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 disease (angiofollicular lymph node hyperplasia), 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 disease is presented separately. (See "HHV-8/KSHV-associated multicentric Castleman 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 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 disease are still being investigated.
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, 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 beta (IL-1ß), 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-ß1 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 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].
EPIDEMIOLOGY — POEMS syndrome is a rare disorder. The exact incidence is unknown due to the complexity of the clinical manifestations that are multisystemic. As with other plasma cell dyscrasias, POEMS syndrome commonly presents in the fifth to sixth decade [1,16,17]. 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 [1].
CLINICAL FEATURES
Overview — The clinical manifestations of POEMS syndrome are protean and usually develop over a period of weeks to months. 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 osteosclerotic lesions. Castleman disease is present in approximately 15 percent [1]. 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 (table 1).
In the Mayo Clinic series of 99 patients, the following features were present [1]:
●Polyneuropathy – 100 percent
●Monoclonal plasma cell disorder – 100 percent
●Increased cerebrospinal fluid protein (>50 mg/dL) – 100 percent
●Osteosclerotic bone lesions – 97 percent
●Skin changes – 68 percent
●Endocrinopathy – 67 percent
●Organomegaly (hepatomegaly, splenomegaly, lymphadenopathy) – 50 percent
●Weight loss (>10 pounds) – 37 percent
●Fatigue – 31 percent
●Papilledema – 29 percent
●Edema, ascites, pleural effusion – 29 percent
●Castleman disease – 15 percent
●Clubbing – 5 percent
In addition, elevated vascular endothelial growth factor (VEGF) levels have been reported in approximately two-thirds of patients with POEMS syndrome [18].
Based on this and other series, clinical features have been divided into mandatory criteria, major criteria, and minor criteria for the diagnosis of POEMS syndrome (table 2). Other signs and symptoms that do not fall into these criteria can be present as well. (See 'International Myeloma Working Group (IMWG) 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 [1,19]. 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 results 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 be confined to a wheelchair. Autonomic symptoms are not a feature. (See 'International Myeloma Working Group (IMWG) 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 occur. Cranial nerves are not affected.
Electromyographic studies show slowing of nerve conduction, prolonged distal latencies, and severe attenuation of compound muscle action potentials [1]. Conduction block is rarely found [20], 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 [21], 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 [22].
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 or lymph node in the case of Castleman disease. (See 'International Myeloma Working Group (IMWG) criteria' below.)
Findings based on the Mayo Clinic series are listed below [1]:
●Overall, 88 percent of patients had a monoclonal (M)-protein in the serum and/or urine.
●Eighty-five percent had an M 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 [16].
●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 M protein can be overlooked if immunofixation is not performed. (See "Laboratory methods for analyzing monoclonal proteins".)
●Forty percent had an M 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 [23]. The associated heavy chain was IgA, IgG, or IgM in 44, 40, and 1 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 an M 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 [1,16,24]. 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.
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), which are seen in 97, 68, and 15 to 25 percent, respectively.
Osteosclerotic bone lesions — Osteosclerotic lesions appeared in conventional radiographs in 97 percent of patients in the Mayo Clinic study (image 1) [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 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 has 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.
Imaging with computed tomography (CT) scan or bone scintigraphy is more sensitive for the detection of bone lesions than plain films [25,26]. Since the lesions have variable FDG uptake, positron emission tomography (PET) scan may not detect all lesions seen on CT [27-30]. However, PET/CT may be helpful in monitoring response to treatment in patients with high baseline FDG uptake. (See 'Response assessment' below.)
On pathologic examination, bone biopsy demonstrates diffuse infiltration of light chain restricted plasma cells. 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 [31].
Elevated 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. While the normal reference ranges for these tests and the optimal cutoff for the diagnosis of POEMS are not well defined, the Mayo Clinic criteria for diagnosis consider a VEGF level at least three to four times the upper limit of normal to be a major criterion for diagnosis. Importantly, when comparing VEGF values over time, the method of VEGF measurement used for both values must be the same. (See 'Response assessment' below.)
In general, serum VEGF levels tend to be more than 5- to 10-fold higher in POEMS syndrome compared with normal controls and those seen in other neuropathic disorders [13,32]. 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 [33].
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 [18]. 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.
Castleman disease — Castleman disease (giant cell lymph node hyperplasia, angiofollicular lymph node hyperplasia) and POEMS syndrome have been frequently associated [34]. In one small series, two of three patients with POEMS syndrome were reported with Castleman disease [35]. Antibodies to human herpesvirus 8 (HHV-8), a virus implicated in the pathogenesis of Castleman disease, mainly HIV-associated, were reported in seven of nine patients with POEMS syndrome and Castleman disease. Nine of 18 patients had circulating anti-HHV-8 antibodies, while six of seven patients with POEMS syndrome and Castleman disease had HHV-8 DNA sequences [36]. (See "HHV-8/KSHV-associated multicentric Castleman disease".)
Approximately 15 percent of patients in the Mayo Clinic series with POEMS syndrome also have Castleman disease [1], similar to the 19 to 24 percent noted in two other major series [16,24]. 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 [37]. (See 'Organomegaly' below.)
Minor criteria — The six minor criteria for the diagnosis of POEMS syndrome are endocrine abnormalities, skin changes, organomegaly, extravascular volume overload, thrombocytosis/polycythemia, and papilledema, which are seen in 67, 68, 50, 29, 50, and 29 percent, respectively [1].
Endocrine abnormalities — Numerous endocrine abnormalities have been described. Findings based on the Mayo Clinic series are listed below [1,38]:
●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 a Mayo Clinic study of 64 patients [38].
●Hypogonadism is the most common endocrine abnormality. Elevated levels of follicle stimulating hormone in the absence of primary hypogonadism levels have been reported [39]. In a Mayo Clinic study of 170 patients with POEMS syndrome, over 70 percent of males tested were found to have hypogonadism [38]. In this study, 10 (seven men and three women) of 35 patients tested had hyperprolactinemia, and 10 of 38 men had gynecomastia. Serum estradiol levels were normal in all four women in whom it was measured [38].
●Fourteen of 48 patients (29 percent) in the Mayo Clinic study [38] had hypothyroidism requiring therapy. An additional 14 patients 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.
Given the high prevalence of diabetes mellitus and hypothyroidism in the general population, these endocrine abnormalities are not considered to be sufficient to fulfill the minor criteria for the diagnosis of POEMS syndrome.
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 [40-42]. These lesions, termed glomeruloid hemangioma, present as multiple red-purple lesions on the trunk and proximal limbs.
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.
A retrospective review of 107 patients from the Mayo Clinic reported that 90 percent had at least one skin manifestation [42]. 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 was associated with improvement in hemangiomas, white nails, sclerodermoid changes, hyperpigmentation, hypertrichosis, and vascular skin changes [42]. Further studies are needed to investigate whether specific skin findings are associated with prognosis.
Organomegaly — Fifty percent of patients in the Mayo Clinic series had organomegaly (hepatomegaly, splenomegaly, and/or lymphadenopathy) [1]. Each was present in approximately 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 [16,24]. 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 — 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 [1]. 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.
Hematologic features — Organomegaly, polycythemia, and thrombocytosis are minor criteria for the diagnosis of POEMS syndrome. Polycythemia and thrombocytosis are present in 15 and 50 percent, respectively. 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). (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. 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 approximately two-thirds of patients, typically in a background of increased polytypic plasma cells [31]. 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 [31].
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). No patients in our series died of typical multiple myeloma. (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 [1] and in 40 to 55 percent of patients in the two other major series [16,24].
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 [43]. The total cell count is typically normal.
Other signs and symptoms
Renal disease — In one study, 18 cases with acute and chronic renal failure associated with POEMS syndrome were reported [44]. 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 [45].
Another report examined 52 cases of POEMS syndrome with renal pathology described in the literature [46]. 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 [47].
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 in patients receiving immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide)".)
Data regarding thromboembolic events in patients with POEMS syndrome largely come from retrospective registry studies [1,48-50]. As examples:
●In a registry study from the University College London Hospitals, 25 of 83 patients (30 percent) with POEMS syndrome experienced 16 arterial and 11 venous thromboses, including two patients who had both arterial and venous events [48]. Arterial events included stroke (7 patients), peripheral arterial occlusion (5 patients), myocardial infarction (3 patients), and microvascular disease (1 patient). Venous events included deep venous thrombosis (4 patients), pulmonary embolism (3 patients), catheter-associated thromboses (3 patients), and portal vein thrombosis (1 patient). Most events occurred with active disease (23 before starting treatment and 7 during treatment). Use of thromboprophylaxis was variable.
●In a case series from the Mayo Clinic, 41 thrombotic events occurred in 18 patients [1]. These most often consisted of cerebral infarction, myocardial infarction, or Budd-Chiari syndrome. Three patients presented with heart failure and cardiomyopathy that resolved following treatment of POEMS syndrome. Four other patients developed heart failure, which occurred during an exacerbation of POEMS syndrome.
●In another report of the Mayo Clinic experience, 19 of 208 patients (9.2 percent) with POEMS syndrome diagnosed between 1973 and 2008 developed cerebral infarction at a median age of 53 years [49]. 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 to 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.
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 [51].
Pulmonary involvement — Depending upon the definition used for pulmonary hypertension, up to half of patients with POEMS syndrome will have pulmonary hypertension at some point during their disease course. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults".)
In one small series, two of six patients with POEMS syndrome had pulmonary hypertension [52]. Two additional patients with pulmonary hypertension and POEMS syndrome have been described [53]. In a third series, pulmonary hypertension developed in 5 of 20 patients with POEMS syndrome over a 10-year follow-up [6]; overproduction of IL-1ß, IL-6, TNF-alpha, and VEGF 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 [54]. 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 'Prognosis' below.)
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. 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.
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 neurological 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 'Hematologic features' above.)
●Evaluation of serum and 24-hour urine collection with electrophoresis and immunofixation – 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 "Laboratory methods for analyzing monoclonal proteins".)
●Metastatic bone survey – 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. If patients have a normal or indeterminate bone survey in the setting of bone pain, additional imaging with computed tomography (CT) should be performed.
●If respiratory symptoms are present, pulmonary function testing and echocardiography should be performed.
●A 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 "Diagnosis of adrenal insufficiency in adults".)
International Myeloma Working Group (IMWG) criteria — The IMWG criteria (derived from previously published Mayo Clinic studies) for the diagnosis of POEMS syndrome require the presence of (table 2) [55,56]:
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 (at least three to four times the upper limit of normal)
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 paraprotein) have been described [57-59]. 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, 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 [31].
DIFFERENTIAL DIAGNOSIS — The median time from onset of symptoms to diagnosis of POEMS is 13 to 18 months [1,37]. 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 [60-63].
Multiple myeloma — Polyneuropathy is uncommon in classical multiple myeloma (MM), and when present is usually due to the presence of amyloidosis. Features suggestive of MM include the presence of osteolytic bone lesions but no sclerotic changes, anemia, hypercalcemia, renal 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 [64].
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 [65,66]. 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).
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 [67,68]. 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".)
Waldenström macroglobulinemia — Waldenström 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 Waldenström 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, 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)'.)
CIDP — Both chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and POEMS syndrome are characterized by a subacute motor-dominant demyelinating polyradiculoneuropathy. Nerve conduction study and electromyography can effectively distinguish POEMS syndrome from CIDP [69,70]. 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 "Chronic inflammatory demyelinating polyneuropathy: Etiology, clinical features, and diagnosis".)
THERAPY
Overview — There is no standard treatment for POEMS syndrome and no randomized controlled clinical trials of treatment exist in the available literature [71-73]. In general, the mode of therapy is based on whether the patient has limited or widespread sclerotic bone lesions. Radiation therapy (RT) is employed for those with limited disease (eg, one to three isolated bone lesions), while therapy similar to that used for multiple myeloma is recommended for those with widespread bone lesions. High dose melphalan with autologous hematopoietic cell transplantation (HCT, rescue) should be considered for younger patients with widespread osteosclerotic lesions and for patients with rapidly progressive neuropathy. With this approach, approximately 75 percent of patients have some response to therapy, as discussed below. (See 'Hematopoietic cell transplantation (HCT)' below.)
Limited disease — The preferred treatment of patients with one to three isolated bone lesions and no evidence of bone marrow involvement is targeted RT. The use of targeted RT has been based on the extrapolation of data from patients with solitary plasmacytoma of the bone and case series of patients with POEMS syndrome. Radiation is a simple and effective therapy. Patients who progress despite initial RT can be successfully treated with chemotherapy with or without HCT.
Radiation therapy — Limited field radiation at a dose of 40 to 50 Gy is the preferred treatment modality for patients with POEMS syndrome and one to three isolated bone lesions and no evidence of bone marrow involvement. Following such treatment, systemic and skin symptoms tend to respond within one month. More than 50 percent of patients treated with radiation show substantial improvement of the neuropathy, although the improvement in some patients is not apparent for six months or longer [1]. We have seen patients who have continued to improve for two to three years following RT.
A retrospective study from the Mayo Clinic identified 146 patients with newly diagnosed POEMS syndrome [74]. Definitive radiation at a median dose of 45 Gy (range 35 to 54) administered over 25 fractions was offered as the initial therapy to 38 patients (26 percent). Patients had a median number of one bone lesion (range 1 to 6), which involved the spine (22 percent), pelvis (52 percent), long bones (9 percent), and other areas (17 percent) including the ribs, scapula, clavicle, and sternum. The following results were reported:
●Complete or partial hematologic response, VEGF response, FDG PET response, and clinical responses were seen in 31, 14, 22, and 47 percent, respectively.
●Improvements were seen in peripheral neuropathy, anasarca, organomegaly, papilledema, skin changes, serum M-spikes, and plasma VEGF levels.
●At a median follow-up of 43 months, the estimated overall and event-free survival at four years was 97 and 52 percent.
Further therapy was administered to 17 patients (48 percent) with a median time to second therapy of 7.6 months (range: 2 to 73 months) after radiation. The most common indications for additional therapy were neurological worsening, insufficient neurologic improvement, and radiographic worsening. Secondary therapies included transplant (10 patients) and additional radiation (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.
Advanced disease — Patients with widespread osteosclerotic lesions or evidence of bone marrow involvement on bone marrow aspirate and biopsy are treated with chemotherapy with or without autologous HCT similar to that used for the treatment of multiple myeloma. Eligibility criteria for autologous HCT vary across countries and institutions. In most European countries, transplantation is offered primarily to patients less than 65 years of age. In the United States, a strict age limit is not used. Instead, decisions are made on a case-by-case basis, based on "physiologic age," and vary across institutions. Comorbidities that may limit the use of autologous HCT in patients with POEMS include renal insufficiency, pulmonary hypertension, capillary leak syndrome, and active infection. (See "Determining eligibility for autologous hematopoietic cell transplantation".)
Chemotherapy — Systemic chemotherapy is the preferred treatment option for patients with POEMS syndrome with widespread osteosclerotic lesions or bone marrow involvement [73,75]. Regimens are modelled after those used in other plasma cell dyscrasias and include:
●Lenalidomide-based therapy
●Bortezomib-based therapy
Data from older melphalan-based regimens support the use of systemic therapy in patients with multifocal lesions or widespread disease [75]. However, given the results in myeloma, melphalan-based regimens have been replaced by bortezomib-based or lenalidomide-based regimens.
There is a paucity of data to guide the choice among these newer regimens. For most patients, we suggest the use of systemic therapy similar to that used for the treatment of multiple myeloma, such as bortezomib, cyclophosphamide, dexamethasone (VCD) (table 3) or lenalidomide plus dexamethasone (Rd) (table 4). Bortezomib should be given subcutaneously and at weekly intervals. This reduces the risk of neuropathy which is often a side effect of bortezomib. If an increase in neuropathy occurs, the dosage of bortezomib must be modified or discontinued. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Proteasome inhibitors'.)
The following reports illustrate the efficacy of systemic therapy in this patient population:
●In a Mayo Clinic study, melphalan plus prednisone was given to 48 patients with POEMS syndrome, 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 [76]. 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).
●Several case reports have demonstrated clinical improvement after treatment with lenalidomide with or without dexamethasone [77-84]. Two small prospective trials of lenalidomide plus dexamethasone have reported responses in over 70 percent with 60 to 75 percent progression free at three years [85,86]. Importantly, lenalidomide does not appear to impair stem cell collection for those proceeding to HCT. Thalidomide has also shown activity, but is associated with greater toxicity [87].
●Bortezomib has demonstrated activity in case reports, although neurotoxicity may limit its use in this population [88-90]. VCD has shown a response rate of 76 percent in a study from China [91].
Case reports suggest the use of agents with anticytokine/anti-VEGF activity (eg, bevacizumab) may be helpful in ameliorating some or all of the signs and symptoms of this disorder [92-95]. Given the anecdotal nature of this data, these agents are not recommended outside the context of clinical trials. (See 'Pathophysiology' above.)
Hematopoietic cell transplantation (HCT) — Autologous HCT following high-dose melphalan is an important consideration for younger patients with multiple osteosclerotic lesions. If HCT is contemplated, initial treatment with melphalan-based regimens should be avoided. Most of the time there is no need for cytoreductive chemotherapy prior to HCT and patients usually proceed directly to HCT without induction. (See "Multiple myeloma: Use of autologous hematopoietic cell transplantation", section on 'Initial chemotherapy'.)
The largest series was a report of 59 patients with POEMS syndrome treated with autologous HCT using peripheral blood stem cells at the Mayo Clinic [27]. 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 [96]. 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 [14,97-101]. These studies support autologous HCT as one of the most active therapies for POEMS syndrome.
Adjunctive care — Patients with POEMS syndrome often need additional 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. 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 in patients receiving immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide)".)
RESPONSE ASSESSMENT — The goals of treatment are twofold: to stabilize or reverse organ dysfunction and to eliminate or inactivate clonal plasma cells. Universal response criteria have not been published. The ideal response criteria would evaluate organ response and hematologic response. Other clinicians have used serum free light chain assays to assess hematologic response. We use the following response criteria, which are modified from the uniform response criteria used for multiple myeloma [74].
Serum paraprotein levels are monitored monthly while on therapy. A full response assessment is usually performed three to six months after initiating therapy. In general, a good response to therapy should occur within six months. Response to treatment is determined using a whole body fluorodeoxyglucose positron emission tomography (FDG PET) scan, complete blood count (CBC), vascular endothelial growth factor (VEGF) level, serum protein electrophoresis with immunofixation, and 24-hour urine protein electrophoresis with immunofixation. Markers of endocrinopathy should only be tracked if they were abnormal at baseline. Either serum or plasma VEGF level can be used, but when comparing VEGF values over time, the method of VEGF measurement used for both values must be the same.
Hematologic response:
●Complete response (CRH) – Negative bone marrow and negative immunofixation of the serum and urine. Patients are not required to have a repeat bone marrow aspirate if the baseline bone marrow was negative.
●Very good partial response (VGPRH) – A 90 percent reduction in the M protein or immunofixation positive only as long as M protein was at least 0.5 g/dL at baseline.
●Partial response (PRH) – A 50 percent reduction in M protein or immunofixation positive as long as baseline M protein was at least 1.0 g/dL.
●No response – Less than a PRH.
VEGF response:
●Complete response (CRV) – Normalization of VEGF (<87 pg/mL).
●Partial response (PRV) – Decrease of ≥50 percent (baseline must be ≥200 pg/mL).
●No response (NRV) – Less than a PRV.
Radiologic response by FDG PET:
●Complete radiologic response (CRR) – Initial FDG avidity on a baseline PET scan that disappears.
●Partial radiologic response (PRR) – Initial FDG avidity that was 50 percent improved.
●No radiologic response – Not meeting CRR or PRR.
Clinical response: A clinical response assessment incorporates information regarding peripheral neuropathy, organomegaly, papilledema, erythrocytosis, thrombocytosis, endocrinopathy, extravascular fluid overload (ascites, effusions, edema), and abnormal pulmonary function tests. There are four clinical response categories, which include clinical improvement (IC), clinical progression (PC), mixed clinical response (MC), and clinical stability (SC).
Others have used the Overall Neuropathy Limitation Scale (ONLS) score to assess neurologic response [102]. 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.
PROGNOSIS — 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 [27]. 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' above.)
SUMMARY AND RECOMMENDATIONS
●Definition – POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes) is a rare condition characterized by the presence of a monoclonal plasma cell disorder and peripheral neuropathy, along with other systemic symptoms.
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 for a monoclonal plasma cell disorder (table 1). 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 2). 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 the various clonal plasma cell (or lymphoplasmacytic) disorders, cryoglobulinemia, and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). (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:
•We recommend that patients with one to three isolated bone lesions and no evidence of bone marrow involvement 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.)
•There is a paucity of data to guide the choice of initial chemotherapy. We generally prefer melphalan plus dexamethasone rather than other combinations based on the greater experience with this regimen that has demonstrated good response rates with an acceptable toxicity profile. Lenalidomide-based regimens may be an acceptable alternative, but further studies are necessary prior to their routine use. (See 'Chemotherapy' above.)
•We suggest autologous HCT (rescue) following high dose melphalan for younger transplant-eligible patients with widespread osteosclerotic lesions and/or severe symptoms, especially progressive neuropathy (Grade 2C). (See 'Hematopoietic cell transplantation (HCT)' above.)
●Response assessment – Response to therapy is generally evaluated based on changes in the hematologic profile, imaging studies, VEGF levels, and symptom improvement. 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.)
