Ixazomib in POEMS syndrome: 'Ixa'ctly what we need?

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.

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.

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.

Paraproteinemic neuropathies.

The diagnostic evaluation of a peripheral neuropathy includes testing for the presence of monoclonal gammopathy, which can be found in about 10% of patients with peripheral neuropathy. Our role, as physicians, is to determine whether the neuropathy is directly related to the gammopathy or whether the co-occurrence of these two disorders is purely coincidental. The evaluating physician needs to be familiar with the different types of neuropathies associated with monoclonal gammopathies, their clinical and electrodiagnostic characteristics, and their appropriate diagnostic evaluation and management. Testing for monoclonal protein disorders includes serum protein electrophoresis (SPEP) and immunofixation of blood, and in some cases of urine, as well as measurement of free light chains and quantitative immunoglobulins. Specific antibody testing is directed by paraprotein type and neuropathy phenotype. Patients with abnormal free light chains in association with sensory and autonomic neuropathy should be evaluated for AL amyloidosis. When a lambda monoclonal protein is identified together with a clinical phenotype of chronic inflammatory demyelinating neuropathy (CIDP), a diagnosis of polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes (POEMS) syndrome should be considered. Patients with IgM paraprotein associated neuropathy should be assessed for distal acquired demyelinating sensorimotor (DADS) neuropathy, with or without anti myelin associated glycoprotein (MAG) antibody or CANOMAD syndrome. In many cases, a monoclonal gammopathy of uncertain significance (MGUS) is incidental and unrelated to the neuropathy. Collaboration with oncology is critical in evaluating patients with monoclonal proteins to assess for underlying plasma cell neoplasms or B cell lymphomas.

Giant papillary hemangioma-A rare tumor with an exceptional size.

Papillary hemangioma (PH) is a recently described vascular tumor with a predilection for the skin of the head and neck. Histopathologically, it is characterized by a bland endothelial proliferation arranged in a papillary configuration, bearing resemblance to glomeruloid hemangioma seen in the context of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes syndrome. The largest cutaneous PH reported to date measured 1.5 cm in greatest dimension. Here, we report a case of PH with an alarming size of 10 cm. We present this case to add to the limited literature on this rare tumor, highlight the histopathologic differences between PH and its mimics, and emphasize the variable nature of PH tumor size.

Regular assessment of serum vascular endothelial growth factor levels to monitor POEMS syndrome.

BACKGROUND: To investigate the utility of regular serum VEGF (sVEGF) levels assessment in the monitoring of POEMS syndrome. METHODS: We retrospectively reviewed data of 30 patients with POEMS syndrome whose sVEGF was tested regularly every 6 months. sVEGF levels after treatment were measured and correlated with disability (Overall Neuropathy Limitations Scale, ONLS), clinical impairment (measured with the modified Clinical Response Evaluation Scale, mCRES), and relapse-free survival. The ability of sVEGF to predict disease flares during remission and refractory disease was also analysed. RESULTS: Patients with normalised serum VEGF levels (< 1000 pg/ml) at 6 months showed prolonged relapse-free survival (at 3-year 94% for complete VEGF response, 57% partial, 0% none, p < 0.001) and greater later clinical improvement (median ΔmCRES complete VEGF response -5 vs partial -4, p = 0.019, and vs no VEGF response -2, p = 0.006). After remission, the sensitivity of 6-month sVEGF monitoring in predicting clinical relapse was 58% with a specificity of 100%. In patients refractory to treatment, the sensitivity in predicting further clinical worsening was 15%. In addition, in 25% of the patients in remission and 16% of those refractory to therapy, sVEGF levels only increased at the time of relapse. CONCLUSIONS: Regular sVEGF assessment is a valid biomarker in the prediction of disease reactivation in POEMS syndrome and was particularly useful during the phase of remission.

A Multicenter Analysis of Clinical Features and Long-Term Outcomes of POEMS Syndrome in Korea.

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.

[A race against time: POEMS syndrome]. / "Verseny az idovel": a POEMS szindróma.

Background - POEMS syndrome is a potentially well manageable disease with an ascendant therapeutic arsenal nowadays. The early recognition of the syndrome is key to prevent serious multiorgan damage, and that is still a big challenge for physicians. With the following two case reports the authors aimed to highlight the consequences of late recognition of the disease and summarize the potential therapeutic options for POEMS syndrome.

Results - We have presented two patients’ cases with a long history of examination and treatment because of uncleared polyneuropathy. Through these cases we could see how serious could be the consequences of late diagnosis and despite multiorgan impairment there are still therapeutic options which could improve the patient’s condition. Although the diagnosis of POEMS syndrome is not easy, it must raise our mind the thought and be prudent when we start a treatment in polyneuropathy.

Small vessel platelet thrombosis in the peripheral nerves in POEMS syndrome.

INTRODUCTION/AIMS: Vascular thrombosis is prevalent among patients with polyneuropathy, organomegaly, endocrinopathy M-protein, and skin changes (POEMS) syndrome. The endothelial cells in the endoneurium are often hypertrophied and the lumen is frequently occluded. Consequent local hypoxia may increase vascular endothelial growth factor (VEGF), which induces hypercoagulation and vascular permeability. METHODS: This study presents two patients in the fifth decade of life, who had rare nerve biopsy findings of vascular occlusion mainly by platelets. Before the cases presented here, we encountered nine confirmed POEMS patients whose nerve biopsies did not show similar findings. RESULTS: A small artery and a vein were occluded, but no atherosclerotic changes were observed. The endothelial cells that adhered to the packed platelets lost their junctions. DISCUSSION: Platelet aggregation, degranulation, and ischemia may cause a loose endothelial barrier and leak proinflammatory cytokines, such as interleukin-12. This may increase production of VEGF and may cause nerve demyelination. Small vessel platelet thrombosis may contribute to the pathogenesis of this disorder.

Treatment-responsive glycogen storage myopathy in a patient with POEMS syndrome: A new monoclonal gammopathy-associated myopathy.

BACKGROUND: Myopathies associated with monoclonal gammopathy are relatively uncommon and underrecognized, treatable myopathies, and include sporadic late onset nemaline myopathy, light chain amyloid myopathy, and a recently described vacuolar myopathy with monoclonal gammopathy and stiffness (VAMGS). Herein, we report a new subtype of monoclonal gammopathy-associated myopathy (MGAM) in a polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) patient. METHOD: Case report. RESULTS: A 51-year-old woman presented with a 6-month history of progressive bilateral foot drop, lower limb edema, and a 15-lb weight loss. She denied muscle stiffness. Neurologic exam showed severe distal weakness, mild proximal weakness, and length-dependent sensory deficits. Laboratory studies revealed biclonal gammopathy (IgG kappa and IgA lambda), thrombocytosis, and elevated vascular endothelial growth factor. Creatine kinase was normal. Electrodiagnostic studies identified mixed demyelinating and axonal polyradiculoneuropathy and a superimposed proximal myopathy. Gluteus medius biopsy demonstrated scattered fibers with glycogen-filled vacuoles, similar to VAMGS, with additional rare myofibers containing polyglucosan bodies. She was diagnosed with POEMS syndrome and concomitant glycogen storage myopathy. Next-generation sequencing of glycogen storage and polyglucosan body myopathy-related genes was unrevealing. Proximal weakness resolved after autologous stem cell transplant. CONCLUSIONS: This patient expands a spectrum of MGAM. Recognition of this condition and other subtypes of MGAM is of utmost important because they are treatable.

Pulmonary manifestations of POEM syndrome: a retrospective analysis of 282 cases.

BACKGROUND: Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare multisystemic clonal plasma cell disorder. Pulmonary involvement is frequently found in patients with POEMS syndrome, manifesting various clinical features. Therefore, to improve diagnostic accuracy and provide treatment strategies, a comprehensive analysis of pulmonary manifestations of POEMS syndrome is needed. METHODS: This retrospective study included patients with POEMS syndrome at Peking Union Medical College Hospital, a major referral medical center in China, between June 1, 2013, and June 1, 2023. Demographic data, laboratory findings, pulmonary function test results, echocardiograms, and chest imaging data were extracted. Continuous variables were compared using the t-test or Mann-Whitney method. Pearson's chi-square test or Fisher's exact test was conducted to compare categorical data. RESULTS: Overall, 282 individuals diagnosed with POEMS syndrome were included in this study, of which 56% were male with an average age of 48.7 years. Respiratory symptoms were found in 40.1% of the patients, with dyspnea as the most common symptom (34.4%). Chest computed tomography and echocardiography findings showed that 56.4% of patients exhibited pleural effusion, 62.8% displayed mediastinal or hilar lymphadenopathy, 46.5% presented pleural thickening, 27.3% demonstrated bone lesions of the ribs or thoracic vertebra, 7.8% showed lung interstitial abnormalities, and 35.5% had pulmonary hypertension. Decreased diffuse capacity and restrictive ventilatory patterns were identified in 85.2% (115 cases) and 47.4% (64 cases) of patients, respectively. Patients with respiratory symptoms exhibited higher declined lung function measures than those having no respiratory symptoms. High-risk patients with poor prognosis showed more pulmonary function abnormalities. CONCLUSION: Abnormalities in pulmonary manifestations constitute the significant features of POEMS syndrome. Several patients with POEMS syndrome presented with respiratory symptoms at the initial evaluation. These findings underscore the importance of early identification and accurate diagnosis of POEMS syndrome by clinicians, particularly in cases involving lung and multisystem.

The role of interleukin 6 in the pathogenesis and therapy of Castleman disease - an immunologist's perspective.

Castleman disease (CD) is a heterogeneous group of diseases characterized by lymphadenopathy and systemic inflammatory manifestations. CD can be divided into uni- (UCD) and multicentric form (MCD) according to the disease extent. MCD is usually accompanied by the features of a systemic inflammatory response including fever, weight loss, hepatosplenomegaly, ascites, and edema. In these patients, we can also observe elevation of inflammatory parameters and anemia within the laboratory assessment. Based on etiological nature, the CD can be further divided into human herpesvirus-8-associated (HHV8-associated) and idiopathic form. Interleukin 6 (IL-6) plays a central role in the disease pathogenesis. Inhibition of IL-6 has been shown to be an effective treatment modality. Currently, siltuximab, a chimeric monoclonal antibody targeting IL-6, is the only approved treatment for MCD. Its short-term and long-term efficacy and safety have been demonstrated in a few clinical studies.

[POEMS Syndrome with Peripheral Edema and Ascites as the Main Manifestations:Report of One Case].

POEMS syndrome is a rare disease caused by monoclonal plasma cell proliferative disorder.The typical signs include peripheral neuropathy,organ enlargement,endocrine disease,M proteinemia,and skin changes.In clinical practice,the atypical,complex,and changeable clinical manifestations of this syndrome can easily lead to misdiagnosis and missed diagnosis.A case of POEMS syndrome with peripheral edema and ascites as the main manifestations is reported in this paper.

[Identification of transcriptional features and surface markers of plasma cell clones in POEMS syndrome by single-cell RNA sequencing].

POEMS syndrome is a rare monoclonal plasma cell disorder with unique symptoms distinct from other plasma cell neoplasms. To identify and find the transcriptional features of clonal plasma cells in POEMS syndrome (POEMS clones), single-cell RNA sequencing was performed on patient-derived bone marrow plasma cells. POEMS clones were identified in 5 out of 10 patients, and the proportions of POEMS clones in the plasma cells were markedly smaller than that of other plasma cell malignancies such as multiple myeloma and MGUS. The transcriptional features of POEMS clones differed from those of other plasma cell diseases, and representative MM-related oncogenes were not upregulated in POEMS clones. Notably, POEMS clones are negative for CD19 and express significantly lower MHC-II levels than normal plasma cells; thus, CD19- HLA-DRlo is confirmed as a useful marker to identify POEMS clones in patients. These findings unveil the unique features of POEMS clones and contribute to the understanding of the pathogenesis of POEMS syndrome.

Now is no longer the time for poets.

A reflection piece-on rethinking the return of a Martial Law dictator in the form of his namesake, the newly elected president of the Philippines; the gamut of conversations on (un)covered facts, post-truth, appearances, interpolations, populism, revisionism and transformations, as well as the power of (trans)national media and images entangled with participatory publics; and how might a younger generation and/or transgender poet, such as myself, who did not experience first-hand the atrocities of military rule and learned them only through dominant narratives, might create and/or open capacious spaces for empathic opacity, new understandings, and possible coalitions and resistances within a historical moment concurrent with a present and/or imagined dystopia-expressed as a suit of three poems: To write another eye; Now is no longer the time for poets; Requisite condemnation.

Castleman disease and TAFRO syndrome.

Although Castleman disease was first described in 1956, this disease includes various conditions, including unicentric Castleman disease with hyaline vascular histology, human herpesvirus-8 (HHV-8) related multicentric Castleman disease, idiopathic multicentric Castleman disease, and mimics of Castleman disease associated with other conditions. To date, Castleman disease remains incompletely understood due to its rareness and difficulties in clinical and pathological diagnosis. TAFRO syndrome was reported in Japan in 2010. Because lymph node histology is similar in patients with TAFRO syndrome and Castleman disease, TAFRO syndrome is described as a related disorder of Castleman disease. Clinically, however, these conditions differ markedly. Although elevated interleukin-6 (IL-6) expression is characteristic of Castleman disease, increased expression of IL-6 may occur in patients with other diseases, making elevated IL-6 unsuitable for differential diagnosis. Further understanding of these disorders requires the identification of novel disease-specific biomarkers. This review article therefore outlines the characteristics of Castleman disease and TAFRO syndrome.

Rasch-built overall disability scale for POEMS syndrome (POEMS-RODS).

Patient-reported outcome measures engage patients in disease severity measurement and the metrics reported can be meaningful to their lives. The Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein and Skin changes syndrome (POEMS) is a complex multisystem disorder with disabling neuropathy which is distinct from other acquired inflammatory neuropathies. No current POEMS-specific validated disability scales exist. To address this, we have produced a Rasch-built overall disability scale (RODS) specific to POEMS. A 146-item preliminary questionnaire containing relevant activity and participation items for neuropathic disability was applied to 49 clinically stable patients with POEMS from the UK national POEMS cohort. A total of 123 items not fulfilling Rasch model expectations were sequentially removed. The final 23-item POEMS-RODS fulfilled Rasch model expectations and showed acceptable test-retest reliability. The 23-item POEMS-RODS is a disease-specific patient-reported outcome measure able to detect activity limitations within the range of ability demonstrated by the UK POEMS cohort. Larger international studies are needed to confirm the broader applicability and responsiveness of this scale in other countries.

Chronic diarrhea - The poetic masquerade.

Chronic diarrhea, by definition, is the passage of loose/liquid stools, with increased frequency (more than three times/day), or an output of over 200 g/day, lasting for a duration of four or more weeks. The clinical approach to identify the cause of chronic diarrhea generally depends on the local socioeconomic status. In high-income countries, systemic causes such as irritable bowel syndrome (IBS), inflammatory bowel disease, malabsorption syndromes (lactose intolerance/coeliac disease) are primarily considered. In mid- to low-income countries, infective causes like chronic bacterial, mycobacterial, fungal infections, HIV, bowel cancer are considered before systemic causes/malabsorption syndromes. Amyloidosis, more accurately, reactive amyloidosis is one of the rarer causes of chronic/persistent diarrhea. Inflammatory colitis secondary to POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) as a cause for chronic diarrhea has been reported only in a handful of cases and is often missed. We present such a case of chronic diarrhea in a middle-aged man, who was eventually diagnosed to have POEMS syndrome.

Multiple myeloma: a review of atypical imaging features and other distinct plasma cell disorders that demonstrate similar imaging features.

Multiple osteolytic lesions are a well-recognized and typical imaging feature of multiple myeloma as well as several other plasma cell disorders. Given the high volume of imaging studies obtained of multiple myeloma patients, radiologists will likely encounter a subset of multiple myeloma patients with less common or "atypical" findings during their practice. These atypical findings include osteosclerotic lesions, extramedullary lesions, and amyloid deposition. Similar imaging findings that are considered atypical for multiple myeloma can also be detected in other plasma cell disorders that are distinct from multiple myeloma. For instance, POEMS syndrome is a distinct plasma cell disorder from multiple myeloma, but also can present with osteosclerotic lesions. This article reviews the atypical findings associated with multiple myeloma and also reviews other plasma cell disorders that can have a similar spectrum of imaging findings. Special attention is paid to the musculoskeletal imaging findings.

POEMS Syndrome Diagnosis in a Patient with Mixed Polyneuropathy: Case Report.

POEMS syndrome is a rare condition of paraneoplasic origin characterized by the presence of a sensorimotor polyneuropathy associated with the presence of a proliferative disorder of plasmatic monoclonal cells and overproduction of vascular endothelial growth factor. The acronym "POEMS" represents multisystem findings including polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder and skin changes; nevertheless, clinical presentation is heterogeneous. We describe a clinical case, the diagnostic and therapeutic approach in a patient with sensorimotor polyneuropathy in whom POEMS syndrome was diagnosed; to understand this pathology, its clinical and paraclinical manifestations in order to make a diagnosis or to avoid a delayed one and to provide an adequate treatment.

POEMS Syndrome: Clinical and Laboratory Approach Towards Diagnosis.

Polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes (POEMS) syndrome is a rare multisystem paraneoplastic disorder. Here we describe a case of a 50 year old post-menopausal female who presented with chief complaints of difficulty in walking, getting up from squatting position and tingling sensation of bilateral lower limbs since 1 month. Additional unusual features in the patient included hepatosplenomegaly, endocrinal involvement in the form of hypothyroidism and elevated estradiol levels for her age. There were skin changes in the form of hyperpigmentation. M protein was not noted on serum electrophoresis but was visible on serum protein immunofixation (IgA lambda). She was investigated as a case of polyneuropathy and later a provisional clinical diagnosis of POEMS was made based on the presence of major and minor criteria. The patient was managed with methyl prednisolone, calcium carbonate and vit D3 and topical antibiotics for local infections.