POEMS syndrome

INTRODUCTION — POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal plasma cell disorder, Skin changes) is a paraneoplastic process characterized by the presence of a monoclonal plasma cell disorder, peripheral neuropathy, and other features. Other terms that have been used for this entity include osteosclerotic myeloma, Crow-Fukase syndrome, PEP syndrome (plasma cell dyscrasia, endocrinopathy, polyneuropathy), and Takatsuki syndrome.

For diagnosis, there are two mandatory criteria — the polyradiculoneuropathy and the plasma cell disorder — and three additional major criteria, one of which must be present, and six minor criteria, one of which must be present (table 1).

The acronym POEMS captures two of the mandatory criteria and three of the minor criteria. The acronym PEST can assist in recalling many of the other features: papilledema, extravascular volume overload, sclerotic bone lesions, and thrombocytosis. Other important clinical features include: Castleman disease (angiofollicular lymph node hyperplasia), increased levels of serum vascular endothelial growth factor (VEGF), and impaired diffusion capacity of carbon monoxide.

The clinical features, diagnosis, and treatment of POEMS syndrome will be discussed here. Castleman disease is presented separately.

●(See "HHV-8/KSHV-associated multicentric Castleman disease".)

●(See "HHV-8-negative/idiopathic multicentric Castleman disease".)

●(See "Unicentric Castleman disease".)

PATHOPHYSIOLOGY — The cause of POEMS syndrome is unknown, although chronic overproduction of proinflammatory and other cytokines (eg, vascular endothelial growth factor [VEGF]) appears to be a major feature of this disorder, potentially manifesting with edema, effusions, increased vascular permeability, neovascularization, polyneuropathy, pulmonary hypertension, leukocytosis, and thrombocytosis [1-3].

Although VEGF is the cytokine that correlates best with disease activity [3-5], it is likely not the driving force of the disease, given the overall lack of response seen with therapeutic antibodies directed against VEGF [3-12]. Platelets [13] and plasma cells [14,15] are a major source of VEGF, a potent inducer of increased vascular permeability.

Other cytokines that can be elevated in this disease are: interleukin-1 beta (IL-1ß), tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-12 (IL-12) [1,16]. 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 [17]. Elevated levels of IL-6 have also been reported in pericardial fluid in these patients [18].

Elevation of matrix metalloproteinases and tissue inhibitor of metalloproteinases (TIMP-1) have also been reported in POEMS syndrome [19].

EPIDEMIOLOGY — POEMS syndrome is a rare disorder. The exact incidence is unknown; POEMS is often underdiagnosed because the clinical manifestations are complex and involve multiple systems. A national survey conducted in Japan in 2003 showed a prevalence of approximately 0.3 cases per 100,000 persons [20].

POEMS syndrome commonly presents in the fifth to sixth decade [21-23]. 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 [21]. In a large series from China, only 40 percent of patients were over age 50 [24].

CLINICAL FEATURES

Spectrum of findings — The clinical manifestations of POEMS syndrome are protean and usually develop over a period of weeks to months. The distribution of findings across several series is shown in the table (table 2).  

Two acronyms can assist in recalling many of the clinical features:

●POEMS – Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal plasma cell disorder, Skin changes

●PEST – Papilledema, Extravascular volume overload, Sclerotic bone lesions, and Thrombocytosis.

Other important clinical features include: Castleman disease (angiofollicular lymph node hyperplasia), increased levels of serum vascular endothelial growth factor (VEGF) and impaired diffusion capacity of carbon monoxide though important are not included in either acronym.

By definition, all patients have peripheral neuropathy and a monoclonal plasma cell disorder, almost always of the lambda light chain isotype. In addition, most patients have osteosclerotic lesions. One should therefore be cautious about diagnosing POEMS syndrome in the absence of osteosclerotic lesions.

The prevalence of other manifestations (eg, organomegaly, endocrinopathy, skin changes, edema, and papilledema) varies greatly.

Other common features include increased cerebrospinal fluid (CSF) protein (>50 mg/dL) in 100 percent of those tested, 10 pound or more weight loss in 37 percent, fatigue in 31 percent, and finger nail clubbing in 5 percent [21].

Elevated vascular endothelial growth factor (VEGF) levels have been reported in approximately two-thirds of patients with POEMS syndrome [6]. Castleman disease is present in approximately 15 percent [21].

Other signs and symptoms that do not fall into these criteria can be present as well. (See 'Diagnostic criteria' below.)

Mandatory criteria — By definition, all patients with POEMS syndrome have peripheral neuropathy and a monoclonal plasma cell disorder, almost always of the lambda light chain type.

Peripheral neuropathy — Peripheral neuropathy is required for the diagnosis of POEMS syndrome, and usually dominates the clinical picture [21,25,26].

●Neurologic symptoms – Symptoms usually develop over a period of weeks to months. They 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 can result in an inability to climb stairs, rise 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 require a wheelchair. Autonomic symptoms are not a feature. (See 'Diagnostic criteria' below.)

●Neurologic examination – 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 occur. Cranial nerves are not affected.

●Electromyographic (EMG) studies – EMG studies show slowing of nerve conduction, prolonged distal latencies, and severe attenuation of compound muscle action potentials [21].

Compared with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), there is greater axonal loss (reduction of motor amplitudes and increased fibrillation potentials), greater slowing of the intermediate nerve segments, less common temporal dispersion and conduction block, and absent sural sparing [27,28]. (See 'Chronic inflammatory demyelinating polyradiculopathy (CIDP)' below.)

●Nerve biopsy findings – Biopsy of the sural nerve usually shows both axonal degeneration and demyelination; severe endoneurial edema may also be seen [21,29]. A loss of myelinated fibers and an increased frequency of axonal degeneration in teased fibers have been reported [30], along with high expression of VEGF in vasa nervorum and some non-myelin-forming Schwann cells [3].

As compared to CIDP, the nerves of patients with POEMS syndrome have significantly less endoneurial mononuclear inflammation on paraffin sections and immunostains and have more epineurial vessels. Unlike CIDP, large onion bulbs are not seen [29]. In one series, endoneurial deposits of immunoglobulins of the same type as in the serum have been reported in three of four patients with POEMS syndrome [31], but most other series have not demonstrated immunoglobulin deposits.

Monoclonal plasma cell disorder — All patients by definition 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 or lymph node in the case of Castleman disease. (See 'Diagnostic criteria' below.)

Typical findings include:

●Approximately 88 percent of patients have a monoclonal (M)-protein in the serum and/or urine [21,32]. For the remainder, a clonal lambda plasma cell proliferative process is demonstrated by immunohistochemical staining of biopsy specimen.

●The monoclonal protein is small and detectable only by serum and urine immunofixation in 39 percent of those patients with a detectable monoclonal protein [21].

●The magnitude of serum monoclonal protein is small, with fewer than 7 percent of patients having an M-spike of more than 2 g/dL [21].

●The type of light chain seen in POEMS syndrome is almost always lambda [21,32,33]. There is an unexpectedly high usage of the IgA heavy chain (40 to 65 percent). An IgG monoclonal protein is seen in 20 to 40 percent of cases. IgM occurs approximately 1 percent of the time.

●Although the serum immunoglobulin free light chains are elevated in the majority of patients with POEMS syndrome, the ratio is abnormal in fewer than 20 percent [34].

A random bone marrow examination is most often nondiagnostic, showing a hypercellular, "reactive-appearing," or normal-appearing marrow. The median level of bone marrow plasmacytosis is <5 percent. Depending on the series 2 to 15 percent have bone marrow plasmacytosis >10 percent [21,22,32,35]. Fewer 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.

Major criteria — The three major criteria for the diagnosis of POEMS syndrome are osteosclerotic bone lesions, elevated VEGF levels, and Castleman disease (angiofollicular lymph node hyperplasia).

Osteosclerotic bone lesions — Osteosclerotic bone lesions are a major criterion for POEMS syndrome, and the standard diagnostic evaluation includes cross sectional imaging (eg, computer tomography [CT] or combined positron emission tomography [PET]/CT). (See 'Diagnostic evaluation' below.)

In large case series, the frequency of bone lesions has ranged from 27 to 97 percent with the lower rates reported in studies that primarily used plain films for imaging [21,22,32,35]. Imaging with CT, PET/CT, or bone scintigraphy is more sensitive for the detection of bone lesions than plain films [36,37]. Since the lesions have variable FDG uptake, PET scan may not detect all lesions seen on CT [38-41]. Clinicians should maintain a high index of suspicion as lesions may be small and misinterpreted as benign bony sclerosis. In addition, a small sclerotic rim surrounding a large lytic lesion may be easily overlooked.

In a US study, osteosclerotic lesions appeared in conventional radiographs in 97 percent (image 1) [21]; 47 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 patients with bone lesions. A solitary bone lesion was found in 45 percent of patients, while the remainder had 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 unless there is coexisting hyperparathyroidism. 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.

On pathologic examination, a bone biopsy may demonstrate diffuse infiltration of light chain restricted plasma cells; however, it is not unusual for a needle biopsy of a sclerotic lesion to be non-diagnostic due to sampling issues. Upon bone marrow biopsy, the histopathologic finding of lambda-restricted plasma cell rimming around lymphoid aggregates and megakaryocytic hyperplasia in bone marrow is highly suggestive of POEMS syndrome rather than other plasma cell dyscrasias [42]. There is stereotypic usage of the IGLV genes, favoring IGLV1-40 and IGLV1-44 [43].

Elevated VEGF levels — Elevation of serum or plasma VEGF levels is a major diagnostic criterion for POEMS syndrome and can be followed to assess response to therapy. (See 'Response assessment' below.)

The normal reference ranges for these tests and the optimal cutoff for the diagnosis of POEMS are not well defined. Studies that have applied sensitivity analyses suggest the following:

●Plasma or serum VEGF ≥200 pg/mL has a specificity of 95 percent and a sensitivity of 68 percent [6]

●Serum VEGF ≥1920 pg/mL has a specificity of 98 percent and a sensitivity of 73 percent [44]

Importantly, when comparing VEGF values over time, the method of VEGF measurement used for both values must be the same. (See 'Response assessment' below.)

Both serum and plasma VEGF can differentiate between POEMS and other peripheral neuropathies and plasma cell disorders, as the other disorders are not associated with elevated VEGF [6,8].

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 [45].

Castleman disease — Castleman disease (giant cell lymph node hyperplasia, angiofollicular lymph node hyperplasia) and POEMS syndrome have been frequently associated [46]. POEMS-associated multicentric Castleman disease (MCD) is a clinical subtype of HHV8-negative/idiopathic MCD. (See "HHV-8-negative/idiopathic multicentric Castleman disease", section on 'POEMS-associated MCD'.)

Approximately 15 percent of patients in the Mayo Clinic series with POEMS syndrome also have Castleman disease [21], similar to the 19 to 24 percent noted in two other major series [22,35]. This may be an underestimation since many patients do not undergo lymph node biopsy. In one series, 25 of 43 biopsied lymph nodes demonstrated Castleman disease [32]. (See 'Organomegaly' below.)

Minor criteria — The six minor criteria for the diagnosis of POEMS syndrome and their estimated incidence at diagnosis are: endocrine abnormalities (67 percent), skin changes (68 percent), organomegaly (50 percent), extravascular volume overload (29 percent), thrombocytosis/polycythemia (50 percent), and papilledema (29 percent) [21].

Endocrine abnormalities — Endocrine abnormalities are a minor criterion for the diagnosis of POEMS syndrome, and a common cause of morbidity. Approximately two-thirds of patients present with at least one endocrine abnormality [21,47]. They can also develop later, during the course of the disease, for a total incidence of 84 and 92 percent in two studies [47,48].

Endocrine abnormalities seen in POEMS syndrome are described below. Given the high prevalence of diabetes mellitus and hypothyroidism in the general population, these endocrine abnormalities are not sufficient to fulfill the minor criteria for the diagnosis of POEMS syndrome.

●Hypogonadism and/or hyperprolactinemia – Hypogonadism is the most common endocrine abnormality in patients with POEMS syndrome and may manifest with erectile dysfunction, early menopausal symptoms, and/or infertility. Some patients experience galactorrhea. Symptoms of hypogonadism may improve with definitive plasma cell directed therapy [49]. (See "Clinical features and diagnosis of male hypogonadism" and "Clinical manifestations and evaluation of hyperprolactinemia".)

Case series report hypogonadism and/or hyperprolactinemia in approximately 70 percent of cases [47-49]. In a Mayo Clinic study of 170 patients with POEMS syndrome, over 70 percent of males tested had hypogonadism; 10 (seven men and three women) of 35 patients tested had hyperprolactinemia; and 10 of 38 men had gynecomastia [48]. Serum estradiol levels were normal in all four women in whom it was measured [48]. In another case series from the United Kingdom of 59 patients with POEMS syndrome, hyperprolactinemia was identified at diagnosis in 24 percent, and at some point in the disease course in 56 percent [47]. Elevated levels of follicle stimulating hormone in the absence of primary hypogonadism levels have been reported [50].

●Hypothyroidism – Case series report hypothyroidism in up to 54 percent of patients [47-49]. In the Mayo clinic study, 14 of 48 patients (29 percent) had hypothyroidism requiring therapy [48]. An additional 14 patients had a mild increase in thyroid stimulating hormone level but normal thyroxine levels. Symptoms of hypothyroidism may improve with definitive plasma cell directed therapy [49]. (See "Diagnosis of and screening for hypothyroidism in nonpregnant adults".)

●Adrenal insufficiency – Case series report abnormalities of the adrenal-pituitary axis in 14 to 19 percent of patients [48,49,51]. In the Mayo clinic study, 16 percent had abnormalities of the adrenal-pituitary axis at presentation; five additional patients developed adrenal insufficiency later in the course of their disease [48]. The symptoms and signs of adrenal insufficiency depend upon the rate and extent of loss of adrenal function, whether mineralocorticoid production is preserved, and the degree of stress. (See "Clinical manifestations of adrenal insufficiency in adults" and "Determining the etiology of adrenal insufficiency in adults".)

●Diabetes mellitus – Abnormal glucose metabolism has been reported in 3 to 7 percent of patients at diagnosis, and up to 24 percent during follow-up [47,48]. (See "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults".)

●Hyperparathyroidism – In the Mayo clinic study, serum levels of parathyroid hormone were increased in three of four patients in whom it was measured [48]. In contrast, parathyroid abnormalities were not reported in some other case series [47,49]. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)

●Elevated insulin-like growth factor – In the UK case series, 8 patients (15 percent) had high insulin-like growth factor on at least two different occasions [47]. Only one patient had features of acromegaly. (See "Causes and clinical manifestations of acromegaly".)

Skin changes — Skin changes are a minor criterion for the diagnosis of POEMS syndrome. They are noted in the vast majority of patients, and many patients will have multiple dermatologic manifestations [21,52].

The major dermatologic findings include:

●Hyperpigmentation – Hyperpigmentation is present in almost one-half of patients, and can be easily overlooked [52]. Hyperpigmentation most often involves the extremities, but may also involve other areas (eg, torso, areola complex, head and neck) or be generalized.

●Hemangioma and telangiectasia – Hemangiomas are found in almost one-half of patients and present as multiple red-purple lesions on the trunk and proximal limbs. These lesions, termed glomeruloid hemangioma have histopathologic features similar to those found in renal glomeruli [52-54]. Telangiectasia are less common (present in 10 percent of cases).

●Hypertrichosis – Hypertrichosis, manifested by coarse black hair, appears on the extremities in approximately 40 percent of patients [52]. It is either generalized or limited to certain body areas, such as the extremities or face.

●Acrocyanosis – Acrocyanosis can manifest with a blue or dusky appearance of the extremities [52].

●White nails – Nail changes may include a diffuse, opaque whitish discoloration involving most of the fingernail plate [52].

●AESOP syndrome – A minority of patients may present with "AESOP" syndrome (adenopathy and extensive skin patch overlying a plasmacytoma), which includes regional lymphadenopathy and a slowly expanding red or brown patch (or plaque) overlying what appears to be a solitary plasmacytoma of the bone [55-60].

A retrospective review of 107 patients from the Mayo Clinic reported that 90 percent had at least one skin manifestation [52]. The mean number of skin findings per patient was 2.9 (median 3; range 0 to 7). Findings included:

●Hyperpigmentation – 47 percent

●Hemangioma – 47 percent

●Hypertrichosis – 38 percent

●Acrocyanosis – 34 percent

●White nails – 30 percent

●Sclerodermoid changes – 26 percent

●Raynaud phenomenon – 20 percent

●Hyperemia/erythema – 20 percent

●Flushing – 16 percent

●Rubor – 11 percent

●Clubbing – 6 percent

Treatment has been associated with improvement in hemangiomas, white nails, sclerodermoid changes, hyperpigmentation, hypertrichosis, and vascular skin changes [52].

Organomegaly — Organomegaly (hepatomegaly, splenomegaly, and/or lymphadenopathy) is a minor criterion for the diagnosis of POEMS syndrome.

Organomegaly was present in 50 percent of patients in the Mayo Clinic series [21]. Hepatomegaly, splenomegaly, and lymphadenopathy were each present in approximately one-fourth of the patients. Two other major series reported higher rates of hepatomegaly (68 to 78 percent), splenomegaly (35 to 52 percent), and lymphadenopathy (52 to 61 percent) [22,35]. When present, organomegaly is mild, and massive enlargement of any of these organs is unusual. In the few liver biopsies that were performed, only nonspecific reactive changes were found, without an infiltrative process.

Biopsy of enlarged lymph nodes, if present, reveals either Castleman disease or reactive changes. (See 'Castleman disease' above.)

Extravascular volume overload — Extravascular volume overload is a minor criterion for the diagnosis of POEMS syndrome. Refractory, unexplained ascites and peripheral edema can cause significant morbidity.

In the Mayo Clinic series, extravascular volume overload was seen in 29 percent of patients [21]. 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.

Polycythemia and thrombocytosis — Polycythemia and thrombocytosis are minor criteria for the diagnosis of POEMS syndrome. Polycythemia and thrombocytosis are present in 15 and 50 percent, respectively. (See 'Organomegaly' above.)

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 [21]. In distinction with TEMPI syndrome (telangiectasias, erythrocytosis with elevated erythropoietin, MGUS, perinephric fluid collections, and intrapulmonary shunting), erythropoietin levels are not elevated in POEMS syndrome [42]. A high hemoglobin increases the risk for arterial thrombotic events [61]. (See 'Thromboembolic disease' below.)

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 patients in the Mayo Clinic series, respectively [21].

Bone marrow examination shows monotypic plasma cells (usually lambda) in approximately two-thirds of patients, typically in a background of increased polytypic plasma cells [42]. In approximately 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 [42].

Lymph node biopsies are most often read as showing either Castleman 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). (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Diagnosis'.)

CNS involvement/papilledema — Papilledema is a minor criterion for the diagnosis of POEMS syndrome. Papilledema was seen in 29 percent of patients with POEMS in the Mayo Clinic series [21] and in 40 to 55 percent of patients in two other major series [22,35].

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 [62]. The total cell count is typically normal.

Approximately 10 percent of patients have a thrombotic cerebrovascular event [61,63]. (See 'Thromboembolic disease' below.)

Risk factors for arterial thrombosis (cerebral or otherwise) include thrombocytosis, elevated hemoglobin/hematocrit, extravascular volume overload, and splenomegaly [61].

Other signs and symptoms

Kidney disease — Involvement of the kidneys has been described, but kidney involvement is not included in the diagnostic criteria.

The largest report compiled 52 cases of POEMS syndrome with kidney pathology described in the literature [64]. Kidney 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.

Another report described 18 cases with acute and chronic kidney failure associated with POEMS syndrome [65]. Prominent glomerular changes manifested as mesangial proliferation and thickening of the capillary wall.

Those with kidney involvement appear to have similar levels of IL-1, IL-6, and TNF-alpha when compared with those without this feature [7].

Thromboembolic disease — Thromboembolic events have been described in up to 30 percent of patients with POEMS syndrome. Arterial events appear to be slightly more common than venous events. Potential risk factors include active disease and use of immunomodulatory agents (eg, lenalidomide). Our approach to thromboprophylaxis in patients with POEMS syndrome is the same as for patients with multiple myeloma, as discussed separately. (See "Multiple myeloma: Prevention of venous thromboembolism".)

Data regarding thromboembolic events in patients with POEMS syndrome largely come from retrospective registry studies [21,61,63,66,67].

In one of the larger retrospective studies from the Mayo clinic, 62 of 230 patients (27 percent) with POEMS syndrome developed thrombosis [61]. Arterial events were slightly more common than venous. Baseline features associated with arterial thrombosis included thrombocytosis, elevated hemoglobin/hematocrit, extravascular volume overload, and splenomegaly. Hyperprolactinemia was a risk factor for venous thrombosis. Most events happened prior to POEMS-directed therapy, and most that occurred during therapy happened within three months of diagnosis.

Elevation of fibrinogen, fibrinopeptide-A, and thrombin-antithrombin complexes during the active phase has been noted [68]. 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.

Pulmonary involvement — Pulmonary abnormalities are common in patients with POEMS syndrome, but not included in the diagnostic criteria. 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 [69]. Significant radiographic findings such as pleural effusion, elevated diaphragm, and increased cardiac silhouette were seen in 28 percent of patients.

Pulmonary hypertension is a common feature of POEMS syndrome and is associated with signs of extravascular volume overload (peripheral edema, ascites, pleural effusion) [70,71]. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults".)

In a retrospective study of 154 patients with POEMS syndrome who underwent echocardiography, 27 percent had pulmonary hypertension defined as an estimated pulmonary artery systolic pressure ≥50 mmHg [71]. When compared with the rest of the cohort, those with pulmonary hypertension had a longer median time from onset to diagnosis (26 versus 14 months) and had higher rates of:

●Dyspnea (50 versus 19 percent)

●Peripheral edema (98 versus 87 percent)

●Ascites (71 versus 51 percent)

●Pleural effusion (62 versus 37 percent)

●Restrictive abnormality on pulmonary function testing (83 versus 50 percent)

●Decreased diffusion capacity of carbon monoxide (96 versus 72 percent)

These results illustrate an increased rate of extravascular volume overload in those with pulmonary hypertension; however, the extravascular volume overload did not appear to be causally related to the pulmonary hypertension since there was no evidence of right ventricular failure (ie, the patients had normal right ventricular dimension and normal inferior vena cava dimension). The investigators suggested that a similar pathway/mechanism could be causing both pulmonary hypertension and extravascular volume overload as downstream effects.

Treatment of POEMS syndrome has been associated with improvements in related pulmonary morbidity [70,71].

DIAGNOSIS

When to suspect the diagnosis — The diagnosis of POEMS syndrome should be suspected in patients presenting with peripheral neuropathy of unknown origin, refractory ascites or peripheral edema, and gynecomastia or organomegaly of unknown origin. Clinicians should have a high index of suspicion for the disease since it is an uncommon syndrome that manifests with varied clinical features (table 2).

Diagnostic evaluation — Patients suspected of having POEMS should initially undergo a complete history and physical examination. The history should pay specific attention to complaints of neurologic symptoms, skin changes, extravascular volume overload, and symptoms suggestive of an endocrine disorder (eg, gynecomastia, irregular menses). As in any complex illness, a detailed physical examination is critical, with emphasis on the funduscopic examination for papilledema, neurologic examination, 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.

In addition, we perform the following studies as an initial screen to look for POEMS syndrome:

●A complete blood count and differential with examination of the peripheral blood smear. (See 'Polycythemia and thrombocytosis' above.)

●Evaluation of serum and 24-hour urine collection with electrophoresis and immunofixation, quantitative immunoglobulins, and serum free light chain assay. 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 1.0 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 "Laboratory methods for analyzing monoclonal proteins".)

●Serum or plasma vascular endothelial growth factor (VEGF)

●CT skeletal survey or PET-CT imaging 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. (See 'Osteosclerotic bone lesions' above.)

●Pulmonary function testing and echocardiography to evaluate right sided heart pressures.

●Thyroid stimulating hormone (TSH), prolactin, estradiol, testosterone, AM cortisol, and fasting glucose should be measured in all patients. In men, we measure testosterone in addition to estradiol. There should be a low index of suspicion to perform an adrenocorticotropin hormone (ACTH) and a Cortrosyn stimulation test because hypoadrenalism can easily be overlooked. A more thorough endocrine evaluation may be appropriate in patients with signs and symptoms suggestive of hypogonadism, hypothyroidism, or adrenal disorders. (See "Diagnosis of and screening for hypothyroidism in nonpregnant adults" and "Clinical features and diagnosis of male hypogonadism" and "Determining the etiology of adrenal insufficiency in adults".)

Diagnostic criteria — The diagnosis requires the clinical features of polyneuropathy, the pathologic identification of a monoclonal plasma cell proliferative disorder, and the presence of at least one major and one minor criterion on physical examination, imaging, or laboratory evaluation (table 1).

International Myeloma Working Group (IMWG) diagnostic criteria require the presence of [72,73]:

Both mandatory criteria (see 'Mandatory criteria' above):

●Polyneuropathy

●Monoclonal plasma cell proliferative disorder

Plus at least one major criterion (see 'Major criteria' above):

●Osteosclerotic or mixed sclerotic/lytic lesion visualized on plain films or computed tomography

●Castleman disease

●Elevated serum or plasma vascular endothelial growth factor (VEGF) levels. While the IMWG suggest using a cutoff of at least three to four times the upper limit of normal, the normal reference ranges for these tests and the optimal cutoff for the diagnosis of POEMS are not well defined. For the diagnosis of POEMS syndrome, plasma VEGF ≥200 pg/ml has a specificity of 95 percent and sensitivity of 68 percent [6], and serum VEFG ≥1920 pg/ml has a specificity of 98 percent and sensitivity of 73 percent [44]. (See 'Elevated VEGF levels' above.)

Plus at least one minor criterion (see 'Minor criteria' above):

●Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy)

●Extravascular volume overload (peripheral edema, ascites, or pleural effusion)

●Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, or pancreatic disorder excluding diabetes mellitus or hypothyroidism)

●Skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, plethora, acrocyanosis, flushing, white nails)

●Papilledema

●Thrombocytosis or polycythemia

"Atypical" cases (eg, without polyneuropathy or without a monoclonal plasma cell disorder) have been described [74-76]. In general, such cases should be monitored for the development of diagnostic symptoms rather than proceeding with treatment. However, atypical cases with debilitating symptoms, such those with severe, refractory ascites, may be considered for treatment similar to that used for typical cases.

The absence of both osteosclerotic lesions and Castleman 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 VEGF, reduced DLCO (diffusing capacity for carbon monoxide), thrombocytosis, and polycythemia are common features of the syndrome and are helpful when the diagnosis is difficult. (See 'Elevated VEGF levels' above.)

Recognizing the disease early on may be difficult. Caution should be used when making the diagnosis in patients with M protein with a kappa light chain unless other M protein-related disorders can be excluded. The histopathologic finding of lambda-restricted plasma cell rimming the lymphoid aggregates and megakaryocytic hyperplasia in bone marrow is highly suggestive of POEMS syndrome rather than other plasma cell dyscrasias [42].

DIFFERENTIAL DIAGNOSIS — The median time from onset of symptoms to diagnosis of POEMS is 13 to 18 months [21,32]. Many patients are initially misdiagnosed as having other disorders, such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). In addition, 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 [77-80].

Chronic inflammatory demyelinating polyradiculopathy (CIDP) — Both CIDP and POEMS syndrome are characterized by a subacute motor-dominant demyelinating polyradiculoneuropathy. Patients with CIDP do not have elevated VEGF or thrombocytosis. Nerve conduction study and electromyography can help distinguish POEMS syndrome from CIDP [20,28]. Compared with CIDP, POEMS demonstrates greater axonal loss (reduction of motor amplitudes and increased fibrillation potentials), greater slowing of the intermediate nerve segments, less common temporal dispersion and conduction block, and absent sural sparing. (See 'Peripheral neuropathy' above and "Chronic inflammatory demyelinating polyneuropathy: Etiology, clinical features, and diagnosis".)

Clonal plasma cell disorders — POEMS syndrome must be differentiated from other plasma cell dyscrasias that may be accompanied by neuropathy.

●Multiple myeloma (MM) – Polyneuropathy is uncommon in classical MM, and when present is usually due to the presence of amyloidosis. Features suggestive of MM include the presence of osteolytic bone lesions (without sclerotic changes), anemia, hypercalcemia, kidney failure, pathologic fractures, and a high percent of plasma cells in the bone marrow. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Diagnosis'.)

In rare instances, MM 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 MM and do not have the other characteristics of POEMS syndrome [81].

●Solitary plasmacytoma of bone (SPB) – 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 peripheral neuropathy, endocrinopathy, and skin changes are absent in SPB. The presence of an osteoblastic component to the bone lesion and/or other criteria for POEMS (table 1) should distinguish patients with POEMS from those with SPB. (See "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 [55,82]. 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), and similar cases have been reported [55-60]. (See 'Skin changes' above.)

●Monoclonal gammopathy of undetermined significance (MGUS) – 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 [83,84]. The presence of at least one other major and minor criterion (table 1) should serve to distinguish POEMS from MGUS. (See "Diagnosis of monoclonal gammopathy of undetermined significance" and "Clinical course and management of monoclonal gammopathy of undetermined significance", section on 'Monoclonal gammopathy of clinical significance'.)

●Waldenström macroglobulinemia (WM) – WM is a lymphoplasmacytic lymphoma with the additional presence of an IgM monoclonal gammopathy and may be complicated by polyneuropathy. Fewer than 1 percent of patients with POEMS syndrome have an IgM heavy chain. Moreover, 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 1), should serve to distinguish WM from POEMS. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Diagnosis'.)

●Immunoglobulin light chain (AL) amyloidosis – AL amyloidosis is a low “tumor burden” plasma cell disorder that is more often lambda. Approximately 15 percent of patients with AL amyloidosis have peripheral neuropathy, but unlike POEMS syndrome the peripheral neuropathy it is not a demyelinating neuropathy. Most often it is a small fiber peripheral neuropathy. The diagnosis of AL amyloidosis is made by biopsy of an involved tissue (fat aspirate or biopsy, bone marrow, gastrointestinal tract, kidney, heart, sural nerve) 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" and "Monoclonal immunoglobulin deposition disease".)

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 'Mixed cryoglobulinemia (types II/III)'.)

MANAGEMENT

Limited disease

Radiation therapy — For patients with limited disease that can be contained within a radiation field with minimal toxicity (eg, one to three isolated bone lesions and no evidence of clonal bone marrow involvement), we recommend limited field radiation therapy (RT) rather than systemic therapy. RT is given with curative intent at a dose of 40 to 50 Gy. Following such treatment, systemic and skin symptoms tend to respond within one month; 50 to 70 percent of patients show substantial improvement of the neuropathy, although the improvement in some patients is not apparent for six months or longer [21]. We have seen patients who have continued improvement for two to three years following RT.

Our approach is consistent with guidelines from the European Myeloma Network [85]. The use of limited field RT is based on the extrapolation of data from patients with solitary plasmacytoma of the bone (SPB) and case series of patients with POEMS syndrome. RT is a simple and effective therapy with limited toxicity. Patients who progress despite RT can be successfully treated with chemotherapy with or without autologous hematopoietic cell transplantation. The use of RT in SPB is discussed separately. (See "Solitary plasmacytoma of bone", section on 'Radiation'.)

The largest study of RT in POEMS was a single-center retrospective series of patients with newly diagnosed, limited disease POEMS syndrome [86-88]. Definitive RT was given at a median dose of 45 Gy (range 35 to 54) administered over 25 fractions. Clinical features improved following RT, including peripheral neuropathy, anasarca, organomegaly, papilledema, skin changes, serum M-spikes, and plasma VEGF levels. In an initial analysis of 38 patients with a median follow-up of 43 months, the estimated overall survival and event-free survival rates at four years were 97 and 52 percent. Updated publications of this series have reported estimated six-year progression-free survival of 62 percent and ten-year overall survival of 70 percent.

Further therapy was administered to 17 patients (48 percent) from the initial report with a median time to second therapy of 7.6 months (range: 2 to 73 months) after RT. The most common indications for additional therapy were neurologic worsening, insufficient neurologic improvement, and radiographic worsening. This study had a high number of patients who received subsequent therapy within 12 months of initial RT and, given the slow neurologic responses seen with RT, it is not known whether those treated for insufficient improvement would have demonstrated further improvement if subsequent therapy had been delayed. Secondary therapies included transplant (10 patients) and additional RT (3 patients).

This study supports the use of RT as the initial therapy in patients with limited disease. The excellent overall survival demonstrates that patients who progress after initial RT can be successfully managed with other therapies, including transplant. Similar response rates but inferior progression-free and overall survival outcomes were demonstrated in another small study of RT for POEMS syndrome that included patients with more extensive disease deemed too sick for chemotherapy [89].

Advanced disease

Chemotherapy — For most patients with widespread osteosclerotic lesions and/or bone marrow involvement, we suggest systemic chemotherapy with or without autologous hematopoietic cell transplantation (HCT, rescue) rather than radiation therapy (RT) alone [85,90]. Neither RT nor systemic therapy is curative in these scenarios. Treatment is given with the goals of alleviating symptoms, decreasing end-organ damage, improving quality of life, and prolonging overall survival.

RT may be a reasonable alternative initial treatment for those with a single large bone lesion and very minimal bone marrow involvement, reserving systemic therapy until the time of progression. Adjuvant RT may be incorporated into the management of patients with large bone lesions with a significant lytic component. The decision to proceed with RT is individualized and typically postponed until at least six months following completion of systemic therapy. (See 'Radiation therapy' above.)

Our approach is consistent with guidelines from the European Myeloma Network [85]. There is no standard preferred chemotherapy regimen and the choice largely depends on whether the patient is a candidate for high-dose melphalan with autologous HCT:

●Eligible for HCT – Patients who may be eligible for autologous HCT should be referred to a transplant center to discuss candidacy, the role of HCT, and preferred timing. Eligibility criteria vary across countries and institutions. Comorbidities that may limit its use in patients with POEMS syndrome include pulmonary hypertension, markedly abnormal pulmonary function tests, severe debility, and capillary leak syndrome. (See "Determining eligibility for autologous hematopoietic cell transplantation".)

The ability to collect hematopoietic stem cells is influenced by age, exposure to certain drugs (eg, melphalan), and the duration of treatment prior to collection. For POEMS syndrome, there is typically no need for cytoreductive chemotherapy prior to HCT and patients usually proceed directly to stem cell collection followed by high-dose melphalan and HCT without separate induction cytoreductive chemotherapy. (See 'Hematopoietic cell transplantation (HCT)' below.)

●Not eligible for HCT – Patients ineligible for or without access to autologous HCT are treated with regimens that target the underlying plasma cell dyscrasia and are modelled after those used in other plasma cell dyscrasias (eg, multiple myeloma). Regimens may include immunomodulatory agents (eg, lenalidomide), proteasome inhibitors (eg, bortezomib), low-dose alkylators (eg, cyclophosphamide), and/or an anti-CD38 monoclonal antibody (eg, daratumumab).

Support for systemic chemotherapy in POEMS syndrome come from small, prospective trials and retrospective case series [85,91]. Data from studies using older melphalan-based regimens support the use of systemic therapy in patients with multifocal lesions or widespread disease [21,92,93]. However, except for the use of high-dose melphalan for HCT, melphalan-based regimens have been replaced by lenalidomide-based or bortezomib-based regimens largely based on studies showing the superiority of these regimens in patients with multiple myeloma. (See "Multiple myeloma: Initial treatment".)

There is a paucity of data to guide the choice among the newer regimens. For most patients, we offer regimens similar to those used for multiple myeloma, such as:

●Lenalidomide plus dexamethasone (Rd) (table 3)

●Daratumumab, lenalidomide, and dexamethasone (DRd) (table 4)

●Bortezomib, cyclophosphamide, and dexamethasone (VCd) (table 5)

Support for therapy directed at the underlying plasma cell dyscrasia comes from a small, prospective trial of melphalan plus dexamethasone in which 80 percent of patients demonstrated a hematologic response and all patients showed neurologic improvement at a median time of 12 months (range: 3 to 15 months) [93]. Subsequent studies suggest that more modern regimens are effective:

●Immunomodulatory agents – Several case reports and two small prospective trials have demonstrated clinical improvement after treatment with lenalidomide with or without dexamethasone [94-103]. In the trials, over 70 percent demonstrated a hematologic response with 60 to 75 percent progression free at three years [102,103]. Thalidomide has also shown activity, but is associated with greater toxicity, including neurotoxicity [104,105].

●Proteasome inhibitors – Bortezomib has demonstrated activity in case reports [106-108], and VCd has shown a response rate of 76 percent in a study from China [109]. Peripheral neuropathy is a common toxicity seen with bortezomib. If used, bortezomib is given subcutaneously and at weekly intervals to reduce the risk of neuropathy. If neuropathy worsens, bortezomib must be dose reduced or discontinued. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Bortezomib'.)

●Anti-CD38 monoclonal antibodies – Case reports have demonstrated responses to daratumumab as a single agent or in combination with lenalidomide- or bortezomib-based therapy [110-116].

Case reports suggest the use of agents with anticytokine/anti-VEGF activity (eg, bevacizumab) may ameliorate the signs and symptoms of this disorder [117-120], but for most reports the drug was given after or contemporaneously with anti-plasma cell therapy, obscuring the validity of these reports. Given the anecdotal nature of these data, these agents are not recommended outside the context of clinical trials. (See 'Pathophysiology' above.)

Treatment with plasmapheresis, other immunosuppressive agents (azathioprine, cyclosporine), and/or intravenous immunoglobulin do not appear to be effective [21].

Hematopoietic cell transplantation (HCT) — Patients with advanced disease who may be eligible for autologous HCT should be referred to a transplant center to discuss candidacy, the role of HCT, and preferred timing. Eligibility criteria vary across countries and institutions. Comorbidities that may limit its use in patients with POEMS syndrome include pulmonary hypertension, markedly abnormal pulmonary function tests, severe debility, and capillary leak syndrome. (See "Determining eligibility for autologous hematopoietic cell transplantation".)

The ability to collect hematopoietic stem cells is influenced by age, exposure to certain drugs (eg, melphalan), and the duration of treatment prior to collection. For POEMS syndrome, there is typically no need for cytoreductive chemotherapy prior to HCT and patients usually proceed directly to stem cell collection followed by high-dose melphalan and HCT without separate induction cytoreductive chemotherapy.

A large series included 59 patients with POEMS syndrome treated with autologous HCT using peripheral blood stem cells at the Mayo Clinic [38]. Clinical improvement was nearly universal in these patients. Responses were relatively rapid with patients demonstrating response by 100 days post-transplant. Maximal neurologic improvement was seen at three years post-transplant. At a median follow-up of 45 months, five-year overall and progression-free survival rates were 94 and 75 percent, respectively. Of the 14 patients with progressive disease post-transplant, none had clinical symptoms. Instead, the progressions manifest as hematologic abnormalities, radiographic findings, or increased VEGF levels.

Details regarding neurologic improvement were available for 60 patients from the Mayo Clinic followed for a median of 61 months after autologous HCT [121]. All demonstrated improvement in their peripheral neuropathy post-HCT. Prior to HCT, the majority required either a wheelchair (45 percent) or walker/foot brace (29 percent) for mobility. On long-term follow-up, a minority needed assistance with mobility (no wheelchairs, 38 percent with foot brace). At last follow-up, six patients had died, one secondary to failed engraftment, one due to relapsed POEMS, and four from other malignancies.

Other reports of autologous HCT in POEMS have also described clinical improvement, with often dramatic neurologic improvement [5,88,122-127]. These studies support autologous HCT as one of the most active therapies for POEMS syndrome.

There is a case report of anti-BCMA CAR-T in a patient with POEMS syndrome without serious cytokine release syndrome [128].

Adjunctive care — Patients with POEMS syndrome often need adjunctive therapy directed at alleviating symptoms due to neuropathy, extravascular volume overload, and endocrine abnormalities.

●Neuropathy – Physical therapy evaluation is important in patients with significant weakness. Appropriate use of ankle-foot orthoses, splints, and walking assistance devices can significantly improve lifestyle in the face of significant disability. Pharmacologic therapy directed at painful neuropathy is similar to that used in other polyneuropathies. (See "Overview of polyneuropathy", section on 'Treatment of symptoms and prevention of complications'.)

●Extravascular volume overload – Ascites and pleural effusions often respond to the administration of diuretics but may require mechanical drainage with paracentesis or thoracentesis. (See "Management of malignant pleural effusions".)

●Endocrine abnormalities – Patients with hypothyroidism or adrenal insufficiency should receive hormone replacement with thyroxine and corticosteroids, respectively. Testosterone replacement may be useful in men with deficiency. Ongoing evaluation of the endocrine abnormalities with treatment of the underlying plasma cell disorder is critical to prevent drug overdoses. (See "Treatment of primary hypothyroidism in adults" and "Treatment of adrenal insufficiency in adults".)

●Thromboprophylaxis – Patients with POEMS syndrome are at increased risk for thromboembolic events. In addition, treatment with immunomodulatory drugs (eg, lenalidomide) has been associated with venous thromboembolism (VTE). All patients with POEMS syndrome should have an assessment of their VTE risk so that appropriate prophylaxis may be employed. Our approach to thromboprophylaxis in patients with POEMS syndrome is the same as for patients with multiple myeloma, as discussed separately. (See 'Thromboembolic disease' above and "Multiple myeloma: Prevention of venous thromboembolism".)

RESPONSE ASSESSMENT — The goals of treatment are three-fold:

●To stabilize or reverse organ dysfunction

●To eliminate or inactivate clonal plasma cells

●To drive down the serum or plasma VEGF level

Universal response criteria have not been published. The ideal response criteria would evaluate organ response and hematologic response. We use response criteria modified from the uniform response criteria used for multiple myeloma (table 6) [38,86]. Initial improvement is seen in serum paraproteins and VEGF levels. Response on imaging (FDG-PET) can lag by 6 to 12 months. The neurologic response is the slowest category because remyelination and axonal repair takes months to years.

We monitor serum paraprotein levels monthly while on therapy and usually perform a full response assessment three to six months after initiating therapy. The studies included depend on the abnormalities found on baseline studies.

The VEGF level is the single most important response criterion followed by M-protein response and FDG-PET response. The first two categories can be followed in real time, though VEGF may be high within a month of high-dose chemotherapy with hematopoietic cell transplantation. Either serum or plasma VEGF level can be used to measure response, but when comparing VEGF values over time, the method of VEGF measurement used for both values must be the same.

Serum protein electrophoresis with immunofixation and immunofixation of urine are most important for measuring hematologic response. Although the serum immunoglobulin free light chains are elevated in the majority of patients with POEMS syndrome, the ratio is abnormal in fewer than 20 percent [34].

Neuropathy typically takes approximately three months to stabilize and six months to begin to improve, with maximal improvement seen two to three years after definitive therapy. Measurement of neurologic response is complex. Patients will report improvement no sooner than three to six months from therapy, and maximal response is not typically seen until two to three years after therapy. The Overall Neuropathy Limitations Scale (ONLS) is a relatively crude measure but does not require the assistance of a neurologist [129]. More complicated scores like the Neurology Impairment Score (NIS) can be informative but require specialized testing and examination by a peripheral nerve specialist.

Follow-up should also include monitoring for adenopathy, extravascular volume overload, complete blood count (CBC), markers of endocrinopathy, lung function, and right sided heart pressures.

PROGNOSIS — POEMS syndrome is a chronic condition. Without treatment, patients experience a progressive, debilitating peripheral neuropathy leading to a bedridden or chairbound state. With modern therapies, most patients will experience a slow improvement in their systemic and skin manifestations and live with their disease for more than a decade.

●Overall survival – Historically, patients with POEMS syndrome survived more than three times longer than patients with multiple myeloma. At a time when the median survival for patients with multiple myeloma was three years, the median survival for patients with POEMS syndrome was approaching 12 years [21]. Overall survival has improved with advances in diagnosis, evaluation, treatment, and adjunctive care. In a study of patients diagnosed between 1974 and 2014, the estimated 10-year overall survival rate increased from 55 to 79 percent among patients diagnosed before and after 2003, respectively [88]. The investigators noted that this improvement likely reflects earlier diagnosis, more extensive evaluation for complications, and an increased use of autologous transplantation in the later time frame.

●Prognostic factors – The overall survival among patients with POEMS syndrome varies and studies have evaluated prognostic factors.

In a report from the Mayo Clinic, favorable prognostic factors for overall survival included: albumin at diagnosis >3.2 g/dL, attainment of a complete hematologic response, and younger age (eg, <50 years) [88]. Low albumin was associated early death but was not prognostic in a 12-month landmark analysis suggesting that expedited treatment is especially important in this population.

Investigators from China have developed a risk nomogram that includes age >50, presence of a pleural effusion, an eGFR <30 mL/min/1.73 m², and pulmonary hypertension [24].

Other risk factors predicting for shorter overall survival include: co-existing Castleman disease [32], fingernail clubbing, extravascular volume overload (ie, effusions, edema, and ascites) [21], respiratory symptoms [69], pulmonary hypertension [71] impaired DLCO, papilledema [130], and clinical hypothyroidism [49].

The number of POEMS features does not affect survival [21,35,131]. However, patients with monoclonal light chains in the urine may be more likely to develop additional POEMS features [38].

●Natural history – 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 kidney failure had coexistent ascites and a capillary leak-like syndrome. Light chain deposition was not observed.

SUMMARY AND RECOMMENDATIONS

●Definition – POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal plasma cell proliferative disorder, Skin changes) is a rare condition characterized by the presence of a monoclonal plasma cell disorder and peripheral neuropathy, along with other systemic symptoms (table 2).

The cause of POEMS syndrome is unknown, although chronic overproduction of proinflammatory and other cytokines appears to be a major feature of this disorder. (See 'Pathophysiology' above.)

●Clinical features – This condition should be suspected in a patient with polyneuropathy and evidence of a lambda restricted monoclonal plasma cell disorder. Peripheral neuropathy is required for the diagnosis, and usually dominates the clinical picture. Symptoms typically develop over a period of weeks to months. (See 'Clinical features' above.)

●Diagnosis – The diagnosis of POEMS syndrome requires the presence of both mandatory criteria (ie, polyneuropathy plus monoclonal plasma cell disorder), plus at least one major criterion (ie, osteosclerotic bone lesion[s], Castleman disease, or elevated serum or plasma vascular endothelial growth factor [VEGF] levels), along with at least one of the six minor criteria (table 1). The absence of both osteosclerotic myeloma and Castleman disease should make the diagnosis of POEMS syndrome suspect. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis of POEMS syndrome includes chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), other clonal plasma cell (or lymphoplasmacytic) disorders, and cryoglobulinemia. (See 'Differential diagnosis' above.)

●Treatment – There is no standard treatment for this disorder and there have been no randomized controlled clinical trials of treatment for POEMS syndrome. In general, the mode of therapy is based on whether the patient has limited or widespread sclerotic bone lesions:

•Limited disease – For patients with limited disease that can be contained within a radiation field with minimal toxicity (eg, one to three isolated bone lesions and no evidence of clonal bone marrow involvement), we recommend limited field radiation therapy (RT) rather than systemic therapy (Grade 1C). Unlike systemic therapy, RT can be administered with curative intent and has limited toxicity. This strategy also allows for systemic therapy in those with progression. (See 'Radiation therapy' above.)

•Advanced disease – For most patients with widespread osteosclerotic lesions and/or bone marrow involvement, we suggest systemic chemotherapy with or without autologous hematopoietic cell transplantation (HCT, rescue) rather than RT (Grade 2C). Our preference for systemic therapy is stronger for patients with severe symptoms. RT may be a reasonable alternative initial treatment for those with a single large bone lesion and very minimal bone marrow involvement, reserving systemic therapy until the time of progression. (See 'Chemotherapy' above.)

The choice of initial chemotherapy largely depends on whether the patient is a candidate for high-dose melphalan with autologous HCT:

-Patients who may be eligible for autologous HCT, we suggest referral to a transplant center (Grade 2C), in order to discuss the role of HCT and preferred timing. For POEMS syndrome, there is typically no need for cytoreductive chemotherapy prior to HCT and patients usually proceed directly to stem cell collection followed by high-dose melphalan and HCT without separate induction cytoreductive chemotherapy. (See 'Hematopoietic cell transplantation (HCT)' above.)

-For those who are not eligible for HCT, we offer lenalidomide-based or bortezomib-based regimens similar to those used for multiple myeloma. If used, bortezomib is given subcutaneously and at weekly intervals to reduce the risk of neuropathy. (See 'Chemotherapy' above.)

●Response assessment – Response to therapy is generally evaluated based on changes in the VEGF levels, hematologic profile, imaging studies, and symptom improvement (table 6). Neuropathy typically takes approximately three months to stabilize and six months to begin to improve, with maximal improvement seen two to three years after definitive therapy. (See 'Response assessment' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert A Kyle, MD, who contributed to earlier versions of this topic review.