Intact Immunoglobulin or Fragments Thereof Can Be Detected in Urine in a Proportion of Patients with Multiple Myeloma and Are Associated with Reduced Survival At Presentation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1828-1828
Author(s):  
Heinz Ludwig ◽  
Philip Young ◽  
Dejan Milosavljevic ◽  
Niklas Zojer ◽  
Wolfgang Hübl ◽  
...  

Abstract Abstract 1828 Introduction: Intact immunoglobulin or fragments thereof (intact/fragmented Ig) can be found in the urine due to nephrotic injury or the preferential scavenging of albumin by the renal FcRn receptor leading to immunoglobulin catabolism. Until now the occurrence, frequency and clinical impact of this phenomenon has not been assessed in patients with multiple myeloma (MM). Here we determine the incidence of intact/fragmented Ig in urine and evaluate its prognostic relevance. Patients and Methods: 94 patients with MM, median age 70 years old (range 41–87) with a male / female ratio 28/66, ISS stage I (48), stage II (23), stage III (28), 69 IgG (43 IgGk/26 IgGl) and 25 IgA (15 IgAk/7 IgAl) were enrolled. Serum free light chain concentrations (sFLC) were measured using commercially available immunoassays (Freelite™, The Binding Site, Birmingham, UK) and compared to electrophoresis results (Hydrasys, Sebia, Paris, France). Overall survival was estimated by the product limiting method of Kaplan-Meyer and survival was compared by the log rank test. Results: Overall, sFLC ratios had a greater sensitivity than urine immunofixation (uIFE) for the detection of monoclonal light chains 86/94 vs. 46/94. In 13/46 (28%) uIFE positive patients intact immunoglobulins or significant fragments (intact/fragmented Ig) thereof were detected, 12 IgG, (12/69, 17%) and 1 IgA (1/25, 4%). Three of these patients had normal urine protein concentrations (<250mg/L) and 2/13 patients had glomerular injury identified by increased levels of albumin excretion. There was no difference in creatinine levels between patients with or without intact/fragmented Ig (p=0.673). Analysis of overall survival in patients stratified at presentation according to uIFE results, namely the presence of intact/fragmented Ig, abnormal serum free light chain ratio-, and negative uIFE results revealed significantly shorter overall survival for the intact/fragmented Ig group (median OS: 34.5 vs. 66.0, vs. 80.6 months, respectively, p< 0.048) (figure 1). Discussion: Our findings confirm the superiority of the serum free light chain assay for detection of monoclonal free light chains as compared to urine immunofixation. However, the serum free light chain assay is inadequate for detection of intact/fragmented Ig in urine. The most important finding presented here is the observation that intact and/or fragment immunoglobulin is present in a substantial number of patients with MM. This phenomenon is mainly restricted to IgG isotypes. There are two possible explanations for these findings: first, the presence of glomerular injury, but this phenomenon (increased albumin leakage) was only seen in two patients and hence is unlikely to account for this observation. The second explanation relies upon disruption of the FcRn receptor function in immunoglobulin scavenging. This receptor will preferentially scavenge albumin in the renal setting, but dysfunction may lead to increased immunoglobulin catabolism and the presence of intact and/or fragmented Ig (Sarav, JASN, 20: 1941–1952, 2009). The results may reflect a hitherto unidentified subtle renal dysfunction. In line with this notion overall survival in our patients intact/fragmented Ig was found to be significantly shorter. Conclusion: We observed an unexpected high incidence of intact/fragmented Ig in the urine of our patients with MM. Patients with urinary excretion of intact/fragmented immunoglobulin had significantly shorter survival. These findings should be validated in further studies. Disclosures: Young: Binding Site: Employment. Harding:Binding Site: Employment.

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5698-5698
Author(s):  
Abhishek Chilkulwar ◽  
Prerna Mewawalla ◽  
Anna Miller ◽  
Gina Berteotti ◽  
Entezam Sahovic ◽  
...  

Abstract 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 Table 1 Table 1. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4880-4880
Author(s):  
Efstathios Koulieris ◽  
Stephen Harding ◽  
Marie-Christine Kyrtsonis ◽  
Caroline Bradley ◽  
Mark T Drayson ◽  
...  

Abstract Abstract 4880 Serum free light chain ratios (FLCr) are important prognostic markers in B cell malignancies and their measurement has recently been included in multiple myeloma (MM) international guidelines. In contrast, serum IgG and IgA concentrations are not prognostic in MM. Novel immunoassays have been developed which target the specific conformational, junctional epitopes between the heavy and light chains of the immunoglobulin making it possible to measure Ig'kappa and Ig'lambda and produce an Ig'kappa /Ig'lambda ratio. Here we describe the use of FLCr and heavy/light chain ratios (HLCr) to predict survival in MM patients. Archived sera from a historic MRC and a more recent Velcade, Adriamycin, dexamethazone (PAD) MM trail were utilised and the data combined using each study as a categorical variable. 85 MRC and 73 PAD samples were analysed retrospectively using serum free light chain and serum heavy / light chain nephelometric assays (The Binding Site Group). Kaplan Meier curves and Cox regression analysis were constructed comparing the upper quartile to the lower three quartiles for involved intact immunoglobulin, FLC, HLC and FLC + HLC. All analysis was completed using SPSS v14.0. FLCr and HLCr values were not correlated (Pearson's = -0.037 p=0.66). There was no significant difference in survival when comparing the lower three quartiles and upper quartile of the involved intact immunoglobulin (Hazard Ratio [HR]=1.16: p=0.585). However, comparison of the upper quartile to the lower three quartiles did reveal significant differences in survival times for FLCr (HR=2.16: p=0.003), HLCr (HR=1.94: p=0.01) and FLCr+HLCr (HR=3.34: p=0.001). Intact immunoglobulin concentration was not prognostic in this study in keeping with current international prognostic guidelines. As with previously published data, FLCr was a prognostic indicator in MM (van Rhee 2007, Kyrtsonis 2007). It is likely FLCr is more predictive of outcome than the concentration of tumour FLC production (data not shown) because it includes a measure of immunoparesis. HLCr was an independent prognostic indicator of survival in this study. HLCr measurement may be superior to intact immunoglobulin in predicting outcomes because: 1) Changes in haematocrit and plasma volume in MM can cause Ig to change by more than 50% regardless of tumour production. 2) Serum IgG is susceptible to variable clearance rates (related to saturation of the FcRn receptor for IgG). 3) Ig measurements using serum protein electrophoresis or nephelometry include all or some of the non-tumour Immunoglobulins and may be non-linear. The summated FLCr and HLCr is a stronger prognostic marker than either measurement independently. This maybe because, as shown by Ayliffe (2007) myeloma cells can produce intact immunoglobulin, FLC or both. Therefore, in patients with very low intact immunoglobulin production and high FLC production, FLCr is likely to be the most prognostic marker and visa versa for patients with low FLC production. Conclusion In this combined study FLCr, HLCr and FLCr + HLCr were found to be predictive of overall survival in MM patients. Larger studies comparing HLCr and FLCr with B2M and Albumin as used in the international staging system are needed. Disclosures Harding: The Binding Site Group Ltd: Employment. Bradley:The Binding Site Group Ltd: Employment. Bradwell:The Binding Site Group Ltd: Shareholder.


Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2956-2956
Author(s):  
Tatiana Prokaeva ◽  
Brian Spencer ◽  
Fangui Sun ◽  
Nathaniel McConnell ◽  
Richard M O'hara ◽  
...  

Abstract Background: Serum and urine immunofixation electrophoreses (SIFE/UIFE) are routinely used for detection of clonal immunoglobulins (Ig) in AL amyloidosis. Serum free light chain (FLC) assays (Freelite®, The Binding Site Ltd., Birmingham, UK) have significantly improved the management of patients with AL amyloidosis by providing quantitative measure for the detection and monitoring of clonal plasma cell disease. However, up to 20% of patients with AL amyloidosis may have uninformative serum free light chain values. Objective: To assess the quantitative potential of serum Heavy/Light Chain (HLC) pairs (Hevylite®, The Binding Site Ltd., Birmingham, UK) assay in identification of clonal plasma cell disease in AL amyloidosis. Methods: One hundred and ninety-nine untreated patients with AL amyloidosis were included in this study. Patients with multiple myeloma or B cell lymphoproliferative diseases associated AL amyloidosis were excluded. Serum sampleswere obtained at initial evaluation and stored at -20°C. SIFE/UIFE were performed at the time of sample collection. HLC pairs were assessed by the Hevylite® assay. HLC κ/λ normal ratios (HLCR) were: 1.12-3.21 for IgG κ/λ; 0.78-1.94 for IgA κ/λ; and 1.18-2.74 for IgM κ/λ. FLCs were assessed by the Freelite® assay; FLC κ/λ normal ratio (FLCR) was 0.26-1.65. In 103 cases, FLC testing was performed at the time of sample collection; 96 cases were tested at The Binding Site. Vital status of patients was obtained from either medical records or Social Security Death Index. Follow-up ended in June 2014. Results: An abnormal HLCR was found in 74 (37.2%), an abnormal FLCR in 163 (81.9%), and SIFE/UIFE positivity in 187 (94%) of 199 patients with AL amyloidosis. Of 36 patients with a normal FLCR, 23 (63.9%) were noted with an abnormal HLCR compared to 51 (31.3%) patients in an abnormal FLCR group (P = 0.001). In total 186/199 (93.5%) patients with AL amyloidosis had abnormalities in either HLCR or FLCR, compared to 187/199 (94%) of patients who were SIFE/UIFE+ (Table 1). The combined use of both FLCR and HLCR yielded quantifiable information in 93.5% of cases; the use of both tests in combination with SIFE/UIFE identified plasma cell clonality in 100% of patients. Seventy-two cases presented with an abnormal HLCR for a single isotype and 2 in multiple Ig isotypes. In all cases, involved LC type of abnormal HLCR matched LC type identified by SIFE/UIFE. None of 12 cases that were negative on the SIFE/UIFE presented with an abnormal HLCR, however, all showed abnormalities in FLCR. Table 1. Comparative efficiency of FLCR, HLCR and Serum/Urine Immunofixation in AL Amyloidosis patients. SIFE/UIFE+ (n=187) SIFE/UIFE- (n=12) HLCR+/FLCR+ 51 (27.2%) - HLCR+/FLCR- 23 (12.3%) - HLCR-/FLCR+ 100 (53.5%) 12 (100%) HLCR-/FLCR- 13 (7%) - Overall survival was similar in patients with and without abnormal HLCR (Log rank p=0.092; Figure 1), whereas patients with an abnormal FLCR had a significantly inferior overall survival compared to those with a normal FLCR (Log rank p=0.027; Figure 2). Combined use of both HLCR and FLCR demonstrated a trend toward superior overall survival in a group of patients with an abnormal HLCR / normal FLCR (Wilcoxon p=0.037; Log rank p=0.107; Figure 3). Conclusions: The Hevylite® assay provided information in addition to other laboratory tests for clonal plasma cell disease in AL amyloidosis. The combined use of the HLCR and FLCR provided quantifiable information in 93.5% of patients. The use of both assays in combination with SIFE/UIFE detected clonal disease in all patients. HLCR has potential to quantify clonal disease in patients with uninformative FLCR results. An abnormal HLCR was not predictive of overall survival, while an abnormal FLCR was, in this series of patients. Combined use of HLCR and FLCR could be beneficial in prognostication of outcome in AL amyloidosis. Disclosures McConnell: The Binding SIte: Employment. O'hara:The Binding Site: Employment.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 376-376
Author(s):  
Thomas Dejoie ◽  
Michel Attal ◽  
Philippe Moreau ◽  
Herve Avet-Loiseau

Abstract Introduction Guidelines for monitoring light chain multiple myeloma (LCMM) patients currently rely on measurements of the monoclonal protein in urine (Bence Jones proteinuria). However, the presence of light chains in the urine is highly influenced by the individual free light chain, production rate and renal function, which may make accurate monitoring challenging. Serum free light chain measurements are recommended as diagnostic aid for identifying patients with monoclonal gammopathies and as tools to monitor patients with AL amyloidosis and oligo-secretory MM. The correlation between 24hr urine and serum free light chain (sFLC) measurements is insufficient to consider the tests interchangeable, which has prevented recommendations for replacing urine with serum assessment. Here we compare the performance of serum and urine measurements for monitoring 113 newly diagnosed LCMM patients enrolled onto the IFM-2009 trial; and assess the impact of monitoring by either method with clinical outcome. Methods The IFM-2009 trial randomised patients into either arm A (8xRVD) or arm B (3xRVD followed by high-dose Melphalan with autologous stem cell rescue, and 2 further RVD treatments). All patients received one year of Lenalidomide maintenance therapy. Urine protein electrophoresis (UPEP) and immunofixation electrophoresis (uIFE) were performed prospectively using standard laboratory procedures. sFLC concentrations were measured nephellometrically using κ sFLC and λ sFLC Freelite®assays (The Binding Site Group Ltd, UK). Minimal residual disease (MRD) was assessed by 7-color flow cytometry at the end of consolidation therapy. Results At diagnosis, clonal disease was identified in 100% of patients either by an abnormal κ/λ sFLC ratio or by uIFE. However, whilst all patients had measurable disease by the sFLC assay only 64% had measurable disease using UPEP. The discordance in sensitivity was replicated throughout monitoring and monoclonal light chains were quantifiable after cycle 1 and cycle 3 in 71% vs. 37% patients, and 46% vs. 18%, using sFLC vs. 24hr urine measurements, respectively; in keeping with previous reports. To understand the clinical significance of these discordant findings we compared the depth of response determined by sFLC measurement to those determined by urine electrophoresis after 3 cycles of therapy. Patients with quantifiable disease by sFLC or an abnormal κ/λ sFLC ratio had dismal PFS (median PFS: 36 months vs. not reached, p=0.006; 33 months vs. not reached, p<0.0001, respectively). Whereas quantifiable disease by UPEP was uninformative for PFS (36 vs. 47 months, p=0.260), and abnormal vs. normal uIFE only tended towards significance (36 vs. 47 months, p=0.072); suggesting that monitoring with the sFLC assay is more clinically relevant than with 24hr urine after 3 cycles of therapy. Separating the population into patients with negative UPEP at cycle 3 (n=82), patients with a normal sFLC levels had longer PFS than those with abnormal concentrations (not reached vs. 34 months, p=0.015). Concordant with these results, in 78 patients with negative uIFE, an abnormal κ/λ sFLC ratio still heralded a poorer PFS (34 months vs. not reached, p<0.0001) and importantly overall survival (75% OS: 44 months vs. not reached, p=0.016). In contrast, separating the patients into those with identifiable disease by sFLC or an abnormal κ/λ sFLC ratio, the addition of the urine assessment provided no further discriminatory value. The absence of malignant plasma cells in the bone marrow has been proposed as an important end-point for clinical studies, and therefore we assessed the relationship between early monoclonal light chain removal, as determined by serum and urine assessment, and subsequent elimination of malignant plasma cells. Normalisation of κ/λ sFLC ratio after both 1 and 3 treatment cycles had 100% positive predictive value (PPV) for the prediction of MRD negativity post-consolidation, i.e. all patients whose serum FLC ratio normalised during induction went on to achieve MRD negative status post-consolidation; by contrast patients becoming urine IFE negative at cycles 1 and 3 had PPVs of 81% and 78%, respectively. Conclusions Serum FLC measurements offer improved sensitivity and better correlation with clinical outcome than urine assessments, hence providing a strong basis for recommending the former for monitoring LCMM patients. Disclosures Attal: amgen: Consultancy, Research Funding; celgene: Consultancy, Research Funding; janssen: Consultancy, Research Funding; sanofi: Consultancy. Moreau:Amgen: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria. Avet-Loiseau:amgen: Consultancy; celgene: Consultancy; sanofi: Consultancy; janssen: Consultancy.


Blood ◽  
2001 ◽  
Vol 97 (9) ◽  
pp. 2900-2902 ◽  
Author(s):  
Mark Drayson ◽  
Lian X. Tang ◽  
Roger Drew ◽  
Graham P. Mead ◽  
Hugh Carr-Smith ◽  
...  

Abstract Using sensitive, automated immunoassays, increased concentrations of either κ or λ free light chains (and abnormal κ/λ ratios) were detected in the sera of 19 of 28 patients with nonsecretory multiple myeloma. Four other patients had suppression of one or both light chains, and the remaining 5 sera had normal or raised free light-chain concentrations with substantially normal κ/λ ratios. Six of the patients with an elevated single free light chain, who were studied during follow-up, had changes in disease activity that were reflected by the changes in free light-chain concentrations. It is concluded that quantification of free light chains in serum should prove useful for the diagnosis and monitoring of many patients with nonsecretory myeloma.


2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Joanna Margarita Santos ◽  
Maria Kristina L Alolod

Abstract Background and Aims Multiple myeloma is a plasma cell neoplasm that results in the production of monoclonal immunoglobulin. Renal failure is a common complication of multiple myeloma, occurring in approximately one-half of patients on initial presentation and is associated with increased mortality. Cast nephropathy in particular, is considered to be one of the major mechanisms of renal failure in multiple myeloma, and is characterized by precipitation of free light chains in the distal nephron, leading to intratubular obstruction, inflammation and fibrosis. Recent studies have demonstrated the use of extracorporeal methods such as plasmapheresis and high-cutoff membrane dialysis as an adjunctive therapy to chemotherapy in the management of cast nephropathy, however currently there are no existing guidelines in the use of extracorporeal therapies in the management of complications of multiple myeloma. Hemoperfusion is an extracorporeal treatment technique which utilizes adsorption in the removal of specific toxins. The HA 130 cartridge in particular has a resin pore size distribution of 500Da- 40 KDa and is able to remove molecules at 5-30kDa. In this case report we describe the use of HA 130 hemoperfusion cartridge in the treatment of cast nephropathy in Multiple Myeloma. Method A 58-year-old male, diabetic, non-hypertensive came in for 5-day history of generalized body weakness, associated with myalgia, lumbar pain and undocumented fever, with 1-day history of loose stools and vomiting. Upon admission blood tests done revealed anemia with a hemoglobin of 7.8g/dl, creatinine of 9.97mg/dL and potassium of 5.5mmol/L. He was diagnosed with acute renal failure and underwent hemodialysis on the second hospital day. On workup he had lytic bone lesions in the spine, pelvis and cranium on CT scan and x-ray. Serum Protein Electrophoresis (SPEP) and Serum Free Light Chain (sFLC) tests showed a monoclonal gammopathy. Serum beta 2 microglobulin was elevated at 12,618ng/ml. Free kappa and lambda light chains were also elevated at 19,250mg/L and 25.7mg/L, respectively. Bone marrow biopsy was done, with findings of markedly hypercellular marrow with 80% plasma cells confirming the diagnosis of Multiple Myeloma. Combined hemodialysis with hemoperfusion were done using HA 130 filter and hi flux dialyzer for 2.5 hours then hemodialysis for three times a week. Patient was also started on chemotherapy using Bortezomib with Dexamethasone for 2 cycles. Results Patient had a total of 14 sessions of combined hemoperfusion with hemodialysis. On repeat free kappa light chains decreased to 212.5mg/L. Patient was maintained on hemodialysis three times a week and was discharged after 55 hospital days. Outpatient hemodialysis was continued three times a week, and after 2 weeks, patient showed signs of renal recovery with a repeat creatinine of 2.1mg/dL. Four weeks after discharge, patient was independent of hemodialysis with a repeat creatinine of 1.3mg/dL. Conclusion This report highlights the use of hemoperfusion using HA 130 cartridge in combination with chemotherapy using Bortezomib in reducing free light chain levels in a 58-year-old male that developed renal failure secondary to cast nephropathy. Patient was able to achieve reduction in free light chain levels, improvement in renal function and eventually independence from hemodialysis four weeks after the last hemoperfusion treatment. Further studies using a randomized control trial on the use of hemoperfusion in directly reducing serum free light chain levels is recommended. The value of hemoperfusion on the rate of independence from hemodialysis, as well as survival rates among patients with renal failure secondary to multiple myeloma may also be worth investigating using larger studies.


2018 ◽  
Vol 64 (04/2018) ◽  
Author(s):  
Yanis Meddour ◽  
Momahed Rahali ◽  
Salah Belakehal ◽  
Fatma Ardjoun ◽  
Samia Chaib ◽  
...  

2018 ◽  
Vol 93 (10) ◽  
pp. 1207-1210 ◽  
Author(s):  
Marcella Tschautscher ◽  
Vincent Rajkumar ◽  
Angela Dispenzieri ◽  
Martha Lacy ◽  
Morie Gertz ◽  
...  

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