POEMS Syndrome: Indian Experience From a Tertiary-Care Institute.

INTRODUCTION: POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) syndrome is a rare multisystem paraneoplastic syndrome characterized by peripheral neuropathy and monoclonal plasmacytosis. Retrospective institutional experiences from the Mayo Clinic as well as Chinese, European, and Japanese series have provided important insights into the characteristics and treatment of this disease, but Indian data are extremely limited. We retrospectively analyzed 49 cases from our institute including 10 patients who underwent autologous stem-cell transplantation (ASCT). PATIENTS AND METHODS: We analyzed clinical and laboratory characteristics, treatment details and outcome of all patients diagnosed with POEMS syndrome between 1993 and 2017. RESULTS: Complete medical records were available for 49 patients with a median age of 44 years. Male/female ratio was 38:11. Twenty patients (40.8%) had Eastern Cooperative Oncology Group performance status of 4. Before 2012, melphalan/prednisolone was the most common regimen provided, while bortezomib/dexamethasone and lenalidomide/dexamethasone were used later. Hematologic response was available for 40 patients, 15 (37.5%) of whom experienced complete response, 13 (32.5%) partial response, and 11 (27.5%) stable disease. The median modified Rankin score at baseline was 4 (range, 1-5), which improved to 3 (range, 1-5). Ten patients underwent consolidation ASCT after a median of 4 cycles of induction. Median melphalan dose was 140 mg/m2. Engraftment syndrome was observed in 4. After ASCT, all 10 patients experienced hematologic complete response and clinical improvement. CONCLUSION: This retrospective analysis provides important information on the clinical characteristics of POEMS syndrome in Indian patients, which will help the clinician's decision-making process.

What is the best first-line treatment for POEMS syndrome: autologous transplantation, melphalan and dexamethasone, or lenalidomide and dexamethasone?

POEMS syndrome is a rare plasma cell dyscrasia. This study compared the responses to and survival of 347 POEMS syndrome patients given three first-line treatment regimens: autologous stem cell transplantation (ASCT, N = 165) and melphalan + dexamethasone (MDex, N = 79), or lenalidomide + dexamethasone (LDex, N = 103). After a median 45-month follow-up, overall hematologic complete remission (CRH) was 46.4%, vascular endothelial growth factor complete remission (CRV) was 55.1%, and neurological remission (RN) was 93.8%. CRH was better with ASCT (49.7%) than with MDex (37.7%, p = 0.001). CRV was better with ASCT (66.2%) than with MDex (38.5%, p = 0.001) or LDex (47.7%, p = 0.008). Differences in RN achieved by three regimens (91.5% vs. 100% vs. 93.8%, p = 0.234) were not significant. Overall 3-year progression-free survival (PFS) was 80.5% and overall 3-year overall survival (OS) was 90.8%. PFS was 87.6% with ASCT and 64.9% with LDex (p = 0.003). OS in the three regimens did not differ (p = 0.079). In medium-high risk patients, ASCT had better CRH and CRV than MDex, and better PFS than LDex. Therefore, although all three treatments had reasonable responses and survivals, patients with higher risk may benefit more from ASCT treatment.

A prospective phase II study of low dose lenalidomide plus dexamethasone in patients with newly diagnosed polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome.

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.

Efficacy and Long-Term Outcomes of Autologous Stem Cell Transplantation in POEMS Syndrome: A Nationwide Survey in Japan.

POEMS syndrome is a rare plasma cell dyscrasia presenting with polyneuropathy, λ-type M protein, vascular endothelial growth factor elevation, and systemic manifestations. The standard treatment has not been established, but autologous stem cell transplantation (ASCT) has exhibited effectiveness in this syndrome. However, the efficacy and long-term outcomes of ASCT have not been systematically studied. To clarify the efficacy and long-term outcomes of ASCT-treated patients in Japan, we performed a multicenter retrospective study assessing the clinical course of patients registered to the Japan Society for Hematopoietic Cell Transplantation Transplant Registry Unified Management Program (TRUMP) database. Between January 2000 and December 2011, 95 patients (58 men) were registered to the TRUMP database with a median age of 53 years (range, 28 to 72). The conditioning regimen was melphalan in 93 of 94 patients (99%), and 69 patients (74.2%) received a melphalan dose ≥ 200 mg/m2. The median CD34 cell dose was 2.47 × 106/kg (range, .31 to 20). After ASCT, patient performance status was dramatically improved (Eastern Cooperative Oncology Group performance status 0 to 1: 20.0% versus 71.6%, P < .0001). Over a median follow-up of 46.6 months 10 patients died, and 5-year overall survival was 88.8% (n = 95). Progression-free survival at 3 years was 78.3% (n = 70; median follow-up, 54.4 months). These data support the promising role of ASCT in patients with POEMS syndrome for both prolonging survival and improving quality of life. However, disease recurrence remains a major issue for long-term survivors.

POEMS Syndrome: an Enigma.

POEMS syndrome is a paraneoplastic disorder secondary to an underlying plasma cell dyscrasia. By definition, all patients with POEMS syndrome must display polyneuropathy and monoclonal plasma cell disorder. In addition, at least one major criterion (Castleman's disease, sclerotic bone lesions, or vascular endothelial growth factor elevation) and one minor criterion (organomegaly, extravascular volume overload, endocrinopathy, skin changes, papilledema, thrombocytosis, or polycythemia) are required for diagnosis. Treatment is based on extent of the disease. Radiotherapy is used for localized disease. Systemic therapy is required for disseminated disease, with bone marrow involvement by clonal plasma cells, or in patients who progress shortly after radiation. Upfront autologous stem cell transplantation is the treatment of choice for transplant-eligible patients. Outcomes are typically superior to that of standard myeloma. Herein, using a case vignette, we outline the latest evidence regarding the prognostication and management of POEMS syndrome, with a focus on its relapsing-remitting course.

Prognostic study for overall survival in patients with newly diagnosed POEMS syndrome.

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) is a multisystem disorder with a good long-term prognosis. In its dozens of clinical features, those with independent prognostic value are still not well characterized. We retrospectively included 362 patients with newly diagnosed POEMS syndrome at our institute from 2000 to 2015. On the basis of a randomized sample splitting, we first identified four baseline clinical variables, including age >50 years (hazards ratio (HR) 4.07, 95% confidence interval (CI) 1.41-11.76, P=0.009), pulmonary hypertension (HR 3.99, 95% CI 1.44-11.04, P=0.008), pleural effusion (HR 3.81, 95% CI 1.23-11.79, P=0.02) and estimated glomerular filtration rate <30 ml/min/1.73 m2 (HR 8.25, 95% CI 2.18-31.25, P=0.002), associated with inferior overall survival in the derivation cohort, with the use of multivariate Cox regression model. These factors were incorporated together to develop a prognostic nomogram. Concordance index calculation (0.727, 95% CI 0.601-0.853, P=0.018) and calibration curve plotting demonstrated its significant predictive and discriminatory capacity in the validation cohort. This nomogram could be a useful and convenient tool in clinical practice to evaluate individualized prognosis in patients with newly diagnosed POEMS syndrome.

High-dose therapy and autologous stem cell transplantation in patients with POEMS syndrome: a retrospective study of the Plasma Cell Disorder sub-committee of the Chronic Malignancy Working Party of the European Society for Blood & Marrow Transplantation.

POEMS syndrome is a rare para-neoplastic syndrome secondary to a plasma cell dyscrasia. Effective treatment can control the disease-related symptom complex. We describe the clinical outcome of autologous stem cell transplantation for patients with POEMS syndrome, determining the impact of patient- and disease-specific factors on prognosis. One hundred and twenty-seven patients underwent an autologous stem cell transplantation between 1997-2010 with a median age of 50 years (range 26-69 years). Median time from diagnosis to autologous stem cell transplantation was 7.5 months with 32% of patients receiving an autologous stem cell transplantation more than 12 months from diagnosis. Engraftment was seen in 97% patients and engraftment syndrome was documented in 23% of autologous stem cell transplantation recipients. Hematologic response was characterized as complete response in 48.5%, partial response in 20.8%, less than partial repsonse in 30.7%. With a median follow up of 48 months (95%CI: 38.3, 58.6), 90% of patients are alive and 16.5% of patients have progressed. The 1-year non-relapse mortality was 3.3%. The 3-year probabilities of progression-free survival and overall survival are 84% and 94%, respectively, with 5-year probabilities of progression-free survival and overall survival of 74% and 89%. In a cohort of graft recipients, detailed organ-specific symptom response demonstrated clear symptom benefit after autologous stem cell transplantation especially in relation to neurological symptom control. The data analyzed in this study demonstrate the clinical utility of autologous stem cell transplantation for patients with POEMS syndrome.

Remarkable expression of vascular endothelial growth factor in bone marrow plasma cells of patients with POEMS syndrome.

Vascular endothelial growth factor (VEGF) is pathognomonically elevated in patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) syndrome. However, its source of overproduction is unclear. As clinical improvement is almost always associated with VEGF reduction after anti-plasma cell therapy, its increase at diagnosis has been attributed to the underlying monoclonal gammopathy, although direct evidence is still lacking. In the current study, we systemically measured VEGF levels in POEMS patients, before and after treatment. Bone marrow plasma cells showed remarkable VEGF expression, in both mRNA and protein levels, which decreased gradually in response to therapy. Of note, statistically linear correlations were observed between serum and bone marrow plasma cell VEGF levels (mRNA vs. serum, rho 0.343, p=0.003; protein vs. serum, rho 0.644, p<0.0001), supporting bone marrow plasma cells as the main source of circulating VEGF. Intriguingly, immunophenotyping revealed that bone marrow plasma cells were polyclonal in most patients at diagnosis. A clear monoclonal population, coexistent with polytypic cells, was only detectable in 11 cases (18%), in which comparable intracellular VEGF expression was observed between these two plasma cell populations (p=0.594), while monoclonal cells showed higher intracellular interleukin-6 expression (p=0.006). These patients had more serum monoclonal protein, less post-therapeutic complete remission, and inferior overall (p=0.027) and progression-free survival (p=0.002). Collectively, bone marrow plasma cells, mainly polyclonal population, are the major source of VEGF overproduction in POEMS patients.

Long-term outcome of patients with POEMS syndrome: An update of the Mayo Clinic experience.

Over the past decade, a number of changes have occurred in the diagnostic evaluation, management, and long-term follow-up of patients with POEMS syndrome at our institution. This study included 291 patients with POEMS syndrome diagnosed at the Mayo Clinic between 1974 and 2014. Patients diagnosed after 2003 had more features of the syndrome identified at diagnosis and were more likely to receive an autologous transplant (49% versus 8%, P < 0.0001) and to have achieved a hematologic complete response (CR) to treatment (41% vs 25%, P < 0.0001). With 2273 person-years of follow-up, 10-year overall survival (OS) was 62% (95% C.I., 56%, 67%). On multivariate analysis, the three factors associated with superior OS were younger age (RR 0.98 [0.96-1.00]), albumin greater-than 3.2 g/dL (RR 0.5 [0.32-0.89]) and attainment of complete hematologic response (RR 0.4 [0.2, 0.9]). This study confirms the very good long-term outcomes of patients with POEMS syndrome and identifies two new prognostic risk factors: albumin at diagnosis and attainment of complete hematologic response. Am. J. Hematol. 91:585-589, 2016. © 2016 Wiley Periodicals, Inc.

Prognostic value of serum heavy/light chain ratios in patients with POEMS syndrome.

POEMS syndrome is a rare plasma cell dyscrasia. Serum concentrations of the monoclonal protein in this disorder are typically low, and inapplicable to monitor disease activity in most cases, resulting in limited practical and prognostic values. Novel immunoassays measuring isotype-specific heavy/light chain (HLC) pairs showed its utility in disease monitoring and outcome prediction in several plasma cell dyscrasias. We report results of HLC measurements in 90 patients with POEMS syndrome. Sixty-six patients (73%; 95% confidence interval, 63-82%) had an abnormal HLC ratio at baseline. It could stratify the risk of disease relapse and was strongly associated with worse progression-free survival in a multivariate analysis (P = 0.021; hazard ratio [HR] 6.89, 95% CI 1.34-35.43). After therapy, HLC ratios improved, with 43 patients (48%) remaining abnormal. The post-therapeutic HLC ratio, if abnormal, also remained as an independent prognostic factor associated with worse progression-free survival (P = 0.019; HR 4.30, 95% CI 1.27-14.56). These results suggest the prognostic utility of HLC ratios in clinical management of POEMS patients.

Risk factors for and outcomes of patients with POEMS syndrome who experience progression after first-line treatment.

Although clinical improvement is almost universal with therapy in patients with POEMS (an acronym for polyneuropathy, organomegaly, endocrinopathies, monoclonal protein and a variety of skin changes) syndrome, outcomes and management of patients who relapse or progress (R/P) after first-line treatment have not been described. We retrospectively identified 262 patients with POEMS syndrome treated at the Mayo Clinic from 1974 to 2014 and who had follow-up information. The 5-year progression-free survival (PFS) and overall survival (OS) was 58% and 78%, respectively. Median time to R/P was 42 months. Seventy-nine patients (30%) had an R/P, with 52 (19%) experiencing a symptomatic R/P. Eighteen patients relapsed with symptoms or signs that were not documented at diagnosis. Median times to vascular endothelial growth factor, hematologic, radiographic and clinical R/P were 35 months (range, 4-327 months), 72 months (range, 4-327 months), 51 months (range, 4-327 months) and 48 months (range, 6-311 months), respectively. On multivariate analyses, low albumin at diagnosis and failure to achieve a complete hematologic response to first-line therapy were independent risk factors for PFS. Thirty patients had documentation of a second R/P at a median of 26 months from diagnosis of the first R/P. An early R/P was a risk factor for death, but most patients with an R/P had salvageable disease. A majority of patients are still without R/P at 5 years from diagnosis.

Efficacy and safety of low-dose lenalidomide plus dexamethasone in patients with relapsed or refractory POEMS syndrome.

Although autologous stem cell transplantation or melphalan-based chemotherapy has significantly improved the prognosis of POEMS syndrome, a few patients will relapse or be refractory to primary therapy, and there is a lack of studies regarding these patients. In this study, we used low-dose lenalidomide (10 mg daily) and dexamethasone (40 mg, once weekly) to treat twelve patients with relapsed (n = 8) or refractory (n = 4) POEMS syndrome. After a median follow-up time of 20 months, the overall hematologic response rate was 77% with 44% having a complete response. Eight (67%) patients had neurological response, and the median overall neuropathy limitation scale score was reduced from 3 (range, 1-9) to 2 (range, 0-6). Serum vascular endothelial growth factor response rate was 91% and 46% of patients had normal serum VEGF levels. One patient had progression of the disease 3 months after the end of treatment and subsequently died from the disease. Therefore, the estimated 2 year overall survival and progression-free survival were 92%. The low-dose lenalidomide and dexamethasone regimen was well tolerated, with no treatment-related death or any grade 3 or 4 toxicity. In conclusion, low-dose lenalidomide plus dexamethasone therapy is an effective and safe regimen for patients with relapsed or refractory POEMS syndrome.

The role of radiotherapy in the management of POEMS syndrome.

BACKGROUND: POEMS syndrome is a paraneoplastic syndrome caused by an underlying plasma cell proliferative disease. In this study, we examined the treatment outcomes and role of radiotherapy in the management of POEMS syndrome. METHODS: In total, 33 patients diagnosed with POEMS syndrome were analyzed. These patients presented with osteosclerotic myeloma (OSM, n = 13), Castleman's disease (CD, n = 4), OSM with CD (n = 10), and vascular endothelial growth factor elevation without gross lesions (VEGFe, n = 6), respectively. The patients were treated by radiotherapy alone (n = 4), chemotherapy alone (n = 16), or a combination thereof (n = 9). RESULTS: The clinical response rates of radiotherapy, chemotherapy, and radiotherapy plus chemotherapy were 75%, 69%, and 89%, respectively. In addition, the hematologic response rates were 50%, 69%, and 71%, respectively. Among the six patients with limited multiple lesions who underwent radiotherapy, the clinical symptoms were improved in five patients after radiotherapy. The median progression-free survival (PFS) was 51 months, and the median overall survival (OS) was 65 months. In univariate analysis, the administration of chemotherapy was significantly associated with better PFS (p = 0.007) and OS (p = 0.020). In contrast, underlying VEGFe was a significant factor worsening PFS (p = 0.035) and OS (p = 0.008). CONCLUSIONS: Radiotherapy produces a reliable clinical response and is effective in improving POEMS-associated symptoms that are refractory to chemotherapy in selected patients with clustered or limited multiple lesions that can be covered by single radiation field.

Papilloedema is an independent prognostic factor for POEMS syndrome.

POEMS syndrome is a potentially fatal disease, and prediction of prognostic factors for POEMS syndrome is important for clinicians. Papilloedema is an early sign of the syndrome. The present study was carried out to evaluate whether papilloedema is a prognostic factor for POEMS syndrome. Between January 2003 and December 2012, 94 patients with POEMS syndrome were enrolled in this study. The patients were divided into groups with and without papilloedema. Logistic regression was performed to identify risk factors related to papilloedema. Prognostic factors were analysed with Cox proportional hazard regressions for POEMS syndrome-related prognoses, and survival curves were plotted using the Kaplan-Meier method and compared by the log-rank test. Papilloedema was found in 52.1 % of the patients with POEMS syndrome. Raised intracranial pressure [hazard ratio (HR) 3.06, 95 % confidence interval (CI) 1.24-7.41; P = 0.011] and elevated cerebrospinal fluid protein levels (HR 2.03, 95 % CI 1.07-4.51; P = 0.043) were independently associated with papilloedema. Papilloedema, decreased diffusing capacity of the lung for carbon monoxide (DLCO) and treatment with corticosteroids alone were related to poor prognosis in POEMS syndrome. In multivariate analysis, papilloedema (HR 1.58, 95 % CI 1.05-2.46; p = 0.027) and decreased DLCO (HR 2.17, 95 % CI 1.12-3.39; p = 0.023) were independent factors for POEMS syndrome-related death. Papilloedema and decreased DLCO are important prognostic factors for patients with POEMS syndrome, which can help clinicians predict the risk of mortality and provide better medical care for these patients.

Lenalidomide in patients with POEMS syndrome: a systematic review and pooled analysis.

The purpose of this pooled analysis was to synthesize all available data so as to evaluate the efficacy and safety of lenalidomide in patients with POEMS syndrome. Eligible articles were identified by a search in MEDLINE and ClinicalTrials.gov databases using a predefined combination. Eligible cases of patients treated in our department were additionally included. Overall, 51 patients were included. The median age of patients was 54.5 years (range: 32-79 years). Lenalidomide was given as first- or second-line treatment in 28.6% and 47.6% of patients, respectively. Hematological responses included complete response in 18.6%, very good partial response in 39.5% and partial response in 37.2% of cases. Vascular endothelial growth factor (VEGF) reduction was reported in all cases. Neuropathy improved in 92.0% of cases and stabilized in 8%. The progression-free survival (PFS) estimate at 12 months was 93.9%. Lenalidomide can represent a safe and effective option for the treatment of patients with POEMS.

Outcomes of patients with POEMS syndrome treated initially with radiation.

POEMS syndrome is a rare plasma cell dyscrasia presenting with polyneuropathy and other systemic findings. Patients with 1 to 3 bone lesions and negative bone marrows are often treated with involved field radiation therapy as the initial and potentially definitive therapy. Long-term outcomes of patients treated with this approach have not been systematically studied. Of the 146 patients with POEMS syndrome seen at the Mayo Clinic between January 1999 and September 2011, 38 (26%) were given targeted radiation as their initial primary therapy and are the ones studied here. The median number of bone lesions was 1 (range: 1-6). The median dose of radiation administered was 45 Gy (range: 35-54 Gy). Complete or partial hematologic, vascular endothelial growth factor, fluorodeoxyglucose-positron emission tomography, and clinical responses were documented in 31%, 14%, 22%, and 47%, respectively. With median follow-up of 43 months, the 4-year overall survival is 97% and event-free survival is 52%. Risk factors for needing salvage therapy included reduced pulmonary diffusing capacity of carbon monoxide and increased urinary total protein. The presence of 3 lesions compared with 1 or 2 did not increase risk for treatment failure. Among selected patients with POEMS syndrome, radiation produces durable, meaningful responses.

Pulmonary hypertension in POEMS syndrome.

POEMS syndrome is a rare clonal plasma cell disease. Patients with POEMS syndrome are at risk of developing pulmonary hypertension, but the data on its incidence and impact on outcome are limited. We reviewed records of 154 POEMS syndrome patients with complete duplex echocardiography data for estimation of pulmonary artery systolic pressure (sPAP) at the time of diagnosis. Forty-two (27%) of 154 patients with pulmonary hypertension (estimated sPAP ≥50 mmHg) were identified. Median age was 46 years (range 31-71 years). Patients with pulmonary hypertension were more likely to have peripheral edema (P=0.04), ascites (P=0.02), pleural effusion (P=0.005), and have longer time from onset to diagnosis (P=0.004) when compared with those without pulmonary hypertension. Restrictive abnormalities and decreased diffusion capacity of carbon monoxide were observed in 83% and 96% patients with pulmonary hypertension, compared with 50% and 72% in patients without pulmonary hypertension, respectively. Reversibility of pulmonary hypertension was observed after treatment of POEMS syndrome. After median follow of 32 months, survival of patients with pulmonary hypertension was worse than those without (median overall survival 54 months vs. median not reached, P=0.021). In conclusion, pulmonary hypertension is a common feature of POEMS syndrome, and is associated with signs of extravascular volume overload. Although active treatment of POEMS syndrome can reverse pulmonary hypertension, survival of these patients is worse than those without pulmonary hypertension.