Xu-fei Huang

The clinical spectrum of IgM monoclonal gammopathy: A single center retrospective study of 377 patients.

OBJECTIVES We retrospectively evaluated the clinical features, serum levels of IgM, and prevalence of IgM related diseases in patients with serum immunofixation electrophoresis (sIFE) confirmed IgM monoclonal gammopathy at our center. METHODS We included patients with sIFE confirmed IgM monoclonal gammopathy between January 2008 and December 2014 in this retrospective study. We evaluated clinical data, sIFE, serum IgM levels, and diagnosis. RESULTS In total, 7107 patients had sIFE confirmed monoclonal gammopathy, with 377 (5.3%) patients having the IgM type. The median age was 62 years (range, 19-105 years). The median level of serum IgM is 8.3g/L (range, 0.24-150g/L). The diagnosis included monoclonal gammopathy of undetermined significance (MGUS, 157 patients, 41.6%), Waldenstrom macroglobulinemia (WM, 105 patients, 27.9%), B cell non-Hodgkins lymphoma (69 patients, 18.3%), primary cold agglutinin disease (pCAD, 16 patients, 4.2%), primary amyloidosis (14 patients, 3.7%), cryoglobulinaemia (six patients, 1.6%), IgM MGUS associated neuropathy (five patients, 1.3%), multiple myeloma (three patients, 0.8%), and POEMS syndrome (two patients, 0.5%). Levels of serum IgM>15.5g/L were 80.6% sensitive and 89.2% specific for the diagnosis of WM. Kappa type light chain indicated the diagnosis of WM, pCAD, IgM MGUS associated neuropathy and cryoglobulinaemia, while lambda type light chain indicated POEMS and amyloidosis. There were 41/157 (26.1%) MGUS patients diagnosed with complications due to IgM-unrelated autoimmune diseases. CONCLUSION IgM monoclonal gammopathy contains a broad spectrum of diseases. Levels of serum IgM and the type of light chain can be used to help with differential diagnosis. The association between MGUS and some autoimmune diseases requires further investigation.

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.

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.

OCULAR MANIFESTATIONS AND TREATMENT OUTCOMES IN CHINESE PATIENTS WITH POEMS SYNDROME.

Purpose: To evaluate the relationship of serum vascular endothelial growth factor (VEGF) levels and ocular manifestations in Chinese patients with POEMS syndrome. Methods: This is a prospective study. Forty-one treatment-naive patients were enrolled from April 2014 to November 2014. Among the 41 patients, 40 had complete ocular examination, spectral domain optical coherence tomography scan, and serum VEGF measurement before treatment and every 3-month interval after lenalidomide and dexamethasone treatment. Results: Twenty-seven (67.5%) patients had optic disk edema (ODE) at baseline. Retinal manifestations included retinal hemorrhage, subretinal fluid, macular edema, and cotton wool spot. The difference in mean serum VEGF concentrations between patients with and without ODE was significant (P = 0.017). Among patients with ODE, there was a significant positive correlation between mean serum VEGF levels and the binocular mean retinal nerve fiber layer thickness (P = 0.008), as well as mean peripapillary retinal thickness (P = 0.020) before treatment. After 3 months to 17 months treatment, mean serum VEGF concentrations decreased significantly (P < 0.001). Mean retinal nerve fiber layer thickness and mean peripapillary retinal thickness decreased significantly (P < 0.001). The remission rate of ODE was 87.5%, and complete remission rate was 58.3%. Conclusion: The ODE is a common manifestation in POEMS syndrome, and raised VEGF might explain the development and mechanism. Systemic treatment could lead to decrease in serum VEGF levels accompanied by regression of ODE.

Light chain amyloidosis: Where are the light chains from and how they play their pathogenic role?

Amyloid light-chain (AL) amyloidosis is a plasma-cell dyscrasia, as well as the most common type of systematic amyloidosis. Pathogenic plasma cells that have distinct cytogenetic and molecular properties secrete an excess amount of amyloidogenic light chains. Assisted by post-translational modifications, matrix components, and other environmental factors, these light chains undergo a conformational change that triggers the formation of amyloid fibrils that overrides the extracellular protein quality control system. Moreover, the amyloidogenic light-chain itself is cytotoxic. As a consequence, organ dysfunction is caused by both organ architecture disruption and the direct cytotoxic effect of amyloidogenic light chains. Here, we reviewed the molecular mechanisms underlying this sequence of events that ultimately leads to AL amyloidosis and also discuss current in vitro and in vivo models, as well as relevant novel therapeutic approaches.

Prognostic value of serum vascular endothelial growth factor and hematological responses in patients with newly-diagnosed POEMS syndrome

Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS) syndrome is a rare plasma cell dyscrasia characterized by high serum levels of vascular endothelial growth factor (VEGF). Bone marrow plasma cells are the likely source of this angiogenic cytokine, which is responsible for the characteristic symptoms of this disorder, including extravascular volume overload, hemagiomata and papilledema. A reduction of VEGF level after treatment usually correlates with symptomatic improvement. The main treatment strategy is to target plasma cell clones, and monoclonal protein and VEGF levels are used to monitor disease activity. Hematologic complete response (CRH) has proved to be a significant predictor of disease outcome. However, some patients without CRH still show reasonable survival rates, suggesting that this group is highly heterogenous and requires better prognostic indicators. VEGF response after treatment showed good prognostic value in a retrospective study of 20 patients. Those achieving a normal serum VEGF value after treatment attained prolonged relapse-free survival. However, previous studies were limited by patient number and follow-up time, and lacked OS outcome and comparison with hematologic response. A total of 476 patients were newly-diagnosed POEMS syndrome and treated at our institute between January 2000 and October 2016. Of these, 190 patients (39.9%, and baseline clinical characteristics were not significantly different from all patients), who had both baseline and post-treatment serum M protein and VEGF data, and whose post-treatment serum samples were collected for half a year since the treatment began, were enrolled in the present study. All patients had been followed for at least 6 months and had elevated baseline serum VEGF levels ( > 600 pg/mL). All patients met the diagnostic criteria proposed by Dispenzieri. Primary therapies included autologous stem cell transplantation (77 patients), melphalan-based therapy (21 patients) and novel agentbased (thalidomide, lenalidomide, bortezomib) therapy (92 patients). The median length of follow-up was 32 months (range, 6–179 months). Detailed clinical features and laboratory information were collected at the time of diagnosis, as described previously. (Online Supplementary Table 1) Serum VEGF was measured with a human Quantikine ELISA Kit (R&D Systems, Minneapolis, MN, USA). All patients provided informed consent, and the study was approved by the Institutional Review Board of Peking Union Medical College Hospital, in accordance with the Declaration of Helsinki. The upper limit of the normal serum VEGF range was 600 pg/mL in our institute, as previously described. The complete response of VEGF (CRV) was a normalization of serum VEGF levels. A VEGF partial response (PRV) was a reduction of > 50% (baseline must ≥ 1200 pg/mL, 3% patients were between 600 and 1200 pg/mL at baseline). Others were considered as VEGF non-response (NRV) patients. Hematologic response included CRH (a confirmed negative immunofixation electrophoresis (IFE) test and for patients with only light-chain secreting clone also undetectable light chain with serum and urine samples)

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.