Detection of clonal plasma cells in POEMS syndrome using multiparameter flow cytometry.

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein [M-protein], and skin changes) is a rare systemic disorder characterized by various symptoms caused by underlying plasma cell (PC) dyscrasia. Detection of monoclonal PCs is mandatory for the diagnosis of POEMS syndrome; however, the usefulness of EuroFlow-based next-generation flow cytometry (EuroFlow-NGF) in POEMS syndrome for detecting monoclonal PCs in bone marrow (BM) and the gating strategy suitable for flow cytometry study of POEMS syndrome remain unknown. We employed EuroFlow-NGF-based single-tube eight-color multiparameter flow cytometry (MM-flow) and established a new gating strategy (POEMS-flow) to detect the monoclonal PCs in POEMS syndrome, gating CD38 broadly from dim to bright and CD45 narrowly from negative to dim compared to MM-flow. MM-flow detected monoclonal PCs in 9/25 (36.0%) cases, including 2/2 immunofixation electrophoresis (IFE)-negative cases (100%). However, POEMS-flow detected monoclonal PCs in 18/25 cases (72.0%), including 2/2 IFE-negative cases (100%). POEMS-flow detected monoclonal PCs with immunophenotypes of CD19- in 17/18 (94.4%). In six cases where post-treatment samples were available, the size of the clones was significantly reduced after the treatment (P = 0.031). POEMS-flow can enhance the identification rate of monoclonal PCs in POEMS syndrome and become a valuable tool for the diagnosis of POEMS syndrome.

[POEMS Syndrome].

POEMS syndrome is a multisystem disorder associated with monoclonal plasma cell proliferation and the overproduction of vascular endothelial growth factors. The prognosis of POEMS syndrome has significantly improved owing to anti-myeloma treatments such as thalidomide and autologous stem cell transplantation. Therefore, early diagnosis and appropriate treatment are becoming increasingly important. A thorough and comprehensive evaluation of both systemic symptoms and laboratory abnormalities associated with the disease is essential for early diagnosis. The collaboration between neurology and hematology is indispensable to ensure proper treatment.

Prevalence and clinical profiles of anti-myelin-associated glycoprotein neuropathy in Japan: A nationwide survey study of 133 patients.

BACKGROUND AND PURPOSE: The aim of this study was to determine the prevalence of anti-myelin-associated glycoprotein (MAG) neuropathy and the current status of such patients in Japan. METHODS: We conducted a nationwide survey in 2021 using established epidemiological methods. Questionnaires were sent to all neurology and pediatric neurology departments throughout Japan to identify patients with anti-MAG neuropathy. An initial questionnaire was used to determine the number of patients, with a second one used to collect detailed clinical information. RESULTS: The estimated number of patients with anti-MAG neuropathy was 353, with a prevalence of 0.28 per 100,000 and an incidence of 0.05 per 100,000. The detailed clinical profiles of 133 patients were available. The median (range) age of onset was 67 (30-87) years, with a prominent peak in the age range 66-70 years, and the male-to-female ratio was 3.6. Most patients had distal sensory-predominant polyneuropathy, and neuropathic pain (50%), or sensory ataxia (42%), while 18% had Waldenström's macroglobulinemia or multiple myeloma. Intravenous immunoglobulin was the most frequently used treatment (65%), but the response rate was <50%, whereas rituximab was given in 32% of patients, and 64% of these showed improvement. At the last visit, 27% of patients could not walk independently. CONCLUSIONS: This study on anti-MAG neuropathy provides updated insights into the epidemiology of this disease, clinical profiles, and treatment approaches in Japan. Rituximab therapy, used for only one-third of the patients, demonstrated efficacy. During the final visit, a quarter of the patients were unable to walk independently. Further studies are warranted to determine the optimal management of this rare and intractable disorder.

Efficacy and safety of mirogabalin for chemotherapy-induced peripheral neuropathy: a prospective single-arm trial (MiroCIP study).

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a painful, dose-limiting adverse effect of commonly used chemotherapeutic agents. The purpose of this exploratory study was to evaluate the efficacy and safety of mirogabalin in patients with moderate to severe CIPN during chemotherapy and the effects of 12 weeks' intervention on chemotherapy completion and CIPN severity. METHODS: Patients experiencing moderate to severe CIPN while undergoing oxaliplatin- or taxane-containing chemotherapy for colorectal, gastric, non-small-cell lung, or breast cancer received mirogabalin at between 5 and 15 mg twice daily. The primary endpoint was change in numeric rating scale (NRS) score for pain from baseline to week 12. Secondary endpoints included NRS scores for tingling and sleep, completion of chemotherapy, severity of CIPN, and quality of life (QOL) scores. The safety endpoint was incidence of adverse events. RESULTS: Of 58 patients who consented to participation, 52 were eligible and constituted the full analysis set and safety analysis set. From baseline to week 12 (last observation carried forward [LOCF]), NRS score decreased by 30.9%: mean change (95% confidence interval [CI]), - 1.7 (- 2.4 to - 1.0) (p < 0.001). Patients with baseline NRS of ≥ 6 experienced a 44.0% reduction in score from baseline to week 12 (LOCF): mean change (95% CI), - 3.3 (- 5.0 to - 1.5) (p = 0.002). Chemotherapy was discontinued in 18 (34.6%) patients; CIPN led to discontinuation in only 2 (3.8%). There was no notable worsening of CIPN severity in terms of Common Terminology Criteria for Adverse Events grade or Modified Total Neuropathy Score-reduced, although use of pain medications during chemotherapy might cause worsening of CIPN due to underestimation of subjective symptoms. QOL score based on the EuroQol five-dimensional descriptive system did not worsen during the 12 weeks. Thirty-one percent of patients experienced adverse drug reactions, and the most common event was somnolence (13.5%). Serious adverse events and death occurred in 3 patients and 1 patient, respectively; however, they were unrelated to mirogabalin treatment. CONCLUSIONS: Intervention with mirogabalin during chemotherapy may be effective and safe for cancer patients with moderate to severe CIPN. It can contribute to completion of chemotherapy without worsening of CIPN. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCTs031210101, registered 20/5/2021).

Alterations in choroidal vascular structures due to serum levels of vascular endothelial growth factor in patients with POEMS syndrome.

A higher serum vascular endothelial growth factor (VEGF) level can cause choroidal thickening in the choroid of patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome. We aimed to determine whether fluctuations in serum VEGF levels affect choroidal vascular structures in patients with POEMS syndrome. This retrospective observational case series examined 17 left eyes of 17 patients with POEMS syndrome. Enhanced depth imaging optical coherence tomography (EDI-OCT) images were obtained, and serum VEGF levels were measured at baseline and 6 months after transplantation with dexamethasone (n = 6), thalidomide (n = 8), or lenalidomide (n = 3). EDI-OCT images were binarized using ImageJ software, and we calculated the areas of the whole choroid and the luminal and stromal areas. Subsequently, we determined whether the choroidal vascular structure had changed significantly between baseline and 6 months after treatment. Six months after treatment, serum VEGF levels and the whole choroid, luminal, and stromal areas had decreased significantly compared to the baseline values (all, P < 0.001). The mean luminal area to the whole choroidal area ratio at 6 months after treatment was 0.70 ± 0.03, which was significantly smaller than the ratio at baseline (0.72 ± 0.03; P < 0.001). Whole choroid and luminal area fluctuations were significantly positively correlated with fluctuations in serum VEGF levels (r = 0.626, P = 0.007 and r = 0.585, P = 0.014, respectively). Choroidal thickening induced by VEGF might be caused by increases in the choroidal vessel lumen area. These results may offer insights into the pathogenesis of POEMS syndrome and the role of serum VEGF in choroidal vascular structure, which may apply to other ocular diseases.

Combined Therapy with Ixazomib, Lenalidomide, and Dexamethasone for Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Gammopathy, and Skin Changes Syndrome.

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.

Unraveling unique features of plasma cell clones in POEMS syndrome with single-cell analysis.

POEMS syndrome is a rare monoclonal plasma cell disorder, with unique symptoms distinct from those of other plasma cell neoplasms, including high serum VEGF levels. Because the prospective isolation of POEMS clones has not yet been successful, their real nature remains unclear. Herein, we performed single-cell RNA-Seq of BM plasma cells from patients with POEMS syndrome and identified POEMS clones that had Ig λ light chain (IGL) sequences (IGLV1-36, -40, -44, and -47) with amino acid changes specific to POEMS syndrome. The proportions of POEMS clones in plasma cells were markedly smaller than in patients with multiple myeloma (MM) and patients with monoclonal gammopathy of undetermined significance (MGUS). Single-cell transcriptomes revealed that POEMS clones were CD19+, CD138+, and MHC class IIlo, which allowed for their prospective isolation. POEMS clones expressed significantly lower levels of c-MYC and CCND1 than MM clones, accounting for their small size. VEGF mRNA was not upregulated in POEMS clones, directly indicating that VEGF is not produced by POEMS clones. These results reveal unique features of POEMS clones and enhance our understanding of the pathogenesis of POEMS syndrome.

Cerebral large artery stenosis and occlusion in POEMS syndrome.

BACKGROUND: This study aimed to investigate the frequency and risk factors for cerebral artery stenosis and occlusion in patients with polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome. METHODS: We reviewed results of magnetic resonance angiography (MRA) or computed tomography angiography (CTA) in 61 patients with POEMS syndrome seen between 2010 and 2017. Stenosis or occlusion was assessed in the initial MRA/CTA. Multivariate analysis was used to identify risk factors for artery stenosis/occlusion. In an autopsy case, pathologic examination was conducted of the occluded middle cerebral arteries. RESULTS: Stenosis (> 50 %) or occlusion of the major cerebral arteries was found in 29 (47.5 %) patients on the initial MRA/CTA. The internal carotid artery was involved most frequently (32.8 %), followed by the anterior (21.3 %) and middle (16.4 %) cerebral arteries. The basilar (1.3 %) and vertebral (3.6 %) arteries were rarely affected. Cerebral infarction developed in eight (13.1 %) patients. The serum vascular endothelial growth factor (VEGF) level was an independent predictor for stenosis/occlusion (odds ratio, 1.228; 95 % confidence interval, 1.042-1.447; P = 0.014). An autopsy study showed occluded middle cerebral arteries by fibrous and myxomatous thickening of intima with splitting of the internal elastic lamina. Follow-up MRA in 23 patients showed improved, worsened, and unchanged stenosis in 20.7 %, 8.7 %, and 69.6 %, respectively. CONCLUSIONS: Cerebral large-vessel stenosis or occlusion is frequently seen in approximately half of patients with POEMS syndrome. Vasculopathy was related to serum VEGF levels and thereby disease activity. Assessment of cerebral vessels is recommended in these patients to improve management.

Dispersion of mean consecutive differences in single-fiber electromyography increases diagnostic sensitivity for myasthenia gravis.

INTRODUCTION: In this study we aimed to investigate the dispersion of mean consecutive difference (MCD) of concentric needle jitter studies of patients with myasthenia gravis (MG) and its effect on diagnostic sensitivity for MG. METHODS: One hundred fifty-three patients, including 76 patients with MG and 77 controls with possible MG who later received another diagnosis, underwent stimulated concentric needle jitter studies of the frontalis muscle. MCD mean, standard deviation (SD), and coefficient of variation (CV) were calculated. Diagnostic sensitivity and specificity were determined using receiver operating characteristic (ROC) analyses. RESULTS: MG patients showed a significantly greater MCD mean (MG: control, 26.3 µs; 13.5 µs [median]; P < .0001), MCD SD (MG: control, 12.8 µs; 5.1 µs [median]; P < .0001), and MCD CV (MG: control, 46.1; 37.5 [median]; P < .001) than those without MG. An ROC curve of SD showed a large area under the curve (0.88), and a cut-off value of 7.2 µs, which was calculated by maximum Youden index, exhibited high diagnostic sensitivity (86%) for MG. Combined MCD mean, outliers, and SD criteria showed higher sensitivity (88%) than conventional criteria alone (82%), at the expense of lower specificity. Five MG patients with normal MCD mean and abnormal MCD SD had only ocular symptoms. DISCUSSION: The dispersion of MCD as measured by MCD SD greater than 7.2 µs is significantly increased in patients with MG and may be a useful measure of abnormal jitter in the diagnosis of MG, especially for identifying patients with mild disease.

Treatment response and prognosis of POEMS syndrome coexisting with Castleman disease.

POEMS (polyneuropathy, organomegaly, endocrinopathy monoclonal gammopathy, and skin changes) syndrome is occasionally associated with Castleman disease (CD) and their prognosis is considered as poorer than that in POEMS alone patients. To elucidate recent prognosis of POEMS syndrome coexisting with CD, we reviewed clinical data of 102 patients with POEMS syndrome treated at our institution between 2000 and 2018 and compared clinical characteristics, response to treatment, and prognosis between POEMS patients with biopsy-proven CD (POEMS-CD) and those without it. Fourteen POEMS-CD patients and 56 POEMS alone patients were identified, and the remaining 32 patients with unbiopsied lymphadenopathy were excluded. POEMS-CD patients significantly showed earlier onset and less severe neuropathic symptoms. Most of the POEMS-CD patients were treated with thalidomide and dexamethasone (n = 10, 71%), and subsequently received autologous stem cell transplantation (n = 6, 43%). Response to thalidomide was better in patients with POEMS-CD than those with POEMS alone (90% vs 43% clinical response, [p = .012]; 80% vs 45% normalization of serum VEGF levels, [p = .079]). The 10-year overall survival (95% confidence interval) was 89% (50-98%) in POEMS-CD patients and 61% (42-77%) in those with POEMS alone. POEMS syndrome associated with CD constitutes a subgroup of POEMS syndromes characterized by earlier onset, mild polyneuropathy, and favorable response to treatment. Recognition of this subgroup is significant for determination of therapeutic strategy.

Lenalidomide Treatment for Thalidomide-refractory POEMS Syndrome: A Prospective Single-arm Clinical Trial.

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.

Correlation of changes in serum level of VEGF and peripapillary retinal thickness in patients with POEMS syndrome.

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.

Prevalence, clinical profiles, and prognosis of POEMS syndrome in Japanese nationwide survey.

OBJECTIVE: To elucidate current epidemiological, clinical profiles, and treatment of polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome. METHODS: We conducted a nationwide survey in 2015 using an established epidemiologic method. Data processing sheets were sent to all neurology and hematology specialist departments throughout Japan to identify patients with POEMS who were seen between April 2012 and March 2015. RESULTS: The estimated number of patients with POEMS was 392 (95% confidence interval [CI] 320-464), and the prevalence was 0.3 per 100,000. Detailed clinical profiles were available for 167 patients. Median age at onset was 54 years (range, 21-84 years), and the ratio of male to female was 1.5. All patients showed polyneuropathy; 89% had monoclonal plasma cell proliferation; and 84% had elevated vascular endothelial growth factor level in whom pretreatment serum or plasma was available (n = 87). Other common features were skin changes (84%), edema/effusion (81%), and organomegaly (76%). A total of 160 patients were treated with any of the following: radiation, corticosteroids, melphalan, thalidomide, lenalidomide, bortezomib, or autologous stem cell transplantation. Primary therapeutic options were thalidomide (n = 86) and autologous stem cell transplantation (n = 71). Thirty-nine patients (24%) were initially treated with corticosteroid alone. The 10-year overall survival was 93% (95% CI 86%-96%). DISCUSSION: This study showed current epidemiologic and clinical status of POEMS syndrome in Japan. A quarter of patients were still inadequately treated with corticosteroid alone, whereas either autologous stem cell transplantation or immunomodulatory drugs improved the prognosis.

Genetic and transcriptional landscape of plasma cells in POEMS syndrome.

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.

Proposal of new clinical diagnostic criteria for POEMS syndrome.

OBJECTIVE: To propose the optimal diagnostic criteria for polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome using appropriate statistical methods and disease controls. METHODS: This retrospective cohort study included 104 consecutive patients with suspected POEMS syndrome, among whom a gold standard group of 60 patients with definitive POEMS syndrome diagnosis were followed for at least 12 months to strictly exclude other disorders mimicking POEMS syndrome and to confirm response to POEMS syndrome-specific treatment. Thirty patients with chronic inflammatory demyelinating polyradiculoneuropathy (demyelinating polyradiculoneuropathy controls) and 30 with multiple myeloma or immunoglobulin light chain amyloidosis (monoclonal plasma cell proliferation controls) were also included. Logistic regression analyses were performed to determine optimal combination of clinical and laboratory abnormalities, characteristic of POEMS syndrome. RESULTS: The diagnostic criteria were statistically defined as the presence of the three major criteria (polyneuropathy (typically demyelinating), monoclonal plasma cell proliferative disorder and elevated vascular endothelial growth factor) and at least two of the four minor criteria (oedema/effusion, skin changes, organomegaly and sclerotic bone lesions), based on best performance by area under the receiver operating characteristic curve analyses. The sensitivity and specificity were 100% and 100%, respectively; the diagnostic accuracy of the proposed criteria was equivalent to somewhat complicated previous criteria. CONCLUSIONS: The statistically defined, simple diagnostic criteria for POEMS syndrome could accelerate early diagnosis and treatment, thereby contribute to better outcome in patients with this serious disease. Prospective larger studies are required to confirm the validity.

Clonal immunoglobulin λ light-chain gene rearrangements detected by next generation sequencing in POEMS syndrome.

Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare plasma cell dyscrasia characterized by polyneuropathy, organomegaly, endocrinopathy, extravascular fluid overload, M protein, and a myriad of skin changes. The pathogenesis is poorly understood, but monoclonal plasma cells are λ-restricted and these immunoglobulin λ light chain variable (IGLV) region genes are derived from only two germlines, either IGLV1-44 or 1-40. Here we analyzed the clonal IGLV gene rearrangements of genomic DNA samples of bone marrow mononuclear cells using next-generation sequencing (NGS) to understand the clonal composition of IGLV genes in patients with POEMS syndrome (n = 30). The dominant IGLV gene rearrangement of POEMS syndrome-specific germline sequences were significantly increased in 11 POEMS patients (36.7%; IGLV1-44: n = 9, IGLV1-40: n = 2). In some cases, IGLV gene rearrangement clone was not detected as significant increase but was detected using cDNA samples by heteroduplex (HD) analysis and Sanger sequencing, suggesting that the quite small number of monoclonal plasma cells may produce large quantity of mRNA of monoclonal proteins. However, significant increase of dominant clone sizes was not directly linked to the initial disease status. On the other hand, in cases with significantly increased dominant clones, they decreased and increased accompanying with disease remission and relapse. These data demonstrate that monoclonal plasma cells are related to the pathogenesis of POEMS syndrome.