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Objectives: Daratumumab, a monoclonal antibody against CD38, is increasingly used in the treatment of multiple myeloma, other hematological malignancies and autoimmune diseases. Little is known about its CNS toxicity. We present a case of a patient with POEMS syndrome (syndrome of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) who developed an acute leukoencephalopathy shortly after initiation of therapy with daratumumab., Methods: Case report following the CARE case report guidelines., Results: The patient presented with symptoms of headache and diffuse worsening of a pre-existing tetraparesis. MRI showed a rapidly progressive leukoencephalopathy. Extensive diagnostic evaluation revealed no specific cause, suggesting the leukoencephalopathy to be caused by daratumumab., Discussion: Our report highlights a probably rare, but clinically significant adverse effect of daratumumab and underlines the necessity of raised vigilance for neurological side effects in patients treated with daratumumab., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Steinegger, Nierobisch, De Vere-Tyndall, Schreiner, Roth, Kappos, Kana and Herwerth.)

This open-label, prospective trial evaluated the combination of ixazomib, cyclophosphamide and dexamethasone (ICD) in 12 newly diagnosed POEMS syndrome patients. The study is registered with the Chinese Clinical Trials Registry (ChiCTR2000030072). The treatment protocol consisted of 12 cycles of the ICD regimen compromising ixazomib (4 mg on Days 1, 8 and 15), oral cyclophosphamide (300 mg on Days 1, 8 and 15) and dexamethasone (20 mg weekly). A total of 12 patients received a median of 10 (range: 3-23) cycles of the ICD regimen. The haematological response could be evaluated in 10 patients. The overall haematological response rate was 80% (8/10), with 30% (3/10) achieving complete haematological response, and the overall serum VEGF response rate and neurological response were 100% and 83.3% respectively. Two patients experienced grade 3/4 AEs, including diarrhoea (n = 1) and leukopenia (n = 1). The combination of ixazomib, cyclophosphamide and dexamethasone demonstrated both efficacy and safety in newly diagnosed POEMS syndrome, making it a viable treatment option., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

The role of the proteasome inhibitor ixazomib in the treatment of POEMS syndrome continues to evolve. He and colleagues present the results of a study investigating ixazomib in combination with cyclophosphamide and dexamethasone in newly diagnosed POEMS patients. The triplet showed excellent efficacy and tolerability, and constitutes an effective treatment option for patients with POEMS. Commentary on: He et al. An open-label, prospective trial to evaluate the efficacy and safety of ixazomib in combination with cyclophosphamide and dexamethasone in patients with newly-diagnosed POEMS syndrome. Br J Haematol 2024;205:478-482., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome is a rare form of plasma cell dyscrasia often treated with high-dose chemotherapy and autologous stem cell transplantation (ASCT). ASCT has resulted in satisfactory and sustained therapeutic outcomes. However, a substantial number of patients eventually experience disease progression, requiring second-line treatment. Therefore, it would be of further benefit to identify patients who will acquire the best long-term survival after ASCT. The aim of this study was to fully reveal the outcomes of patients undergoing ASCT in a large series with long-term follow-up. Long-term outcomes of 239 patients with newly diagnosed POEMS syndrome undergoing ASCT at a single center were evaluated retrospectively. Rates of hematologic complete response (CR H ) and vascular endothelial growth factor (VEGF) complete response (CR V ) were 57.3% and 68.6%, respectively, with 90.5% of patients achieving an overall clinical response. At a median follow-up of 94 months, the 5-year overall survival (OS) rate was 92.8%, and the 5-year time to next-line treatment (TTNT) rate was 72.2% (median TTNT, 96 months). Patients achieving CR H (5-year TTNT rate, 82.5% versus 60.7%; P < .0001) or CR V (5-year TTNT rate 83.7% versus 54.2%; P < .0001) had better survival outcomes compared to non-CR group patients. Dual hematologic and VEGF complete responses carry further benefit for survival (median TTNT, 129 months versus 68 months; P < .0001). Seven cases of second primary malignancy were recorded, all of which were solid tumors. Front-line ASCT resulted in excellent long-term survival in patients with POEMS syndrome, with the best survival observed in those achieving dual hematologic and VEGF CRs., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: POEMS syndrome is a rare form of plasma cell dyscrasia characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal proteins, and skin changes. Owing to its low incidence, there are few reports regarding this syndrome. This multicenter study included 84 patients diagnosed with POEMS syndrome in South Korea., Methods: We retrospectively evaluated 84 patients diagnosed with POEMS syndrome at 8 hospitals in South Korea between January 2000 and October 2022. The clinical characteristics and treatment outcomes were analyzed., Results: The median patient age was 53 years (range, 26-77 years), and 63.1% of the patients were male. All patients had peripheral neuropathy, and 81 (96.4%) had monoclonal plasma cell proliferation. Plasma vascular endothelial growth factor levels were available for 32 patients with a median of 821 pg/mL (range, 26-12,900 pg/mL). Other common features included skin changes (54.2%), volume overload (71.4%), and organomegaly (72.6%). Of the 84 patients, 75 received initial treatment (local radiotherapy, 6 [8.0%]; chemotherapy, 17 [22.7%]; both chemotherapy and local radiotherapy, 9 [12.0%]), upfront autologous stem cell transplantation (ASCT), 43 (57.3%; with induction chemotherapy, n = 12, 16.0%; without induction chemotherapy, n = 31, 41.3%). The median follow-up duration was 40.7 months. The 5-year overall survival (OS) was 78%, and the 5-year progression-free survival (PFS) was 55%. Patients who underwent upfront ASCT and were diagnosed after 2014 had a longer OS and PFS., Conclusion: The demographics of Korean patients with POEMS syndrome were similar to those reported previously. Because of the introduction of new treatment agents and the reduced rate of transplant-related mortality related to ASCT, the treatment outcomes of Korean patients with POEMS syndrome have improved in recent years., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Objectives: POEMS syndrome is a rare disorder which has been increasingly recognized. The clonal origin is controversial. Some people argue that POEMS syndrome originates from abnormal plasma cell clones. So, treatment frequently targets the plasma cell clone. Nevertheless, others believe that both plasma cells and B cells can be the potential culprit in POEMS syndrome., Methods: A 65-year-old male came to the emergency department of our hospital with the complaints of bilateral soles numbness and weight loss for half a year, abdominal distension for half a month, and chest tightness and shortness of breath for one day. He was then diagnosed as POEMS syndrome complicated with monoclonal B-cell lymphocytosis (non-CLL type). A standard bendamustine plus rituximab (BR) regimen combined with low dose of lenalidomide was administered., Results: After four cycles of treatment, the ascites of the patient was absent and the neurological symptom disappeared. The renal function, the IgA level, and the VEGF level all returned to normal., Discussion: POEMS syndrome, a multi-system disorder, is easily misdiagnosed. The clonal origin of POEMS syndrome is controversial and needs further study. For now, there are no approved treatment regimens. Treatments mainly target the plasma cell clone. This case suggested that other therapy besides anti-plasma cell treatment may also be effective in POEMS syndrome., Conclusion: We report a patient with POEMS syndrome who achieved complete response after treatment with the combination of a standard BR regimen and low dose of lenalidomide. POEMS syndrome's pathological mechanisms and therapies warrant further studies.

POEMS syndrome is a rare form of plasma cell dyscrasia. Difficulties arise already at the stage of making the diagnosis (complex and heterogeneous clinical picture) and continue during the course of treatment (lack of guidelines for therapy, data coming mainly from reports and short series of patients). In this article we review the current state of knowledge on POEMS syndrome diagnostics, clinical characteristics, prognosis, reported treatment outcomes and the emergence of the new therapeutic strategies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The standard therapies for polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS) syndrome are radiation therapy, high-dose chemotherapy followed by autologous stem cell transplantation, and lenalidomide combined with dexamethasone. Daratumumab was reported to be effective for treatment-naive and relapsed POEMS syndrome, but treatment options for relapsed POEMS syndrome with poor prognostic factors or cytogenetic abnormalities have not been established due to a lack of studies in these patients. Here, we describe a case of relapsed POEMS syndrome with bone plasmacytoma harboring a newly detected 17p deletion after high-dose chemotherapy followed by autologous stem cell transplantation and radiation therapy in a male patient. He was successfully treated with daratumumab plus lenalidomide and dexamethasone (Dara-Rd). Dara-Rd could be effective in relapsed POEMS syndrome with 17p deletion, which is known as a poor cytogenetic abnormality in multiple myeloma. This report may broaden the application of Dara-Rd for POEMS syndrome., (© 2022. Japanese Society of Hematology.)

POEMS syndrome is a rare multisystem paraneoplastic disorder due to an underlying low-level plasma cell dyscrasia. Due to its rarity, there are limited data to guide treatment and there are no consensus guidelines. Therapy choices are dictated by patient characteristics, disease factors and local funding arrangements. The goals of therapy are to eradicate the underlying clone in order to improve quality of life and overall survival. Most evidence has been garnered in the front-line setting. Localised disease responds well to radiotherapy, whilst for those with systemic disease, the best outcomes are demonstrated with induction chemotherapy followed up with high-dose melphalan and stem cell rescue if eligible. For transplant-ineligible patients lenalidomide-dexamethasone remains a preferred treatment option. Data in the relapse setting are scarce. Supportive care including management of neuropathy, endocrinopathy, thrombotic risk and anti-infective agents is necessary. Future international collaboration is crucial to define optimal treatment strategies particularly in the relapse setting., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: To describe the multimodal imaging findings of cystoid macular edema (CME) in POEMS syndrome and to demonstrate the effectiveness of the dexamethasone intravitreal implant in this condition., Methods: A case report of a patient with POEMS syndrome. Multimodal imaging, including optical coherence tomography and ultra-wide field fluorescein angiography, was used to evaluate the CME and its response to treatment., Results: A 66-year-old man with a history of POEMS syndrome in clinical remission after chemotherapy presented with blurry vision in the left eye. Vitreomacular traction and CME were noted on optical coherence tomography. After pars plana vitrectomy, the patient had persistent CME in the left eye and developed new CME in the right eye, which worsened over the next year. Visual acuities at this time were 20 of 60 in both eyes. The CME was unresponsive to topical ketorolac and prednisolone acetate and intravitreal bevacizumab but partially response to intravitreal and sub-Tenon's triamcinolone acetate injections. Intravitreal dexamethasone implant was given bilaterally with full resolution and visual acuities improvement to 20 of 40 in the right eye and 20 of 30 in the left eye. However, CME recurred after 3 months. Ultra-wide field fluorescein angiography demonstrated bilateral CME and diffuse peripheral vascular leakage. Serum vascular endothelial growth factor levels were normal., Conclusion: Cystoid macular edema may develop in POEMS syndrome in the absence of systemic findings, elevated serum vascular endothelial growth factor, or optic nerve edema. Previously unreported peripheral vascular leakage was demonstrated on ultra-wide field fluorescein angiography. Dexamethasone implant was the most effective of used therapies to treat CME.

Objective: To evaluate the clinical characteristics and outcomes of patients with nephropathy associated with POEMS syndrome who received novel agents in combination with dexamethasone therapy, and renal pathological changes based on repeat biopsy in some patients after these novel-agent-based therapies., Methods: The records of patients with nephropathy associated with POEMS syndrome in a single hospital from May 2017 to February 2021 were retrieved and studied in detail. All the patients received four cycles of initial novel-agent-based regimens such as bortezomib and dexamethasone (BD) or thalidomide plus dexamethasone (TD) or lenalidomide plus dexamethasone (RD) treatment. We further evaluated the pathological efficacy of these novel agents by repeat renal biopsy., Results: Twelve patients with an average age of 48.6 ± 8.3 years diagnosed with nephropathy associated with POEMS syndrome were enrolled in this study. The duration from disease onset to renal biopsy was 28(8.3 ~ 54.5) months. All patients achieved good clinical responses in different degree after four cycles of initial novel agents in combination with dexamethasone therapy. After the treatment with novel-agent-based regimens, the levels of proteinuria decreased in most patients and were negative in five patients. The levels of serum creatinine (SCr) decreased in ten patients. Serum M protein was negative in four patients and still positive in the other eight patients. The levels of serum vascular endothelial growth factor (VEGF) were detected in seven patients, which were all decreased. The levels of interleukin-6 (IL-6) were detected in eight patients, which were also decreased. Repeat biopsies were performed after four cycles of novel-agent-based therapies in four patients who were all treated with BD treatment. Mesangiolysis, mesangial cells proliferation, endothelial cells proliferation, subendothelial space widening and acute renal tubulointerstitial lesions improved, the chronic renal tubulointerstitial lesions were stable., Conclusions: Novel agents improved clinical manifestations in patients with nephropathy associated with POEMS syndrome. In addition, novel-agent-based regimens such as BD treatment improved renal pathological manifestations, which suggested that novel agents could improve renal prognosis of the patients from the perspective of renal pathology., (© 2022. The Author(s).)

Objective Immunomodulatory drugs and proteasome inhibitors are therapeutic options for polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome. This study aimed to evaluate the efficacy and safety of the combination of ixazomib, lenalidomide, and dexamethasone (IRd) for POEMS syndrome. Methods Six consecutive patients with POEMS syndrome who were treated with the IRd regimen at Chiba University Hospital between April 2018 and August 2021 were included. Serum M-protein and serum vascular endothelial growth factor (sVEGF) levels, overall neuropathy limitation scales (ONLS), clinical symptoms, and adverse events were assessed. Results Of the six patients, five had received prior treatments. Patients received a median of 5 cycles (range, 3-28 cycles) of IRd. Following treatment, serum M-protein disappeared in two patients, sVEGF levels returned to normal in two patients, two patients showed a reduction in the ONLS of 1, and clinical symptoms improved in four patients. The median level of sVEGF decreased from 2,395 pg/mL (range, 802-6,120 pg/mL) to 1,428 pg/mL (range, 183-3,680 pg/mL) in three months. Adverse events, including rash, neutropenia, sensory peripheral neuropathy, and nausea, were observed in three patients, which necessitated dose reduction or discontinuation of treatment. Conclusion IRd can be a therapeutic option for POEMS syndrome, albeit with careful monitoring of adverse events.

Case Presentation: A 65-year-old man with no past medical history sought treatment at the hospital with lower extremity swelling, pain, tingling in a stocking-glove distribution, and syncope. He reported a 23-pound unintentional weight loss. He felt unsteady walking with a couple of falls, and his exercise tolerance was limited to several hundred feet. He did not report vision changes, dysphagia, bowel or bladder problems, tremor, orthopnea, lightheadedness, or chest pain. He did not report any history of substance misuse, high-risk sexual behavior, or concerning exposures. The patient was admitted for further workup., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy/edema, monoclonal plasma protein [M protein], and skin changes) is a rare paraneoplastic disorder associated with underlying plasma cell neoplasia. Although limited-stage disease can be treated with radiotherapy, treatment for the more advanced disease remains unclear. The most commonly used therapies for POEMS syndrome include alkylators and steroids, high-dose chemotherapy with autologos stem cell transplantation, lenalidomide, and bortezomib. In general, patients tend to have excellent prognosis if the diagnosis is made early and appropriate therapy is used. Here we present a systematic review of the efficacy and safety of treatment regimens used to treat POEMS syndrome in the adult population. Combinations of immunomodulatory agents with corticosteroids were most frequently utilized regimens with durable hematological and neurological responses. Combinations of proteasome inhibitors and alkylating agents with corticosteroids, although less frequently utilized, appear to have reasonable safety and efficacy profiles., (Copyright © 2021 Elsevier Inc. All rights reserved.)

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome is a rare plasma cell dyscrasia without standard front-line treatment. Merely, few studies have reported the responses and outcomes of bortezomib plus dexamethasone (BDex) in POEMS syndrome. In this study, a total of 69 patients (40 males) treated with front-line BDex were included. The median age at diagnosis was 50 years (range, 30-78 years). After a median of 9 cycles BDex (range 1-9), fifty-two (88.1%), thirty-two (46.4%), and forty-seven (71.2%) patients achieved the best neurologic response, hematological complete response, and serum vascular endothelial growth factor (VEGF) response, respectively. The extravascular overload, pulmonary hypertension, and renal impairment also substantially improved. No treatment-related death occurred. Two patients developed grade-1 bortezomib-induced peripheral neuropathy and were reversible after drug withdrawal. After a median follow-up of 22.5 months, the estimated 2-year overall survival and time to next treatment were 95.7% and 65.6%, respectively. In conclusion, the combination of bortezomib and dexamethasone is effective, with a high response rate and safety profile for patients with newly diagnosed POEMS syndrome., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Competing Interests: The authors report no conflicts of interest.

Importance: POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome is a rare plasma cell disorder characterized by demyelinating peripheral neuropathy and clonal plasma cell proliferation. Clinical manifestations are believed to be associated with a surge of inflammatory and angiogenic mediators, including interleukins and vascular endothelial growth factor (VEGF), elicited by clonal and polyclonal plasma cells. The clinical manifestations of POEMS syndrome can be debilitating; therefore, early diagnosis is essential. This review discusses several aspects of POEMS syndrome and includes the most recently published findings, with a special emphasis on diagnosis and treatment strategies., Observations: POEMS syndrome may be underdiagnosed because of its rarity, and it can be mistaken for chronic inflammatory demyelinating polyneuropathy; this misdiagnosis may lead to delayed therapy and progressive worsening of symptoms, especially neuropathy. Therefore, in addition to measurement of the VEGF level, patients with a monoclonal protein detected in blood and/or urine and neuropathy should be evaluated for POEMS syndrome with use of imaging to assess whether sclerotic bone lesions, effusions, and organomegaly are present. Clinical trials are scant, and treatment is largely based on small case series in which plasma cell-directed therapies, borrowed from the myeloma armamentarium, were used. High-dose melphalan and autologous hematopoietic cell transplantation may be offered to eligible patients. Lenalidomide and dexamethasone can be prescribed for patients who are ineligible for transplants. The main goals of therapy are to attain complete hematologic and VEGF responses and to reduce symptoms, although it may take up to 3 years for neurologic deficits to be ameliorated., Conclusions and Relevance: POEMS syndrome should be considered in the differential diagnosis for patients who have peripheral neuropathy and paraproteinemia among other multisystem manifestations. The syndrome can be debilitating if not recognized early in its course; thus, appropriate diagnosis and treatment are important for optimal clinical outcomes.

POEMS syndrome is a rare plasma cell disorder. Lenalidomide has recently emerged as a therapeutic option for POEMS syndrome. Cereblon has been identified as the direct target of lenalidomide, and high cereblon expression is associated with better response and outcome to lenalidomide therapy in multiple myeloma patients. Here, we analyzed the predictive value of cereblon, IKZF1, and IKZF3 in CD138 + selected plasma cells from forty-one newly diagnosed POEMS syndrome patients treated with lenalidomide in combination with dexamethasone at both gene and protein levels. We found that patients with high cereblon expression tended to achieve better hematologic response compared to those with low expression (p = 0.024 for gene expression; p = 0.01 for protein expression). Multivariate Cox regression analysis revealed high cereblon mRNA expression as an independent prognostic marker for longer progression-free survival (hazard ratio 0.542; 95% CI 0.337-0.871; p = 0.011). In conclusion, our results emphasized the role of cereblon mRNA expression as a unique biomarker for predicting the clinical response and outcome of lenalidomide-based therapy in newly diagnosed POEMS syndrome patients.

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome is rare, with polyneuropathy and monoclonal plasma cell disorder generally considered as essential diagnostic symptoms. We report two cases of POEMS syndrome without monoclonal protein expression. The first case was a 72-year-old man who had experienced recurrent edema of the lower limbs for 2 years and abdominal distention for 2 months. The other case was a 62-year-old man with a 5-year history of recurrent numbness of the extremities and muscle weakness, which had become serious over the preceding 3 months. Both patients had various symptoms that matched those of POEMS syndrome, but neither had monoclonal protein expression. However, a diagnosis of POEMS syndrome was made in each case. Both patients were treated with lenalidomide and dexamethasone, after which their symptoms improved and laboratory test results normalized. The findings in these two cases suggest the possibility that POEMS syndrome may occur without monoclonal protein expression. The diagnostic criteria of POEMS syndrome may thus need further investigation.

We herein report a case of multiple myeloma and polyneuropathy, organomegaly, endocrinopathy, myeloma protein, and skin changes (POEMS) syndrome. The patient experienced exacerbated gait disturbance due to weakness and numbness in the lower limbs. Thoracic magnetic resonance imaging revealed an extramedullary tumor with spinal compression that required surgical resection. Plasmacytoma was diagnosed based on a biopsy. Radiation, betamethasone, and chemotherapy were therefore administered. Surgical removal of extramedullary tumors improved his symptoms, motor conduction velocity, and amplitude of the muscle action potential in the peroneal and tibial nerves, as shown by the nerve conduction study. Surgery also decreased the serum vascular endothelial growth factor levels. The patient required additional chemotherapy due to multiple myeloma and showed better outcomes nine months after discharge. The benefits of some treatments remain controversial due to the small number of patients. However, our findings reveal that an early diagnosis and comprehensive treatment may result in better outcomes in such patients.

Endocrinopathy is an important characteristic of POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome. However, endocrine responses to different regimens were unknown so far. Here we investigated endocrine characteristics in 383 patients with newly diagnosed POEMS syndrome and thyroid responses 1 year after treatment with autologous peripheral stem cell transplantation, melphalan plus dexamethasone, or lenalidomide plus dexamethasone. Overt hypothyroidism and subclinical hypothyroidism were noted in 20.6% (79/383) and 36.0% (138/383) of patients. Adrenal insufficiency was noted in 13.6% (43/316) of patients. Hyperprolactinemia was noted in 62.7% (207/330) of patients. Hypogonadism was noted in 48.0% (60/125) of female and 22.6% (51/226) of male patients. Thyroid function was significantly related with baseline risk stratification ( p < 0.001) and significantly improved regardless of initial regimens. Patients with baseline hypothyroidism had a significant inferior progression-free survival (PFS) ( p = 0.028) and overall survival (OS) ( p = 0.006). Three-year PFS in patients with and without baseline hypothyroidism were 68.9 vs. 82.5%, respectively. Three-year OS rates in patients with and without baseline hypothyroidism were 82.8 vs. 92.8%, respectively. In summary, hypothyroidism, hyperprolactinemia, and hypogonadism are common endocrinopathies in POEMS syndrome. Thyroid function significantly improved regardless of the initial regimens. Thyroid function parallels with baseline risk stratification, and patients with baseline hypothyroidism have significantly inferior OS and PFS., (Copyright © 2020 Yang, Zhao, Gao, Huang, Cao, Zhou, Xia and Li.)

Background: Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS) syndrome is a rare paraneoplastic syndrome involving multisystem. Optic disc edema (ODE) is the most common ocular manifestation in patients with POEMS syndrome and serves as an independent prognostic factor. However, parameters previously used to estimate its severity were inconvenient and costly. This study was designed to bring forward a novel and practical parameter, optic disc edema area, to evaluate ODE in patients with this disease and applied it to assess effectiveness of lenalidomide combined with dexamethasone in respect of ODE., Results: Forty-one treatment-naive patients with POEMS syndrome were enrolled in this single-center prospective study and treated with lenalidomide combined with dexamethasone. They received ocular examination to determine optic disc edema (ODE) area and other optic manifestations. Meanwhile, serum VEGF was measured before and after treatment. Among 41 enrolled patients, 38 received complete ocular examinations, and 25 of which had ODE at initial visit. Binocular mean ODE area of patients with ODE was significantly related to ODE grade (r = 0.620, p = 0.003) and peripapillary retinal thickness (r = 0.760, p < 0.001) before treatment. Serum VEGF was significantly higher in patients with ODE than their counterparts (p = 0.025) and positively correlated with binocular mean ODE area (r = 0.460, p = 0.036). After treatment, ODE area, along with serum VEGF, decreased markedly (p < 0.001)., Conclusion: ODE area was a reliable index to evaluate ODE severity and could precisely reflect ODE improvement through systemic treatment. Additionally, it was related to serum VEGF, a key factor in disease pathogenesis, suggesting its potential as an indicator of the overall severity of this disease., Trial Registration: Clinicaltrials, NCT01816620. Registered March 222,013.

Objective A randomized controlled trial has shown the efficacy of thalidomide against polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome; however, there are still refractory patients. We studied the effects of lenalidomide, a derivative of thalidomide, on patients refractory to thalidomide. Methods This prospective single-arm trial evaluated the safety and efficacy of lenalidomide plus dexamethasone in refractory or recurrent patients with POEMS syndrome. The regimen was administered as six 28-day cycles with lenalidomide on days 1-21 (15 mg in cycle 1, and 25 mg in cycle 2-6) plus dexamethasone once a week (20 mg). The primary endpoints were the rate of reduction in the serum vascular endothelial growth factor (VEGF) level at 24 weeks and the incidence of adverse events. This trial was registered with ClinicalTrial.gov, NCT02193698. Results Between July 2014 and December 2015, five men were enrolled. All patients had been refractory to thalidomide plus dexamethasone for more than 24 weeks. The mean rate of reduction in the serum VEGF level at 24 weeks was 59.6%±8.3% (p=0.0003). The mean serum VEGF level decreased from 2,466±771 pg/mL to 974±340 pg/mL. No serious adverse events were observed, and all patients completed six cycles treatment. Discussion Lenalidomide is a therapeutic option for thalidomide-refractory patients with POEMS syndrome.

A 70-year-old woman experienced pain in both gastrocnemius muscles, numbness in the toes, and muscle weakness in both the legs that lasted for two months. After getting admitted to our hospital, the muscle weakness extended to both her arms, and nerve conduction studies revealed decreased nerve conduction velocity, which was more prominent in the elbow and the axilla than in the wrist. A magnetic resonance imaging revealed a tumor in the right femoral neck, which was histologically diagnosed as plasmacytoma. Laboratory findings revealed IgA lambda type M protein and an elevated VEGF level of 2,320 pg/ml; edema was present in both the legs. After a diagnosis of POEMS syndrome, lenalidomide and dexamethasone treatment were initiated simultaneously, along with irradiation. The treatment improved polyneuropathy, along with a decrease in the VEGF level. Increased vascular permeability due to elevated VEGF led to the development of neuropathy of POEMS syndrome, and treatment against proliferating monoclonal plasma cells is effective. In the present case, we believe that a prompt control of the plasmacytoma with novel therapeutic agents for myeloma with irradiation resulted in the improvement of the neurological symptoms.

Aim: To determine whether changes in the serum levels of vascular endothelial growth factor (VEGF) after thalidomide therapy will affect the peripapillary retinal thickness (pRT) associated with optic disc oedema (ODE) in patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS) syndrome., Methods: This was a retrospective, observational case series of 23 right eyes of 23 treatment-naïve patients with POEMS syndrome and ODE whose intracranial pressure was within the normal range. The pRT was determined by spectral-domain optical coherence tomography, and the serum level of VEGF was determined by ELISA at baseline and 6 months after the thalidomide therapy. We determined whether a change in the pRT from baseline was significantly correlated with the serum level of VEGF from that at 6 months after the thalidomide treatment., Results: Six months after treatment, the mean serum level of VEGF was significantly reduced from 7153±4214 pg/mL to 1067±769 pg/mL (p<0.001), and the pRT was significantly decreased from 471.2±203 µm to 318.1±53.9 µm (p<0.001). The change in the pRT from baseline was significantly and linearly correlated with the change in the serum level of VEGF from that at 6 months after treatment (r=0.67, p=0.00039)., Conclusions: The close relationship between the pRT and the serum level of VEGF may offer clues on the pathogenesis of POEMS syndrome and potentially add a new candidate cause for the pathogenesis of ODE., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Polyneuropathy is a key feature of polyneuropathy, organomegaly, endocrinopathy, monoclonal band, and skin changes syndrome, which is a paraneoplastic manifestation of an underlying lymphoproliferative neoplasm. We report the first case of polyneuropathy, organomegaly, endocrinopathy, monoclonal band, and skin changes syndrome presenting with a pseudosensory level., Case Presentation: A 59-year-old Tamil woman with long-standing diabetes mellitus and hypertension developed painless, progressive inguinal lymphadenopathy. A contrast-enhanced computed tomography scan showed mild hepatomegaly and intra-abdominal lymphadenopathy. A histological examination of an enlarged inguinal lymph node showed features of a plasma cell-type Castleman disease. She was treated with rituximab. Six months later, she developed gradually ascending numbness and weakness of both lower limbs. On examination, she had flaccid paraparesis (power 3/5) with a sensory level to pinprick at thoracic level 9. Joint position sense was preserved. Her cranial nerves and upper limbs were neurologically normal. Nerve conduction studies confirmed peripheral neuropathy with conduction slowing and a magnetic resonance imaging of her spine did not show cord or root compression. Serum protein electrophoresis showed a monoclonal band. A bone marrow biopsy showed a hypercellular marrow with 30% plasma cells. A repeat contrast-enhanced computed tomography scan showed sclerotic bony lesions involving multiple vertebrae in addition to mild hepatomegaly and intra-abdominal lymphadenopathy. Polyneuropathy, organomegaly, endocrinopathy, monoclonal band, and skin changes syndrome was diagnosed and she was treated with intravenously administered pulse therapy of dexamethasone and cyclophosphamide. After three cycles of treatment, she regained normal muscle power and sensation., Conclusions: Polyneuropathy in polyneuropathy, organomegaly, endocrinopathy, monoclonal band, and skin changes syndrome can present as a pseudosensory level.

A 48-year-old woman with polyneuropathy, organomegaly, endocrinopathy, M-protein, skin change (POEMS) syndrome suddenly presented with numbness of her right upper limb. Magnetic resonance imaging showed multiple acute infarctions in her left cerebrum, and magnetic resonance angiography (MRA) showed multiple intra-cranial vascular lesions, which contrasted with previously normal MRA results obtained eight months prior to the stroke. After completing successful treatment for POEMS syndrome, there were no recurrent stroke episodes. A six-month follow-up scan showed that although the vascular lesions did not progress, they did not improve much either. POEMS syndrome is associated with the rapid extension of large blood vessels-vasculopathy-resulting in nearly irreversible brain lesions.

A 72-year-old man presented with a 6-month history of systemic edema. Hyperpigmentation, hemangioma, pleural effusion, IgG-kappa-type monoclonal protein, high vascular endothelial growth factor values, renal failure, and nerve conduction study abnormalities were also present. Multiparameter flow cytometry (MFC) showed 0.2% neoplastic plasma cells (CD38-, CD56-, and kappa-positive; CD19-, CD27-, and lambda-negative) in the bone marrow leading to POEMS syndrome. Cases involving kappa-type POEMS syndrome are extremely rare. A kidney biopsy revealed membranous proliferative glomerulonephritis-like changes in our case. Lenalidomide-dexamethasone therapy improved the renal function. Detection of neoplastic plasma cells by MFC was useful for the accurate diagnosis and treatment evaluation.

Although cardiac involvement is rare in polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome, the clinical course becomes considerably worse on complication with cardiac lesions. The increased release of various cytokines has been observed in the pathogenesis of POEMS syndrome, and serum vascular endothelial growth factor (VEGF) levels are known to be associated with the disease activity. We herein report a patient with POEMS syndrome who showed left ventricular systolic dysfunction and was treated with lenalidmide therapy. Of note, the reduction in extracellular edema in the left ventricular wall was clearly visualized by changes in the native T1 values and extracellular volumes on cardiac magnetic resonance imaging.

POEMS syndrome is a rare paraneoplastic disease associated with monoclonal plasma cells; however, the pathogenic importance of plasma cells remains unclear. We performed comprehensive genetic analyses of plasma cells in 20 patients with POEMS syndrome. Whole exome sequencing was performed in 11 cases and found a total of 308 somatic mutations in 285 genes. Targeted sequencing was performed in all 20 cases and identified 20 mutations in 7 recurrently mutated genes, namely KLHL6, LTB, EHD1, EML4, HEPHL1, HIPK1, and PCDH10. None of the driver gene mutations frequently found in multiple myeloma (MM) such as NRAS, KRAS, BRAF, and TP53 was detected. Copy number analysis showed chromosomal abnormalities shared with monoclonal gammopathy of undetermined significance (MGUS), suggesting a partial overlap in the early development of MGUS and POEMS syndrome. RNA sequencing revealed a transcription profile specific to POEMS syndrome when compared with normal plasma cells, MGUS and MM. Unexpectedly, disease-specific VEGFA expression was not increased in POEMS syndrome. Our study illustrates that the genetic and transcriptional profiles of plasma cells in POEMS syndrome are distinct from MM and MGUS, indicating unique function of clonal plasma cells in its pathogenesis.

Skin changes, including peripheral edema, hyperpigmentation, hypertrichosis, and hemangioma are frequent and early manifestations of POEMS (polyneuropathy, organomegaly, enndocrinopathy, M-protein, and skin changes) syndrome. Hemangiomata is presumably caused by overproduction of the vascular endothelial growth factor, and hypertrichosis results from the deposition of melanin; however, the pathogenesis of the skin symptoms are poorly understood. Nevertheless, recognition of the skin changes facilitates early diagnosis and treatment. Novel treatments, such as autoplantation, thalidomide/lenalidomide, and proteasome inhibitors have been availoble since 2000, and outcomes of the disorder have significantly improved. Appropriate understanding of the skin manifestations is clinically important for the early diagnosis of this intractable disorder.

The diagnosis of polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome requires polyneuropathy and monoclonal plasma cell proliferation as two mandatory criteria. Our aim was to summarize clinical manifestations and treatment responses of POEMS variants with no evidence of monoclonal gammopathy. We queried all medical documentation of patients referred to Peking Union Medical College Hospital from August 2012 to July 2017, and reviewed the clinical and laboratory features of 13 patients with atypical POEMS syndrome with undetectable monoclonal gammopathy, and compared to prototypes published. The prevalence of polyneuropathy, organomegaly, skin changes, and extravascular fluid overload were 100%, 100%, 92%, and 100%, respectively. Other clinical manifestations, such as endocrinopathy, pulmonary hypertension, papilledema, thrombocytosis, and polycythemia affected similar percentages of patients as seen in prototypes. POEMS variants enrolled had a median serum vascular endothelial growth factor (VEGF) level of 4998 pg/ml (range 2155-11,029 pg/ml). Long-term follow-up found that all 12 patients received autologous stem cell transplant, melphalan-based therapy or lenalidomide/thalidomide-based therapy obtained clinical improvement, of which eight experienced decreased levels of VEGF by 50% or back to normal. The median progression-free survival was 101.5 months. Our findings raised a variant of POEMS syndrome variants with featured clinical manifestations, elevated VEGF levels, and good response to therapies targeting plasma cell.

Hypothyroidism is the most common endocrine disorder in POEMS syndrome. In this single-center prospective study, 36 patients with newly diagnosed POEMS syndrome were treated with lenalidomide (10 mg daily for 21 days) and dexamethasone (40mg once per week) for 12 cycles. Hypothyroidism was demonstrated in 58.5% (24/41) at baseline, including 25% (6/24) of clinical hypothyroidism and 75% (18/24) of subclinical hypothyroidism. After 12-month treatment, the percentages of clinical hypothyroidism and subclinical hypothyroidism had decreased 11.8% and 27.2%, respectively. Percentage of euthyroidism had increased from 41.5% to 80.5%. There was a strong relation between VEGF response and thyroid function improvement (p = .028). Patients with clinical hypothyroidism at baseline had an inferior 1-year OS (50% vs. 100%, p < .043) than euthyroidism and subclinical hypothyroidism groups. Clinical hypothyroidism was associated with decreased overall survival and this combination treatment was effective in improving thyroid function in POEMS syndrome.

We report three cases of POEMS syndrome treated with lenalidomide and dexamethasone who presented with peripheral neuropathy. All of them had markedly elevated serum vascular endothelial growth factor (VEGF) levels treated with lenalidomide and dexamethasone for severe peripheral neuropathy, which normalized serum VEGF levels and improved peripheral neuropathy. The standard treatment of POEMS syndrome has not been established, but has been effectively treated with high-dose chemotherapy with autologous stem cell transplantation. Newer agents currently used for plasma cell dyscrasias include bortezomib and immunomodulatory drugs, such as thalidomide and lenalidomide. A randomized controlled trial on thalidomide plus dexamethasone for POEMS syndrome showed reduced serum VEGF levels after therapy; however, the incidence of peripheral neuropathy, a well-known side effect of both thalidomide and bortezomib, increased. Lenalidomide is associated with lower incidence of peripheral neuropathy compared to thalidomide and bortezomib, making it a reasonable treatment option for POEMS syndrome.

Purpose of Review: To provide an overview of polyneuropathy organomegaly endocrinopathy M-protein and skin changes (POEMS) syndrome, detailing new insights into pathogenesis, prognostic factors, treatments, and outcome scores., Recent Findings: With the development of large multicentre national cohorts of patients, POEMS syndrome is evolving into a well characterized multisystem hematoneurological syndrome. Without early diagnosis significant disability results from the neuropathy. Vascular endothelial growth factor (VEGF) is a useful and accurate biomarker supporting diagnosis and following disease activity. The past decade has seen a number of therapeutics become available to patients with POEMS, repurposed from myeloma treatment. Simple treatment algorithms are based on the extent of monoclonal proliferation and the performance status of patients. Risk factors, prognostic scores, and their impact on outcome measures have been developed from deeply phenotyped patient cohorts to predict response rate, progression-free survival and overall survival., Summary: Understanding links between the monoclonal lambda plasma cell disorder and resulting proinflammatory cytokine milieu is fundamental to determining POEMS syndrome pathophysiology. Similarities to chronic inflammatory demyelinating polyradiculoneuropathy and some other monoclonal proliferative diseases makes POEMS misdiagnosis common. A range of treatments are available, and more work to identify pathogenic mechanisms and treatment targets and prognostic scores will further enable treatment stratification for optimum outcomes.

Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare plasma dyscrasia without standard treatment. This phase II prospective trial evaluates the safety and response of 12 cycles of low dose lenalidomide (10 mg) plus dexamethasone (Rdex) in patients with newly diagnosed POEMS syndrome. Forty-one patients (28 men) were enrolled and the median age at diagnosis was 49 years (range, 21-70 years). Twenty-one patients (46%) achieved complete hematologic response and the neurologic response rate was 95%. The median serum vascular endothelial growth factor (VEGF) declined from 5155 pg/mL (range, 534-14 328 pg/mL) to 832 pg/mL (95-6254 pg/mL) after therapy. The overall VEGF response rate was 83%, and the median time to response was 2 months, with a mean VEGF reduction of 43% at the first month. In terms of clinical response, Rdex substantially relieved extravascular volume overload, organomegaly, and pulmonary hypertension. No treatment-related deaths occurred and no patients suffered from lenalidomide-related grade 3 or above adverse events. After a median follow-up of 34 months, median overall survival (OS) and progression-free survival (PFS) were not reached, with an estimated 3-year OS and PFS of 90% and 75%, respectively. In conclusion, Rdex was active with high hematologic, VEGF and organ response rate and well tolerated for patients with newly diagnosed POEMS syndrome. This trial was registered at www.clinicaltrials.gov as #NCT01816620., (© 2018 Wiley Periodicals, Inc.)

We describe the case of a 34-year-old woman with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome. She developed transient ischemic attack after the introduction of lenalidomide plus dexamethasone (Rd) therapy despite no vascular risk factors. Magnetic resonance and computed tomography angiographies showed bilateral internal carotid artery stenosis. Rd therapy was suspended because of its thromboembolic risk. She had been neurologically stable during the suspension of Rd therapy. After Rd therapy was restarted, however, she repeated ischemic cerebrovascular disease. Rd therapy was switched to carfilzomib plus dexamethasone therapy. Thereafter, she had been neurologically stable. Multivessel stenosis is infrequently seen in POEMS syndrome. Therefore, magnetic resonance angiography should be performed before introducing Rd therapy in POEMS syndrome., (Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Introduction: Arterial and venous thromboses occur in almost one in five patients with POEMS syndrome and usually in macrocirculation., Case Report: We report a 67-year-old male with a POEMS syndrome who presented initially with a blue toe syndrome. He complained of Raynaud's syndrome and left foot paresthesia. Physical examination showed gynecomastia, lymphadenopathies and skin lesions. Cardiovascular investigations excluded atrial fibrillation, unstable atherosclerotic lesions and vascular calcifications. Imaging studies showed diffuse osteosclerotic lesions. Monoclonal protein with lambda light chain was discovered and serum level of VEGF was increased at 2900pg/ml., Conclusion: This is to our knowledge the first case of thrombotic microangiopathy in POEMS syndrome without embolic cause or calciphylaxis., (Copyright © 2017 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

POEMS syndrome is a rare paraneoplastic syndrome secondary to a plasma cell dyscrasia. Recognition of a combination of peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasmaproliferative disorder, skin changes, papilledema, extravascular volume overload, sclerotic bone lesions, thrombocytosis, and Castleman disease is the first step in managing the disease. Increased blood levels of vascular endothelial growth factor are usually confirmatory. This rare disorder should not be missed, especially if the patient has a putative diagnosis of chronic inflammatory polyradiculoneuropathy, a lambda restricted monoclonal gammopathy, and thrombocytosis, and is not responding as expected to immunomodulatory therapy commonly used for chronic inflammatory polyradiculoneuropathy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Given its anti-angiogenic activity, lenalidomide may have a role in the treatment of POEMS (Peripheral neuropathy, Organomegaly, Endocrinopathy, Monoclonal plasma cell disorder and Skin changes) syndrome. This prospective, open-label, pilot study evaluated the combination of lenalidomide + dexamethasone (RD) in 18 POEMS syndrome patients (13 pre-treated, 5 newly-diagnosed but ineligible for high-dose therapy). Treatment consisted of six cycles of lenalidomide (25 mg/day for 21 days followed by 7 days rest) plus dexamethasone (40 mg/once a week). Patients responding after six cycles continued treatment until progression or unbearable toxicity. The primary endpoint was the proportion of patients with either neurological or clinical improvement. The RD combination was considered as deserving further evaluation if 9 of the first 15 patients responded. Ten responses were observed among the first 15 enrolled patients, meeting the primary endpoint. Fifteen of 18 patients (83%) completed six RD cycles: 13 (72%) patients responded and nine had both clinical and neurological improvement. Among the 15 patients who completed the six RD cycles, four were still on treatment after a 25-month follow-up. At 39 months of follow-up, all patients were alive with a 3-year progression-free survival of 59%. No patient discontinued RD for toxicity. Overall, the RD regimen showed a high incidence of prolonged symptoms improvement and was well tolerated in most POEMS patients., (© 2017 John Wiley & Sons Ltd.)