fluid in these patients [9].

Others have demonstrated that platelets [10] or plasma cells [11,12] were a major source
of vascular endothelial growth factor (VEGF), a potent inducer of increased vascular
permeability. In addition, elevated levels of VEGF were noted to decrease significantly
in patients with POEMS syndrome following successful therapy [7,13,14]. (See
"Overview of angiogenesis inhibitors", section on 'Vascular endothelial growth factor'.)

Elevation of matrix metalloproteinases and tissue inhibitor of metalloproteinases

(TIMP-1) have also been reported in POEMS syndrome [15].

CLINICAL FEATURES The clinical manifestations of POEMS syndrome are

protean. By definition, all patients have peripheral neuropathy and a monoclonal plasma
cell disorder, almost always of the lambda light chain type. In addition, almost all
patients have either osteosclerotic myeloma (solitary or multiple) or Castleman's disease
[1]. One should therefore be cautious about diagnosing POEMS syndrome in the
absence of either osteosclerotic lesions or Castleman's disease. The prevalence of other
manifestations (eg, organomegaly, endocrinopathy, skin changes, edema, and
papilledema) varies greatly (table 1).

In a Mayo Clinic series of 99 patients with this syndrome, the median age was 51 years
(range: 30 to 83) and 63 percent were males.

Peripheral neuropathy and CNS involvement Peripheral neuropathy is required for

the diagnosis of POEMS syndrome, and usually dominates the clinical picture [1].
Symptoms begin in the feet and consist of tingling, paresthesias, and feelings of
coldness. Motor involvement follows the sensory symptoms. Both are distal, symmetric,
and progressive, with a gradual proximal spread. Severe weakness occurs in more than
half of patients and results in an inability to climb stairs, arise from a chair, or grip
objects firmly with the hands, consistent with a predominantly motor chronic
inflammatory demyelinating polyneuropathy. The course is progressive and patients
may be confined to a wheelchair. Autonomic symptoms are not a feature. (See 'Mayo
Clinic criteria' below.)

Physical examination reveals a symmetric sensorimotor neuropathy involving the

extremities. Muscle weakness is more marked than sensory loss. Touch, pressure,
vibratory, and joint position senses are often involved. Less frequently, loss of
temperature discrimination and nociception occurs. Cranial nerves are not affected.

Cerebrospinal fluid protein levels are increased in virtually all patients, with more than
half of patients having a cerebrospinal fluid protein level >100 mg/dL [16]. The total
cell count is typically normal.

Electromyographic studies show slowing of nerve conduction, prolonged distal

latencies, and severe attenuation of compound muscle action potentials [1]. Conduction
block is rarely found [17], but slowing of motor conduction is proportionately greater
than the reduction in the compound muscle action potential amplitude. Distal fibrillation
potentials are found on needle electromyography.

Biopsy of the sural nerve usually shows both axonal degeneration and demyelination;
severe endoneurial edema may also be seen [1]. A loss of myelinated fibers and an
increased frequency of axonal degeneration in teased fibers have been reported [18],
along with high expression of VEGF in vasa nervorum and some non-myelin- forming
Schwann cells [7]. Endoneurial deposits of immunoglobulins of the same type as in the
serum have been reported in three of four patients with POEMS syndrome [19].

Papilledema was seen in 29 percent of patients with POEMS in the Mayo Clinic series
[1] and in 40 to 55 percent of patients in the two other major series [20,21].

Organomegaly Fifty percent of patients in the Mayo Clinic series had organomegaly
(hepatomegaly, splenomegaly, and/or lymphadenopathy) [1]. Each was present in about
one-fourth of the patients. These figures are lower than those seen in two other major
series, in which hepatomegaly, splenomegaly, and lymphadenopathy were present in 68
to 78, 35 to 52, and 52 to 61 percent, respectively [20,21]. When present, organomegaly
is mild, and massive enlargement of any of these organs is unusual. In the few liver
biopsies that were performed, only non-specific reactive changes were found, without
an infiltrative process.

Biopsy of enlarged lymph nodes, if present, reveals either Castleman's disease or

reactive changes (see 'Castleman's disease' below).

Endocrine abnormalities Numerous endocrine abnormalities have been described.

Findings based on the Mayo Clinic series are listed below [1,22]:

Two-thirds of patients had at least one endocrine abnormality at presentation.

Endocrine abnormalities can also develop later, during the course of the disease,
for a total incidence of 84 percent in our series [22].

Hypogonadism is the most common endocrine abnormality. Elevated levels of

follicle stimulating hormone (FSH) in the absence of primary hypogonadism
levels have been reported [23]. Over 70 percent of males have erectile
dysfunction and all but 4 of the 28 who had serum testosterone levels measured
had a reduction. Seventeen men had gynecomastia without elevation of prolactin
levels. Two women had irregular menses, one of whom also had galactorrhea;
serum estradiol levels were normal in all four women in whom it was measured.
 Fourteen patients had hypothyroidism requiring therapy. An additional 12
percent had a mild increase in thyroid stimulating hormone level but normal
thyroxine levels.

Sixteen percent had abnormalities of the adrenal-pituitary axis at presentation;

five additional patients developed adrenal insufficiency later in the course of
their disease. Three percent of patients had diabetes mellitus. Serum levels of
parathyroid hormone were increased in three of four patients in whom it was
measured.

Monoclonal plasma cell disorder All patients by definition must have evidence of a
monoclonal plasma cell proliferative disorder, either on serum and/or urine
immunofixation studies, or on immunostaining or flow cytometric studies done on the
bone marrow. (See 'Mayo Clinic criteria' below.)

Findings based on the Mayo Clinic series are listed below [1]:

Eighty-five percent had a monoclonal protein in the serum. The magnitude of

serum monoclonal protein was small, with a median serum M-spike of 1.1 g/dL;
only seven patients had an M-spike of more than 2 g/dL. This is similar to the 75
percent reported in another series of 102 patients with this syndrome [20].

Serum protein electrophoresis is normal in one-fourth of patients and some

patients can have a pattern suggesting the presence of a polyclonal gammopathy.
In these patients the monoclonal protein can be overlooked if immunofixation is
not performed. (See "Recognition of monoclonal proteins".)

Overall, 88 percent of patients had a monoclonal protein in the serum and/or

urine. Of these, 40 patients had a monoclonal protein in the urine; the amount
was small, with a median value of 100 mg/24 hours.

The type of light chain seen in POEMS syndrome is almost always lambda [24].
The associated heavy chain was IgA, IgG, or IgM in 44, 40, and one patient
each, respectively.

A clonal lambda plasma cell proliferative process was demonstrated by

immunohistochemical staining of biopsy specimens in all 12 patients who did
not have a monoclonal protein in their serum or urine.

A random bone marrow examination is most often nondiagnostic, showing a

hypercellular, "reactive-appearing", or normal-appearing marrow. Less than 15
percent have bone marrow plasmacytosis >10 percent [1,20,21]. Less than 5
percent have >20 percent plasma cells, but this is not accompanied by lytic bone
lesions or anemia suggestive of the diagnosis of multiple myeloma. An increase
in plasma cells is typically only seen in sclerotic bone lesions.

Vascular endothelial growth factor (VEGF) levels Elevation of serum or plasma

VEGF levels is an important feature of the POEMS syndrome, and can be followed to
assess response to therapy. However, the normal reference ranges for these tests, and the
optimal cut-off for the diagnosis of POEMS are not well defined. In general, serum
VEGF levels tend to be more than five- to 10-fold higher in POEMS syndrome
compared with normal controls and those seen in other neuropathic disorders [13,25].
However, serum levels of VEGF are affected by the unpredictable release of platelet-
derived VEGF because of ex vivo platelet activation during the clotting process as well
as the presence of thrombocytosis in some patients [26].

Plasma VEGF levels appear to be at least as good as, if not better than, serum levels. In
a study of 105 patients (29 with POEMS, 9 with Castleman disease, 15 with monoclonal
plasma cell disorders, 52 with other disorders), a plasma VEGF level >200 pg/mL had a
sensitivity and specificity of 68 and 95 percent, respectively, in support of a diagnosis of
POEMS syndrome [27].

In this study, all patients who had treatment showed both clinical improvement as well
as a reduction in plasma levels of VEGF. However, there was no significant difference
in plasma VEGF levels on day 180 or last follow-up between those who did or did not
achieve complete clinical remission.

Skin changes Overall, skin changes (hyperpigmentation, hypertrichosis,

acrocyanosis, plethora, hemangioma/telangiectasia) are noted in two-thirds of patients.
The major dermatologic findings consist of hyperpigmentation and hemangiomas, with
the latter having histopathological features similar to those found in renal glomeruli
[28,29].

Hyperpigmentation is present in almost one-half of patients; this finding can be easily

overlooked. Hypertrichosis, manifested by coarse black hair, appears on the extremities
in one-fourth of patients. It is either generalized or limited to certain body areas, such as
the extremities or face. Occasional patients have skin thickening. Acrocyanosis and
plethora are seen in approximately 20 percent of patients. Telangiectasia and
hemangiomas (present in 10 percent of cases) are less frequent.

Bone lesions Osteosclerotic lesions appeared in conventional radiographs in 97

percent of patients in the Mayo Clinic study [1]. Forty-seven percent had only sclerotic
lesions, 51 percent had mixed sclerotic and lytic lesions, while lytic lesions without
evidence of sclerosis were seen in only 2 percent of our patients with bone lesions.
These lesions may be small in size and misinterpreted as benign bony sclerosis. In
addition, a small sclerotic rim surrounding a large lytic lesion may be easily overlooked.

A solitary osteosclerotic bone lesion is found in 45 percent of patients, while the

remainder have multiple lesions. The pelvis, spine, ribs, and proximal extremities were
most often involved. Bone pain and pathologic fractures are rare; hypercalcemia does
not occur at presentation. Although osteosclerotic myeloma is a characteristic feature of
POEMS syndrome, there are occasional patients with multiple myeloma who have
osteosclerotic bone lesions in the absence of POEMS syndrome.

Castleman's disease Castleman's disease (giant cell lymph node hyperplasia,

angiofollicular lymph node hyperplasia) and POEMS syndrome have been frequently
associated [30]. In one small series, two of three patients with POEMS syndrome were
reported with angiofollicular lymph node hyperplasia [31]. Antibodies to human
herpesvirus 8 (HHV 8), a virus implicated in the pathogenesis of Castleman's disease,
were reported in seven of nine patients with POEMS syndrome and Castleman's disease.
Nine of 18 patients had circulating anti-HHV 8 antibodies, while six of seven patients
with POEMS syndrome and Castleman's disease had HHV-8 DNA sequences [32]. (See
"Castleman's disease".)

Approximately 15 percent of patients with POEMS syndrome also have Castleman's

disease, similar to the 19 to 24 percent noted in the two other major series [20,21]. This
may be an underestimation, since many patients do not undergo lymph node biopsy.
(See 'Organomegaly' above.)

Renal disease In one study, 18 cases with acute and chronic renal failure associated
with POEMS syndrome were reported [33]. Prominent glomerular changes manifested
by mesangial proliferation and thickening of the capillary wall were seen. There was no
difference in IL-1, IL-6, or TNF-alpha levels in four cases of POEMS with renal
involvement when compared with those without this feature [34].

Another report examined 52 cases of POEMS syndrome with renal pathology described
in the literature [35]. Renal tissue was reviewed in 22 patients. Approximately one-half
of the patients had creatinine levels above 1.5 mg/dL; 10 percent required dialysis. The
major pathologic changes were glomerular and included glomerular enlargement,
cellular proliferation, mesangiolysis, and marked swelling of the endothelial mesangial
cells. Endarteritis-like lesions were found in the small renal arteries. In one reported
case, POEMS syndrome subsequently developed in a patient who presented with light
chain deposition disease producing nephrotic syndrome [36].

Cardiovascular disease Both arterial and venous thromboses have been described in
POEMS syndrome. Fifteen patients reported in the literature had gangrene, ischemia,
myocardial infarction, splenic infarcts, or strokes. Four patients have been reported with
POEMS syndrome who had an acute arterial thrombotic event [37]; all had elevated
cytokines. In a 31-year-old patient with POEMS, ischemic cardiomyopathy was
attributed to inflammation of the coronary arteries [38].

Forty-one thrombotic events occurred in 18 patients reported in the Mayo Clinic series
[1]. These most often consisted of cerebral infarction, myocardial infarction, or Budd-
Chiari syndrome. Three patients presented with heart failure and cardiomyopathy which
resolved following treatment of POEMS syndrome. Four other patients developed heart
failure, which occurred during an exacerbation of POEMS syndrome.

Extravascular volume overload was seen in 29 percent of patients. Peripheral edema

was found in 24 percent; ascites (7 percent) and pleural effusion (3 percent) were much
less common. Pericarditis developed in two patients within a few months of
presentation; pericardial effusion was seen in a single patient.

Elevation of fibrinogen, fibrinopeptide-A, and thrombin-antithrombin complexes during

the active phase has been noted. The endothelium of small vessels stained with
antithrombin antibody in two previously untreated patients. More than half of the
endoneurial blood vessels had narrowed or closed lumina with thickened basement
membranes [39].
Stroke In the Mayo Clinic experience, 208 patients were diagnosed with POEMS
syndrome between 1973 and 2008, of whom 19 (9.2 percent) developed cerebral
infarction at a median age of 53 years [40]. In the subgroup of 90 patients diagnosed
with POEMS syndrome between 2000 and 2008, 9 (10 percent) had a stroke at a median
of 23 months (range: 0.5-64 months) after the onset of peripheral neuropathy symptoms,
for a five-year risk of stroke of 13.4 percent. None of the stroke events occurred after
the successful treatment of the underlying syndrome.

On multivariate analysis, bone marrow plasmacytosis and an elevated platelet count

were significantly predictive for cerebral infarction, while traditional stroke risk
variables (eg, increased age, diabetes mellitus, hypertension, smoking, cardiac
arrhythmia) were not.

Pulmonary involvement In one small series, two of six patients with POEMS
syndrome had pulmonary hypertension [41]. Two additional patients with pulmonary
hypertension and POEMS syndrome have been described [42]. In a third series,
pulmonary hypertension developed in 5 of 20 patients with POEMS syndrome over a
10-year follow-up [6]; overproduction of interleukin-1beta, interleukin-6, tumor
necrosis factor-alpha, and vascular endothelial growth factor was found in all cases in
this latter series.

In the Mayo Clinic series of 137 patients with POEMS syndrome, pulmonary
manifestations were present in 28 percent, and included pulmonary hypertension,
restrictive lung disease, respiratory muscle weakness, and an isolated diminished
diffusing capacity [43]. Significant radiographic findings such as pleural effusion,
elevated diaphragm, and increased cardiac silhouette were seen in 28 percent of
patients. Respiratory muscle weakness and cough were associated with a poor
prognosis. (See 'Clinical course' below.)

Hematologic features As noted above, hepatomegaly, splenomegaly, and

lymphadenopathy are commonly seen in POEMS syndrome. These patients may also
have a variety of systemic complaints and findings, including fatigue, weight loss, fever,
bone and joint pain, and an elevated erythrocyte sedimentation rate, which might
otherwise suggest the presence of a malignant disorder (eg, non-Hodgkin lymphoma,
multiple myeloma), a collagen-vascular disorder (eg, lupus erythematosus), or systemic
infection (eg, tuberculosis).

Anemia (hemoglobin concentration <11 g/dL) is present in <5 percent of patients, while
a hemoglobin >16 g/dL (eg, polycythemia) is seen in approximately 15 percent. Blood
volume studies, erythropoietin levels, and reticulocyte counts have not been routinely
obtained for evaluating elevated hemoglobin levels.

The total white blood cell count and platelet count are elevated (ie, >10,500 and
>450,000/microL, respectively) in approximately 20 and 50 percent of our patients,
respectively.

Bone marrow examination shows monotypic plasma cells (usually lambda) in about
two-thirds of patients, typically in a background of increased polytypic plasma cells
[44]. In about half of the patients, lymphoid aggregates surrounded by a rim of plasma
cells can be seen. Megakaryocyte hyperplasia and clusters are also frequent. The
constellation of lambda-restricted monoclonal gammopathy, plasma cell rimming
around lymphoid aggregates, and megakaryocyte hyperplasia may be highly suggestive
of this diagnosis [44].

Lymph node biopsies are most often read as showing either Castleman's disease or
reactive changes. Criteria for the diagnosis of multiple myeloma are not met in any
patient (eg, multiple bone fractures, progressive bone marrow failure, or
hypercalcemia). No patients in our series died of typical multiple myeloma. (See
"Clinical features, laboratory manifestations, and diagnosis of multiple myeloma",
section on 'Diagnosis'.)

Other signs and symptoms Other findings commonly seen in POEMS syndrome
include [1]:

Increased cerebrospinal fluid protein (>50 mg/dL) 100 percent

Weight loss (>10 pounds) 37 percent

Fatigue 31 percent

Papilledema 29 percent

Edema, ascites, pleural effusion 29 percent

Clubbing 5 percent

DIAGNOSIS In the three major series of patients with POEMS syndrome, all
presented with polyneuropathy and 75 to 100 percent had initial evidence for a
monoclonal plasma cell disorder [1,20,21]. The immunoglobulin light chain type in
POEMS syndrome is almost always lambda. The other three key features defining this
syndrome (organomegaly, endocrinopathy, skin changes) were variably met (table 1).

Mayo Clinic criteria In a series of 99 patients at the Mayo Clinic, only 29 had all five
of the originally described features of this syndrome [1]. On the basis of these
observations, the current Mayo Clinic criteria for POEMS syndrome are based on five
major (two of them mandatory) and six minor criteria (table 2). The diagnosis of
POEMS syndrome requires the presence of at least three major criteria (polyneuropathy,
monoclonal plasma cell disorder plus any one of the following three: osteosclerotic
myeloma, Castlemans disease, or elevated serum or plasma VEGF levels at least three
to four times the upper limit of normal), along with the presence of at least one of the
six minor criteria (excluding diabetes mellitus or hypothyroidism) [45]. Atypical
cases (eg, without polyneuropathy or without a monoclonal paraprotein) have been
described [46-48].

The absence of either osteosclerotic myeloma or Castleman's disease should make the
diagnosis of POEMS syndrome suspect. Not every patient who meets the above criteria
will have POEMS syndrome; the abnormal features should have a temporal relationship
to each other and no other attributable cause. Elevations in plasma or serum levels of
vascular endothelial growth factor, thrombocytosis, and polycythemia are common
features of the syndrome and are helpful when the diagnosis is difficult. (See 'Vascular
endothelial growth factor (VEGF) levels' above.)

Diagnostic workup The diagnosis of POEMS syndrome depends on the

demonstration of a monoclonal immunoglobulin in the serum or urine, or increased
numbers of monoclonal plasma cells in a biopsy specimen from the osteosclerotic lesion
or the bone marrow. The M-protein in the serum and urine is almost always present in a
low concentration (usually less than 2.0 g/dL), and may be easily overlooked unless
immunofixation is performed on both serum and a 24-hour urine collection. In almost
all patients the light chain type is lambda. (See "Recognition of monoclonal proteins".)

A metastatic bone survey must be done in a search for osteosclerotic lesions. These
lesions can be subtle and easily confused with benign bony sclerosis, fibrous dysplasia,
or a vertebral hemangioma. Osteolytic lesions may have a sclerotic rim, which is a
helpful diagnostic finding.

As in any complex illness, a detailed physical examination is critical, with emphasis on

the fundoscopic examination for papilledema, evaluation for organomegaly,
examination of the skin, and evaluation for the presence of peripheral edema, pleural or
pericardial effusion, ascites, clubbing, heart failure, and cardiomyopathy.

If respiratory symptoms are present, pulmonary function testing and echocardiography

should be performed. Similarly, a thorough endocrine evaluation may be appropriate in
patients with signs and symptoms suggestive of hypogonadism, hypothyroidism, or
adrenal disorders.

DIFFERENTIAL DIAGNOSIS A number of conditions are associated with a plasma

cell disorder and polyneuropathy, with or without osteosclerotic bone lesions, and need
to be distinguished from POEMS syndrome [49-52]. (See "Paraneoplastic syndromes
affecting peripheral nerve and muscle", section on 'Association with plasma cell
dyscrasias'.)

Multiple myeloma Polyneuropathy is uncommon in classical multiple myeloma, and

when present is usually due to the presence of amyloidosis. The presence of anemia,
hypercalcemia, renal failure, pathologic fractures, and a high percent of plasma cells in
the bone marrow all serve to distinguish classical multiple myeloma from POEMS
syndrome. However, this distinction is less easily made in patients with smoldering
myeloma or low cell mass myeloma. (See "Clinical features, laboratory manifestations,
and diagnosis of multiple myeloma", section on 'Diagnosis'.)

In rare instances, multiple myeloma may be associated with the presence of diffuse
osteosclerotic bone disease in areas of active hematopoiesis, different from the focal
sclerotic lesions seen in POEMS. Such patients have the typical clinical and laboratory
features of multiple myeloma and do not have the other characteristics of POEMS
syndrome [53].

Solitary plasmacytoma of bone In general, patients with solitary plasmacytoma of

bone (SPB) have only a single osteolytic bone lesion, whereas in POEMS syndrome the
bone lesions are osteosclerotic. Biopsy of the bone lesion shows infiltration with
monoclonal plasma cells in both disorders. Systemic signs and symptoms, such as
anemia, hypercalcemia, and renal insufficiency are absent in SPB. The presence of an
osteoblastic component to the bone lesion and/or other minor criteria for POEMS (table
2) should distinguish patients with POEMS from those with SPB. (See "Diagnosis and
management of solitary plasmacytoma of bone".)

Occasionally, distinguishing SPB from POEMS syndrome may not be straightforward.

In one publication, four patients with POEMS syndrome had a violaceous skin patch
overlying a solitary plasmacytoma of bone along with enlarged regional lymph nodes.
One patient had POEMS syndrome while another patient developed POEMS syndrome
after excision of the plasmacytoma. These authors and others suggested the term
"AESOP" syndrome for this combination of findings (adenopathy and extensive skin
patch overlying a plasmacytoma) [54,55].

Monoclonal gammopathy of undetermined significance Monoclonal gammopathy of

undetermined significance (MGUS) is classically associated with a plasma cell disorder
in the absence of other systemic findings. Polyneuropathy may be seen in patients with
MGUS, often associated with an antibody reactive against neural antigens [56,57]. The
presence of at least one other minor criterion (table 2) should serve to distinguish
POEMS from MGUS. (See "Diagnosis of monoclonal gammopathy of undetermined
significance".)

Waldenstrom macroglobulinemia Waldenstrom macroglobulinemia (WM) is

lymphoplasmacytic lymphoma with the additional presence of an IgM monoclonal
gammopathy, and may be complicated by polyneuropathy. In patients with WM there is
infiltration of the bone marrow and/or lymph nodes with abnormal lymphoplasmacytic
cells. These abnormal cellular infiltrates along with absence of other minor criteria for
POEMS (table 2) should serve to distinguish WM from POEMS. (See "Epidemiology,
pathogenesis, clinical manifestations and diagnosis of Waldenstrm
macroglobulinemia", section on 'Diagnosis'.)

Primary amyloidosis Primary (AL) amyloidosis is a plasma cell disorder often

associated with monoclonal gammopathy, skin lesions, and polyneuropathy. The
diagnosis of AL amyloidosis is made by biopsy of an involved tissue (fat aspirate or
biopsy, bone marrow, GI tract, kidney, heart) showing the presence of typical amyloid
fibrils, which are not seen in patients with POEMS syndrome. (See "Clinical
presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain
(AL) amyloidosis (primary amyloidosis)" and "Pathogenesis of immunoglobulin light
chain (AL) amyloidosis and light and heavy chain deposition diseases".)

Cryoglobulinemia Mixed cryoglobulinemia (Type II) may be associated with

peripheral neuropathy and the presence of a monoclonal gammopathy. It is most often
associated with an underlying lymphoma, viral infection (eg, hepatitis C virus, HIV), or
a chronic inflammatory state, such as a connective tissue disease. The diagnosis rests
principally in the laboratory demonstration of serum cryoglobulins in association with
characteristic clinical signs and symptoms. (See "Overview of cryoglobulins and
cryoglobulinemia", section on 'Types II and III CG'.)

CLINICAL COURSE The course of POEMS syndrome is chronic; patients survive

three times longer compared with multiple myeloma. In one study, the only factors
predictive of the development of additional POEMS features on univariate analysis
were a serum M-protein >1 g/dL, the presence of monoclonal light chains in the urine,
and the absence of radiation therapy [58]. On multivariate analysis only the presence of
a urinary monoclonal protein was predictive of the development of additional features
of the POEMS syndrome.

The natural history is one of progressive peripheral neuropathy until the patient is
bedridden. Death usually occurs from inanition or a terminal bronchopneumonia. The
most commonly identified causes of death in our series were cardiorespiratory failure
and infection. None of our patients died of classic myeloma with progressive bone
marrow failure, pathologic fractures, or hypercalcemia. Those patients who died of renal
failure had coexistent ascites and a capillary leak-like syndrome. Light chain deposition
was not observed.

Overall median survival was 13.7 years in the Mayo Clinic series [1], while those with
clubbing or extravascular volume overload had median survivals of 2.6 and 6.6 years,
respectively. Survival was not related to the number of minor criteria present at the time
of diagnosis. Patients who received radiation therapy with a good response to treatment
had superior survival. (See 'Radiation therapy' below.)

THERAPY There is no standard treatment for POEMS syndrome and no randomized

controlled clinical trials of treatment exist in the available literature [59,60]. However,
approximately 75 percent of patients have some response to therapy, as discussed below.
In general, the mode of therapy is based on whether the patient has limited or
widespread sclerotic bone lesions, with radiation therapy employed for those with
limited disease, and therapy similar to multiple myeloma for those with widespread
bone lesions. Hematopoietic cell transplantation should be considered for patients with
rapidly progressive neuropathy and also in younger patients with widespread
osteosclerotic lesions. (See 'Hematopoietic cell transplantation' below.)

Radiation therapy Single or multiple osteosclerotic lesions in a limited area should

be treated with radiation in a dose of 40 to 50 Gy. Following such treatment, systemic
and skin symptoms tend to respond within one month. More than 50 percent of patients
treated with radiation showed substantial improvement of the neuropathy, although the
improvement in some patients was not apparent for six months or longer [1]. We have
seen patients who have continued to improve for two to three years following radiation
therapy. Of the 13 patients who did not respond to radiation, nine received <40 Gy.

Chemotherapy If the patient has widespread osteosclerotic lesions, systemic therapy

is necessary, although experience is limited to determine the optimal regimen.

One option is melphalan plus prednisone. In a Mayo Clinic study, melphalan

plus prednisone (MP) was given to 48 patients, with improvement noted in 44
percent [1]. In this study, single agent corticosteroids produced responses in 15
percent of patients, while treatments such as plasmapheresis,
immunosuppressive agents (azathioprine, cyclosporine), and intravenous
immunoglobulin did not appear to have any benefit.

In a separate series of 31 newly diagnosed patients, oral melphalan (10 mg/m2)

plus oral dexamethasone (40 mg/day) were given on days 1 through 4 of every
28-day cycle, for a total of 12 planned cycles [61]. Complete and partial
 remissions were noted in 39 and 42 percent, respectively. Neurologic
improvement was noted in 77 percent at three months, increasing to 100 percent
at a median time of 12 months (range: 3 to 15 months). As a result we prefer the
melphalan plus dexamethasone regimen over MP.

The role of lenalidomide or thalidomide in the treatment of POEMS syndrome is

not clear, but these agents can be used in a manner similar to that employed in
multiple myeloma in selected patients with multiple osteosclerotic lesions or
neuropathy [62-65]. Bortezomib may be considered in special circumstances,
but one must be aware of its neurotoxicity.

Hematopoietic cell transplantation Autologous hematopoietic cell transplantation

(HCT) following high-dose melphalan is an important consideration for younger
patients with multiple osteosclerotic lesions. If HCT is contemplated, stem cells should
be collected before the patient is exposed to alkylating agents (eg, melphalan). (See
"Autologous hematopoietic cell transplantation in multiple myeloma", section on 'Initial
chemotherapy'.)

Fifty-nine patients with POEMS syndrome have undergone autologous HCT using
peripheral blood stem cells at the Mayo Clinic [58]. Clinical improvement was nearly
universal in these patients with five-year overall and progression-free survivals of 94
and 75 percent, respectively. Other reports of autologous HCT in POEMS have also
described clinical improvement, with often dramatic neurologic improvement [14,66-
68]. These studies illustrate that for transplant eligible patients, autologous HCT is one
of the most important treatment advances in the treatment of POEMS syndrome.

Other treatment The use of agents with anticytokine/anti-VEGF activity may be

effective in ameliorating some or all of the signs and symptoms of this disorder [5],
although case reports of successful treatment with such agents are anecdotal at this time
[62,63,69-74]. (See 'Pathophysiology' above and "Cytokine networks in rheumatic
diseases: Implications for therapy".)

SUMMARY AND RECOMMENDATIONS The cause of POEMS syndrome is

unknown, although chronic overproduction of pro-inflammatory and other cytokines
appears to be a major feature of this disorder. (See 'Pathophysiology' above.)

POEMS syndrome is characterized by the presence of the following elements (table 1).

Polyneuropathy

Organomegaly

Endocrinopathy

Monoclonal protein

Skin changes
This condition should be suspected in a patient with polyneuropathy and evidence for a
monoclonal plasma cell disorder (table 1). (See 'Clinical features' above.)

The diagnosis of POEMS syndrome requires the presence of at least three major
criteria (ie, polyneuropathy plus monoclonal plasma cell disorder plus any one
of the following three: osteosclerotic bone lesion(s), Castlemans disease, or
elevated serum or plasma VEGF levels), along with the presence of at least one
of the six minor criteria (table 2). The absence of either osteosclerotic myeloma
or Castleman's disease should make the diagnosis of POEMS syndrome suspect.
(See 'Diagnosis' above.)

The differential diagnosis of POEMS syndrome includes the various clonal

plasma cell (or lymphoplasmacytic) disorders and cryoglobulinemia. (See
'Differential diagnosis' above.)

There is no standard treatment for this disorder and there have been no
randomized controlled clinical trials of treatment for POEMS syndrome.
However, approximately 75 percent of treated patients have had some response
to therapy.

We recommend that symptomatic patients with a single osteosclerotic lesion (or

multiple lesions in a limited area) be treated with radiation in a dose of 40 to 50 Gy
rather than no treatment or systemic therapy (Grade 1C). (See 'Radiation therapy'
above.)

If the patient is symptomatic and has widespread osteosclerotic lesions or severe

symptoms, we recommend systemic therapy similar to that employed in multiple
myeloma (eg, chemotherapy, hematopoietic cell transplantation (HCT)) over no
treatment or radiation therapy alone, although experience with these modalities is
limited (Grade 1C). (See 'Therapy' above.)

The best chemotherapeutic responses to date have been seen following treatment with
melphalan and dexamethasone, although the role of novel agents used effectively in
multiple myeloma (eg, lenalidomide, bortezomib) has not been well studied. (See
'Chemotherapy' above.)

We suggest that autologous HCT following high-dose melphalan be considered for

younger transplant-eligible patients with widespread osteosclerotic lesions and/or severe
symptoms, especially progressive neuropathy (Grade 2C). (See 'Hematopoietic cell
transplantation' above.)

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Topic 6662 Version 15.0

GRAPHICS
Clinical features of POEMS syndrome
Mayo series (n Soubrier, et al. (n Nakanishi, et al. (n =
Criterion
= 99) = 25) 102)
Polyneuropathy 100 100 100
Organomegaly 50 NA NA
Hepatomegaly 24 68 78
Splenomegaly 22 52 35
Lymphadenopathy 26 52 61
Endocrinopathy 67 NA NA
Diabetes mellitus 3 36 25
Monoclonal plasma cell
100 100 75
disorder
Skin changes 68 NA NA
Hyperpigmentation 46 48 93
Hypertrichosis 26 24 74
This table indicates the percent of patients from three major series of patients with
POEMS who satisfied each of the original five components of this syndrome.
NA: data not available.
Data from: Dispenzieri, A, et al. Blood 2003; 101:2496.
Criteria for the diagnosis of POEMS syndrome
Mandatory major criteria (both required)
Polyneuropathy
Monoclonal plasma cell proliferative disorder (almost always lambda)
Other major criteria (one required)
Sclerotic bone lesions
Castleman's disease
Elevated levels of vascular endothelial growth factor (VEGF)*
Minor criteria (one required)
Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy)
Extravascular volume overload (edema, pleural effusion, or ascites)
Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic)
Skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, plethora,
acrocyanosis, flushing, white nails)
Papilledema
Thrombocytosis/polycythemia
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.
* The source data do not define an optimal cut off value for considering elevated VEGF
level as a major criterion. We suggest that VEGF measured in the serum or plasma
should be at least three- to fourfold higher than the normal reference range for the
laboratory that is doing the testing to be considered a major criterion. In order to
consider endocrinopathy as a minor criterion, an endocrine disorder other than diabetes
or hypothyroidism is required since these two disorders are common in the general
population.
Original figure modified for this publication. Dispenzieri A. POEMS syndrome. Blood
Rev 2007; 21:285. Illustration used with the permission of Elsevier Inc. All rights
reserved.