Recent Advances in the Treatment and Supportive Care of POEMS Syndrome.

1. Introduction

Osteosclerotic myeloma (OM) [ 1 ], Takatsuki syndrome [ 2 ], or Crow-Fukase syndrome [ 3 ] are rare entity characterized by a single or multiple bony lesions, often associated with a rare paraneoplastic syndrome: POEMS. An estimated, one third of patients with OM have neuropathy and half the patients with myeloma and neuropathy have osteosclerotic lesions [ 4 ]. Clinicians consider, as of recently, that OM and POEMS are along one spectrum of plasma cells dyscrasias [ 5 ]. One of the first associations proposed between OM and POEMS was by Crows et al. back in the 1950s when he published an article describing two case reports presenting with osteosclerotic plasmacytoma associated with neuritis, odd skin changes, mild lymphadenopathy, and ankle weakness [ 3 ].

The name of this syndrome is a mnemonic of the clinical features of patients: P for polyneuropathy, O for Organomegaly, E for Endocrinopathy, M for Monoclonal (M)-proteins, and S for Skin changes. As the mnemonic suggests, it is a multisystem disorder [ 1 , 6 , 7 ]. When diagnosed and treated early, the median survival of patients is 13.7 years [ 4 ]. Yet, if the disease is left untreated, it can progress to affect the respiratory and nervous systems at a higher degree and can be fatal.

2. Pathogenesis of the Disease

The pathogenesis of POEMS syndrome is complex and not fully understood. It has been suggested that it is caused by two entities: the expansion of clonal and polyclonal plasma cells and the surge of pro-inflammatory and angiogenic cytokines. The messenger ribonucleic acid (mRNA) levels of vascular endothelial growth factor (VEGF) are higher in CD138 positive plasma cells derived from the bone marrow relative to the CD138 negative plasma cells. Interestingly, when Wang et al. immunophenotyped the cells considered to be the major source of serum VEGF, these cells were polyclonal in nature confirming that the polyclonal plasma cells in POEMS play an important role for production of these cytokines leading to the constellation of signs and symptoms [ 8 ]. However, when Isshiki et al. utilized single-cell RNA-Seq of bone marrow plasma cells from patients with POEMS syndrome, VEGF mRNA was not upregulated in POEMS clones, directly indicating that serum VEGF is not produced by POEMS clones [ 8 ]. In comparison, monoclonal plasma cells in POEMS, exhibited an increase in the production intracellular interleukin-6 (IL-6) expression, a pro-inflammatory cytokine and inducer of VEGF expression and secretion from the cells [ 7 , 9 ]. Hence, pathogenesis is an interplay between monoclonal and polyclonal plasma cells in POEMS.

Recently, treatments that target the plasma cells producing the M-protein have shown excellent clinical responses. This suggests that the M-protein might be one of the driving factors of the disease. The plasma cell clone producing the M protein is usually λ light chain restricted, but atypically can also present with Kappa light chain restriction [ 10 , 11 ]. Clonal immunoglobulin λ light variable chain (IGLV) was strictly derived from IVLG-1–40 and IVLG-1–44 genes. Additionally, patients with an M-protein restricted to IVLG-1–40 experienced severe clinical symptoms [ 12 ]. In some cases, IGLV gene rearrangement clone was not significantly increased suggesting a small number of monoclonal plasma cells responsible for producing this large serum concentration of monoclonal proteins. On the other hand, the size of the dominant clone is decreased and increased with disease remission and relapse, respectively [ 13 ].

The serum VEGF level is elevated in most patients with POEMS. This multifunctional cytokine is produced physiologically by cells derived from the bone marrow such as plasma cells, osteoblasts, and platelets [ 14 , 15 ]. Its role is pivotal in the regulation of angiogenesis, microvascular permeability, and migration of hematopoietic stem cells. Its main target is the VEGFR1 receptors on endothelial cells. The exaggeration of these physiologic effects might be related to the full clinical presentation of POEMS including volume overload, papilledema, and hemangiomata. Its high levels are suspected to be the cause of an increase in the intraneural pressure leading to edema and vascular permeability, which may result in nerve damage [ 16 ], instead of direct neuronal invasion [ 17 ]. However, patients treated with bevacizumab, an anti-VEGF monoclonal antibody, did not show clinical improvement. VEGF is induced upstream by the hypoxia transcription factor-1 (HTP-1) [ 16 ]. Specifically, the nerve VEGF was highly expressed in blood vessels and non-myelin forming Schwann cells in patients with POEMS syndrome.

The probability to have POEMS gets higher with greater serum VEFG levels [ 18 , 19 ]. Serum VEFG decreases rapidly post-treatment and usually takes six months to stabilize back to baseline. Add to that, patients with normalized serum VEGF were relapse free and had a better overall clinical improvement. The rate at which serum VEGF was reduced in the first six months of therapy correlated with an increase in grip strength, and a compound muscle action amplitude at 12 months post treatment [ 20 ]. Note that other cytokines such as tumor necrosis factor alpha (TNF-α), Il-6, and Il-12 are also involved in disease progression [ 16 , 17 , 21 , 22 ] but the levels of these cytokines are not routinely measured and followed up in clinical practice.

3. Clinical Presentation and Diagnosis

The diagnosis of POEMS is mostly clinical, complemented by laboratory studies and radiographic imaging. Any sign or symptom should elicit an in-depth investigation for POEMS particularly in a patient with monoclonal gammopathy and peripheral neuropathy. To diagnose POEMS mandatory criteria are required, along with one major and one minor criteria [ 23 ]. The cardinal criteria are polyradiculoneuropathy [ 24 ] and plasma cell proliferative disorder causing monoclonal gammopathy ( Table 1 ).

On laboratory findings, Wang et al., identified a new marker for POEMS syndrome: N-terminal of type I collagen with a cut-off of 70 ng/mL [ 31 ] but it has not been used in clinical practice yet. Patients with POEMS are usually at an increased risk of venous or arterial thrombosis (likely due to the thrombogenic potential of elevated VEGF and due to an increase in fibrinopeptide A and thrombin-antithrombin complexes), with nearly 20–30% presenting with one of these complications [ 32 , 33 ]. The serum VEGF is markedly elevated and correlates with the activity of the disease [ 7 , 14 , 19 ]. Other cytokines such as IL-1β, TNF-α, and IL-6 are often increased as well, but the high level of serum VEGF is highly suggestive of POEMS. Measuring VEGF levels is an essential component of POEMS initial work up and to follow up on response to therapy and disease activity.

Classic bone marrow findings have been described and are shown in Figure 1 .

Oftentimes the bone marrow plasma cell clone is of small size (~5% in 50% of patients), typically lambda monotypic with concomitant polyclonal plasmacytosis and the clonal plasma cell proliferation can be detected by bone marrow biopsy in ~66% of patients. Reactive non-clonal lymphoid aggregates are frequently present, and clustering and hyperplasia of megakaryocytes are observed in POEMS patients with peripheral thrombocytosis. In one study, megakaryocytes clustering with high expression of VEGF as well as lymphoid aggregates was present in 94% of the cases, which was not the case in patients with MGUS, MM, or amyloidosis [ 34 ]. Typically, in POEMS, sensory neuropathy occurs first followed by motor neuropathy over time causing distal weakness and even atrophy (foot drop). Dysautonomia, which is a feature of systemic AL amyloidosis, is uncommon with POEMS. Nerve conduction studies show slowing of nerve conduction which suggests demyelination in the nerve trunk rather than the terminals. Though a routine nerve biopsy is not needed in clinical practice but on nerve biopsy, demyelination is often axonal, favoring lower limbs which will help in the differentiation of POEMS from CIDP [ 35 , 36 , 37 , 38 , 39 ]. Diagnostic work up should also include computed tomography (CT) or magnetic resonance imaging (MRI) to detect bone lesions as the whole-body bone survey radiography may miss the smaller focal osteoclerotic bone lesions. Positron emission tomography (PET) with CT scan may demonstrate fluorodeoxyglucose (FDG)-avid bone lesions which can be targeted for core needle biopsy for diagnostic purposes. Serum and urine electrophoresis with immunofixation and serum free light chain levels need to be measured. Screening for endocrinopathies should be achieved by measuring appropriate hormone levels, and funduscopic examination should be completed in all patients regardless of the presence or absence of ocular symptoms.

The differential diagnoses to keep in mind are chronic inflammatory polyradiculoneuropathy (CIPD), anti-myelin-associated-glycoprotein (MAG) neuropathy, monoclonal gammopathy of undetermined significance (MGUS), and immunoglobulin light chain (AL) amyloid neuropathy. Any differential diagnosis where the patient does not respond to the usual treatment (e.g., for CIDP) should elicit further investigation for POEMS syndrome. Due to the debilitating nature of POEMS syndrome, early detection and intervention is critical to mitigate the risk of permanent neurologic disability.

Last, it is also important to note that He et al. described a group of patients with clinical manifestations highly resembling POEMS syndrome except for no evidence of monoclonal gammopathy [ 40 ]. In these patients, elevated VEGF levels may help in teasing out such variants of POEMS syndrome [ 40 ]. Thus, a variant form of POEMS syndrome arises. This was suggested according to characteristic constellations, elevated VEGF levels, and responsiveness to therapies directly targeting plasma cells [ 40 ].

4. Treatment

Due to the rarity of this disease, there is a lack of clear evidence-based guidelines for treatment. Clinicians use therapeutic strategies mostly based on retrospective case series of POEMS syndrome with proven efficacy in MM and systemic AL amyloidosis ( Figure 2 ).

Back in the 1990s, the treatment of POEMS syndrome shifted towards suppressing plasma cell proliferation and secretion of pro-inflammatory and pro-angiogenic cytokines.

The treatment of POEMS syndrome can be divided into two major categories: targeting the clone by specific anti-plasma cell directed therapy and targeting the symptoms with symptomatic and supportive care. To have a better overall outcome, physicians aim to incorporate both strategies in their treatment plan. During treatment, hematologic response is monitored by measuring the M-protein concentration and the serum VEGF levels. Clinical response is most of the times dissociated from the hematological response [ 41 , 42 ]. Serum immunoglobulin free light chains are elevated, with the exception of 18% of the patients, making this test also of limited value in the follow up [ 43 ]. The most efficacious strategy is taking the baseline parameters assessing them every visit or every other visit [ 44 ].

5. Targeting the Clone

The role of radiotherapy

This strategy relies on the presence or absence of bone marrow involvement upon bone marrow aspiration and biopsy and the number of bone lesions seen in the imaging studies [ 45 , 46 ]. If diagnostic imaging tests (CT scan, MRI, or PET scan) reveal 1–3 bone lesions with no bone marrow involvement then radiation therapy is the first line of therapy with excellent long-term outcomes [ 47 , 48 , 49 ]. The main goal of radiation therapy is to ablate the boney lesions without significant toxicity. A suggested dose of radiotherapy between 30 and 54 Gy (median dose ~45Gy) can achieve a high cure rate of approximately 82% [ 50 ]. If the patient is rapidly deteriorating, simultaneous use of corticosteroids, e.g., dexamethasone (40 mg/day 1–4 times a week for 2 weeks) or prednisone (1 mg/kg daily for two weeks) is a reasonable adjuvant therapy to radiotherapy. Corticosteroids can be tapered gradually over the next months with follow up and vigilance for adrenal insufficiency [ 45 , 46 ]. In most patients, clinical improvement is seen in approximately 3 months post-treatment but may take up to 36 months post-therapy with neuropathic symptoms taking the longest for improvement. Patients with more than three skeletal lesions are best treated with systemic anti-plasma cell therapy. Similarly, approximately 66% of patients with POEMS syndrome have bone marrow involvement at diagnosis and are treated with systemic anti-plasma cell therapy ( Figure 2 ). In this scenario, radiation therapy alone is not effective, and it should be combined with systemic anti-plasma cell chemotherapy or autologous stem cell transplant (ASCT) after high dose melphalan chemotherapy.

Autologous Stem Cell Transplant (ASCT)

In cases of bone marrow involvement or more than three bone lesions, melphalan based conditioning followed by ASCT is considered the first line treatment by many; given the patient is able to tolerate the treatment based on functional status and adequate organs function [ 42 ]. Several retrospective studies and case series support the role of upfront ASCT in eligible patients [ 51 ]. It has been proven effective in improving neuropathy decrease in morbidity, disability, and in improving quality of life [ 52 ]. For patients undergoing ASCT, high dose melphalan (140–200 mg/m 2 ) is used as conditioning regimen.

Induction therapy may reduce the incidence of complication [ 53 ]. Normalization of serum VEGF level at ASCT may prolong OS and PFS [ 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 ].

In contrast with the ASCT in MM and AL amyloidosis, the patients with POEMS syndrome are at a high risk of engraftment syndrome (ES), in approximately 50% of the cases, and respond well to corticosteroid steroid therapy. ES is characterized by a fever (most common symptom), rash, diarrhea, weight gain and respiratory symptoms which can be severe enough to cause respiratory failure needing mechanical ventilation. This can occur between day 7 and 15 post stem cell infusion with a higher mortality rate compared to patients with MM undergoing the same treatment (7.4% vs. 2%, respectively) [ 42 ]. A positive correlation was found between splenomegaly/lymphadenopathy and risk of ES. It is worth mentioning that POEMS patients typically have a delayed neutrophil engrafting (median of 16 days) and may require platelets and erythrocytes transfusions [ 41 ]. The use of granulocyte colony stimulating factor (G-CSF) solely had major adverse events and was associated with an increase in vascular permeability and fluid overload [ 17 ]. Pre-ASCT treatment reduces the incidence of ES among patients who already had decreased level of VEGF [ 68 ].

Overall, ASCT is a safe and effective choice in many patients and can provide durable response in about 90% of eligible patients. Different studies and retrospective analysis confirmed high rates of overall survival (OS) and progression free survival (PFS), 98% at one year, following ASCT [ 51 , 52 , 69 , 70 ], with a significantly lower rate of relapse [ 69 , 70 ] in a median of 5 months post treatment [ 68 , 71 ]. Relapses of patients after ASCT is positively correlated with immunoglobulin G-λ monoclonal gammopathy presence of FDG-avid lesions on baseline PET scan and inability to achieve hematologic response with ASCT [ 72 ]. Persistent or relapse disease post-ASCT can be treated with anti-plasma cell therapy such as lenalidomide.

Immunomodulatory Drugs (IMiDs): Lenalidomide and thalidomide therapy

Given the anti-angiogenic effect of IMiD, such as thalidomide or lenalidomide, and their effectiveness in the treatment of MM, they were an option to consider in POEMS syndrome. Thalidomide and bortezomib should be used with caution due to their potential to induced neuropathy or worsen pre-existing neuropathy [ 73 ]. For that reason, lenalidomide is the IMiD of choice in POEMS syndrome where neuropathy is the feature of the disease itself [ 30 , 55 , 74 , 75 ]. Lenalidomide has been shown to be more potent than thalidomide in its direct apoptotic effect against myeloma cells, as well as in inhibition of inflammatory cytokine production and stimulation of T cells and NK cells [ 76 ]. It does not cause sedation, bradycardia, or constipation, and the incidence of neuropathy is lower [ 77 ]. Both thalidomide and lenalidomide dare associated with increased incidence of deep-vein thrombosis (DVT) and thromboembolism, especially when combined with anthracycline and dexamethasone [ 78 ]. In a study by Gay et al., patients receiving lenalidomide/dexamethasone had longer time to progression (median, 27.4 vs. 17.2 months; p = 0.019), PFS (median, 26.7 vs. 17.1 months; p = 0.036) and OS (median not reached vs. 57.2 months; p = 0.018) than patients receiving lenalidomide/dexamethasone [ 78 ]. Lenalidomide/dexamethasone appears well-tolerated and more effective than thalidomide/dexamethasone [ 78 ]. Randomized trials are needed to confirm these results.

Patients treated with lenalidomide experienced systemic improvement, including a decrease in the severity of polyneuropathy, fluid overload and organomegaly. A decrease in the monoclonal protein and VEGF levels was observed as well [ 79 , 80 , 81 ]. The neuropathy relief was the most important advance in terms of the quality of life of the patients [ 41 , 45 , 82 , 83 ]. Patients who presented at baseline with hypothyroidism had an inferior OS than euthyroid patients even though the combination of lenalidomide and corticosteroids improved their overall thyroid function [ 81 , 84 , 85 , 86 , 87 , 88 ].

The recommended treatment is lenalidomide (15–25 mg orally) taken days 1–21 every 28 days with weekly dexamethasone 20–40 mg. These patients had a dramatic improvement up to one-year post-treatment [ 83 ]. An open-label prospective study using lenalidomide with dexamethasone regimen (LDex) in patients who were also ineligible to undergo ASCT was conducted. More than two-thirds (72%) responded to treatment and had clinical and neurological improvement with low toxicity rates. At 39 months of follow up post therapy, all patients were alive and PFS was 59% at 3 years of follow up [ 86 ]. Approximately 30% of POEMS patients have arterial and venous thrombosis, a number significantly higher than originally reported [ 89 ]. A patient at risk of thrombosis, bleeding or of falling must be assessed when taking the decision to initiate LDex. All IMiDs including lenalidomide have thrombogenic potential. Unless there is a contraindication thromboprophylaxis is recommended at least with aspirin therapy or even full anticoagulation depending on the thrombotic risks associated with a particular patient. A randomized, double-blinded, placebo-controlled, phase 2/3 trial in Japan of patients not eligible for ASCT was performed using either oral thalidomide or placebo. Serum VEGF was significantly reduced by thalidomide therapy with a high risk of cardiotoxicity and bradycardia.

A Phase II multicenter trial ( NCT02921893 ) in Mayo clinic, Rochester, United states is recruiting patients to test different combination of treatments randomizing patients into two groups. One arm will receive ixazomib citrate (a drug that is approved for MM and works by proteasome inhibition), with lenalidomide, dexamethasone, and ASCT, and another arm will receive ixazomib citrate, lenalidomide, and dexamethasone only. Patients will be observed for toxicity and adverse events as well as the difference between the two arms in the efficacy of normalizing serum VEGF and hematologic response.

Melphalan and corticosteroid

Melphalan combined with dexamethasone (MDex) is also used in different plasma cell disorders [ 90 ]. The first prospective study tackling the treatment of patients newly diagnosed with POEMS syndrome showed an efficacy and low toxicity with MDex combination, 10 mg/m 2 of melphalan added to dexamethasone 40 mg/day on days 1 to 4 of every 28-day cycle, then ASCT vs. another arm of patients who received only MDex. An 80.6% of patients had a hematologic response and 77.4% had a neurologic response at 3 months post initiation of therapy with a median to maximal response of 12 months. Patients treated with MDex had a substantial improvement in the serum VEGF, relief from organomegaly, extravascular fluid overload, and pulmonary hypertension, with a median PFS of 21 months. Interestingly, despite the hematologic response, both arms had a neurologic response to MDex therapy. In comparison, another study performed in Japan by Suichi et al. in 2019, showed a 100% improvement rate of neurological signs after 1 to 3 months post ASCT [ 91 ]. MDex was 100% effective in neurological signs with a relatively short initial response of 3 months compared to the ASCT with less toxicity and side effects.

Younger patients need a longer follow up period to assess long term complications of oral melphalan therapy because it is associated with myelodysplasia (MDS) as well as therapy related acute myeloid leukemia (AML) [ 42 ]. Furthermore, damage of stem cells is a possibility so it might not be always suitable to treat patients with it prior to ASCT [ 92 , 93 ]. MDex is not used in routine clinical practice in the USA due to the availability and effectiveness of other therapies such as lenalidomide based or bortezomib-based therapies.

Bortezomib and dexamethasone

Bortezomib, a proteasome inhibitor, inhibits the secretion of VEGF and IL-6, stops angiogenesis, and induces B cell apoptosis in a dose-dependent manner [ 93 ]. The combination of cyclophosphamide, bortezomib, and dexamethasone (CyborD or VCD) had a high efficacy in treatment but due to presence of baseline neuropathy in most patients with POEMS syndrome, bortezomib based therapy may not be the first preferred therapy [ 94 , 95 ]. Due to this reason, we prefer lenalidomide plus dexamethasone over bortezomib based therapy in POEMS syndrome. The major adverse events with bortezomib based therapy in POEMS syndrome was painful neuropathy which can be reduced (but not eliminated) with the subcutaneous administration of the medication. Yet, the risk is there, and it is especially increased to 50% after a cumulative dose ≥45 mg/m 2 [ 96 ]. Bortezomib can help in decreasing pleural effusions, ascites, and pulmonary hypertension in POEMS. Case reports highlight the use of BorDex therapy with radiation or ASCT that resulted in a dramatic improvement in serum VEGF as well as peripheral neuropathy without significant toxicity [ 97 ]. In patients relapsed or resistant to treatment including ASCT, lenalidomide or bortezomib regimens as a salvage treatment showed significant improvement [ 98 ].

In one report, bortezomib-dexamethasone improved peripheral neuropathy and resulted in a complete response. The regimen was well tolerated in many patients with only a few reported adverse effects, and it was adequate for collection of hematopoietic stem cells for ASCT [ 99 ] when used for induction therapy pre-ASCT.

Monoclonal Antibody Therapy Anti-CD38 monoclonal antibodies (Daratumumab and Isatuximab) Daratumumab combined with lenalidomide in relapsed MM was proven effective [ 100 , 101 ] and the responses to daratumumab in light chain amyloidosis have been well documented [ 102 ]. In patients with POEMS syndrome, the response to daratumumab and lenalidomide was remarkable as well based on case reports. This suggests that this combination is a promising less toxic alternative to ASCT that warrants further exploration in both newly diagnosed and relapsed/refractory patients [ 103 ]. Importantly, this regimen provides rapid, deep and durable responses and restores their functionality [ 104 ]. This regimen was suggested in multidrug resistant patients but needs further evaluation using prospective studies [ 103 ]. A phase II clinical trial ( NCT04396496 ) at the University of Arkansas in the United States is currently investigating the effects of daratumumab combined with lenalidomide (up to 12 four-week cycles) with the primary objective being the outcome of neuropathy and performance status of patients. Another anti-CD38 immunotherapy isatuximab which is approved for relapsed/refractory MM may also be effective in the treatment of POEMS syndrome but its use in POEMS syndrome has not yet been reported. Anti-VEGF monoclonal antibody (Bevacizumab) In theory the use of bevacizumab was appealing in many cases [ 19 , 74 , 104 , 105 , 106 , 107 , 108 ]. The benefit was noticed in patients who received bevacizumab during alkylator therapy or preceding therapy [ 105 , 106 ]. The treatment was combined with ASCT or high dose chemotherapy [ 70 , 74 ] or with radiation therapy and cyclophosphamide. Clinical response and anti-VEGF response within 6 months of therapy were observed [ 86 ]. Yet, other reports where the patients were treated with bevacizumab died shortly after treatment [ 68 , 107 , 108 ]. When bevacizumab was used solely, serum VEGF decreased rapidly. However, the number of patients included in different studies was small, and a significant proportion of patients did not respond or died during treatment [ 108 , 109 , 110 ]. Due to lack of efficacy and potential for increasing mortality in some reports, bevacizumab should not be used in clinical practice for treatment of POEMS syndrome. Chimeric antigen receptor T (CAR-T) therapy Because the treatments for MM were expected to be useful in many patients with POEMS, chimeric antigen receptor T (CAR-T) cells targeting B cell maturation antigen (BCMA) have been used in the treatment of relapsed and refractory multiple myeloma (RRMM) with excellent response. Recently, a report of treatment by anti-BCMA CAR-T cells in POEMS demonstrated that the treatment may be a feasible therapeutic option for patients with POEMS syndrome and RRMM who do not respond well to traditional therapies [ 111 ]. We caution against routine referral of POEMS syndrome for CAR-T therapy because the experience so far is very limited. Comparison of all regimens A retrospective analysis of 347 patients compared ASCT to MDex and LDex groups. ASCT was well tolerated and had the highest response and PFS rates out of all three regimens [ 70 ]. One explanation is that ASCT eradicates the underlying plasma cell clones. Yet, patients undergoing ASCT were younger with better organ function and therefore lower risk patients compared to MDex and LDex groups who were typically higher risks not eligible for ASCT. No significant difference in OS was observed between all three treatments. MDex therapy in low-risk patients achieved a response similar to that of ASCT, but that was not the case in patients categorized as medium or high-risk. LDex was highly effective in patients newly diagnosed with a similar response rate and OS as those treated with ASCT. PFS was inferior in high-risk patients even after ASCT therapy. Therefore, utilizing LDex for newly diagnosed patients is a consideration especially those who do not want ASCT or are not candidate for it [ 112 ].

6. Targeting the Symptoms of the Disease

Peripheral neuropathy

Neuropathy of POEMS as previously described is peripheral, symmetrical, ascending in nature. It involves the sensorimotor neurons and demyelinating in nature sometimes leading to radiculopathy. Pain and hyperesthesia occur to start with and may be the dominant parts of the neuropathy [ 113 ]. Motor neuropathy usually occurs later than sensory neuropathy and can affect the distal extremities first (e.g., foot drop). The best way to target peripheral neuropathy is by targeting the clone by anti-plasma cell therapy. Neuropathy is slow to recover and can take months to a few years after successful eradication of the plasma cell clone. Physical and occupational therapy might have a role in improving the symptoms with stretching, strengthening and balance exercises. Ankle braces, walkers, and wheelchairs should be used as needed in patients. To alleviate the pain of neuropathy, different drugs can be used: gabapentin, pregabalin, amitriptyline, duloxetine, topical lidocaine patches, topical ketamine, lidocaine, etc. [ 44 , 114 , 115 ]. Neurorehabilitation is an essential part of the treatment plan, and it is essential for sensory as well as motor impairment of the patient. Orthopedic shoes are needed to prevent foot drop. Ankle-foot orthotics (AFO) and other supporting devices are essential in patients with debilitating neuropathy to improve the quality of life of patients. The mainstay of treatment is anti-plasma cell therapy such as IMiD or ASCT which will relieve polyneuropathy in most if not all of patients over times [ 116 ].

Targeting extravascular fluid overload

The majority of patients will present with signs of fluid overload and anasarca [ 117 ], mainly attributed to the activity of serum VEGF and its contribution to capillary leak. Other signs are peripheral edema, ascites, pleural and pericardial effusions [ 27 , 118 ]. In extreme cases third spacing is resistant to diuretics, and patients even may go into renal failure. The serial use of paracentesis and albumin-forced diuresis may in some cases provide benefit for patients [ 46 ]. Using anti-VEGF bevacizumab to alleviate third spacing is controversial and should not be used in treating volume overload. When targeting the clone using cyclophosphamide-dexamethasone or bevacizumab, third spacing was not alleviated [ 19 ]. In other cases, the combination of treatment using cyclophosphamide, bortezomib, and dexamethasone (CyborD or VCD) alleviated the symptoms dramatically where the patient was back to normal weight, independent of diuretics [ 83 , 119 ].

Renal disease

Creatinine values are normal with an approximate of 6% of patients having a value that exceeds 1.5 mg/dL [ 4 ] and fewer than 10% of patients have proteinuria of 0.5 g/24 h. Yet, cystatin C, a surrogate renal marker is high in 71% of the patients [ 95 ] It is worth noting that some ethnic differences come into play as a study from China addressed the same issue and found that approximately 37% of patients had a creatinine clearance of less than 60 mL/min, 9% less than 30 mL/min, and 15% with microscopic hematuria [ 42 ]. The most likely association with renal disease morbidity is the concurrence of Castleman syndrome. Renal disease is highly associated with uncontrollable ascites and anasarca. Sometimes, a significant renal pathology warrants a biopsy of the kidneys with the most common findings being membranoproliferative features and evidence of endothelial injury [ 58 ]. Therapy to renal disease specifically is not established, but targeting the clone is the mainstay of treatment with an overall alleviation of signs and symptoms. Renal replacement therapy is seldom necessary.

Abnormal pulmonary and heart functions

Pulmonary function tests are abnormal in most of cases, yet respiratory complaints are limited [ 62 , 79 ]. The most common manifestation is pleural effusion; others may be pulmonary hypertension [ 17 ], restrictive lung disease, impaired neuromuscular respiratory function, and impaired diffusion capacity of carbon monoxide [ 28 , 29 , 120 ]. Screening for sleep apnea is indicated in patients who have a severe neuromuscular weakness so that treatment with continuous positive airways pressure or bilevel positive airway pressure can be initiated if necessary. According to He et al., patients with POEMS had subclinical impairment of systolic and diastolic functions of both the right and left heart [ 79 , 97 , 121 ] as well as left ventricular dysfunction [ 107 , 122 ]. Pulmonary function tests significantly improved in patients’ post-ASCT [ 33 ].

Organomegaly

Hepatosplenomegaly/lymphadenopathy does not have a mass effect and does not cause local discomfort or require specific therapy. Often, a biopsy of an organ or lymph node is taken during the diagnosis of the disease. The organomegaly and lymphadenopathy resolve with the specific treatment of underlying clonal plasma cell disorder. In up to 30% of the cases Castleman disease can coexist with POEMS syndrome [ 44 ]. The approach to organomegaly and general aspect of the disease directed therapy is not different, but addition of IL-6 levels should be measured at diagnosis and followed up during therapy. In this case, elevated IL-6 can be targeted using anti-IL-6 monoclonal antibodies (such as siltuximab), and rituximab can be used for lymphodepletion in addition to the usual anti-plasma cell therapy [ 122 ].

Endocrinopathy

Endocrinopathy is central in the disease process with hypogonadism being the most common abnormality followed by different endocrinopathies such as thyroid dysfunction, glucose metabolism abnormalities, adrenal insufficiency, and hyperprolactinemia. Above 80% of patients are affected by some form of endocrine dysfunction. For that reason, endocrinopathy is one of the minor criteria in the diagnosis of the disease. In patients with endocrine dysfunction, the appropriate hormone replacement is necessary until anti-plasma cell therapy kicks in. Usually, signs and symptoms decrease after proper chemotherapy regimens. After chemotherapy admission, tapering of thyroid, androgen, and corticosteroid replacement therapy should be considered particularly if hematologic and VEG-F response is achieved [ 27 , 123 , 124 , 125 ].

Papilledema

About 30% of the patients may present with papilledema, and it may be one of the signs of increased intracranial pressure. Juxtapupillary hemorrhage and optic disc edema may also be seen [ 126 ]. Despite patients being asymptomatic for most of the times, a formal ophthalmologic exam is recommended [ 127 ], and treatment is necessary when intraocular pressures are very high. The use of acetazolamide and corticosteroids has been effective [ 128 ]. In rare cases, where there is an increase in intracranial pressure, serial lumbar punctures may be beneficial. In one case report, ventriculoperitoneal shunt was suggested to be helpful in symptomatic management of hydrocephalous associated with POEMS [ 129 ]. Ocular symptoms can also be improved with local treatment using intravitreal bevacizumab and posterior sub-Tenon injection of triamcinolone, with the systemic treatment being the best option for long-term control of the symptoms [ 130 , 131 , 132 ]. Thalidomide was reported to reduce choroidal thickness and optic disc edema as well [ 133 ].

Sclerotic bone lesions

Osteosclerotic lesions are found in the majority of cases and are usually confused with bone islands, aneurysmal bone cysts, non-ossifying fibromas, and fibrous dysplasia [ 134 ]. The morphology of the lesions differs on CT scans yet FDG-PET)/CT [ 135 ] and bone scintigraphy [ 136 ] are useful tools in screening for POEMS. If baseline FDG-avidity is present in the PET scan, repeating the scan is useful in monitoring the response to therapy [ 137 ]. These lesions typically are non-painful (unless there is a lytic component) and do not usually threaten the integrity of the skeleton. Radiotherapy is one of the mainstays of treatments for <3 bone lesions in POEMS. Additionally, using radiotherapy to lesions that are still FDG-PET-avid after 12 months post-ASCT may be appropriate [ 46 ].

Targeting skin changes

As previously mentioned, a whole skin exam is necessary since POEMS is recognized as a potential cause of calciphylaxis [ 138 ]. Skin changes observed in POEMS do not require a specific treatment, and they all improve after systemic therapy. Calciphylaxis can be devastating, and it has been reported many times in the literature with very poor prognosis [ 139 , 140 , 141 ]. Bisphosphonates such as etidronate have been shown to be effective in case reports. Local wound care and acetic acid gauze changes and topical potassium permanganate have all been shown to be effective [ 46 ].

Thrombocytosis, polycythemia, and thrombosis

Thrombosis is prevalent in patients with POEMS reaching as high as 50% of the cases, and it can be the first manifestation of the disease [ 142 ]. The hyperplasia of megakaryocytes and even clustering of megakaryocytes can be seen in POEMS syndrome but the myeloproliferation in POEMS is JAK2 negative speaking against a clonal myeloproliferation [ 34 ]. Until recently, there were no data that indicated the necessity to lower the platelet count using hydroxyurea or JAK inhibitor ruxolitinib to lower the risk of cardiovascular events [ 143 , 144 ]. In our clinical practice, until the initiation of clone targeting therapy, we recommended to start hydroxyurea (HU) in order to decrease platelet counts, especially in cases where the patient present with thrombotic events [ 145 ]. Cerebral and retinal artery infarcts that have recently been reported may be the result of a vasculopathy induced by serum VEGF [ 146 ]. It should be noted that a stroke may precede neuropathy in young patients presenting with POEMS [ 147 ].

7. Response Assessment

The main goal of treatment is to inactivate the plasma cell responsible for this syndrome with the additional goals of preserving and potentially reversing organ dysfunction. The hematologic response and the VEGF response leads to organ responses and symptomatic improvement. For hematologic response assessment International Myeloma Working Group Criteria are used ( Table 2 ) [ 148 ].

One of the ways to monitor the hematologic response is to monitor the serum paraprotein at 3–6 months intervals during therapy. Usually, a response is observed 6 months post therapy initiation. Clinicians can assess the patient status using several methods: FDG-PET scan to assess bone disease and organomegaly, and serum VEGF levels ( Table 2 ). To note endocrinopathies should only be assessed periodically if the patient had an abnormal baseline function. VEGF values can be used to assess the response longitudinally in time ( Table 2 ). A clinical response assessment should always be taken separately, despite the hematologic response. It should always incorporate information regarding peripheral neuropathy, organomegaly and fluid status (ascites, edema, effusions). Some use the Overall Neuropathy Limitation Scale (ONLS) score to assess neurologic response [ 149 ]. Patients can be categorized according to the following: clinical improvement (IC), clinical progression (PC), mixed clinical response (MC), and clinical stability (SC).

8. Prognosis of the Disease

POEMS syndrome is a disease chronic in nature, in which the polyneuropathy can be progressive in nature and correlates with the activity of the plasma cell clone. In comparison to MM patients, POEMS patients have a survival three times longer. A retrospective study revealed that the median survival of the patients with POEMS was 165 months, regardless of how many features of POEMS syndrome are present at the time of diagnosis. However, the patients who, after treatment, still had nail clubbing had a median survival of only 31 months and the patients with extravascular fluid overload had a median survival of 79 months with the two variables being independent of each other. When it comes to the treatments, response to radiotherapy is seen as a good prognostic indicator of survival [ 42 ]. Furthermore, concerning mortality, the cause was known to be due to cardiorespiratory failure or recurrent infections and not due to the classic death related to bone marrow failure, hypercalcemia, or pathologic fractures as seen in patients with myeloma [ 4 ]. Some patients that died from renal failure had coexistent ascites as well as capillary leak-like syndrome.

A registry for adults with plasma cells dyscrasia ( NCT03717844 ) is set to be completed in 2029. This study will be also looking into patients with POEMS syndrome, and it will assess their baseline status along with their development over time. Patients’ functional statuses, co-morbid medical conditions, cognition, psychological statuses, social functioning, support, medication review, and nutritional statuses will all be reviewed. For any rare disease including POEMS syndrome, registry study can be a very valuable tool for research on the natural history of the disease and the effects of the treatments on the outcomes.

9. Conclusions

POEMs syndrome is a multisystem disease with a complex array of signs and symptoms, making the diagnosis, treatment, and follow up of patients challenging. The morbidity and mortality can be reduced with an early diagnosis and prompt treatment. Indications for poor outcomes are fingernail clubbing, respiratory symptoms, and extravascular fluid overload (ascites, pleural effusion, peripheral edema) and lack of complete hematologic response after ASCT. The best therapy has not yet been elucidated through clinical trials, which are challenging to conduct due to the rare nature of the disease. The mainstay of treatment is radiotherapy when there is no bone marrow involvement, and when the disease is limited to fewer than three osteoclerotic bone lesions. When bone marrow involvement is observed, and if the patient is eligible for ASCT, upfront ASCT should be considered. If ASCT is not desired by the patient or they are not eligible due to frailty or multiple organ dysfunction, lenalidomie and dexamethasone is a preferred and well-tolerated regimen. Effective alternatives include proteasome inhibitor boretzomib (though its use may be limited due to baseline neuropathy from the POEMS syndrome). Anti-CD38 immunotherapy daratumumab has shown promising results at the time of relapse in case reports and should be considered in resistant or relapse cases. Further data on its experience are needed for the treatment of POEMS syndrome. Targeting the features of the disease with symptomatic and supportive care as well as emotional support are part of the treatment plan. Follow up and measurement of response are not always easy, because there is no single measure reliable enough. VEGF response usually correlates with disease activity, but M-spike gauzes the hematologic response and provides information on the activity of the underlying plasma cell clone. PET scans can provide valuable information on the activity of the osteosclerotic bone lesions. Adjuvant radiation may be considered if FDG avidity is residual after treatment with ASCT or chemotherapy. If the treatment of the primary lesion was radiotherapy, and there is residual FDG avidity, with a normal VEGF and clinical improvement of the patient, systemic chemotherapy should not be added. The follow up of patients should be completed at least every 3 months for at least several years. It should constitute assessing serial disease symptoms such as peripheral neuropathy, volume status, eyes, skin, and organomegaly as well as of lab values such as M-protein, VEGF, and affected endocrine parameters. Annual pulmonary function tests and bone assessments should be performed as well. After the primary follow up period, all patients should be followed up at least once or twice a year indefinitely. Once the underlying pathogenesis of the disease is better understood, more targeted therapy will be possible.

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Author Contributions

Conceptualization, M.B.Z. and C.P.C.; validation, T.I.G. and S.T.B.; writing—original draft preparation, All authors; writing—review and editing, All authors; All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

1. Bardwick P. Zvaifler N.J. Gill G.N. Newman D. Greenway G.D. Resnick D.L. Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes: The POEMS syndrome. Report on two cases and a review of the literature Medicine 1980 59 311 322 10.1097/00005792-198007000-00006 6248720

2. Sanada I. Takatsuki K. Plasma cell dyscrasia with polyneuropathy and endocrine disorder: Clinical and laboratory features of 109 reported cases Jpn. J. Clin. Oncol. 1983 13 543 556 6315993

3. Crow R.S. Peripheral neuritis in myelomatosis Br. Med. J. 1956 2 802 10.1136/bmj.2.4996.802 13364332 PMC2035359

4. Dispenzieri A. Kyle R.A. Lacy M.Q. Rajkumar S.V. Therneau T.M. Larson D.R. Greipp P.R. Witzig T.E. Basu R. Suarez G.A. POEMS syndrome: Definitions and long-term outcome: Presented in abstract form at the 41st annual meeting of the American Society of Hematology, New Orleans, LA, December 3–7, 1999 Blood J. Am. Soc. Hematol. 2003 101 2496 2506 10.1182/blood-2002-07-2299 12456500

5. Lacy M.Q. Gertz M.A. Hanson C.A. Inwards D.J. Kyle R.A. Multiple myeloma associated with diffuse osteosclerotic bone lesions: A clinical entity distinct from osteosclerotic myeloma (POEMS syndrome) Am. J. Hematol. 1997 56 288 293 10.1002/(SICI)1096-8652(199712)56:4<288::AID-AJH16>3.0.CO;2-5 9395194

6. Watanabe O. Arimura K. Kitajima I. Osame M. Maruyama I. Greatly raised vascular endothelial growth factor (VEGF) in POEMS syndrome Lancet 1996 347 702 10.1016/S0140-6736(96)91261-1 8596427

7. Soubrier M. Dubost J.-J. Serre A.F. Ristori J.-M. Sauvezie B. Cathebras P. Piette J.-C. Chapman A. Authier F.-J. Gherardi R.K. Growth factors in POEMS syndrome: Evidence for a marked increase in circulating vascular endothelial growth factor Arthritis Rheum. Off. J. Am. Coll. Rheumatol. 1997 40 786 787 10.1002/art.1780400430 9125266

8. Isshiki Y. Oshima M. Mimura N. Kayamori K. Miyamoto-Nagai Y. Seki M. Nakajima-Takagi Y. Kanamori T. Iwamoto E. Muto T. Unraveling unique features of plasma cell clones in POEMS syndrome with single-cell analysis JCI Insight 2022 7 e151482 10.1172/jci.insight.151482 36129760 PMC9714781

9. Wang C. Huang X.-F. Cai Q.-Q. Cao X.-X. Cai H. Zhou D. Li J. Remarkable expression of vascular endothelial growth factor in bone marrow plasma cells of patients with POEMS syndrome Leuk. Res. 2016 50 78 84 10.1016/j.leukres.2016.09.017 27697660

10. Gurram M.K. Pulivarthi S. An atypical presentation of POEMS syndrome with IgG kappa type M protein and normal VEGF level: Case report and review of literature J. Cancer Res. Ther. 2018 14 679 10.4103/0973-1482.172123 29893339

11. Ikeda S. Kobayashi T. Saito M. Komatsuda A. Ubukawa K. Kameoka Y. Takahashi N. Multiparameter Flow Cytometry for the Identification of Neoplastic Plasma Cells in POEMS Syndrome with IgG-kappa Gammopathy: Successful Treatment Using Lenalidomide and Dexamethasone Intern. Med. 2019 58 3461 3468 10.2169/internalmedicine.2882-19 31391391 PMC6928515

12. Li J. Huang Z. Duan M.-H. Zhang W. Chen M. Cao X.-X. Guan H.-Z. Tian Z. Zhou D.-B. Characterization of immunoglobulin λ light chain variable region (IGLV) gene and its relationship with clinical features in patients with POEMS syndrome Ann. Hematol. 2012 91 1251 1255 10.1007/s00277-012-1455-9 22453306

13. Kawajiri-Manako C. Mimura N. Fukuyo M. Namba H. Rahmutulla B. Nagao Y. Togasaki E. Shimizu R. Oshima-Hasegawa N. Tsukamoto S. Clonal immunoglobulin λ light-chain gene rearrangements detected by next generation sequencing in POEMS syndrome Am. J. Hematol. 2018 93 1161 1168 10.1002/ajh.25213 30015379

14. Hashiguchi T. Arimura K. Matsumuro K. Otsuka R. Watanabe O. Jonosono M. Maruyama Y. Maruyama I. Osame M. Highly concentrated vascular endothelial growth factor in platelets in Crow–Fukase syndrome Muscle Nerve Off. J. Am. Assoc. Electrodiagn. Med. 2000 23 1051 1056 10.1002/1097-4598(200007)23:7<1051::AID-MUS7>3.0.CO;2-V 10882999

15. Nakano A. Mitsui T. Endo I. Takeda Y. Ozaki S. Matsumoto T. Solitary plasmacytoma with VEGF overproduction: Report of a patient with polyneuropathy Neurology 2001 56 818 819 10.1212/WNL.56.6.818 11274332

16. Scarlato M. Previtali S.C. Carpo M. Pareyson D. Briani C. Del Bo R. Nobile-Orazio E. Quattrini A. Comi G.P. Polyneuropathy in POEMS syndrome: Role of angiogenic factors in the pathogenesis Brain 2005 128 1911 1920 10.1093/brain/awh519 15975949

17. Li J. Zhou D.-B. New advances in the diagnosis and treatment of POEMS syndrome Br. J. Haematol. 2013 161 303 315 10.1111/bjh.12236 23398538

18. Briani C. Fedrigo M. Manara R. Castellani C. Zambello R. Citton V. Campagnolo M. Torre C.D. Lucchetta M. Orvieto E. Pachymeningeal involvement in POEMS syndrome: MRI and histopathological study J. Neurol. Neurosurg. Psychiatry 2012 83 33 37 10.1136/jnnp-2011-300047 21653206

19. D’Souza A. Hayman S.R. Buadi F. Mauermann M. Lacy M.Q. Gertz M.A. Kyle R.A. Kumar S. Greipp P.R. Lust J.A. The utility of plasma vascular endothelial growth factor levels in the diagnosis and follow-up of patients with POEMS syndrome Blood J. Am. Soc. Hematol. 2011 118 4663 4665 10.1182/blood-2011-06-362392 21881050

20. Misawa S. Sato Y. Katayama K. Nagashima K. Aoyagi R. Sekiguchi Y. Sobue G. Koike H. Yabe I. Sasaki H. Safety and efficacy of thalidomide in patients with POEMS syndrome: A multicentre, randomised, double-blind, placebo-controlled trial Lancet Neurol. 2016 15 1129 1137 10.1016/S1474-4422(16)30157-0 27496680

21. Gherardi R.K. Authier F.J. Belec L. Pro-inflammatory cytokines: A pathogenic key of POEMS syndrome Rev. Neurol. 1996 152 409 412 8881441

22. Arimura K. Antibodies directed to voltage-gated potassium channels in sera from acquired neuromyotonia and related disorders Rinsho Shinkeigaku [Clin. Neurol.] 1999 39 1235 1236 10791086

23. Dispenzieri A. POEMS syndrome: 2017 Update on diagnosis, risk stratification, and management Am. J. Hematol. 2017 92 814 829 10.1002/ajh.24802 28699668

24. Kelly J.J. Kyle R.A. Miles J.M. Dyck P.J. Osteosclerotic myeloma and peripheral neuropathy Neurology 1983 33 202 10.1212/WNL.33.2.202 6296727

25. Glazebrook K. Bonilla F.L.G. Johnson A. Leng S. Dispenzieri A. Computed tomography assessment of bone lesions in patients with POEMS syndrome Eur. Radiol. 2015 25 497 504 10.1007/s00330-014-3428-y 25253619

26. Shi X. Hu S. Luo X. Luo M. You H. Zhu Y. Xi X. CT characteristics in 24 patients with POEMS syndrome Acta Radiol. 2016 57 51 57 10.1177/0284185114564614 25571895

27. Gandhi G.Y. Basu R. Dispenzieri A. Basu A. Montori V. Brennan M.D. Endocrinopathy in POEMS Syndrome: The Mayo Clinic Experience Mayo Clinic Proceedings Elsevier Amsterdam, The Netherlands 2007 10.4065/82.7.836 17605964

28. Cui R.-T. Yu S.-Y. Huang X.-S. Zhang J.-T. Tian C.-L. Dou L.-P. Pu C.-Q. Incidence and risk factors of pleural effusions in patients with POEMS syndrome Hematol. Oncol. 2015 33 80 84 10.1002/hon.2135 24519469

29. Allam J.S. Kennedy C.C. Aksamit T.R. Dispenzieri A. Pulmonary manifestations in patients with POEMS syndrome: A retrospective review of 137 patients Chest 2008 133 969 974 10.1378/chest.07-1800 18198255

30. Sinisalo M. Hietaharju A. Sauranen J. Wirta O. Thalidomide in POEMS syndrome: Case report Am. J. Hematol. 2004 76 66 68 10.1002/ajh.20051 15114600

31. Wang C. Zhou Y.-L. Cai H. Cheng X.-Q. Zhang W. Kang W.-Y. Qin X.-Z. Duan M.-H. Han H.-J. Cao X.-X. Markedly elevated serum total N-terminal propeptide of type I collagen is a novel marker for the diagnosis and follow up of patients with POEMS syndrome Haematologica 2014 99 e78 10.3324/haematol.2013.102962 24658817 PMC4040898

32. Lesprit P. Authier F.J. Gherardi R. Bélec L. Paris D. Melliere D. Godeau B. Acute arterial obliteration: A new feature of the POEMS syndrome? Medicine 1996 75 226 232 10.1097/00005792-199607000-00005 8699962

33. Dispenzieri A. POEMS syndrome: Update on diagnosis, risk-stratification, and management Am. J. Hematol. 2012 87 804 814 10.1002/ajh.23288 22806697

34. Dao L.N. Hanson C.A. Dispenzieri A. Morice W.G. Kurtin P.J. Hoyer J.D. Bone marrow histopathology in POEMS syndrome: A distinctive combination of plasma cell, lymphoid, and myeloid findings in 87 patients Blood J. Am. Soc. Hematol. 2011 117 6438 6444 10.1182/blood-2010-11-316935 PMC3123015 21385854

35. Nasu S. Misawa S. Sekiguchi Y. Shibuya K. Kanai K. Fujimaki Y. Ohmori S. Mitsuma S. Koga S. Kuwabara S. Different neurological and physiological profiles in POEMS syndrome and chronic inflammatory demyelinating polyneuropathy J. Neurol. Neurosurg. Psychiatry 2012 83 476 479 10.1136/jnnp-2011-301706 22338030

36. Sung J.-Y. Kuwabara S. Ogawara K. Kanai K. Hattori T. Patterns of nerve conduction abnormalities in POEMS syndrome Muscle Nerve Off. J. Am. Assoc. Electrodiagn. Med. 2002 26 189 193 10.1002/mus.10182 12210381

37. Min J.-H. Hong Y.-H. Lee K.-W. Electrophysiological features of patients with POEMS syndrome Clin. Neurophysiol. 2005 116 965 968 10.1016/j.clinph.2004.11.011 15792906

38. Mauermann M.L. Sorenson E.J. Dispenzieri A. Mandrekar J. Suarez G.A. Dyck P.J. Dyck P.J.B. Uniform demyelination and more severe axonal loss distinguish POEMS syndrome from CID J. Neurol. Neurosurg. Psychiatry 2012 83 480 486 10.1136/jnnp-2011-301472 22396441

39. Piccione E.A. Engelstad J. Dyck P.J. Mauermann M.L. Dispenzieri A. Dyck P.J.B. Nerve pathologic features differentiate POEMS syndrome from CID Acta Neuropathol. Commun. 2016 4 116 10.1186/s40478-016-0389-1 27799073 PMC5088652

40. He T. Zhao A. Zhao H. Cai H. Feng J. Zhang L. Cao X. Zhou D. Li J. Clinical characteristics and the long-term outcome of patients with atypical POEMS syndrome variant with undetectable monoclonal gammopathy Ann. Hematol. 2019 98 735 743 10.1007/s00277-018-03589-4 30612232

41. Dispenzieri A. Lacy M.Q. Hayman S.R. Kumar S.K. Buadi F. Dingli D. Litzow M.R. Gastineau D.A. Inwards D.J. Elliott M.A. Peripheral blood stem cell transplant for POEMS syndrome is associated with high rates of engraftment syndrome Eur. J. Haematol. 2008 80 397 406 10.1111/j.1600-0609.2008.01037.x 18221391 PMC2327207

42. Li J. Zhou D.-B. Huang Z. Jiao L. Duan M.-H. Zhang W. Zhao Y.-Q. Shen T. Clinical characteristics and long-term outcome of patients with POEMS syndrome in China Ann. Hematol. 2011 90 819 826 10.1007/s00277-010-1149-0 21221584

43. Stankowski-Drengler T. Gertz M.A. A Katzmann J. Lacy M.Q. Kumar S. Leung N. Hayman S.R. Buadi F. Kyle R.A. Rajkumar S.V. Serum immunoglobulin free light chain measurements and heavy chain isotype usage provide insight into disease biology in patients with POEMS syndrome Am. J. Hematol. 2010 85 431 434 10.1002/ajh.21707 20513121 PMC2902776

44. Dispenzieri A. Ushering in a new era for POEMS Blood J. Am. Soc. Hematol. 2011 117 6405 6406 10.1182/blood-2011-03-342675 21680803

45. Jaccard A. POEMS Syndrome: Therapeutic Options Hematol. Oncol. Clin. N. Am. 2018 32 141 151 10.1016/j.hoc.2017.09.011 29157615

46. Dispenzieri A. How I treat POEMS syndrome Blood J. Am. Soc. Hematol. 2012 119 5650 5658 10.1182/blood-2012-03-378992 22547581 PMC3425020

47. Morley J.B. Schwieger A.C. The relation between chronic polyneuropathy and osteosclerotic myeloma J. Neurol. Neurosurg. Psychiatry 1967 30 432 10.1136/jnnp.30.5.432 6075207 PMC496220

48. Davis L.E. Drachman D.B. Myeloma neuropathy: Successful treatment of two patients and review of cases Arch. Neurol. 1972 27 507 511 10.1001/archneur.1972.00490180043010 4343458

49. Iwashita H. Ohnishi A. Asada M. Kanazawa Y. Kuroiwa Y. Polyneuropathy, skin hyperpigmentation, edema, and hypertrichosis in localized osteosclerotic myeloma Neurology 1977 27 675 10.1212/WNL.27.7.675 559975

50. Suh Y.-G. Suh C.-O. Kim J.S. Kim S.-J. Pyun H.O. Cho J. Radiotherapy for solitary plasmacytoma of bone and soft tissue Ann. Hematol. 2012 91 1785 1793 10.1007/s00277-012-1510-6 22752147

51. Cook G. Iacobelli S. Van Biezen A. Ziagkos D. Leblond V. Abraham J. McQuaker G. Schoenland S. Rambaldi A. Halaburda K. High-dose therapy and autologous stem cell transplantation in patients with POEMS syndrome: A retrospective study of the Plasma Cell Disorder sub-committee of the Chronic Malignancy Working Party of the European Society for Blood & Marrow Transplantation Haematologica 2017 102 160 27634201 10.3324/haematol.2016.148460 PMC5210246

52. Karam C. Klein C.J. Dispenzieri A. Dyck P.J.B. Mandrekar J. D’Souza A. Mauermann M.L. Polyneuropathy improvement following autologous stem cell transplantation for POEMS syndrome Neurology 2015 84 1981 1987 10.1212/WNL.0000000000001565 25878176 PMC4433461

53. Ho G. Wun T. Muffly L. Li Q. Brunson A. Rosenberg A.S. Jonas B.A. Keegan T.H. Decreased early mortality associated with the treatment of acute myeloid leukemia at National Cancer Institute—Designated cancer centers in California Cancer 2018 124 1938 1945 10.1002/cncr.31296 29451695 PMC6911353

54. Zhao H. Cai H. Wang C. Huang X.-F. Cao X.-X. Zhang L. Zhou D.-B. Li J. Prognostic value of serum vascular endothelial growth factor and hematological responses in patients with newly-diagnosed POEMS syndrome Blood Cancer J. 2018 8 37 10.1038/s41408-018-0073-8 29618787 PMC5884844

55. Kuwabara S. Misawa S. Kanai K. Kikkawa Y. Nishimura M. Nakaseko C. Cho R.K. Hattori T. Autologous peripheral blood stem cell transplantation for POEMS syndrome Neurology 2006 66 105 107 10.1212/01.wnl.0000188757.38495.23 16401856

56. Dispenzieri A. Fajgenbaum D.C. Overview of Castleman disease Blood J. Am. Soc. Hematol. 2020 135 1353 1364 10.1182/blood.2019000931 32106302

57. Giglia F. Chiapparini L. Fariselli L. Barbui T. Ciano C. Scarlato M. Pareyson D. POEMS syndrome: Relapse after successful autologous peripheral blood stem cell transplantation Neuromuscul. Disord. 2007 17 980 982 10.1016/j.nmd.2007.05.004 17611108

58. Sanada S. Ookawara S. Karube H. Shindo T. Goto T. Nakamichi T. Saito M. Matsubara M. Suzuki M. Marked recovery of severe renal lesions in POEMS syndrome with high-dose melphalan therapy supported by autologous blood stem cell transplantation Am. J. Kidney Dis. 2006 47 672 679 10.1053/j.ajkd.2006.01.004 16564945

59. Ganti A.K. Pipinos I. Culcea E. Armitage J.O. Tarantolo S. Successful hematopoietic stem-cell transplantation in multicentric Castleman disease complicated by POEMS syndrome Am. J. Hematol. 2005 79 206 210 10.1002/ajh.20280 15981232

60. Dispenzieri A. Moreno-Aspitia A. Suarez G.A. Lacy M.Q. Colon-Otero G. Tefferi A. Litzow M.R. Roy V. Hogan W.J. Kyle R.A. Peripheral blood stem cell transplantation in 16 patients with POEMS syndrome, and a review of the literature Blood 2004 104 3400 3407 10.1182/blood-2004-05-2046 15280195

61. Jaccard A. Royer B. Bordessoule D. Brouet J.-C. Fermand J.-P. High-dose therapy and autologous blood stem cell transplantation in POEMS syndrome Blood J. Am. Soc. Hematol. 2002 99 3057 3059 10.1182/blood.V99.8.3057 11929800

62. Soubrier M. Ruivard M. Dubost J. Sauvezie B. Philippe P. Successful use of autologous bone marrow transplantation in treating a patient with POEMS syndrome Bone Marrow Transplant. 2002 30 61 62 10.1038/sj.bmt.1703600 12105781

63. Rovira M. Carreras E. Bladé J. Graus F. Valls J. Fernández-Avilés F. Montserrat E. Dramatic improvement of POEMS syndrome following autologous haematopoietic cell transplantation Br. J. Haematol. 2001 115 373 375 10.1046/j.1365-2141.2001.03040.x 11703338

64. Hogan W. Lacy M. Wiseman G. Fealey R. Dispenzieri A. Gertz M. Successful treatment of POEMS syndrome with autologous hematopoietic progenitor cell transplantation Bone Marrow Transplant. 2001 28 305 309 10.1038/sj.bmt.1703108 11536000

65. Zhao H. Huang X.-F. Gao X.-M. Cai H. Zhang L. Feng J. Cao X.-X. Zhou D.-B. Li J. What is the best first-line treatment for POEMS syndrome: Autologous transplantation, melphalan and dexamethasone, or lenalidomide and dexamethasone? Leukemia 2019 33 1023 1029 10.1038/s41375-019-0391-2 30700844 PMC6756085

66. Barete S. Mouawad R. Choquet S. Viala K. Leblond V. Musset L. Amoura Z. Khayat D. Francès C. Skin manifestations and vascular endothelial growth factor levels in POEMS syndrome: Impact of autologous hematopoietic stem cell transplantation Arch. Dermatol. 2010 146 615 623 10.1001/archdermatol.2010.100 20566924

67. Laurenti L. De Matteis S. Sabatelli M. Conte A. Chiusolo P. Sorà F. Piccirillo N. Za T. Tarnani M. Rossi E. Early diagnosis followed by front-line autologous peripheral blood stem cell transplantation for patients affected by POEMS syndrome Leuk. Res. 2008 32 1309 1312 10.1016/j.leukres.2007.11.029 18207237

68. D’Souza A. Lacy M. Gertz M. Kumar S. Buadi F. Hayman S. Dingli D. Zeldenrust S. Kyle R. Ansell S. Long-term outcomes after autologous stem cell transplantation for patients with POEMS syndrome (osteosclerotic myeloma): A single-center experience Blood J. Am. Soc. Hematol. 2012 120 56 62 10.1182/blood-2012-04-423178 22611150

69. Kourelis T.V. Buadi F.K. Kumar S.K. Gertz M.A. Lacy M.Q. Dingli D. Go R.S. Kapoor P. Lust J.A. Hayman S.R. Long-term outcome of patients with POEMS syndrome: An update of the Mayo Clinic experience Am. J. Hematol. 2016 91 585 589 10.1002/ajh.24356 26972803

70. Ohwada C. Sakaida E. Kawajiri-Manako C. Nagao Y. Oshima-Hasegawa N. Togasaki E. Muto T. Tsukamoto S. Mitsukawa S. Takeda Y. Long-term evaluation of physical improvement and survival of autologous stem cell transplantation in POEMS syndrome Blood 2018 131 2173 2176 10.1182/blood-2017-07-795385 29599110 PMC5946762

71. Tomkins O. Keddie S. Lunn M.P. D’Sa S. High-dose therapy and autologous transplantation for POEMS Syndrome: Effective, but how to optimise? Br. J. Haematol. 2019 186 e178 e181 10.1111/bjh.16057 31215033

72. Imai N. Taguchi J. Yagi N. Konishi T. Serizawa M. Kobari M. Relapse of polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome without increased level of vascular endothelial growth factor following successful autologous peripheral blood stem cell transplantation Neuromuscul. Disord. 2009 19 363 365 10.1016/j.nmd.2009.02.004 19269178

73. Katayama K. Misawa S. Sato Y. Sobue G. Yabe I. Watanabe O. Nishizawa M. Kusunoki S. Kikuchi S. Nakashima I. Japanese POEMS syndrome with Thalidomide (J-POST) Trial: Study protocol for a phase II/III multicentre, randomised, double-blind, placebo-controlled trial BMJ Open 2015 5 e007330 10.1136/bmjopen-2014-007330 PMC4289734 25573527

74. Ohwada C. Nakaseko C. Sakai S. Takeda Y. Abe D. Takeuchi M. Sakaida E. Masuda S. Shimizu N. Cho R. Successful combination treatment with bevacizumab, thalidomide and autologous PBSC for severe POEMS syndrome Bone Marrow Transplant. 2009 43 739 740 10.1038/bmt.2008.381 19043459

75. Kim S.Y. Lee S.A. Ryoo H.M. Lee K.H. Hyun M.S. Bae S.H. Thalidomide for POEMS syndrome Ann. Hematol. 2006 85 545 546 10.1007/s00277-006-0119-z 16718498

76. Mazumder A. Jagannath S. Thalidomide and lenalidomide in multiple myeloma Best Pract. Res. Clin. Haematol. 2006 19 769 780 10.1016/j.beha.2006.06.006 16997182

77. Hideshima T. Anderson K.C. Molecular mechanisms of novel therapeutic approaches for multiple myeloma Nat. Rev. Cancer 2002 2 927 937 10.1038/nrc952 12459731

78. Bartlett J.B. Tozer A. Stirling D. Zeldis J.B. Recent clinical studies of the immunomodulatory drug (IMiD®) lenalidomide Br. J. Cancer 2005 93 613 619 10.1038/sj.bjc.6602774 16222306 PMC2361627

79. Takahashi W. Ichikawa M. Okazaki A. Nakamura F. Arai H. Handa T. Nakamura Y. Nakamura Y. Seo S. Sasaki K. Effective treatment of POEMS syndrome accompanied by plasmacytoma with lenalidomide, dexamethasone, and local irradiation Rinsho Ketsueki [Jpn. J. Clin. Hematol.] 2020 61 262 267 32224588 10.11406/rinketsu.61.262

80. Suichi T. Misawa S. Nagashima K. Sato Y. Iwai Y. Katayama K. Sekiguchi Y. Shibuya K. Amino H. Suzuki Y.-I. Lenalidomide Treatment for Thalidomide-refractory POEMS Syndrome: A Prospective Single-arm Clinical Trial Intern. Med. 2020 59 1149 1153 10.2169/internalmedicine.3800-19 32009091 PMC7270764

81. Tomas J.F. Giraldo P. Lecumberri R. Nistal S. POEMS syndrome with severe neurological damage clinically recovered with lenalidomide Haematologica 2012 97 320 10.3324/haematol.2011.041897 22058211 PMC3269496

82. Suyanı E. Yağcı M. Sucak G.T. Complete remission with a combination of lenalidomide, cyclophosphamide and prednisolone in a patient with incomplete POEMS syndrome Acta Haematol. 2011 126 199 201 10.1159/000329896 21849771

83. Al-Mayoof O. Al Sughaiyer H. Abuomar W. Khan M. POEMS syndrome: A rare cause of exudative ascites and chronic peripheral neuropathy Case Rep. 2017 2017 bcr-2016-219022 10.1136/bcr-2016-219022 PMC5534653 28637843

84. Yang H. Zhao H. Huang X. Cao X. Zhou D. Li J. Improvement of thyroid function in POEMS syndrome after combination therapy of lenalidomide and dexamethasone Leuk. Lymphoma 2019 60 483 487 10.1080/10428194.2018.1485909 30407096

85. Nozza A. Terenghi F. Gallia F. Adami F. Briani C. Merlini G. Giordano L. Santoro A. Nobile-Orazio E. Lenalidomide and dexamethasone in patients with POEMS syndrome: Results of a prospective, open--label trial Br. J. Haematol. 2017 179 748 755 10.1111/bjh.14966 29048107

86. Ordway S. Gilbert L. Wanko S. POEMS syndrome: Diagnostic delay and successful treatment with lenalidomide, cyclophosphamide and prednisone followed by autologous peripheral stem cell transplantation Case Rep. 2018 2018 bcr-2017-223168 10.1136/bcr-2017-223168 PMC6067145 30054320

87. Zagouri F. Kastritis E. Gavriatopoulou M. Sergentanis T.N. Psaltopoulou T. Terpos E. Dimopoulos M.-A. Lenalidomide in patients with POEMS syndrome: A systematic review and pooled analysis Leuk. Lymphoma 2014 55 2018 2023 10.3109/10428194.2013.869329 24295131

88. Cai Q.-Q. Wang C. Cao X.-X. Cai H. Zhou D.-B. Li J. Efficacy and safety of low-dose lenalidomide plus dexamethasone in patients with relapsed or refractory POEMS syndrome Eur. J. Haematol. 2015 95 325 330 10.1111/ejh.12492 25401269

89. Sayar Z. Weatherill A. Keddie S. Sive J. Lunn M.P. Thomas M. D’Sa S. High rates of venous and arterial thrombotic events in patients with POEMS syndrome: Results from the UCLH (UK) POEMS Registry Blood Adv. 2020 4 2139 2142 10.1182/bloodadvances.2020001492 32421810 PMC7252560

90. Jaccard A. Moreau P. Leblond V. Leleu X. Benboubker L. Hermine O. Recher C. Asli B. Lioure B. Royer B. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis N. Engl. J. Med. 2007 357 1083 1093 10.1056/NEJMoa070484 17855669

91. Suichi T. Misawa S. Beppu M. Takahashi S. Sekiguchi Y. Shibuya K. Amino H. Tsuneyama A. Suzuki Y.-I. Nakamura K. Prevalence, clinical profiles, and prognosis of POEMS syndrome in Japanese nationwide survey Neurology 2019 93 e975 e983 10.1212/WNL.0000000000008062 31371568

92. Rajkumar S.V. Multiple myeloma: 2016 update on diagnosis, risk-stratification, and management Am. J. Hematol. 2016 91 719 734 10.1002/ajh.24402 27291302 PMC5291298

93. Yang J. Terebelo H.R. Zonder J.A. Secondary primary malignancies in multiple myeloma: An old NEMESIS revisited Adv. Hematol. 2012 2012 801495 10.1155/2012/801495 22851973 PMC3407607

94. Roccaro A.M. Hideshima T. Raje N. Kumar S. Ishitsuka K. Yasui H. Shiraishi N. Ribatti D. Nico B. Vacca A. Bortezomib mediates antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells Cancer Res. 2006 66 184 191 10.1158/0008-5472.CAN-05-1195 16397231

95. Kaygusuz I. Tezcan H. Çetiner M. Kocakaya O. Uzay A. Bayık M. Bortezomib: A new therapeutic option for POEMS syndrome Eur. J. Haematol. 2010 84 175 177 10.1111/j.1600-0609.2009.01341.x 19732138

96. Dimopoulos M.A. Mateos M.V. Richardson P.G. Schlag R. Khuageva N.K. Shpilberg O. Kropff M. Spicka I. Palumbo A. Wu K.L. Risk factors for, and reversibility of, peripheral neuropathy associated with bortezomib–melphalan–prednisone in newly diagnosed patients with multiple myeloma: Subanalysis of the phase 3 VISTA study Eur. J. Haematol. 2011 86 23 31 10.1111/j.1600-0609.2010.01533.x 20874823

97. He H. Fu W. Du J. Jiang H. Hou J. Successful treatment of newly diagnosed POEMS syndrome with reduced-dose bortezomib based regimen Br. J. Haematol. 2018 181 126 128 10.1111/bjh.14497 28146276

98. Vannata B. Laurenti L. Chiusolo P. Sorà F. Balducci M. Sabatelli M. Luigetti M. Giannotta C. De Stefano V. Leone G. Efficacy of lenalidomide plus dexamethasone for POEMS syndrome relapsed after autologous peripheral stem-cell transplantation Am. J. Hematol. 2012 87 641 642 10.1002/ajh.23195 22488443

99. Zeng K. Yang J.-R. Li J. Wei Q. Yang Y.-M. Liu T. Niu T. Effective induction therapy with subcutaneous administration of bortezomib for newly diagnosed POEMS syndrome: A case report and a review of the literature Acta Haematol. 2013 129 101 105 10.1159/000343681 23171959

100. Dimopoulos M.A. Oriol A. Nahi H. San-Miguel J. Bahlis N.J. Usmani S.Z. Rabin N. Orlowski R.Z. Komarnicki M. Suzuki K. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma N. Engl. J. Med. 2016 375 1319 1331 10.1056/NEJMoa1607751 27705267

101. Plesner T. Arkenau H.T. Gimsing P. Krejcik J. Lemech C. Minnema M.C. Lassen U. Laubach J.P. Palumbo A. Lisby S. Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma Blood 2016 128 1821 1828 10.1182/blood-2016-07-726729 27531679 PMC5054695

102. Sher T. Fenton B. Akhtar A. Gertz M.A. First report of safety and efficacy of daratumumab in 2 cases of advanced immunoglobulin light chain amyloidosis Blood J. Am. Soc. Hematol. 2016 128 1987 1989 10.1182/blood-2016-06-722496 27543437

103. Khan M. Stone K. van Rhee F. Daratumumab for POEMS Syndrome Mayo Clinic Proceedings Elsevier Amsterdam, The Netherlands 2018 10.1016/j.mayocp.2018.02.001 29622102

104. Gavriatopoulou M. Ntanasis-Stathopoulos I. Fotiou D. Migkou M. Eleutherakis-Papaiakovou E. Kanellias N. Roussou M. Dialoupi I. Malandrakis P. Theodorakakou F. Upfront Daratumumab with Lenalidomide and Dexamethasone for POEMS Syndrome HemaSphere 2020 4 e381 10.1097/HS9.0000000000000381 32647800 PMC7306302

105. Straume O. Bergheim J. Ernst P. Bevacizumab therapy for POEMS syndrome Blood 2006 107 4972 4974 10.1182/blood-2005-12-5045 16754779

106. Badros A. Porter N. Zimrin A. Bevacizumab therapy for POEMS syndrome Blood 2005 106 1135 10.1182/blood-2005-03-0910 16033956

107. Samaras P. Bauer S. Stenner-Liewen F. Steiner R. Zweifel M. Renner C. Knuth A. Treatment of POEMS syndrome with bevacizumab Haematologica 2007 92 1438 1439 10.3324/haematol.11315 18024383

108. Buxhofer-Ausch V. Gisslinger B. Stangl G. Rauschka H. Gisslinger H. Successful treatment sequence incorporating bevacizumab for therapy of polyneuropathy in two patients with POEMS syndrome Leuk. Res. 2012 36 e98 e100 10.1016/j.leukres.2012.01.018 22365941

109. Kanai K. Kuwabara S. Misawa S. Hattori T. Failure of treatment with anti-VEGF monoclonal antibody for long-standing POEMS syndrome Intern. Med. 2007 46 311 313 10.2169/internalmedicine.46.6246 17380000

110. Sekiguchi Y. Misawa S. Shibuya K. Nasu S. Mitsuma S. Iwai Y. Beppu M. Sawai S. Ito S. Hirano S. Ambiguous effects of anti-VEGF monoclonal antibody (bevacizumab) for POEMS syndrome J. Neurol. Neurosurg. Psychiatry 2013 84 1346 1348 10.1136/jnnp-2012-304874 23463868

111. Xu J. Wang Q. Xu H. Gu C. Jiang L. Wang J. Di Wang D. Bin Xu B. Mao X. Wang J. Anti-BCMA CAR-T cells for treatment of plasma cell dyscrasia: Case report on POEMS syndrome and multiple myeloma J. Hematol. Oncol. 2018 11 128 10.1186/s13045-018-0672-7 30348186 PMC6198365

112. Moreau P. Attal M. Hulin C. Arnulf B. Belhadj K. Benboubker L. Béné M.C. Broijl A. Caillon H. Caillot D. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): A randomised, open-label, phase 3 study Lancet 2019 394 29 38 10.1016/S0140-6736(19)31240-1 31171419

113. Koike H. Iijima M. Mori K. Yamamoto M. Hattori N. Watanabe H. Tanaka F. Doyu M. Sobue G. Neuropathic pain correlates with myelinated fibre loss and cytokine profile in POEMS syndrome J. Neurol. Neurosurg. Psychiatry 2008 79 1171 1179 10.1136/jnnp.2007.135681 18356256

114. Cerri F. Falzone Y.M. Riva N. Quattrini A. An update on the diagnosis and management of the polyneuropathy of POEMS syndrome J. Neurol. 2019 266 258 267 10.1007/s00415-018-9068-4 30264176 PMC6343023

115. Prokop J. Estorninho J. Marote S. Sabino T. De Sousa A.B. Silva E. Agapito A. POEMS syndrome: A rare cause of adrenal insufficiency in a young male Endocrinol. Diabetes Metab. Case Rep. 2019 2019 EDM190010 10.1530/EDM-19-0010 31967972

116. Mauermann M.L. The peripheral neuropathies of POEMS syndrome and Castleman disease Hematol. Oncol. Clin. 2018 32 153 163 10.1016/j.hoc.2017.09.012 29157616

117. Amador-Robles D. Rodríguez-Armida M. Treviño-Frenk I. Uribe-Uribe N.O. Molina-Paredes G.A. López-Sánchez J.A. Mejia-Vilet J.M. Anasarca in a Patient With Polyneuropathy Am. J. Kidney Dis. 2019 74 A11 A14 10.1053/j.ajkd.2019.04.001 31230635

118. Nakanishi T. Sobue I. Toyokura Y. Nishitani H. Kuroiwa Y. Satoyoshi E. Tsubaki T. Igata A. Ozaki Y. The Crow-Fukase syndrome: A study of 102 cases in Japan Neurology 1984 34 712 10.1212/WNL.34.6.712 6539431

119. Warsame R. Kohut I.E. Dispenzieri A. Successful use of cyclophosphamide, bortezomib, and dexamethasone to treat a case of relapsed POEMS Eur. J. Haematol. 2012 88 549 550 10.1111/j.1600-0609.2012.01780.x 22416898

120. Lesprit P. Godeau B. Authier F.J. Soubrier M. Zuber M. Larroche C. Viard J.-P. Wechsler B. Gherardip R. Pulmonary hypertension in POEMS syndrome: A new feature mediated by cytokines Am. J. Respir. Crit. Care Med. 1998 157 907 911 10.1164/ajrccm.157.3.9707095 9517610

121. He T. Tian Z. Liu Y. Li J. Zhou D. Fang Q. Evaluating heart function in patients with POEMS syndrome Echocardiography 2019 36 1997 2003 10.1111/echo.14516 31693226

122. Takahashi Y. Iwano H. Nakano I. Fukushima A. Naya M. Shimizu A. Matsuno Y. Oyama-Manabe N. Anzai T. POEMS syndrome showing left ventricular dysfunction and extracellular edema assessed by cardiac magnetic resonance imaging Intern. Med. 2019 58 2539 2543 10.2169/internalmedicine.2842-19 31118405 PMC6761353

123. Chandrashekaran S. Dispenzieri A. Cha S.S. Kennedy C.C. Pulmonary morbidity improves after autologous stem cell transplantation in POEMS syndrome Respir. Med. 2015 109 122 130 10.1016/j.rmed.2014.11.005 25433952 PMC4758677

124. Van Rhee F. Fayad L. Voorhees P. Furman R. Lonial S. Borghaei H. Sokol L. Crawford J. Cornfeld M. Qi M. Siltuximab, a novel anti–interleukin-6 monoclonal antibody, for Castleman’s disease J. Clin. Oncol. 2010 28 3701 3708 10.1200/JCO.2009.27.2377 20625121

125. Nishimoto N. Kanakura Y. Aozasa K. Johkoh T. Nakamura M. Nakano S. Nakano N. Ikeda Y. Sasaki T. Nishioka K. Humanized anti–interleukin-6 receptor antibody treatment of multicentric Castleman disease Blood 2005 106 2627 2632 10.1182/blood-2004-12-4602 15998837

126. Dong Y. Yin D. White B.E.P. Guo Q. Pi Y. Wei S. Concurrent juxtapapillary hemorrage and optic disc edema as initial presentation of POEMS syndrome Can. J. Ophthalmol. 2018 53 e233 e236 10.1016/j.jcjo.2018.02.015 30503001

127. Kaushik M. Pulido J.S. Abreu R. Amselem L. Dispenzieri A. Ocular findings in patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome Ophthalmology 2011 118 778 782 10.1016/j.ophtha.2010.08.013 21035860

128. Zhang X. Cai Q.-Q. Huang X.-F. Cao X.-X. Cai H. Zhou D.-B. Dai R.-P. Li J. Ocular manifestations and treatment outcomes in Chinese patients with POEMS syndrome Retina 2017 37 1784 1791 10.1097/IAE.0000000000001409 27930460

129. Alvarez-Breckenridge C.A. Attiah M.A. Zachariah M. Gummadavelli A. Yang J. Codd P.J. Ventriculoperitoneal shunt placement for POEMS syndrome J. Clin. Neurosci. 2015 22 1672 1674 10.1016/j.jocn.2015.03.042 26077937

130. Prost M.G. Gilhuis H.J. Brouwer R.E. Gawda P. Local treatment with triamcinolone acetonide and bevacizumab for ocular symptoms in a patient with POEMS syndrome Case Rep. Ophthalmol. 2014 5 416 422 10.1159/000369856 25566064 PMC4280463

131. Kim D.W. Kang S.Y. Bae H.W. Hong S. Gong J.S. Kim C.Y. Intravitreal bevacizumab for the treatment of optic disc edema in a patient with POEMS syndrome Korean J. Ophthalmol. 2015 29 354 10.3341/kjo.2015.29.5.354 26457044 PMC4595264

132. Song H.B. Yu H.G. Optic disc edema responding to localized anti-vascular endothelial growth factor treatment in a patient with POEMS syndrome Korean J. Ophthalmol. 2015 29 357 10.3341/kjo.2015.29.5.357 26457045 PMC4595265

133. Yokouchi H. Oshitari T. Baba T. Yamamoto S. Thalidomide reduces choroidal thickness and optic disc edema in a patient with POEMS syndrome Graefe’s Arch. Clin. Exp. Ophthalmol. 2015 253 1195 1198 10.1007/s00417-014-2892-z 25550097

134. Chong S.T. Beasley H.S. Daffner R.H. POEMS syndrome: Radiographic appearance with MRI correlation Skelet. Radiol. 2006 35 690 695 10.1007/s00256-005-0941-8 16247640

135. Albertí M. Martinez-Yélamos S. Fernandez A. Vidaller A. Narváez J.A. Cano L. Gamez-Cenzano C. Martinez-Matos J. 18F-FDG PET/CT in the evaluation of POEMS syndrome Eur. J. Radiol. 2010 76 180 182 10.1016/j.ejrad.2009.06.004 19581061

136. Shibuya K. Misawa S. Horikoshi T. Kanai K. Isose S. Nasu S. Sekiguchi Y. Noto Y.-I. Fujimaki Y. Nakaseko C. Detection of bone lesions by CT in POEMS syndrome Intern. Med. 2011 50 1393 1396 10.2169/internalmedicine.50.5263 21720058

137. Stefanelli A. Treglia G. Leccisotti L. Laurenti L. Luigetti M. Sabatelli M. Giordano A. Usefulness of F-18 FDG PET/CT in the follow-up of POEMS syndrome after autologous peripheral blood stem cell transplantation Clin. Nucl. Med. 2012 37 181 183 10.1097/RLU.0b013e31823ea154 22228347

138. Araki N. Misawa S. Shibuya K. Ota S. Oide T. Kawano A. Beppu M. Nakatani Y. Kuwabara S. POEMS syndrome and calciphylaxis: An unrecognized cause of abnormal small vessel calcification Orphanet J. Rare Dis. 2016 11 35 10.1186/s13023-016-0421-3 27068711 PMC4828808

139. Yoshikawa M. Uhara H. Arakura F. Murata H. Kubo H. Takata M. Yoshida K. Okuyama R. Calciphylaxis in POEMS syndrome: A case treated with etidronate Acta Derm.-Venereol. 2011 91 98 99 10.2340/00015555-0968 20927488

140. Lee F. Chiu H. POEMS syndrome with calciphylaxis: A case report Acta Derm.-Venereol. 2011 91 96 97 10.2340/00015555-0969 21031277

141. Hineno A. Kinoshita T. Kinoshita M. Arakura F. Naito K.-S. Shimojima Y. Matsuda M. Yoshida K. Ikeda S.-I. Calciphylaxis as a catastrophic complication in a patient with POEMS syndrome Case Rep. Neurol. 2009 1 47 53 10.1159/000259906 20847836 PMC2940264

142. Dumas C. Bienvenu F.-H. Hicks J. Weber E. Sève P. Thrombosis revealing POEMS syndrome: About a case Ann. Biol. Clin. 2020 75 195 197 10.1684/abc.2020.1534 32162605

143. Dupont S.A. Dispenzieri A. Mauermann M.L. Rabinstein A.A. Brown R.D. Cerebral infarction in POEMS syndrome: Incidence, risk factors, and imaging characteristics Neurology 2009 73 1308 1312 10.1212/WNL.0b013e3181bd136b 19841383 PMC2764416

144. Vasilevskiy L. Akhondi H. Wierman A. POEMS syndrome complicated by ischaemic stroke and cerebral vasculitis BMJ Case Rep. CP 2019 12 e229428 10.1136/bcr-2019-229428 31302621 PMC6626473

145. Mehta S. Rajan R. Wilson V. Das B. Singh P. Ahluwalia J. Lal V. Stroke and POEMS syndrome: More than a chance association Neurol. India 2016 64 1318 1319 10.4103/0028-3886.193842 27841210

146. Jindahra P. Dejthevaporn C. Niparuck P. Waisayarat J. Cheecharoen P. Threetong T. Petpiroon P. Sujirakul T. Poonyathalang A. Vanikieti K. Atypical central retinal artery occlusion as the first presentation of POEMS syndrome: A case report BMC Neurol. 2018 18 64 10.1186/s12883-018-1071-y 29739345 PMC5938810

147. Dacci P. Lessi F. Bella E.D. Morbin M. Briani C. Lauria G. Ischemic stroke as clinical onset of POEMS syndrome J. Neurol. 2013 260 3178 3181 10.1007/s00415-013-7180-z 24221644

148. Humeniuk M.S. Gertz M.A. Lacy M.Q. Kyle R.A. Witzig T.E. Kumar S.K. Kapoor P. Lust J.A. Hayman S.R. Buadi F.K. Outcomes of patients with POEMS syndrome treated initially with radiation Blood J. Am. Soc. Hematol. 2013 122 68 73 10.1182/blood-2013-03-487025 PMC4067496 23699599

149. Graham R.C. Hughes R. A modified peripheral neuropathy scale: The Overall Neuropathy Limitations Scale J. Neurol. Neurosurg. Psychiatry 2006 77 973 976 10.1136/jnnp.2005.081547 16574730 PMC2077620