Синдром PEEMS: 2026 Обновленная информация по диагностике, статистике рисков и управлению.

Disease Overview

POEMS syndrome is a rare life‐threatening syndrome due to an underlying plasma cell disorder. The acronym, which was coined by Bardwick in 1980 [ 1 ], refers to several, but not all, of the features of the syndrome: polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes. There are three important points that relate to this memorable acronym: (1) not all of the features within the acronym are required to make the diagnosis; (2) there are other important features not included in the POEMS acronym, including p apilledema, e xtravascular volume overload, s clerotic bone lesions, t hrombocytosis/erythrocytosis (P.E.S.T.), elevated VEGF levels, a predisposition towards thrombosis, and abnormal pulmonary function tests; and (3) there is a Castleman disease variant of POEMS syndrome may is associated with a clonal plasma cell disorder. Other names of the POEMS syndrome that are less frequently used are osteosclerotic myeloma, Takatsuki syndrome or Crow‐Fukase syndrome [ 2 , 3 ]. The disease was initially thought to be more common in patients of Japanese descent given the largest initial reports from Japan [ 2 , 3 ]. However, over the years, large series have also been reported from France, the United States, China, and India [ 4 , 5 , 6 , 7 , 8 ]. A national survey conducted in Japan in 2003 showed a prevalence of approximately 0.3 per 100,000 [ 9 ].

The pathogenesis of the syndrome is not well understood. Distinctive presenting characteristics of the syndrome that differentiate POEMS syndrome from standard multiple myeloma (MM) include the following: (1) dominant symptoms are typically neuropathy, endocrine dysfunction, and volume overload; (2) dominant symptoms have little to nothing to do with bone pain, extremes of bone marrow infiltration by plasma cells, or renal failure; (3) vascular endothelial growth factor (VEGF) levels are high; (4) sclerotic bone lesions are present in the majority of cases; (5) overall survival is typically superior; and (6) lambda clones predominate [ 10 ].

To date, VEGF is the cytokine that correlates best with disease activity [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ], although it may not be the driving force of the disease based on the mixed results seen with anti‐VEGF therapy [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. VEGF is known to target endothelial cells, induce a rapid and reversible increase in vascular permeability, and be important in angiogenesis. It is expressed by osteoblasts, in bone tissue, macrophages, tumor cells [ 29 ] (including plasma cells) [ 30 , 31 ], and megakaryocytes/platelets [ 32 ]. Wang et al. demonstrated the bone marrow plasma cells of patients with POEMS syndrome had higher levels of VEGF mRNA expression than did their CD138 negative cells [ 33 ]. A remarkable observation was that both polyclonal plasma cells and clonal plasma cells had equally high levels of intracellular VEGF though monoclonal PCs had higher levels of intracellular IL‐6 expression. Both IL‐1β and IL‐6 have been shown to stimulate VEGF production [ 29 ]. IL‐12 has also been shown to correlate with disease activity [ 34 ]. Little is known about the plasma cells in POEMS syndrome except that more than 95% of the time they are lambda light chain restricted with restricted immunoglobulin light chain variable gene usage (IGLV1) [ 35 , 36 , 37 , 38 ], and there are some stereotype mutations among the IGLV1‐40 and IGV1‐44 genes [ 38 ]. Translocations, duplications of 1q, and deletion of chromosome 13 have been described [ 39 , 40 , 41 ]. There are emerging but inconsistent findings on the genetic profiles of patients with POEMS syndrome [ 42 , 43 ].

Diagnosis

The diagnosis is made based on a composite of clinical and laboratory features (Table 1 ), and the diagnosis will be missed if it is not considered. Like other monoclonal gammopathies of clinical significance [ 45 ], the clonal burden is typically quite small and can go unrecognized. Most notably, the constellation of neuropathy and any of the following should elicit an in‐depth search for POEMS syndrome: monoclonal protein (especially lambda light chain); thrombocytosis; anasarca; or papilledema. Historically, it was recommended that any patient who carries a diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) that is not responding to standard CIDP therapy should be considered as a possible POEMS syndrome patient, and additional testing should be done to rule in or rule out the diagnosis of POEMS syndrome. An important model‐based cost‐effectiveness analysis suggests this strategy is too little too late [ 46 ]. They compared initial VEGF testing for all patients with an acquired demyelinating neuropathy versus performing VEGF testing only after CIDP therapy had failed. The authors found that treatment associated with an incorrect CIDP diagnosis led to total wasted healthcare expenditures with an average cost‐per‐POEMS‐patient misdiagnosed of £14 701 to £20 214 and estimated that the introduction of mandatory VEGF testing for patients with acquired demyelinating neuropathy would lead to annual cost‐savings of £107 398 for the National Health Service. Moreover, it would prevent misdiagnosis in 16 cases per year, reducing morbidity and the cost associated with delayed diagnosis.

The requirements set forth in Table 1 are designed to retain both sensitivity and specificity, potentially erring on the side of specificity. Making the diagnosis can be a challenge, but a good history and physical examination followed by appropriate testing—most notably radiographic assessment of bones [ 47 , 48 , 49 ], measurement of VEGF [ 13 , 17 , 20 , 50 , 51 ], and careful analysis of a bone marrow biopsy [ 44 ]—can differentiate this syndrome from other conditions like CIDP, monoclonal gammopathy of undetermined significance (MGUS) neuropathy and immunoglobulin light chain amyloid neuropathy. A high platelet count is seen in 54% of POEMS patients as compared to 1.5% of patients with CIDP [ 52 ]. Helpful cut‐offs for plasma and serum VEGF levels to diagnose POEMS syndrome are 200 pg/mL (specificity 95%; sensitivity 68%) [ 20 ] and 1920 pg/mL (specificity 98%; sensitivity 73%) [ 53 ], respectively. Wang and colleagues have identified N‐terminal propeptide of type I collagen as a novel marker for the diagnosis of patients with POEMS [ 53 ]. They found the best cut‐off of N‐terminal propeptide of type I collagen to diagnose POEMS syndrome is 70 ng/mL with a specificity of 91.5% and a sensitivity of 80%. As will be discussed, there is a Castleman's variant of POEMS syndrome that does not have a clonal plasma cell proliferative disorder underlying, but has many of the other paraneoplastic features [ 54 ].

Distinguishing POEMS syndrome from a MGUS, smoldering MM (SMM), MM, or solitary plasmacytoma is important since the treatment, supportive care, and the expected treatment related toxicities are quite different. If a patient with POEMS syndrome is incorrectly deemed to have a MGUS or SMM, then no clone directed treatment will be recommended, existing symptoms will worsen, and the patient will accumulate additional elements of the syndrome. If the patient is diagnosed with MM or plasmacytoma, and standard therapies for these disorders are administered, the likelihood is high that there will be increased treatment related morbidity and inadequate supportive care. Therefore, a patient with POEMS syndrome should be thoroughly evaluated to define a baseline that can be used for future assessments (Table 2 ).

Clinical History

A thorough review of systems and physical examination are required. Estimated frequencies of findings are shown in Table 3 . The variability between series is most likely a function retrospective reporting—that is, if a physician does not order a test or chart a finding, it will not be captured—and local practices, and promptness of diagnosis, rather than ethnic differences [ 2 , 3 , 5 , 7 , 55 ]. The neuropathy is the dominant characteristic. The quality and extent of the neuropathy, which is peripheral, ascending, symmetrical, and affecting both sensation and motor function should be elicited [ 57 ]; in our experience, pain may be a dominant feature in about 10%–15% of patients, though in one report as many as 76% of patients had hyperesthesia [ 9 , 58 ]. Papilledema is present in at least one‐third of patients (Figure 1a ). Of the 33 patients at our institution referred for a formal ophthalmologic examination during a 10 year period, 67% had ocular signs and symptoms, the most common of which was papilledema in 52% of those examined [ 59 ]. The most common ocular symptoms reported were blurred vision in 15, diplopia in 5, and ocular pain in 3. In a series of 41 patients from China, there was a positive correlation between serum VEGF levels and the binocular mean retinal nerve fiber layer thickness [ 60 ]. In another series of 94 patients, papilledema, which was found in approximately 50% of patients, was an adverse prognostic feature for overall survival [ 61 ].

A whole skin examination should be performed looking for hyperpigmentation, a recent out‐cropping of hemangioma, hypertrichosis, dependent rubor and acrocyanosis, white nails (Figure 1b ), sclerodermoid changes, facial atrophy, flushing or clubbing [ 2 , 4 , 5 , 6 , 7 , 8 , 62 , 63 ]. Rarely calciphylaxis is seen [ 64 , 65 ]. Respiratory complaints are usually limited given patients' neurologic status impairing their ability to induce cardiovascular challenges. In a series of 137 POEMS syndrome patients seen at our institution between 1975 and 2003, at presentation the frequency with which patients reported dyspnea, chest pain, cough, and orthopnea, were 20%, 10%, 8%, and 7%, respectively [ 66 ].

Patients are at increased risk for arterial and/or venous thromboses during their course, with as many as nearly 30% of patients experiencing one of these complications [ 10 , 67 , 68 , 69 ]. There are twice as many arterial events prior to instituting therapy as there are venous events [ 68 , 69 ]. Risk factors for arterial thrombosis include elevated hemoglobin/hematocrit, extravascular volume overload, and splenomegaly [ 69 ]. Seven to 10% of patients present with a cerebrovascular event [ 69 ], most commonly embolic or vessel dissection and stenosis [ 70 ]. The median time between peripheral neuropathy symptom onset and the cerebrovascular event was 23 months (range 0.5 to 64 months). Risk factors for cerebral events included thrombocytosis and bone marrow plasmacytosis. Aberrations in the coagulation cascade have been implicated in POEMS syndrome [ 71 ]. In one report, circulating coagulation factors like fibrinopeptide A, thrombin‐antithrombin complex are increased during the active phase of illness, but other factors relating to fibrinolysis, plasminogen, a2 plasmin inhibitor plasmin complex, and FDP did not increase.

Physical Examination

On physical examination, objective evidence of the symptoms described above can be found in addition to non‐bulky adenopathy, gynecomastia, darkened areolae, diminished breath sounds, hepatosplenomegaly, areflexia, and a steppage gait, commonly with a positive Romberg sign. In our experience, finger‐nail clubbing is seen in about 4% of cases, but others have reported rates as high as 49% [ 3 , 66 ].

Testing and Procedures

Laboratory findings are notable for an absence of cytopenias. In fact, half of patients will have thrombocytosis or erythrocytosis [ 55 ]. In the series of Li et al., 26% of patients had anemia, which the authors attributed to impaired renal function [ 7 ]. Their series was enriched with Castleman disease cases (25%), which may have also contributed to this unprecedented rate of anemia.

The bone marrow biopsy reveals megakaryocyte hyperplasia and megakaryocyte clustering in 54% and 93% of cases, respectively [ 44 ]. These megakaryocyte findings are reminiscent of a myeloproliferative disorder, but JAK2 V617F mutation is uniformly absent. One‐third of patients do not have clonal plasma cells on their iliac crest biopsy. These are the patients who present at with a solitary or “multiple solitary plasmacytomas.” The other two thirds of patients have clonal plasma cells in their bone marrow, and 91% of these cases are clonal lambda. The median percent of plasma cells observed is less than 5%. Immunohistochemical staining is more sensitive than is 6‐color flow since the former provides information on bone marrow architecture, which is key in making the diagnosis in nearly half of cases. This finding was validated in another study [ 33 ]. In our study of 67 pretreatment bone marrows biopsies from patients with POEMS syndrome, lymphoid aggregates were found in 49% of cases [ 44 ]. Of these, there was plasma cell rimming in all but one, and in 75% and 4% the rimming was clonal lambda and kappa, respectively. This finding was not seen in bone marrows from normal controls or from patients with MGUS, MM, or amyloidosis. The only other disease that this clonal rimming was seen was in patients with lymphoplasmacytic lymphoma. Overall, only 8/67 (12%) of POEMS cases had normal iliac crest bone marrow biopsies, that is, no detectable clonal plasma cells, no plasma cell rimmed lymphoid aggregates, and no megakaryocyte hyperplasia.

Plasma and serum levels of VEGF are markedly elevated in patients with POEMS [ 11 , 20 , 29 , 72 ] and correlate with the activity of the disease [ 13 , 17 , 20 , 29 ]. The principal isoform of VEGF expressed is VEGF165 [ 13 ]. VEGF levels are independent of M‐protein size [ 13 ]. Increased VEGF has been found in ascitic fluid [ 73 ] and the cerebrospinal fluid [ 17 ]. IL‐1β, TNF‐α, and IL‐6 levels are often also increased. Serum VEGF levels are 10–50 times higher than plasma levels of VEGF [ 74 ], making it unclear which test is preferred. In patients with POEMS, VEGF is found in both plasma cells [ 30 , 31 , 33 ] and platelets [ 72 ]. The higher level observed in serum is attributable to the release of VEGF from platelets in vitro during serum processing. Because plasma is a product of an anticoagulated sample, there is less platelet activation and therefore less platelet VEGF contributing to the plasma measurement than the serum sample. Tokashiki et al. argue that serum VEGF is the better test because it reflects the VEGF contribution from both the serous and platelet compartments [ 74 ]. However, the counter‐argument is that the amount of VEGF released by platelets may vary due to collection and processing technique, making serum measurements of VEGF less reliable.

Extravascular overload most commonly manifests as peripheral edema, but pleural effusion, ascites, and pericardial effusions are also common. The composition of the ascites was studied in 42 patients with POEMS syndrome. The ascitic fluid had low serum ascites albumin gradients consistent with an exudative rather than a portal hypertension process in 74% of cases [ 75 ].

Nerve conduction studies in patients with POEMS syndrome show slowing of nerve conduction that is more predominant in the intermediate than distal nerve segments as compared to CIDP, and there is more severe attenuation of compound muscle action potentials in the lower than upper limbs [ 9 , 76 , 77 , 78 , 79 ]. In contrast to CIDP, conduction block is rare [ 9 , 77 , 79 ]. The conduction findings could suggest that demyelination is predominant in the nerve trunk rather than the distal nerve terminals and axonal loss is predominant in the lower limb nerves [ 9 ]. Axonal loss is greater in POEMS syndrome than it is in CIDP [ 79 ]. The role high‐resolution nerve ultrasound plays in differentiating POEMS from CIDP is still a work in progress, since both display increased cross sectional nerve area in the upper extremities [ 80 ]. The nerve biopsy shows demyelination, often with axonal loss, and typical features of uncompacted myelin lamellae. Large onion bulbs are typically not seen unlike the case with CIDP [ 81 ]. More inflammation is seen in CIDP nerve biopsies. Moreover, when inflammation is observed in POEMS nerve biopsies, it is mostly epineurial perivascular whereas in CIDP the inflammation is endoneurial perivascular and epineurial perivascular. Finally, more epineurial neovascularization is seen in POEMS biopsies than in those of CIDP. In one report, the presence of hyperalgesia was closely related to a reduction in the myelinated, but not unmyelinated, fiber population [ 82 ].

At ultrastructural examination there are no features of macrophage‐associated demyelination, which are seen in some cases of CIDP [ 83 , 84 , 85 , 86 ] In another study, ultrastructural analysis of POEMS nerves revealed endothelial cytoplasmic enlargement, opening of the tight junctions between endothelial cells and presence of many pinocytic vesicles adjacent to the cell membranes, all consistent with an alteration of the permeability of endoneurial vessels [ 17 ]. Arimura et al. studied the direct effects of VEGF on blood nerve barrier function using an animal model and found that VEGF increased the microvascular permeability inducing endoneurial edema [ 87 ]. The authors postulate that this increased permeability could allow serum components toxic to nerves, like complement and thrombin, to induce further damage. In one study of human nerve biopsies of POEMS patients, more than 50% of endoneurial blood vessels had narrowed or closed lumina with thick basement membranes, strong polyclonal immunoglobulin staining in the endoneurium (consistent with blood‐nerve barrier opening), and thrombin‐antithrombin complexes [ 71 ]. Scarlato et al. have proposed that the mechanism of peripheral neuropathy in POEMS syndrome is due to endothelial injury, indirectly or directly caused by an abnormal activation of endothelial cells by VEGF, which is overexpressed in the nerves of patients with POEMS syndrome [ 17 ]. According to these authors there may be hypertrophy and proliferation of endothelial cells with a secondary microangiopathy, which fuels the destructive feedback loop of reduced oxygen supply, expression of HIF‐1a, with a secondary increase in local VEGF expression.

Endocrinopathy is a central but poorly understood feature of POEMS. In one series [ 56 ], approximately 84% of patients had a recognized endocrinopathy, with hypogonadism as the most common endocrine abnormality, followed by thyroid abnormalities, glucose metabolism abnormalities, and lastly by adrenal insufficiency. The majority of patients have evidence of multiple endocrinopathies in the four major endocrine axes (gonadal, thyroid, glucose, and adrenal) [ 88 ]. It is important not to miss subclinical adrenal insufficiency because patients can develop adrenal crisis.

Osteosclerotic lesions occur in approximately 95% of patients in Western series and at lower frequencies in Asian series. These bone lesions can be confused with benign bone islands, aneurysmal bone cysts, non‐ossifying fibromas, and fibrous dysplasia (Figure 1c–e ) [ 3 , 55 , 89 , 90 ]. Some lesions are densely sclerotic, while others are lytic with a sclerotic rim, while still others have a mixed soap‐bubble appearance. Bone windows of CT body images are often very informative, often even more so than FDG‐uptake, which can be variable [ 48 , 49 ]. FDG‐uptake occurs in those lesions which have a lytic component [ 91 ]. The advantage of whole body CT—even low dose like what is used as part of the PET examination or alone as is used routinely for MM—is that other features of the disease are also seen, that is effusions, ascites, adenopathy, and hepatosplenomegaly.

The pulmonary manifestations are protean, including pulmonary hypertension, restrictive lung disease, impaired neuromuscular respiratory function, and impaired diffusion capacity of carbon monoxide, but improve with effective therapy [ 66 , 92 ]. In a series of 20 patients with POEMS, followed over a 10‐year period, 25% manifested pulmonary hypertension [ 92 ]. In a larger series of 137 patients who were not uniformly tested, nearly 10% of patients had restrictive lung disease, reduced diffusing capacity of the lung for carbon dioxide (DLCO), and/or pulmonary hypertension. Nearly 25% had significant chest roentgenogram abnormalities [ 66 ]. Pulmonary hypertension has been reported to occur in 27% of unselected patients with POEMS syndrome [ 93 ]. It is more likely to occur in patients with extravascular overload. Whether the digital clubbing seen in POEMS is a reflection of underlying pulmonary hypertension and/or parenchymal disease is yet to be determined. Impaired DLCO has been shown to be an adverse prognostic factor in another series [ 61 ].

The histologic findings of the dermis have been reported to range from non‐specific to glomeruloid hemangiomata to vascular abnormalities in apparently normal dermis [ 94 , 95 , 96 ]. Biopsies of normal appearing skin demonstrated an extremely complex subpapillary vascular network with largely dilated and frequently anastomotic vessels [ 97 ]. Capillary loops appeared more complex than normal, and most of them were probably clotted.

Serum creatinine levels are normal in most cases, but serum cystatin C, which is a surrogate marker for renal function, is high in 71% of patients [ 98 ]. In our experience, at presentation, fewer than 10% of patients have proteinuria exceeding 0.5 g/24 h, and only 6% have a serum creatinine greater than or equal to 1.5 mg/dL. Four percent of patients developed renal failure as preterminal events [ 55 ]. In a series from China, 22% of patients had a creatinine clearance (CrCl) of less than 60 mL/min/m 2 [ 7 , 99 ]. In our experience, renal disease is more likely to occur in patients who have co‐existing Castleman Disease. In POEMS syndrome, when present, the renal histologic findings are diverse with membranoproliferative features and evidence of endothelial injury being most common [ 100 ]. On both light and electron microscopy, mesangial expansion, narrowing of capillary lumina, basement membrane thickening, sub‐endothelial deposits, widening of the sub‐endothelial space, swelling and vacuolization of endothelial cells, and mesangiolysis predominate [ 101 , 102 , 103 , 104 , 105 , 106 , 107 ]. Standard immunofluorescence is negative [ 102 , 108 ], which differentiates it from primary membranoproliferative glomerulitis [ 100 ]. Rarely infiltration by plasma cells nests or Castleman‐like lymphoma can be seen [ 107 ].

Relationship to Castleman Disease and Castleman Disease Variant of POEMS

Castleman Disease (or angiofollicular lymph node hyperplasia) is a rare lymphoproliferative disorder which has many presentations, ranging from an asymptomatic unifocal mass to multifocal masses with a multitude of symptoms. The symptoms can range from simple B‐symptoms to various autoimmune phenomenon to a frank POEMS syndrome [ 3 , 5 , 55 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 ]. Several published cases of “interesting features” associated with Castleman disease are likely cases of POEMS syndrome [ 143 , 144 , 145 , 146 ]. Multicentric Castleman disease with and without peripheral neuropathy tend to be different; it has even been proposed that the presence or absence of peripheral neuropathy should be part of the multicentric Castleman disease classification system [ 147 ]. Those patients with peripheral neuropathy are more likely to have edema and impaired peripheral circulation [ 144 , 148 , 149 , 150 , 151 , 152 , 153 ], and they are also more likely to have a monoclonal lambda protein in their serum and/or urine [ 154 ].

Between 11% and 30% of POEMS patients who have a documented clonal plasma cell disorder also have documented Castleman disease or Castleman‐like histology [ 1 , 3 , 5 , 7 , 55 ]. In 30 patients with POEMS syndrome, 19 of 32 biopsied lymph nodes showed angiofollicular hyperplasia typical of Castleman disease [ 3 ]. In another series, 25 of 43 biopsied lymph nodes were diagnostic of Castleman disease and 84% of these had hyaline vascular type [ 7 ]. Only those with peripheral neuropathy and a plasma cell clone should be classified as classic POEMS syndrome. Without both of these characteristics, patients can be classified as Castleman disease variant of POEMS.

The neuropathy in Castleman disease patients tends to be more subtle than that of POEMS patients with osteosclerotic myeloma and is more often sensory [ 152 , 155 ]. At its worst, however, it is a mixture of demyelination and axonal degeneration with normal myelin spacing on electron microscopy, and abnormal capillary proliferation, similar to what is seen in the affected lymph nodes, has been described [ 152 ]. In contrast to the osteosclerotic myeloma variant of POEMS in which VEGF is the most consistently elevated cytokine, in Castleman disease IL‐6 is the dominant aberrantly overexpressed cytokine. Castleman disease patients often have a brisk polyclonal hypergammaglobulinemia.

Risk Stratification

To date, there are no known molecular or genetic risk factors that predict for overall survival. Prior to the common use of high‐dose chemotherapy with autologous stem cell support and the renaissance of myeloma therapies, the median survival was nearly 14 years [ 55 , 66 ]. Overall survival has improved over time (Figure 2a ); patients diagnosed before and after 2003 had 10‐year survival rates of 55% and 79%, respectively [ 156 ]. In a report from the Mayo Clinic, favorable prognostic factors for overall survival included albumin greater than 3.2 g/dL, attainment of a complete hematologic response and younger age. Investigators from China have developed a risk nomogram that includes age greater than 50, presence of a pleural effusion, an eGFR < 30 mL/min/1.73 m 2 , and pulmonary hypertension [ 158 ]. In one series, 40% of patients had elevated IL‐6 levels was associated with an inferior overall survival (8‐year OS 64% vs. 97%) [ 159 ]. Other previously described risk factors predicting for shorter overall survival include fingernail clubbing, extravascular volume overload—that is, effusions, edema, and ascites [ 55 ], respiratory symptoms [ 66 ], pulmonary hypertension [ 93 ] impaired DLCO, and papilledema [ 61 ]. The number of POEMS features does not affect survival [ 5 , 10 , 55 ]. A paper studying endocrine findings in patients with POEMS syndrome suggested that patients with clinical hypothyroidism had inferior progression free and overall survival rates [ 160 ]. Patients with co‐existing Castleman disease appear to have shorter PFS and worse overall survival as compared to patients without [ 7 , 155 ]. In a series of 11 patients, lower VEGF levels predicted for better response to therapy, with resolution of the skin changes, improvement of the neuropathic disturbances and reduction all of the features assumed to be related to increased permeability, like papilledema and organomegaly [ 17 ].

Therapy Overview

Despite the relationship between disease response and dropping levels of VEGF, the most experience with successful outcomes has been associated with directing therapy at the underlying clonal plasma cell disorder rather than solely targeting VEGF with anti‐VEGF antibodies. The treatment algorithm is based on the extent of the plasma cell infiltration (Figure 3 ). There are those patients who do not have bone marrow involvement as determined by blind iliac crest sampling and those who do have disseminated disease, that is, either bone diffuse marrow involvement and/or more than three skeletal lesions, and the approach to these two groups of patients differs. In general patients have good progression free survival with modern therapies, with overall 6‐year PFS of more than 50% (Figure 2b ). The longest PFS is observed for those patients who achieve a hematologic complete response (5‐year PFS 88%), but even those patients who do not have CR, 5‐year PFS is 50% (Figure 2c ). Among those patients who relapse, historically their subsequent PFS was 39 months (Figure 2d ). As the options for MM therapies grow, so do the options for patients with POEMS syndrome.

Management of POEMS Syndrome Without Disseminated Bone Marrow Involvement

In the case of patients with an isolated bone lesion without clonal plasma cells found on iliac crest biopsy, radiation is the recommended therapy as it is in the case of a more straightforward solitary plasmacytoma of bone. Not only does radiation to an isolated (or even two or three small isolated) lesion(s) improve the symptoms of POEMS syndrome over the course of 3–36 months, it can be curative. In a series of 35 patients with POEMS syndrome treated at the Mayo clinic, radiation was used as primary therapy [ 161 ]. This resulted in a 4‐year overall survival of 97% and a 4‐year failure free survival of 52%. More than half the “failures” occurred within 12 months of radiation. Whether these were true failures or whether they were driven by patient and physician anxiety over slow response is unclear in this retrospective series. An update of this series, which now included 91 patients receiving radiation therapy, the 10‐year overall survival was 70% [ 156 ] and the 6‐year progression free survival was 62% [ 157 ]. In a review of radiation therapy in management of POEMS syndrome from South Korea, six patients had radiotherapy as primary therapy—two of whom had multiple lesions, but were deemed too sick for chemotherapy—and seven patients received consolidative radiotherapy for persistent M‐spike and/or persistent clinical symptoms [ 162 ]. The response rates in this series for radiation alone were comparable to that of the Mayo series, but in the Korean series both OS and PFS were inferior among those patients who received radiation therapy alone largely due to the fact that these patients were sicker at time of treatment. In a retrospective series from the United Kingdom, 30 patients with a solitary plasmacytoma treated with radiation therapy were studied [ 163 ]. Forty‐seven percent were treated with radiotherapy with adjuvant systemic therapy while the remainder were treated with radiotherapy alone. All but one of the patients treated with systemic therapy received lenalidomide and dexamethasone; one received bortezomib and dexamethasone. Patients were started on the systemic therapy immediately upon diagnosis, with additional cycles after completing radiotherapy. The median number of cycles administered was 4 (range 1–16). There were no significant differences between the groups in terms of overall survival or VEGF response, but there were trends for higher hematologic CR and clinical responses. Three‐year PFS was 100% versus 65% for the combined therapy group versus the RT only group ( p = 0.034). Of the six progressions seen in the RT only group, all but two occurred in the first year.

Management of POEMS Syndrome With Disseminated Bone Marrow Involvement

Once there is disseminated bone marrow involvement, albeit even with a low plasma cell percentage, radiation is not expected to be curative. If the bone lesion (i.e., plasmacytoma) is reasonably large, radiation can be considered as primary therapy despite a positive iliac crest biopsy as long as the clonal plasma cell burden is close to 1%. If this approach is attempted, one should follow symptoms, serum M‐protein and blood VEGF levels over the course of 6–12 months after completing radiation, and then decide upon whether systemic therapy should be added. More commonly, once disseminated clonal plasma cell disease is identified, systemic therapy is recommended. On occasion, a large bony lesions with a significant lytic component may require adjuvant radiation therapy. Decisions about adjuvant radiation should be made on a case by case basis, and typically not until a minimal of 6 months after completing chemotherapy. It is important to remember that the there is a lag between completion of successful therapy and neurologic response, often with no discernible improvement until 6 months after completion of therapy. Maximal peripheral nerve response is not seen until 2–3 years hence. Other features like anasarca, papilledema, and even skin changes typically improve sooner. Optimal FDG‐PET response may also lag by 6–12 months.

Since there is a paucity published randomized clinical trials among patients with POEMS syndrome, treatment recommendations are based on limited trial data, case series and anecdote. Despite the relationship between disease response and dropping levels of VEGF, the most experience with successful outcomes has been associated with directing therapy at the underlying clonal plasma cell disorder rather than solely targeting VEGF with anti‐VEGF antibodies. Table 4 demonstrates a summary of observed outcomes. The treatment armamentarium is borrowed from other plasma cell disorders, most notably MM and light chain amyloidosis.

Alkylator‐Based Therapy Including Autologous Stem Cell Transplantation

The most experience has been with alkylator‐based therapy, more often as part of conditioning for peripheral blood stem cell transplant. The first prospective clinical trial to treat POEMS syndrome included 31 patients who were treated with 12 cycles of melphalan and dexamethasone [ 167 ]. The authors found that 81% of patients had hematologic response, 100% had VEGF response, and 100% with at least some improvement in neurologic status. A limitation of this study is that follow‐up was only 21 months. Personal experience and retrospective reports of the use of cyclophosphamide‐based therapies are also promising.

High‐dose chemotherapy with peripheral blood stem cell transplant can also be quite effective, but selection basis may confound these reports. Very short courses of induction therapy prior to stem cell collection and transplant may be helpful, especially in the sickest patients. One to 2 months of induction while waiting for an appointment to collect and transplant serves several purposes. First, a patient receiving immediate clone directed therapy is less likely to have further deterioration while waiting. Second, data from Li et al. suggest that subjects receiving prior induction had fewer complications during the peri‐ and post‐ASCT period than those who did not receive induction [ 170 ]. Mobilization is most often done with G‐CSF alone [ 171 ] or with on‐demand plerixafor, but cyclophosphamide mobilization is also a viable option.

With ASCT, case series suggest 100% of patients achieve at least some neurologic improvement [ 18 , 62 , 100 , 153 , 157 , 170 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 ], and the more modern studies document hematologic, VEGF, and PET responses [ 157 , 170 , 183 , 185 , 186 , 187 ]. Doses of melphalan ranging from 140 to 200 mg/m 2 have been used, with the lower doses used for sicker patients. In addition, tandem transplant has been applied in one patient, but again, no information is available regarding any added value of the second transplant [ 188 ]. In our experience with 80 patients, 6 year PFS was 72% and 10‐year OS was 89% [ 156 ].

Treatment‐related morbidity and mortality during the peritransplant period can be minimized by recognizing and treating an engraftment‐type syndrome characterized by fevers, rash, diarrhea, weight gain, and respiratory symptoms and signs that occur anytime between days 7 and 15 post‐stem cell infusion [ 180 ]. A starting dose of prednisone ranging between 20 and 1500 mg/day has been used. No evidence‐based recommendation can be given as to the appropriate dose, but of late we have been using 1 mg/kg. The taper can typically start within 2 days and be completed over 7–14 days. Splenomegaly was the baseline factor that best predicted a complicated peri‐transplant course. Patients with engraftment syndrome had a higher than expected transfusion need, with median numbers of platelet and erythrocyte transfusions being 5 apheresis units and 6 units, respectively. They also had delayed engraftment, with a median time to neutrophil engraftment of 16 days, with only 10% engrafting by Day 13. Their times to platelets 20 × 10 9 /L and 50 × 10 9 /L were 14.5 days and 19.5 days, respectively.

Immune Modulators, Proteasome Inhibitors, and Therapeutic Monoclonal Antibodies

Other treatments include lenalidomide, thalidomide, and bortezomib, drugs all of which can have anti‐VEGF and anti‐TNF effects. More recently there are anecdotal data employing daratumumab, carfilzomib, pomalidomide, elotuzumab, and anti‐BCMA therapies to treat patients with POEMS syndrome. Li and colleagues reported a phase II trial of 12 cycles of lenalidomide and dexamethasone in 41 patients [ 164 ]. The complete hematologic response rate was 46%, the neurologic response rate was 95%, and the VEGF response rate was 83%. After a median follow up of 34 months, the estimated 3‐year OS and PFS were 90% and 75%, respectively. Further updates from the same group (see below and Table 4 ) were nearly comparable [ 189 ]. Nozza et al. have reported prospective data on 18 patients (13 previously treated and 5 newly diagnosed, but not eligible for ASCT) treated with lenalidomide and dexamethasone [ 165 ]. Patients responding after 6 cycles continued treatment until progression or toxicity. Endpoints were neurological or clinical improvement. After 6 cycles of Rd, all but 4 had improvement in their ONLS, and at 39 months of follow‐up, all patients were alive with a 3‐year progression‐free survival of 59%. This is consistent with other case series in which all patients respond, but relapses appear to occur 3–10 months after the end of therapy [ 190 , 191 , 192 ]. Given the intrinsic risk patients with POEMS syndrome have for thrombosis, it is imperative that at least an aspirin be used for prophylaxis. The use of low molecular weight heparin, warfarin, or a Xa inhibitor should be balanced against fall risk. Some authors recommend baseline head magnetic resonance angiography prior to starting lenalidomide and dexamethasone due to their experience with lenalidomide‐induced ischemic cerebrovascular disease in a patient with POEMS syndrome [ 60 ].

Zhao and colleagues have performed a retrospective review of nearly 350 patients with POEMS syndrome receiving melphalan and dexamethasone, ASCT, or lenalidomide and dexamethasone and concluded that the highest response rates were seen with ASCT, followed by lenalidomide and dexamethasone, and finally by melphalan and dexamethasone (Table 4 ). Patients receiving lenalidomide and dexamethasone had the shortest PFS and a trend for a shorter OS. It should also be noted that those patients undergoing ASCT had the lowest risk disease [ 189 ]. In a similar vein, Bianco et al. in a much smaller series ( n = 15) systematically compared changes seen among patients receiving ASCT or lenalidomide and dexamethasone and found neurologic changes, and 1 and 2 years were comparable for the two therapies [ 190 , 191 , 192 , 193 , 194 , 195 ]. Thalidomide in combination with dexamethasone has also been shown to produce responses in terms of VEGF, peripheral neuropathy, and extravascular volume overload, but hematologic responses have not been reported [ 196 , 197 , 198 , 199 ]. Enthusiasm for this therapy should be tempered by the risk of peripheral neuropathy induced by thalidomide. Misawa and colleagues have reported on a 25 patient 24‐week randomized double blind trial of thalidomide plus dexamethasone versus dexamethasone alone for patients ineligible for autologous stem cell transplantation [ 169 ]. VEGF levels dropped faster in patients treated with thalidomide, though there were no significant differences in other endpoints between the two groups at 24 weeks. During the 72‐week open label extension study, nerve conduction velocities increased as compared to baseline. Fifty‐four percent of the thalidomide patients had sinus bradycardia and two‐thirds had constipation. There is no mention of worsening neuropathy in the first 24 weeks, but 23% of patients had worsening of their sensory neuropathy in the 48‐week open extension portion.

Like lenalidomide and thalidomide, bortezomib also has anti‐VEGF and anti‐TNF effects. Bortezomib with dexamethasone was used in 69 patients as first line therapy [ 200 ]. The bortezomib was 1.3 mg/m 2 subcutaneously weekly with dexamethasone 40 mg weekly, both 4 weeks out of 5 weeks for a total of 9 cycles. Complete hematologic and complete VEGF responses were documented in 46% and 44% of patients, respectively. An additional 27% of patients had a VEGF VGPR. Median time to complete hematologic response was 9 months and to complete VEGF response was 15 months. The overall clinical response rate was 84%. Only two patients were deemed to have bortezomib‐associated worsening of their PN, which improved after discontinuation of bortezomib. With a median follow‐up of 22 months, 22 patients had received a second line treatment, and the 2‐year OS was 96%.

Another series from Shanghai Changzheng Hospital included 20 patients with newly diagnosed POEMS syndrome who were treated with 3–6 cycles of cyclophosphamide (200 mg intravenously days 1–4), reduced dose bortezomib (1.0 mg/m 2 intravenously days 1, 4, 8, and 11), and dexamethasone (20 mg intravenously days 1–4 and 8–11) [ 201 ]. The overall hematologic response rate was 76% with seven patients achieving complete hematologic response; 88% had VEGF response, with a complete VEGF response in 76%. Ninety‐five percent of patients had a reduction of the ONLS (overall neuropathy limitation scale) by 1 or more. No neurologic worsening was observed. Median follow‐up was only 11 months, though one patient switched to lenalidomide therapy after reaching only stable disease after 5 cycles of bortezomib‐based therapy. This same group reported on 53 patients who had bortezomib as part of their initial therapy, median of 4 (range 2–12) (Table 5 ). Regimens were heterogeneous in terms of dosing (1.0 mg/m 2 weekly vs. 1.3 mg/m 2 ), route of administration (intravenous vs. subcutaneous), how many drugs were included in the regimen, whether or not consolidative stem cell transplant (23%) or maintenance (28%) was employed. Included regimens were dual therapy: bortezomib and dexamethasone (11%); triplet therapy with cyclophosphamide as the third drug (83%); and a potpourri of other added drugs (cisplatin, adriamycin, thalidomide). Although there was no mention of worsening neuropathy, this was a retrospective study and it is impossible to parse out the isolated salutary effect of the bortezomib from this report.

The first case reports of daratumumab combinations in patients with POEMS syndrome were promising [ 204 , 205 , 206 ]: Three instances of daratumumab with lenalidomide and dexamethasone and another of daratumumab with lenalidomide, bortezomib, and dexamethasone. In all three instances, hematologic, VEGF, and neurologic improvements were seen. A subsequent report from the Mayo Clinic included 16 patients with relapsed or refractory POEMS syndrome who received regimens containing any of the following agents: daratumumab, carfilzomib, or pomalidomide [ 203 ]. Of the 14 daratumumab‐based regimens administered, 10 were part of an IMID‐based regimen; the other combinations included daratumumab plus dexamethasone alone, cyclophosphamide or a proteasome inhibitor. Among the daratumumab treated patients, hematologic complete response was achieved in 30% and hematologic VGPR in 26%. More than 40% of patients achieved a VEGF VGPR. TTNT had not been reached, and median duration of therapy exceeded 2.5 years. Of the six patients treated with carfilzomib‐based regimens, three had a hematologic VGPR or better, one a VEGF VGPR. TTNT was 49 months [ 203 ]. No unexpected toxicities were observed. There was also a retrospective report including seven patients treated with single agent daratumumab that yielded hematologic VGPR or better in 28% of patients and VEGF CR in 28% of treated patients with a median TTNT that had not been reached at 28 months [ 207 ]. A study from Japan described 13 regimens in 8 patients using combinations including daratumumab, bortezomib, dexamethasone (DBd, n = 5), daratumumab, lenalidomide, dexamethasone (DLd, n = 3), daratumumab, pomalidomide, dexamethasone (DPd, n = 1), elotuzumab, pomalidomide, dexamethasone (EPd, n = 4) [ 208 ]. Overall, there was only one hematologic complete response, four VEGF complete responses, and two neurologic responses. The only hematologic complete response occurred in an EPd treated patient, and 2 of the 4 VEGF CRs occurred in EPd treated patients (one each in a DBd and DLd). Time to next treatment was 11 months for the entire group.

Anti‐BCMA (B‐Cell Maturation Antigen) Therapies

Xu et al. evaluated rates and intensity levels of BCMA expression in five patients with POEMS syndrome [ 209 ]. Rates of BCMA positivity and BCMA mean fluorescence intensity among patients with AL, POEMS, MGRS, and MGUS. There are two case reports of patients being treated with BCMA CAR‐T, who remain in remission at 10 months [ 210 ] and 6 month follow up [ 211 ].

There is one report of teclistamab (bispecific CD3‐BCMA T‐cell engager) being used in a patient with POEMS syndrome [ 212 ]. The patient was treated with standard weekly dosing for 6 cycles, followed by every other week for cycles 7–12, followed by monthly injections until cycle 20, after which teclistamab was discontinued. At 24 months post initiation, the patient continued to have normal lambda FLC and VEGF.

Other Systemic Therapies

Although an anti‐VEGF strategy is appealing, the results with bevacizumab have been mixed [ 22 , 23 , 24 , 25 , 26 , 27 ]. Five patients who had also received either radiation or alkylator during and/or predating the bevacizumab had benefit [ 24 , 25 , 26 , 213 ], including three who had improvement, but were then consolidated with high‐dose chemotherapy with autologous stem cell transplant [ 25 , 213 ]. Three patients receiving bevacizumab died [ 21 , 22 , 27 ].

Both our experience and the literature would support that single agent intravenous gamma globulin (IVIG) or plasmapheresis is not helpful. One more recent report, however, described reduction in serum VEGF and clinical improvement with single agent IVIG. The response was not durable, which prompted another course of IVIG with radiation to a solitary plasmacytoma [ 214 ]. Other treatments like interferon‐alpha, tamoxifen, trans‐retinoic acid, ticlopidine, argatroban, and strontium‐89 have been reported as having activity mostly as single case reports [ 10 ].

Managing Symptoms of Disease

Attention to supportive care is imperative. Orthotics, physical therapy, and continuous positive airway pressure (CPAP) all play an important role in patients' recovery. Ankle foot orthotics can increase mobility and reduce falls. Physical therapy reduces the risk for permanent contractures and leads to improved function both in the long and short term. For those with severe neuromuscular weakness, CPAP and/or bilevel positive airway pressure provide better oxygenation and potentially reduce the risk of complications associated with hypoventilation like pulmonary infection and pulmonary hypertension. For those with neuropathic pain, medications like gabapentin, pregabalin, and tricyclics may be of value. Patients should also be screened for depression [ 215 ].

Monitoring Response

Patients must be followed carefully on a quarterly basis tracking the status of deficits comparing these to baseline (Table 2 ) [ 183 ]. VEGF responses may occur as soon as 3 months [ 181 ], but they can be delayed. VEGF is an imperfect marker since discordance between disease activity and response has been reported [ 20 , 156 ], so trends rather than absolute values should direct therapeutic decisions. Serum M‐protein responses by protein electrophoresis, immunofixation electrophoresis, or serum immunoglobulin free light chains also pose a challenge. The size of the M‐protein is typically small, making standard MM response criteria inapplicable in most cases. In addition, patients can derive very significant clinical benefit in the absence of an M‐protein response [ 156 , 178 , 216 ]. Finally, despite the fact that the immunoglobulin free light chains are elevated in 67%–90% of POEMS patients, the ratio is normal in all but 13%–18% [ 98 , 217 ], making the test of limited value for patients with POEMS syndrome.

Recommendations about how to approach organ response have been suggested for the purposes of clinical trials since there are more than 2‐dozen parameters that can be assessed in a given patient with POEMS syndrome given the multisystem nature of the disease [ 183 , 218 ]. Alternatively, response criteria for POEMS syndrome could be abridged as follows: (1) hematologic response using a modified amyloid response criteria; (2) VEGF response; (3) 18 FDG‐PET response; (4) and a simplified organ response, which is limited to those systems causing the most morbidity, like peripheral neuropathy assessment, pulmonary function testing, and extravascular overload (Table 6 ).

Cause of Death

As previously mentioned, the prognosis of patients with POEMS syndrome is excellent with 10 year overall survival approaching 80% [ 156 , 158 , 219 , 220 , 221 ]. Among 422 patients followed during the period from 2000 to 2022 at the Mayo Clinic, 89 died during this time frame; 49 had information relating to their death [ 221 ]. Of these 49 patients, 23% died of causes that could not be connected to their POEMS diagnosis, 22% died of second malignancy (half of which were MDS/AML), 10% died of complications of active treatment, and 45% died of POEMS syndrome. No patients died with overwhelming plasmacytosis or light chain cast nephropathy. The most common COD for the patients who died of “POEMS related causes” was what we termed a terminal capillary leak phenotype (CLP), which we defined as a course characterized by unrelenting ascites, effusions, and/or anasarca that ultimately results in hypotension, renal failure and cardiopulmonary failure. Of the 19 patients who died of terminal CLP, there were 6 who presented in this fashion, never had their disease adequately controlled, and died at a median of 4 months after diagnosis. For the remainder, terminal CLP occurred more than 5 years after diagnosis. All four patients who had IL‐6 measured during this terminal period had elevated levels.

Concluding Remarks

In summary, POEMS syndrome is an important syndrome associated with a clonal plasma cell neoplasm. Making the diagnosis can be a challenge, but a good history and physical examination followed by appropriate testing—most notably radiographic assessment of bones, measurement of VEGF, and careful analysis of a bone marrow biopsy—can differentiate this syndrome from other conditions like CIDP, immunoglobulin light chain amyloidosis, and MGUS neuropathy. Once the diagnosis is made, attention to supportive care and treatments that are active in MM are essential; however, application of neurotoxic MM therapies should be used in the context of a clinical trial or at the time of relapsed or resistant disease.

Funding

A.D. and this work are supported in part by the Hematologic Malignancies Fund, the Predolin Foundation, and the Andrew & Lillian A. Posey Foundation. This work was supported by the National Institutes of Health (CA186781).

Ethics Statement

The author has nothing to report.

Consent

The author has nothing to report.

Conflicts of Interest

Research dollars from Celgene, Takeda, Pfizer, ABBVIE and Alnylam; Astra‐Zeneca; Advisory Board for HaemaLogiX.

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