Elevated Serum Free Light Chains Research Articles

Lambda-free light chain: A serum marker of dengue disease via NS3 protease-mediated antibody cleavage

ABSTRACT Dengue poses a significant global public health threat, with diverse clinical manifestations due to complex interactions between the host and the pathogen. Recent reports have highlighted elevated serum-free light chain (FLC) levels in viral infectious diseases. Hence, our study aimed to investigate serum FLC levels in dengue patients. The findings revealed elevated serum λ FLCs, which were associated with the severity of dengue. Receiver operating characteristic curve (ROC) analysis demonstrated that λ FLCs may serve as a serum marker for identifying dengue disease (AUC: 0.7825, sensitivity: 80, specificity: 71.43) and classifying severe dengue (AUC: 0.8102, sensitivity: 75, specificity: 79.52). The viral protease, Dengue virus (DENV) nonstructural protein 3 (NS3), acts as a protease that cleaves viral polyproteins as well as host substrates. Therefore, we proposed that antibodies might be potential targets of NS3 protease, leading to an increase in FLCs. LC/MS-MS analysis confirmed that λ FLCs were the predominant products after antibody degradation by NS3 protease. Additionally, purified NS3 protease cleaved both human IgG and DENV2-neutralizing antibodies, resulting in the presence of λ FLCs. Moreover, NS3 protease administration in vitro led to a reduction in the neutralizing efficacy of DENV2-neutralizing antibodies. In summary, the elevated serum λ FLC levels effectively differentiate dengue patients from healthy individuals and identify severe dengue. Furthermore, the elevation of serum λ FLCs is, at least in part, mediated through NS3 protease-mediated antibody cleavage. These findings provide new insights for developing diagnostic tools and understanding the pathogenesis of DENV infection.

Study on the Correlation between Elevated Serum Free Light Chain and Inferior Clinical Features or Hematological Parameters of Lymphoma Patients in Chengdu Area

To analyze the correlation of the serum free light chain elevated (sFLC) and clinical characteristics and hematological parameters of lymphoma in Chengdu area. 249 cases of non-Hodgkin lymphoma （NHL） out of 274 patients with lymphoma diagnosed in Sichuan People's Hospital from April 2019 to July 2021 were selected, the sFLC, clinical features and hematological parameters of the patients were analyzed retrospectively. The difference of clinical features between the patients with normal sFLC and elevated sFLC was examined by chi-square test. The difference of hematological parameters between patients with normal sFLC and elevated sFLC were examined by chi-square test and nonparametric Mann-Whitney U test. Among the 249 NHL patients, 55.42% （138/249） patients had an elevated sFLC, of which 9.24% （23/138） were being monoclonal and 46.18% （115/138） were polyclonal. The sFLC elevation was common in NHL, but varied according to the types of sFLC secretion （monoclonal or polyclonal）, and types of lymphoma. Furthermore, there were no significant statistical differences in clinical characteristics, including age, sex, stage disease, International Prognostic Index （IPI）, B symptoms, and bone marrow invasion between elevated sFLC and normal sFLC of the NHL patients （P＞0.05）. However, the patients with elevated sFLC had adverse hematological parameters more frequently, including higher WBC, ANC, AMC, hsCRP, Cr, Glb, LDH, and lower Hb, Alb. Elevated sFLC is associated with inferior hematological parameters, revealing the uniqueness of the diagnostic and prognostic value of sFLC in lymphoma in chengdu area.

A Case of Plasma Cell Myeloma with Multilobated and Monocytoid Morphology

Plasma cell myeloma (PCM) accounts for approximately 1% of malignant tumors and 10 to 15% of hematological neoplasms. It is a malignant disease characterized by abnormal proliferation of plasma cells and monoclonal immunoglobulins or free light chains (FLCs). There are many morphological variations of the myeloma plasma cells which include mature, immature, plasmablastic, and pleomorphic types. Here, we report a rare presentation of PCM with normal serum protein electrophoresis but elevated serum FLCs and having convoluted, multilobated, and monocytoid morphology. This type of morphology is related to an aggressive clinical course and resistance to conventional chemotherapy. Moreover, absence of M protein in serum/urine electrophoresis does not rule out the diagnosis of PCM and serum FLC assays plays an important role in this kind of scenarios.

69-Year-Old Man With Dysuria and Right Lower Abdominal Pain

69-Year-Old Man With Dysuria and Right Lower Abdominal Pain

Gastrointestinal amyloidosis in a patient with smoldering multiple myeloma: A case report

BACKGROUNDSmoldering multiple myeloma (SMM) is an asymptomatic plasma cell proliferative disorder that can progress to multiple myeloma (MM). Amyloidosis (light chain) (AL) is the most common form of systemic amyloidosis. There are few reports of SMM coexisting with AL involving the digestive tract. CASE SUMMARYA 63-year-old woman presented with lower limb edema, abdominal distension, abdominal pain, and hematochezia. Gastroscopy showed gastric retention, gastric angler mucosal coarseness, hyperemia, and mild oozing of blood. Colonoscopy showed hyperemic and edematous mucosa of the distal ascending colon and sigmoid colon with the presence of multiple round and irregular ulcers, submucosal ecchymosis, and hematoma. Gastric and colonic tissue biopsy confirmed the diagnosis of AL by positive Congo red staining. MM was confirmed by bone marrow biopsy and immunohistochemistry. The patient had no hypercalcemia, renal dysfunction, anemia, bone lesions or biomarkers of malignancy defined as plasma cells > 60% in bone marrow. Additionally, no elevated serum free light chain ratio, or presence of bone marrow lesions by magnetic resonance imaging (SLiM criteria) were detected. The patient was finally diagnosed with SMM coexisting with AL. She received chemotherapy and was discharged when the symptoms were relieved. She is doing well at nearly five years of follow up.CONCLUSIONThis case highlights that high index of suspicion is required to diagnose gastrointestinal AL. It should be suspected in elderly patients with endoscopic findings of granular-appearing mucosa, ecchymosis, and submucosal hematoma. Timely diagnosis and appropriate therapy can help to improve the prognosis of these patients.

Free Light-Chain Levels in Patients with Transthyretin Amyloid Cardiomyopathy in Attr-ACT

Introduction: In cardiac amyloidosis (CA), immunoglobulin-derived light chains (AL) and transthyretin (TTR) are the most common amyloidogenic proteins infiltrating the heart. 1 Identification of the specific precursor protein leading to amyloid deposition is needed to establish the correct therapeutic approach. 2 In both AL- and TTR-related CA, an early and accurate diagnosis is critical to achieving the best treatment outcomes. TTR amyloid cardiomyopathy (ATTR-CM) is often misdiagnosed as other causes of heart failure (HF), including AL CA. 3 While almost all patients with AL amyloidosis have elevated serum free light-chain (sFLC) levels and abnormal free kappa:lambda (κ:λ) ratios, 4 patients with ATTR-CM can also have abnormal sFLC levels due to either an unrelated monoclonal gammopathy or relative κ-predominance in renal dysfunction. 2,5 Because ATTR-CM most often occurs in elderly adults and is commonly accompanied by renal comorbidity, we theorized that patients with ATTR-CM may have κ:λ ratios that approach, or exceed, the upper limit of the normal reference range (0.26-1.65 6). High light-chain ratios in these patients have the potential to increase the likelihood of misdiagnosis of a monoclonal plasma cell disorder and may lead to unnecessary referrals to hematologists and/or inappropriate treatments. To explore this theory, we evaluated κ:λ ratios in patients with biopsy-proven ATTR-CM who were enrolled in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). 7Methods: In ATTR-ACT, a double-blind, placebo-controlled, randomized study, patients with biopsy-proven ATTR-CM, and without light-chain amyloidosis, received tafamidis or placebo for 30 months. In the current analysis, sFLC levels and κ:λ ratios were assessed in the intent-to-treat population (N=441), excluding patients with a prior diagnosis of monoclonal gammopathies (n=13; defined by MedDRA preferred terms: ‘monoclonal gammopathy’, ‘plasma cell myeloma’, ‘plasma cell disorder’, and ‘hypergammaglobulinemia benign monoclonal‘). Subgroup analyses were performed by estimated glomerular filtration rate (eGFR) category (≥60 vs ≥40 to <60 vs <40 mL/min/1.73 m 2). Findings were summarized using descriptive statistics (min/max, mean, median, and interquartile range [IQR]).Results: In 422 patients with ATTR-CM and available sFLC data, and without a prior diagnosis of monoclonal gammopathies, the mean κ:λ ratio was 1.45 (median, 1.20 [IQR, 0.98, 1.47]) (Figure). The ratio increased with declining renal function: eGFR ≥60 mL/min/1.73 m 2, mean, 1.25 (median [IQR], 1.11 [0.94, 1.38]); ≥40 to <60 mL/min/1.73 m 2, 1.52 (1.22 [0.99, 1.49]); and <40 mL/min/1.73 m 2, 1.62 (1.30 [1.05, 1.68)].Conclusions: In patients with biopsy-proven ATTR-CM without known monoclonal gammopathies who were enrolled in ATTR-ACT, the mean κ:λ ratio showed a κ-predominance, often exceeding the upper range of normal in patients with more advanced kidney dysfunction. The findings suggest that individuals with ATTR-CM can have higher sFLC levels than those normally seen in the general population, and such elevations do not necessarily indicate the presence of monoclonal gammopathy of undetermined significance or AL CA. In an era when most patients with ATTR-CM and without monoclonal gammopathies are diagnosed noninvasively using bone scintigraphy, age- and renal-function-based sFLC norms are critical to ensure appropriate use of diagnostic testing modalities.

Hepatic AL Amyloidosis Without Significant Light Chain Elevation in a Patient Treated with CyBorD Plus Daratumumab

Patient: Female, 60-year-old Final Diagnosis: Amyloid light-chain amyloidosis • hepatic amyloidosis Symptoms: Abdominal pain • anemia • emesis Medication: — Clinical Procedure: Bone marrow biopsy • exploratory laparotomy • hepatectomy • stem cell transplant Specialty: Hematology • Oncology Objective: Unusual clinical course Background:Immunoglobulin light chain (AL) amyloidosis is a plasma cell disorder in which excess light chain deposits in tissues, resulting in organ dysfunction and damage. Typically, AL amyloidosis presents as a systemic disease affecting multiple organs, and most patients have elevated serum free light chains. However, the presentation of AL amyloidosis is highly variable. The purpose of this case report is to raise awareness of the atypical presentations of AL amyloidosis in order to facilitate more rapid diagnosis, which has the potential to prevent additional organ damage when appropriate therapy is provided.Case Report:We describe a case of AL amyloidosis with amyloid deposition confined to the liver and bone marrow and lack of significant serum light chain elevation. The patient initially presented with a spontaneous hepatic hematoma, and was ultimately found to have hepatic AL amyloidosis, with monoclonal plasma cells in the bone marrow and monoclonal protein on serum protein electrophoresis. Our patient responded to treatment with cyclophosphamide-bortezomib-dexamethasone, the anti-CD38 antibody daratumumab, and autologous stem cell transplant, resulting in hematological and organ response.Conclusions:AL amyloidosis can present with end-organ damage confined to isolated organs, and it can present without the expected elevation in serum light chains. Such patients can benefit from appropriate treatment, including traditional chemotherapy, daratumumab, and stem cell transplant. As effective treatments for AL amyloidosis are now available, prompt diagnosis has the potential to limit end-organ damage and potentially improve patient outcomes.

Role of computed tomography texture analysis using dual-energy-based bone marrow imaging for multiple myeloma characterization: comparison with histology and established serologic parameters

ObjectiveTo identify textural features on dual-energy CT (DECT)–based bone marrow images in myeloma which correlate with serum markers of myeloma activity and the degree of medullary involvement.MethodsA total of 110 patients (63.0 ± 11.0 years, 51 female) who underwent unenhanced whole-body DECT between September 2015 and February 2019 were retrospectively included, which was approved by our institutional ethics committee with a waiver of the informed consent requirement. All patients had current hematologic laboratory tests. Using DECT post-processing, non-calcium bone marrow images were reconstructed. The vertebral bodies T10–L5 were segmented for quantification of textural features, which were compared with serologic parameters and myeloma stages by the Mann-Whitney U test. In a subgroup of 56/110 patients with current bone marrow biopsies, textural features were correlated with the degree of bone marrow infiltration.ResultsFirst-order features were higher in patients with advanced stage of myeloma (p < .02), whereas the 2nd-order “gray-level co-occurrence matrix (GLCM) cluster prominence” was lower (p < .04). In patients with elevated serum-free light chains (SFLC) or kappa/lambda SFLC ratio above 1.56, the “entropy” and 2nd-order GLCM features were lower (p < .03). The degree of bone marrow infiltration correlated with 1st-order features (e.g., “uniformity”; rP = 0.49; p < .0001), whereas “entropy” and 2nd-order GLCM features were negatively correlated (e.g., “difference entropy”; rP = − 0.54; p < .0001).ConclusionsCT textural features applied on non-calcium bone marrow images correlate well with myeloma-related serologic parameters and histology showing a more uniform tissue structure and higher attenuation with increasing medullary infiltration and could therefore be used as additional imaging biomarkers for non-invasive assessment of medullary involvement.Key Points• Texture analysis applied on dual-energy reconstructed non-calcium bone marrow images provides information about marrow structure and attenuation.• Myeloma-related serologic parameters and the degree of myeloma cell infiltration correlate with 1st- and 2nd-order features which could be useful as additional imaging biomarkers for non-invasive assessment of medullary involvement.

P0480LENALIDOMIDE PLUS DEXAMETHASONE FOR PROLIFERATIVE GLOMERULONEPHRITIS WITH MONOCLONAL IG DEPOSITS

Abstract Background and Aims To evaluate the efficacy and safety of lenalidomide plus dexamethasone (LD) in patients with proliferative glomerulonephritis with monoclonal Ig deposits (PGNMID). Method Retrospectively analyzed the clinicopathological data of 6 PGNMID patients who treated with LD protocol from January 2010 to October 2019. Results All of the patients received LD treatment for ≥3 months after renal biopsy. 3 patients achieved renal remission. The renal remission rate was 50%. Light microscopy showed membranoproliferative glomerulonephritis and immunofluorescence showed single kappa type IgG3 was deposited in the mesangial region and the vascular loop. Before taking LD scheme, the median urinary protein were 7.76 (1.27,14.57) g/24h, the median serum creatinine 1.34 (0.8,3.27) mg/dL, the median albumin 34.5 (22.4,37.5) g/L. In 5 patients the concentration of serum free kappa and lambda light chain increased, but no patients with abnormal serum free light chain ratio. Complement C3 deteriorated in 2 patients, 2 cases of patients with monoclonal plasma cells, 0.7% and 0.5%, respectively. Immunofixation electrophoresis suggested that 1 patient had positive serum M protein for kappa type IgG3. At the last follow-up, median urine protein was 3.33 (0.33,11.23) g/24h, median serum creatinine was 1.23 (0.91,1.82) mg/dL, and median albumin was 35.9 (24.5,45.6) g/L. The concentration of 4 patients with elevated serum free light chain was lower than that before taking the drug. Two patients with decreased complement C3 increased to normal concentration at the last follow-up. However, the other two patients had a slight decrease in complement C3. The M spike did not turn negative during the follow-up in one patients. Adverse events included anemia, neutropenia, limb numbness, upper respiratory tract infection. Conclusion This study reported that lenalidomide plus dexamethasone may be effective in treating proliferative glomerulonephritis with monoclonal Ig deposits for the first time. More attention needs to be paid to the hematological adverse events during lenalidomide treatment.

Polyclonal serum free light chain elevation is associated with increased risk of monoclonal gammopathies

Monoclonal gammopathies (MG) constitute a spectrum of disorders starting from a monoclonal gammopathy of undetermined significance (MGUS) to active disease requiring therapy such as multiple myeloma. MG are characterized by proliferation of clonal plasma cells (PC) secreting a monoclonal protein either as intact immunoglobulin or free kappa or lambda free light chains (FLC). We hypothesized that a polyclonal elevation of serum FLC may indicate an inflammatory state that precedes development of MG. We studied 15,630 individuals from Olmsted county, who did not have MGUS based on baseline screening studies. At a median follow-up of 18.1 years, 264 patients had developed a clonal PC disorder; 252 with MGUS, 1 with SMM, 8 with MM, and 3 with amyloidosis, translating to an annual incidence of development of a MG of 0.1%. We examined the baseline polyclonal ΣFLC (kappa + lambda FLC) from the initial screening and grouped them into deciles. The highest decile group had a 2.6-fold (95% CI; 1.8, 3.7) increase in the risk of developing a MG, P < 0.001. We demonstrate for the first time, the increased risk of developing MG in patients with elevated serum FLC, suggesting that an underlying inflammatory state may play an etiologic role.

Serum free light chain levels and renal function at diagnosis in patients with multiple myeloma

BackgroundRenal impairment (RI) is common in multiple myeloma (MM) and is associated with poor survival. This study reports the associations between renal function and disease characteristics including serum free light chain (FLC) level at diagnosis in patients with MM.MethodsUsing data from the Medical Research Council Myeloma IX trial, a multicentre, randomized, open-label, phase III and factorial-design trial, we assessed the relationships between renal function, demographic, and disease characteristics, including serum FLC levels, in 1595 newly diagnosed MM patients. Multivariable linear regression was utilised to identify factors that were associated with renal function at diagnosis. A receiver operating characteristic curve (ROC) was used to identify the optimal threshold for serum FLC level at diagnosis to predict severe RI.Results52.8% of patients had an estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m2 (no RI), 37.3% an eGFR 30–59 ml/min/1.73 m2 (mild to moderate RI), and 9.8% an eGFR < 30 ml/min/1.73 m2 (severe RI). In a multivariable analysis, factors independently and negatively associated with eGFR at diagnosis were: higher serum FLC level, female gender, and older age. Elevated serum FLC level at diagnosis, irrespective of the paraprotein type, was strongly associated with severe RI. Receiver operating characteristic curve analysis showed a serum FLC level of > 800 mg/L as the optimal cut-off associated with severe RI (area under curve 0.86, 95% confidence interval 0.77–0.84).ConclusionThere was a strong relationship between higher serum FLC levels at diagnosis and the severity of RI that was irrespective of the paraprotein type. We report an increased risk of severe RI in patients presenting with serum FLC levels above 800 mg/L at diagnosis.

Serum Free Light Chain Concentration (>1000mg/dl) at Diagnosis and at Relapse Predicts for Very Poor Prognosis in Multiple Myeloma

Background: There have been significant improvements in the outcomes for patients with multiple myeloma over the past 10 years. The course of the disease remains highly variable. While some patients experience 10-15 year survivals, others succumb to highly refractory disease within a few months. Many studies have focused on the description of prognostic factors capable of predicting this heterogeneity in survival. Baseline Serum free light chain concentration is a major prognostic indicator for plasma cell neoplasms and normalization of free light chain ratio with treatment has been reported as an indicator for favorable prognosis. High Baseline free light chain concentration at presentation indicates aggressive disease. Furthermore High serum free light chain ratio correlates with elevated serum creatinine, elevated LDH and extensive marrow infiltration.Objectives: To determine if serum free light chain concentration > 1000mg/dl at the time of diagnosis and at disease progression was an independent prognostic marker for multiple myeloma.Methods: The results of all the serum free light chain analyses of patients evaluated at western Pennsylvania hospital between 2007 -2015 were reviewed and patients with serum free light chain concentration >1000mg/dl at the time of initial diagnosis and disease progression were identified Retrospective chart review was done to study the survival in these patients.Results: Total of 15 patients in whom serum free light chain concentration was greater than 1000 mg/dl at diagnosis were identified. Median age at diagnosis was 60.81 years (45.2-77.3). The median survival in this population is 1.85 years (range 0.06-8.85 years), with 5 deaths. Of these 15, 9 patients received an autologous PBSCT as a part of their initial therapy. Six of them are alive with a median overall survival of 2.44 years and mean survival of 3.89 years (range 0.87-8.89). In the remaining 6 patients that did not undergo an auto PBSCT 3 of them are alive with median overall survival of 1.21 years and a mean survival 1.20 years (range 06-2.76 years). There is an overall trend toward very poor prognosis in this specific group of patients irrespective of the age, sex, stage at time of diagnosis, the immunoglobulin subtype and the free light chain subtype (kappa vs lambda).We also conducted a retrospective review of patients in whom serum free light chains concentration was greater than 1000mg/dl at disease progression. Twenty patients were identified all of whom are deceased with a median overall survival from the time of progression with serum free light chains greater than 1000 mg /dl was dismal at 0.27 years and mean survival was 0.53 years (range 0.04-2.52 years)Conclusion: Patients with multiple myeloma who presented with a serum free light chain concentration greater than 1000 mg/dl at diagnosis have very poor prognosis. These specific subgroups of patients should be identified and treated aggressively at the time of diagnosis to prevent complications from multiple myeloma and improve their overall survival. In our small cohort of patients those who underwent auto PBSCT as a part of their initial therapy tend to have better outcomes in terms of overall survival compared to patients who received therapy without auto PBSCT consolidation. Patients with serum free light chains greater than 1000 mg/dl at disease progression will need to be treated aggressively with perhaps a salvage auto PBSCT to improve their overall outcome. A larger study to evaluate elevated serum free light chains (greater than 1000 mg/dl) as a prognostic indicator at diagnosis and progression should be done to further validate these findings [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Correction: Elevated Concentrations of Serum Immunoglobulin Free Light Chains in Systemic Lupus Erythematosus Patients in Relation to Disease Activity, Inflammatory Status, B Cell Activity and Epstein-Barr Virus Antibodies

Objective In this study, we examined the concentration of serum immunoglobulin free light chains (FLCs) in systemic lupus erythematosus (SLE) patients and investigated its association with various disease parameters in order to evaluate the role of FLCs as a potential biomarker in SLE. Furthermore, FLCs’ association with Epstein-Barr virus (EBV) antibodies was examined. Methods Using a nephelometric assay, κFLC and λFLC concentrations were quantified in sera from 45 SLE patients and 40 healthy controls. SLE patients with renal insufficiency were excluded in order to preclude high concentrations of serum FLCs due to decreased clearance. Results Serum FLC concentrations were significantly elevated in SLE patients compared to healthy controls (p<0.0001) also after adjusting for Ig levels (p<0.0001). The concentration of serum FLCs correlated with a global disease activity (SLE disease activity index (SLEDAI)) score of the SLE patients (r = 0.399, p = 0.007). Furthermore, concentrations of FLCs correlated with titers of dsDNA antibodies (r = 0.383, p = 0.009), and FLC levels and SLEDAI scores correlated in the anti-dsDNA-positive SLE patients, but not in anti-dsDNA-negative SLE patients. Total immunoglobulin (IgG and IgA) concentrations correlated with FLC concentrations and elevated FLC levels were additionally shown to associate with the inflammatory marker C-reactive protein and also with complement consumption determined by low C4 in SLE patients. Collectively, results indicated that elevated serum FLCs reflects increased B cell activity in relation to inflammation. SLE patients had an increased seropositivity of EBV-directed antibodies that did not associate with elevated FLC concentrations. An explanation for this could be that serum FLC concentrations reflect the current EBV activity (reactivation) whereas EBV-directed antibodies reflect the extent of previous infection/reactivations. Conclusion SLE patients have elevated concentrations of serum FLCs that correlate with global disease activity scores and especially serologic markers for active disease. These findings are suggestive of circulating FLCs having potential as a new supplementary serologic biomarker in SLE.

Elevated Concentrations of Serum Immunoglobulin Free Light Chains in Systemic Lupus Erythematosus Patients in Relation to Disease Activity, Inflammatory Status, B Cell Activity and Epstein-Barr Virus Antibodies.

ObjectiveIn this study, we examined the concentration of serum immunoglobulin free light chains (FLCs) in systemic lupus erythematosus (SLE) patients and investigated its association with various disease parameters in order to evaluate the role of FLCs as a potential biomarker in SLE. Furthermore, FLCs’ association with Epstein-Barr virus (EBV) antibodies was examined.MethodsUsing a nephelometric assay, κFLC and λFLC concentrations were quantified in sera from 45 SLE patients and 40 healthy controls. SLE patients with renal insufficiency were excluded in order to preclude high concentrations of serum FLCs due to decreased clearance.ResultsSerum FLC concentrations were significantly elevated in SLE patients compared to healthy controls (p<0.0001) also after adjusting for Ig levels (p<0.0001). The concentration of serum FLCs correlated with a global disease activity (SLE disease activity index (SLEDAI)) score of the SLE patients (r = 0.399, p = 0.007). Furthermore, concentrations of FLCs correlated with titers of dsDNA antibodies (r = 0.383, p = 0.009), and FLC levels and SLEDAI scores correlated in the anti-dsDNA-positive SLE patients, but not in anti-dsDNA-negative SLE patients. Total immunoglobulin (IgG and IgA) concentrations correlated with FLC concentrations and elevated FLC levels were additionally shown to associate with the inflammatory marker C-reactive protein and also with complement consumption determined by low C4 in SLE patients. Collectively, results indicated that elevated serum FLCs reflects increased B cell activity in relation to inflammation. SLE patients had an increased seropositivity of EBV-directed antibodies that did not associate with elevated FLC concentrations. An explanation for this could be that serum FLC concentrations reflect the current EBV activity (reactivation) whereas EBV-directed antibodies reflect the extent of previous infection/reactivations.ConclusionSLE patients have elevated concentrations of serum FLCs that correlate with global disease activity scores and especially serologic markers for active disease. These findings are suggestive of circulating FLCs having potential as a new supplementary serologic biomarker in SLE.

Abstract 5074: Elevated serum free light chains and risk of non-Hodgkin lymphoma and the subtype follicular lymphoma in a prospective cohort study

Abstract Background: Serum free light chains (FLC) are plausible biomarkers associated with risks of Hodgkin and non-Hodgkin lymphoma (NHL) or its subtypes. Methods: We investigated the relationship between free light chains and the risks of non-Hodgkin lymphoma (NHL) with a particular focus on two major subtypes - diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) using samples from the prospective Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Kappa and lambda free light chains were analyzed in 292 incident NHL cases [including 62 DLBCL, 45 FL and 122 chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) cases] and 292 controls individually-matched to cases on age, sex, race, study center, and date of baseline blood draw. Conditional logistic regression was performed to compute the odds ratios (ORs) and 95% confidence intervals (CIs). Impact of follow-up time from blood collection to case diagnosis was evaluated by stratifying on 1-4 and 5-10 years of follow-up in cases and the matched controls. Results: Elevated kappa and/or lambda FLC above the upper limit of normal (ULN) were found to be significantly associated with risks of overall NHL [OR(95% CI): 1.74(1.04-2.90)]. Further analysis on risk of NHL by FLC divided into quartiles based on the distribution in controls showed a stronger dose-response relationship with lambda FLC (ptrend=0.034, adjusted for kappa FLC) than kappa FLC (ptrend=0.15, adjusted for lambda FLC). Lambda FLC also showed a stronger relationship with risk of NHL in 5-10 follow-up years [OR(95% CI): 3.11(1.26-7.66) and 3.58(1.36-9.40) for the second highest and the highest vs. lowest quartile, respectively, ptrend=0.0097, adjusted for kappa FLC] in contrast to 1-4 years (ptrend=0.95, adjusted for kappa FLC). Though the clinical definition of abnormal level did not show an association with FL, likely due to small numbers, there was a strong dose-response relationship between quartiles of lambda FLC and risk of FL [OR(95% CI) for highest vs. lowest quartile: 14.51(2.58-81.54), ptrend=0.0054]. No significant associations were observed between FLC and DLBCL. We also found that elevated kappa FLC was associated with CLL/SLL [OR(95% CI) for highest vs. lowest quartile: 1.92(0.85-4.35), ptrend=0.019], consistent with findings from a previous report from this study. Conclusion: These findings suggest that immune activation precedes development of clinically apparent FL. Citation Format: Wei Hu, Ola Landgren, Bryan Bassig, Mark Purdue, Eric Engels, Qing Lan, Nathaniel Rothman. Elevated serum free light chains and risk of non-Hodgkin lymphoma and the subtype follicular lymphoma in a prospective cohort study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5074. doi:10.1158/1538-7445.AM2014-5074

Monoclonal and polyclonal gammopathy measured by serum free light chain and immunofixation subdivide the clinical outcomes of diffuse large B-cell lymphoma according to molecular classification.

Elevated serum free light chain (FLC) is known to be an adverse prognostic factor for diffuse large B-cell lymphoma (DLBCL). We hypothesized that monoclonal gammopathy (MG; elevated kappa [κ] or lambda [λ] FLC with an abnormal κ/λ ratio or a positive IF [immunofixation]) and polyclonal gammopathy (PG; elevated κ and/or λ FLC with a normal κ/λ ratio and a negative IF) would have different clinical outcome according to the molecular classification of DLBCL. In addition, MG would be a poor prognostic factor in patients with activated B-cell like type of DLBCL. Molecular classification of DLBCL, such as germinal center B-cell (GCB) type and non-GCB type, was performed according to the Hans algorithm. Among 175 newly diagnosed DLBCL patients, 96 (54.9 %) patients had an elevated FLC. MG and PG were observed in 34 and 68 patients, respectively. The 2-year overall survival (OS) and event-free survival (EFS) rates were 79.0 % and 71.6 %, respectively. In multivariate analysis, high-intermediate/high International Prognostic Index score and elevated FLC were significant for the OS (P = 0.002, P = 0.005, respectively) and EFS (P < 0.002, P = 0.010, respectively). MG and PG were also associated with inferior OS (P = 0.002, P = 0.011, respectively) and EFS (P = 0.002, P = 0.013, respectively). Ninety-six patients from a total 133 evaluable patients were classified to the non-GCB type. Patients with PG showed inferior clinical outcome for OS and EFS in patients with the GCB type (P = 0.006, P = 0.035, respectively). MG was a significant poor prognostic factor for OS and EFS in patients with the non-GCB type (P = 0.017, P = 0.004, respectively). MG was a poor prognostic maker in patients with the non-GCB type and PG was a poor prognostic indicator for the GCB type of DLBCL who were treated with R-CHOP.

Elevated serum free light chains predict cardiovascular events in type 2 diabetes.

Elevated polyclonal serum immunoglobulin free light chains (FLCs; combined FLCκ+FLCλ [cFLC]) are associated with adverse clinical outcomes and increased mortality; we investigated cFLC and cardiovascular disease (CVD) events in type 2 diabetes. In a cohort study of 352 south Asian patients with type 2 diabetes, serum cFLC, high-sensitivity C-reactive protein (hsCRP), and standard biochemistry were measured. CVD events over 2 years were recorded and assessed using multiple logistic regression. cFLC levels were elevated significantly in 29 of 352 (8%) patients with CVD events during 2 years of follow-up (50.7 vs. 42.8 mg/L; P = 0.004). In multivariate analysis, elevated cFLC (>57.2 mg/L) was associated with CVD outcomes (odds ratio 3.3 [95% CI 1.3-8.2]; P = 0.012) and remained significant after adjusting for age, albumin-to-creatinine ratio, diabetes duration, or treatment. cFLC elevation is a novel marker for CVD outcomes in type 2 diabetes that warrants further investigation.

Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120)

AbstractAll cases of clinical myeloma (CMM) are preceded by an asymptomatic monoclonal gammopathy (AMG), classified as either monoclonal gammopathy of undetermined significance (MGUS) or asymptomatic multiple myeloma (AMM). We analyzed data from AMG patients (n = 331) enrolled in a prospective, observational clinical trial (S0120). Baseline data from clinical variables, gene expression profiles (GEP) of purified tumor cells, and findings of magnetic resonance imaging (MRI) were correlated with the risk of progression to CMM requiring therapy. GEP of purified tumor cells revealed that all molecular subtypes of CMM are also represented in the AMG phase. An increased risk score (>-0.26) (based on a 70-gene signature, GEP70) was an independent predictor of the risk of progression to CMM. Combination of elevated serum free light chain, M-spike, and GEP70 risk score identified a subset with high risk (67% at 2 years) of progression to CMM requiring therapy. Importantly, absence of these factors in AMM patients predicted low risk similar to MGUS. Detection of multiple (>1) focal lesions by MRI also conferred an increased risk of progression. These data demonstrate that signatures associated with high-risk CMM impact disease risk and support inclusion of genomic analysis in the clinical management of AMGs. This trial was registered at www.clinicaltrials.gov as # NCT00900263.Key Points

Combined crystalline podocytopathy and tubulopathy associated with multiple myeloma

Lymphoplasmacytic neoplasms cause a wide range of injuries to the kidney exemplified by light chain cast nephropathy and amyloidosis. Filtered paraproteins can also accumulate within kidney cells and cause direct cytotoxic injury. Rarely, paraproteins that are resistant to proteolysis can crystallize within proximal tubules and cause acute tubular injury. In contrast, accumulation of crystallized paraproteins in other kidney cells, especially podocytes, is exceptional. Here, we report the finding of crystalline inclusions within podocytes and proximal tubules in a patient who presented with a combined nephrotic syndrome and Fanconi syndrome. Further workup revealed previously unsuspected multiple myeloma and elevated serum free light chains, highlighting the protean presentation of paraprotein-mediated injuries to the kidney.

Laryngeal Amyloidosis

Objectives: Amyloidosis constitutes less than 1% of benign laryngeal tumors and may occasionally be associated with systemic disease. It commonly presents with long-standing hoarseness or dyspnea. Diagnosis is established with histological features of acellular, amorphous, eosinophilic deposits which react positively with Congo red. We present 2 such cases of laryngeal amyloidosis, one localized and one with systemic involvement. Literature review, diagnostic work-up, and treatment options are discussed. Methods: Case 1: A 63 year old non-smoking male presented with hoarse voice for 2 months. Flexible laryngoscopy showed diffuse fullness on left hemilarynx. Microlaryngoscopy revealed submucosal lesion in anterior left vocal cord, which on deep biopsy confirmed AL type amyloid. Detailed work-up by a hematologist ruled out systemic disease. Case 2: A 74 year old moderate smoker presented with 6 months of hoarse voice and burning sensation in the tongue. He had a mucosa-covered growth in the right false vocal cord, which on biopsy confirmed amyloidosis (AL type). Further work-up revealed systemic disease with elevated serum free light chains, IgG Kappa paraprotein, and positive abdominal fat biopsy. Results: Patient 1 is under follow-up with no clinical recurrence. Patient two had treatment with CDT chemotherapy and is under hematologist surveillance. Past history includes carpal-tunnel decompression. Localized laryngeal amyloidosis is best treated with cold steel resection or CO2 laser excision and may require repeated removal in some patients. Systemic amyloidosis is caused by plasma-cell dyscrasia and treated with chemotherapy and or radiotherapy. Conclusions: Endolaryngeal treatment is sufficient with localized disease. Systemic disease needs more extensive treatment, and those with associated myeloma have poor prognosis.