Diagnosis Of Monoclonal Gammopathy Research Articles

Identifying therapeutic monoclonal antibodies using target protein collision electrophoresis reflex assay to separate the wheat from the chaff

Monoclonal gammopathies are characterized by the presence of monoclonal immunoglobulins, also known as M-proteins. Therapeutic monoclonal antibodies (t-mAbs) can interfere in laboratory assays used to monitor the state of disease, such as serum protein electrophoresis (SPE) and immunofixation electrophoresis (IFE). To establish a correct interpretation of IFE, Target protein-Collision Immunofixation Electrophoresis Reflex Assay (T-CIERA) was developed to identify t-mAbs in IFE. Here we demonstrate that T-CIERA is applicable to a wide variety of t-mAbs for which the target protein is commercially available. Moreover, the shift observed was characteristic for each t-mAb, and T-CIERA enabled the identification of multiple t-mAbs sharing a common target protein. Additionally, the lower limit of detection (LLOD) was determined objectively, and T-CIERA demonstrated an adequate LLOD for all tested t-mAbs. Furthermore, T-CIERA was also successfully applied to serum samples obtained from patients receiving daratumumab, isatuximab, elotuzumab, and durvalumab treatment. In conclusion, T-CIERA is a suitable reflex assay for identifying a wide variety of t-mAbs, including those for which no commercial assay is available to deal with their interference. Moreover, CD38-CIERA could serve as an alternative or complementary test to the commercially available Hydrashift assay kits. T-CIERA would enable laboratories without mass spectrometry equipment and expertise in this area to distinguish between drug and disease to improve clinical response monitoring and diagnosis of monoclonal gammopathies.

Oligoclonal gammopathy: An analysis of 253 cases.

Oligoclonal gammopathy (OG) is a rare disorder of the lymphoid system that is characterized by the presence of at least 2 distinct monoclonal proteins in a patient's serum or urine. The biological and clinical characteristics of this disease are as yet poorly understood. The study aimed to assess whether there are significant differences between patients with OG regarding the developmental history (i.e., OG diagnosed at the first presentation compared to OG that has developed in patients with an original monoclonal gammopathy) and the number of monoclonal proteins (2 compared to 3). Moreover, we attempted to determine when secondary oligoclonality develops following the original diagnosis of monoclonal gammopathy. Patients were analyzed with regard to their age at diagnosis, sex, serum monoclonal proteins, and underlying hematological disorders. Multiple myeloma (MM) patients were additionally evaluated for their Durie-Salmon stage and cytogenetic alterations. Patients with triclonal gammopathy (TG: n = 29) did not differ significantly from patients with biclonal gammopathy (BG: n = 223) (p = 0.81) in terms of age at diagnosis and the dominant diagnosis (MM was the most common diagnosis (65.0% and 64.7%, respectively)). In both cohorts, myeloma patients were mainly classified to the Durie-Salmon stage III. In the TG cohort, there was a higher proportion of males (69.0%) than among patients with BG (52.5%). Oligoclonality developed at various times after diagnosis (up to 80 months in the investigated cohort). However, the occurrence of new cases was higher during the initial 30-month period following the diagnosis of monoclonal gammopathy. There are only small differences between patients with primary compared to secondary OG, between BG and TG, and most patients have a combination of IgGκ+IgGλ. Oligoclonality could develop at any time after the diagnosis of monoclonal gammopathy, but it happens more frequently during the first 30 months, with advanced myeloma being the most prevalent underlying disorder.

Simultaneous Evaluation of Serum Immunofixation Electrophoresis and Serum Free Light Chain Measurements Used in the Diagnosis of Monoclonal Gammopathy and Smoldering Multiple Myeloma of Uncertain Significance in the Presence of Risk Factors

Simultaneous Evaluation of Serum Immunofixation Electrophoresis and Serum Free Light Chain Measurements Used in the Diagnosis of Monoclonal Gammopathy and Smoldering Multiple Myeloma of Uncertain Significance in the Presence of Risk Factors

Usefulness of serum globulin levels for discriminating patients with monoclonal gammopathies/ paraproteinemias

Introduction and Aim: The confirmatory step in diagnosis of monoclonal gammopathies is bone marrow biopsy and presence of M-protein in serum protein electrophoresis. These tests are relatively expensive & invasive for screening and unavailable in low resource settings. Increased levels of serum globulin are clue to the diagnosis of monoclonal gammopathy. The aim of this study was to assess the relevance of serum globulin levels in discriminating between patients with & without monoclonal gammopathies/ paraproteinemia.
 Materials and Methods: We retrospectively reviewed serum protein electrophoresis (SPE) and related investigations of patients suspected of monoclonal gammopathy. Reports with an M-band were considered as paraproteinemias, and those without as controls. ROC for sensitivities & specificities for serum globulin levels were computed.
 Results: For the case-control study, median serum globulin values in cases were 4.4 (3.5-6.3) g/dL in males and 3.65 (3.33-5.0) g/dL in females. They were significantly higher than those with normal SPE pattern, with a p <0.001. A cut-off value of 3.25 g/dL of globulin could distinguish between paraproteinemias and controls with a sensitivity of 82.1% and specificity of 85.4% in males; a sensitivity of 79.2%, a specificity of 76.7% for females. At a cut-off value of 3.4 g/dL, sensitivity was 77% and specificity 92.7% for males; sensitivity was 75% and specificity 83.7% for females. Alternatively, a cut-off value of 0.458 of globulin/total protein ratio could distinguish at a best sensitivity & specificity of 80% and 89% in males; 83.3% and 83.7% in females.
 Conclusion: Serum globulin values and globulin/total protein ratio can reliably differentiate patients with paraproteinemias.

Diagnosis of haematological diseases with monoclonal gammopathy

AbstractDespite the complexity of lymphoproliferative disorders, the presence of monoclonal immunoglobulins has been providing diagnostic guidance to the haematologist for more than a century. Clinicians may be alerted for the possible presence of serum monoclonal immunoglobulins produced in excess by increased erythrocyte sedimentation rate. Thereafter the diagnosis of monoclonal gammopathy could be proven by serum protein electrophoresis followed by immunofixation to properly identify the M‐protein. In a quarter of the cases, no intact monoclonal immunoglobulin could be detected in the sera, however, free light chains produced in excess may be identified using specialized immunoassays, so called free light chain analysis.Idiopathic monoclonal gammopathy of unknown significance (MGUS) may be present in 1% of the population above age 50 and up to 10% for individuals over 80 years of age. Due to the high frequency of MGUS, between 50‐65% of all monoclonal proteins detected fall into this category and most asymptomatic patients remain undetected for many years. MGUS patients have a 1% per year chance for transformation into malignant monoclonal gammopathies. Presently, it is accepted that most multiple myeloma and amyloidosis patients have their disease developed by transformation from preexisting MGUS. Additionally, some nonmalignant hematological disease also frequently exhibit monoclonal immunoglobulin synthesis, most notably Gaucher’s disease.From the field of neoplastic hematological diseases, smouldering and symptomatic multiple myeloma as well as Waldenström’s macroglobulinaemia almost always exhibit significant amounts of serum M‐protein and/or monoclonal free light chain excess. In case of solitary plasmocytoma, primary AL amyloidosis, cryoglobulinaemia and plasma cell leukemia, the correlation with gammopathy is less strict. Monoclonal gammopathy is less common in different types of non‐Hodgkin lymphoma. Within lymphomas lymphoplasmocytic lymphoma and marginal zone lymphoma more commonly secrete monoclonal immunoglobulins, while other B‐cell lymphomas have 14% cumulative chance for specific gammopathy. In the case of B‐cell chronic lymphocytic leukemia (the most common leukemia), intact monoclonal gammopathy has a 2% appearance, while abnormal free light chains may be detected in a third of the cases. Sporadically monoclonal gammopathy may be detected in chronic myelomonocytic leukemia, refractory anaemia, large granular cell leukemia and angioimmunoblastic lymphoma. Notably, in many of these diseases, the amount of secreted monoclonal immunoglobulin and/or free light chains correlate with the tumor burden and could be used for disease monitoring, especially in indolent hematological neoplasias.

Monoclonal immunoglobulin mediates complement activation in monoclonal gammopathy associated-C3 glomerulonephritis

BackgroundC3 glomerulonephritis (C3GN) is a rare disease caused by inherited or acquired complement alternative pathway (CAP) dysregulation, which could also be secondary to monoclonal gammopathy of undetermined significance (MGUS). Herein, we described a patient presenting with C3GN and monoclonal gammopathy, and the pathogenic association between the two diseases was further explored in vitro.Case presentationA 76-year-old Chinese man presented with low serum C3 level, haematuria and nephrotic syndrome, and experienced rapid worsening of renal function over a period of 10 months. His serum and urine immunofixation electrophoresis both revealed a monoclonal IgGλ. A bone marrow puncture showed plasma cell dyscrasias with the highest plasma cell count of 5.25%. Kidney biopsy showed the presence of C3 glomerulonephritis, with exclusive deposits of C3 visible on immunofluorescence, a membranoproliferative pattern on light microscopy and electron dense deposits in sub-epithelial, intramembranous, sub-endothelial and mesangial regions by electron microscopy. The patient was positive for C3 nephritic factor (C3NeF) activity and anti-CFH autoantibodies, and all became negative during disease remission. The anti-CFH autoantibodies purified from the patient’s plasma exchange fluids were proven to be a monoclonal IgGλ, and could inhibit CFH binding to C3b and accelerate the formation of C3 convertase indirectly by interfering with the formation-impeding activity of CFH. No deficiency of candidate genes, especially variants in CFH, was detected in our patient. Based on the pathological and laboratory findings, the diagnosis of monoclonal gammopathy of renal significance (MGRS)-associated C3GN was finally made.ConclusionsThis is the first demonstration that intact monoclonal immunoglobulin (IgGλ) could act as an anti-CFH antibody and lead to MGRS-associated C3GN by activating the CAP.

A Study on Free Light Chain Assay and Serum Immunofixation Electrophoresis for the Diagnosis of Monoclonal Gammopathies.

Demonstration of monoclonal immunoglobulin molecule in serum forms the mainstay in the diagnosis of monoclonal gammopathies. The major tests that help in this regard are serum protein electrophoresis (SPEP), serum immunofixation electrophoresis (sIFE) and serum free light chain assay (sFLC). Our objectives were to study the accuracy of sFLC and sIFE in the diagnosis of monoclonal gammopathies and also to study the role of combination of SPEP+sIFE+sFLC in the diagnosis of the same. 46 patients who attended the hemato-oncology clinic with signs and symptoms suggestive of monoclonal gammopathy were enrolled in this study. SPEP, sIFE, sFLC and pre-treatment serum beta-2 microglobulin levels were analysed among the study population. Both SPEP and sIFE were performed in the Interlab Genios fully automated machine. Serum beta-2 microglobulin and sFLC were estimated by immunoturbidimetry in Beckman Coulter AU 2700 analyzer. The accuracy of sIFE came to be 80% with respect to sFLC assay. Sensitivity, specificity, positive and negative predictive value of sIFE with respect to sFLC were 81.3, 78.6, 89.7 and 64.7% respectively. It was observed that a combination panel of SPEP+sIFE+sFLC could detect all the cases of myeloma included in this study. Further testing in large samples is required for generalising the findings of this study. The pre-treatment beta-2 microglobulin levels were significantly higher in the group which was positive for myeloma. A combination panel of SPEP+sIFE+sFLC prove to be more useful than individual tests for the detection of myeloma.

Candidate recommendations for protein electrophoresis reporting from the Canadian Society of Clinical Chemists Monoclonal Gammopathy Working Group

Protein electrophoresis is commonly used as an aid in the diagnosis of monoclonal gammopathies and is performed in many laboratories in Canada and throughout the world. However, unlike many other diagnostic tests, there is limited guidance for standardization and neither guidance nor specific recommendations for clinical reporting of serum (SPE) or urine (UPE) protein electrophoresis and immunotyping available in the literature. Therefore, a Canadian effort was undertaken to recommend standards that cover all aspects of clinical reporting with an ultimate goal towards reporting standardization. The Canadian Society of Clinical Chemists (CSCC) Monoclonal Gammopathy Interest Group (MGIG), which is composed of CSCC members with an interest in protein electrophoresis, has formed a Monoclonal Gammopathy Working Group (MGWG) to take initial steps towards standardization of SPE, UPE and immunotyping. Candidate standardization recommendations were developed, discussed and voted upon by the MGWG. Candidate recommendations that achieved 90% agreement are presented as consensus recommendations. Recommendations that did not achieve 90% consensus remain candidate recommendations and are presented with accompanying MGWG discussion. Eleven consensus recommendations along with candidate recommendations for nomenclature, protein fraction reporting, test utilization, interference handling and interpretive reporting options are presented.

Serum Free Light Chain (FLC) Analysis: A Guiding Light in Monoclonal Gammopathy Management.

Monoclonal free light chains (FLCs) were first reported by Dr. Henry Bence Jones over 150 years ago in the urine of patients with multiple myeloma. Now established as important tumor markers, they aid not only in the diagnosis of monoclonal gammopathies but also in their clinical management by indicating the response to treatment and persistence of residual disease. A particular focus over the past 15 years has been on the replacement of urine with serum analysis for monoclonal FLC measurement. Because of the limited sensitivity and practical constraints of urine assessment, a combination of serum electrophoresis and serum FLC analysis has been adopted by many laboratories as a first-line screen for patients with a suspected monoclonal gammopathy. Early myeloma diagnosis may translate into improved clinical outcomes, and a new study, iStopMM, is underway to ascertain the benefit of population-wide screening protocols for early detection of the disease in its asymptomatic phase. Laboratory algorithms that include measurement of both monoclonal intact immunoglobulins and FLCs are important for assessing possible changes in myelomic clones in response to treatment, and recent data from Intergroupe Francophone du Myelome trials validate serum FLC as a clinically relevant disease biomarker. Whether sensitive serum techniques such as FLC analysis can be used to guide the use of more invasive procedures for detection of minimal residual disease is the subject of emerging studies. Here we review the current and evolving utility of serum FLC measurements for the management of patients with monoclonal gammopathies.

Serum Free Light Chain Assay and Kapa/Lamtha Ratio: Performance in Patients With Monoclonal Gammopathy-High False Negative Rate for Kapa/Lamtha Ratio

Background: Serum free light chain assay (SFLCA) and kapa/lamtha ratio, and protein electrophoretic methods are used in the diagnosis and monitoring of monoclonal gammopathies. Methods: Results for serum free light chains, serum and urine protein electrophoreses and immunofixation electrophoreses in 468 patients with a diagnosis of monoclonal gammopathy were compared. The results of the two methods were graded as concordant, non-concordant or discordant with the established diagnoses to assess the relative performance of the methods. Results of k apa/lamtha ratio in samples with monoclonal protein detectable by electrophoretic methods were also analyzed. Results: Protein electrophoreses results were concordant with the established diagnoses significantly more often than k apa/lamtha ratio. The false negative rate for k apa/lamtha ratio was higher than that for electrophoretic methods. K apa/lamtha ratio was falsely negative in about 27% of the 1,860 samples with detectable monoclonal immunoglobulin. The false negative rate was higher in lesions with lambda chains (32%) than those with kappa chains (24%). The false negative rate for k apa/lamtha ratio was over 55% in samples with monoclonal gammopathy of undetermined significance. Even at first encounter, the false negative rates for k apa/lamtha ratios for monoclonal gammopathy of undetermined significance, smoldering myeloma and multiple myeloma were 66.98%, 23.08%, and 30.15%, respectively, with false negative rate for lambda chain lesions being higher. Conclusions: Electrophoretic studies of serum and urine are superior to SFLCA and k apa/lamtha ratio. Abnormal k apa/lamtha ratio, per se , is not diagnostic of monoclonal gammopathy. A normal k apa/lamtha ratio does not exclude monoclonal gammopathy. False negative rates for lesions with lambda chain are higher than those for lesions with kappa chains. Electrophoretic studies of urine are underutilized. Clinical usefulness and medical necessity of SFLCA and k apa/lamtha ratio is of questionable value in routine clinical testing. J Clin Med Res. 2017;9(1):46-57 doi: https://doi.org/10.14740/jocmr2802w

Serum Free Light Chain Assay and κ/λ Ratio: Performance in Patients With Monoclonal Gammopathy-High False Negative Rate for κ/λ Ratio.

BackgroundSerum free light chain assay (SFLCA) and κ/λ ratio, and protein electrophoretic methods are used in the diagnosis and monitoring of monoclonal gammopathies.MethodsResults for serum free light chains, serum and urine protein electrophoreses and immunofixation electrophoreses in 468 patients with a diagnosis of monoclonal gammopathy were compared. The results of the two methods were graded as concordant, non-concordant or discordant with the established diagnoses to assess the relative performance of the methods. Results of κ/λ ratio in samples with monoclonal protein detectable by electrophoretic methods were also analyzed.ResultsProtein electrophoreses results were concordant with the established diagnoses significantly more often than κ/λ ratio. The false negative rate for κ/λ ratio was higher than that for electrophoretic methods. κ/λ ratio was falsely negative in about 27% of the 1,860 samples with detectable monoclonal immunoglobulin. The false negative rate was higher in lesions with lambda chains (32%) than those with kappa chains (24%). The false negative rate for κ/λ ratio was over 55% in samples with monoclonal gammopathy of undetermined significance. Even at first encounter, the false negative rates for κ/λ ratios for monoclonal gammopathy of undetermined significance, smoldering myeloma and multiple myeloma were 66.98%, 23.08%, and 30.15%, respectively, with false negative rate for lambda chain lesions being higher.ConclusionsElectrophoretic studies of serum and urine are superior to SFLCA and κ/λ ratio. Abnormal κ/λ ratio, per se, is not diagnostic of monoclonal gammopathy. A normal κ/λ ratio does not exclude monoclonal gammopathy. False negative rates for lesions with lambda chain are higher than those for lesions with kappa chains. Electrophoretic studies of urine are underutilized. Clinical usefulness and medical necessity of SFLCA and κ/λ ratio is of questionable value in routine clinical testing.

Monoclonal Light Chains Can Remain Unnoticed in Protein Electrophoresis.

Dear Editor It is of great importance to establish an early diagnosis in multiple myeloma (MM), Waldenstrom’s macroglobulinemia and other proliferative disorders of the plasma cells such as AL-amyloidosis, light chain disease. The level of monoclonal immunglobulins, which increases in these disorders, are accumulated in several organs mainly in the kidneys and this accumulation result in various pathological conditions [1]. Early diagnosis and treatment can be lifesaving in these patients. Monoclonal immunoglobulins and their free light chains are important diagnostic markers in the diagnosis of monoclonal gammopathies. Although there is an ongoing controversy as to whether the detection of free kappa/lambda proportion using an immunoassay method recently developed to screen for and early diagnose monoclonal gammopathies is superior to electrophoretic methods, many laboratories are still using serum protein electrophoresis (SPE) and immunofixation electrophoresis (IFE) for diagnostic and screening purposes [2, 3]. The testing algorithm of the laboratories, which utilize electrophoretic methods, generally involve the screening of monoclonal protein (M-protein) peak in SPE followed by subtyping of monoclonal protein using IFE in patients who are found positive for M-protein peak. On the other hand, SPE is limited due to its inability to detect monoclonal proteins in patients with light chain MM, free light chain deposition disease, and AL-amyloidosis. The reason for this is that these free light chains are either too low to be detected in SPE or migrate to one of such bands as alpha 1, alpha-2, or beta in SPE due to their low molecular weights. Serum IFE has a tenfold higher sensitivity compared to SPE [2–5]. However, the IFE method has some disadvantages, such as being semi-automate and time-consuming and most commercial kits screen for four diseases (in other words, four patients are tested at once) and the test requires specialized personnel for analysis and interpretation. At our laboratory, albeit not often, we encounter pathological bands using IFE that could not be detected with SPE (Fig. 1). Althought this stiuation is known, there is no publication demonstrating of that. As mentioned above, it is important to diagnose these disorders early. The bands that are not detected with SPE can cause delays in diagnosis. We suggest clinicians to directly order serum and urine IFE without consuming time with SPE, if strong clinical findings exist such as advanced age, anemia, and kidney disorder. Fig. 1 The SPE of this patient was quite non-specific for a particular disease (A). Clinicians generally focus on gamma region while evaluating a SPE, which in this case looked very much innocent. Only a high index of suspicion would lead the clinician to search ...

Serum Heavy Light Chain Immunoassays Compared To Traditional Serum Based Laboratory Testing For The Diagnosis and Screening Of Monoclonal Gammopathies

BackgroundTraditional laboratory tests for the screening and diagnosis of monoclonal gammopathies, such as monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma, and related disorders like paraproteinemia, include serum protein electrophoresis (sPEP), serum immunofixation electrophoresis (sIFE), and serum free light chain (sFLC) ratio. Pilot studies have shown that immunoassays for the combined heavy-light chain (sHLC) molecule (Hevylite®) are useful for the paired isotype matching of intact immunoglobulins (eg. IgGk/IgGl, IgAk/IgAl, IgMk/IgMl) in an automated, sensitive manner as an alternative to sIFE. MethodsThe primary objective of this study is to compare the results of the quantitative intact immunoglobulin Hevylite™ assay with sPEP and sIFE. Routine requests for the evaluation of monoclonal gammopathy in the Ochsner Medical Center Clinical Chemistry Laboratory were collected prospectively and tested using sPEP and sFLC with reflex sIFE. IgA, IgM and IgG k/λ HLC reagent kits, provided by The Binding Site, Inc, were used on a subset of patients where the serum samples were still available. HLC values were assessed on a SPAplus turbidometer. ResultsSeventy-six (76) samples were available for patients with multiple myeloma (n=18), MGUS (n=28), Waldenstrom's Macroglobulinemia (n=6), IgM paraproteinemia (n= 5) and normal patient sera (n=20). sHLC k/λ ratios were abnormal in 64% of IgG multiple myeloma samples, 100% IgA multiple myeloma samples and 100% IgM paraproteinemia, indicating a high rate of correlation with traditional laboratory testing. Of the four normal IgG k/λ HLC ratios reported, all patients were on active chemotherapy with sPEP M-spikes <0.36 g/dL. Three of these four patients have abnormal sFLC ratio, possibly indicating response to chemotherapy, but presence of residual disease. Previous studies have shown that sHLC values are an important marker in the risk-stratification for progression of MGUS patients. Abnormal sHLC ratios were present in 45-90% of MGUS patients. All of the Waldenstrom's macroglobulinemia patients had an abnormal sHLC ratio indicating that sHLC assays may be a useful diagnostic tool for monitoring this disease. One normal patient with impaired kidney function was shown to have a slightly abnormal FLC ratio skewed to kappa accumulation, which is a well-documented phenomenon as FLC is cleared by the kidneys. Two normal patients have increased IgM k/λ HLC ratios. The underlying cause of this is under further investigation. ConclusionThese data provide support for the use of sHLC k/λ ratios for the screening and diagnosis of monoclonal gammopathies and related disorders. In addition, abnormal ratios were found in a significant subset of MGUS patients which has been shown to be a risk factor for progression. Lastly, the use of sHLC immunoassay in Waldenstrom's macroglobulinemia has not been well studied, but these data indicate that sHLC may be a beneficial in both diagnosis and monitoring of this disease. Disclosures:Wu:Ochsner Medical Center: Employment; The Binding Site Inc: Research Funding, travel fund to ASH meeting, travel fund to ASH meeting Other. Off Label Use: Hevylite® is an immunoassay that is pending FDA approval for the measurement of heavy light chain immunoglobulins. Kuhn:The binding site INC: Employment.

Acquired Fanconi Syndrome Secondary to Monoclonal Gammopathies: A Case Series From a Single Center

Adult-acquired Fanconi syndrome (FS) is a rare kidneycomplication of monoclonal plasma cell disorderscharacterized by dysfunction of the proximal renaltubule, resulting in metabolic changes, bone disease,and progressive renal failure. There are limited data inthe literature, mainly isolated cases reports or smallcase series.We describe our single-institution experience with 4patients diagnosed with FS associated with mono-clonal gammopathy (2 women and 2 men) fromJanuary 2001 to December 2011.The patients had a mean age of 63.5 years at diag-nosis. In 1 patient, diagnosis of monoclonal gamm-opathy and FS was simultaneous, whereas in theremaining 3 patients, FS was recognized during thefollow-up of monoclonal gammopathy.

Efficient use of basic biochemical methods to prove the presence of monoclonal protein in the clinical diagnosis of malignant monoclonal gammopathy

Background: This retrospective study evaluates the diagnostic sensitivity of biochemistry methods for the clinical diagnosis of malignant monoclonal gammopathy. In patients with renal insufficiency, renal reference interval as well as standard reference interval is used for evaluating the ratio of free light chains. Methods: We examined samples in 281 patients who were diagnosed with malignant monoclonal gammopathy. The samples were taken at baseline, prior to treatment. Serum and urine protein electrophoresis, serum and urine immunofixation electrophoresis (SIFE+UIFE) and levels of free light chains in serum (FLC) were investigated. Results: Combination of methods with the highest diagnostic sensitivity is the use of maximal number of tests (SIFE+ UIFE + FLC), which identified 98.6% of patients. The achieved results do not statistically significantly differ from the procedure recommended by the International Myeloma Working Group (IMWG) which omitts the urine testing (SIFE + FLC) and identifies 97.9 % of patients (p = 0.523). By using the renal reference ratio of free light chains in patients with renal insufficiency the number of patients identified decreased to the border of significance (p = 0.06) but the number of patients identified by the combination with serum immunofixation (SIFE + FLC) remained the same. Conclusions: The testing algorithm recommended by IMWG for screening patients with the diagnosis of monoclonal gammopathy is effective, diagnostic sensitivity is not significantly lower than the maximal available. Using the renal reference ratio of FLC for evaluation in combination with immunofixation in the serum does not reduce the diagnostic sensitivity of the test and has been reported to increase specificity.

Incidence, Diagnosis and Prognosis of Cardiac Amyloidosis

Background and ObjectivesCardiac involvement is frequent in systemic amyloidosis and is the most important determinant of the clinical outcome. The aims of this study were to assess the incidence and prognosis of cardiac amyloidosis and discuss the diagnostic issues related to cardiac amyloidosis.Subjects and MethodsWe retrospectively studied all patients diagnosed with systemic amyloidosis who presented to our institution from January 1999 to December 2011.ResultsOf the 129 patients with systemic amyloidosis, cardiac amyloidosis was diagnosed in 62 patients. At the 3 years' follow-up of the patients with systemic amyloidosis, there was a statistically significant difference in mortality between patients with cardiac amyloidosis and the rest of the patients (58.1% vs. 37.3%, p=0.008). In the Cox proportional hazard model, old age {hazard ratio (HR) 18.336, p=0.006}, elevation of cardiac troponin I (cTNI) (HR 13.246, p=0.020), left ventricular (LV) systolic dysfunction (HR 5.137, p=0.041) and diastolic dysfunction (HR 64.595, p=0.022) were independently associated with survival in cardiac amyloidosis. In the diagnosis of monoclonal gammopathy, serum or urine protein electrophoresis was not sensitive enough to be used clinically compared to serum free light chain assay (35.8% vs. 96.4%).ConclusionIn systemic amyloidosis, cardiac involvement was the most important determinant of the prognosis, and old age, elevation of cTNI, LV systolic dysfunction and diastolic dysfunction were independently associated with survival in cardiac amyloidosis.

New Insights into Diagnosis of Monoclonal Gammopathy of Undetermined Significance:Emerging Role of Micro RNAs

Adel Gouri1*, Aoulia Dekaken2, Ahmed Aimen Bentorki1, Amina Yakhlef3, Mehdi Beleilli4, Faiza Mehiddine5 and Nabil Mohie Abdelhamid6 1Laboratory of Medical Biochemistry, IBN ZOHR Public Hospital, Guelma 24000, Algeria 2Department of Internal Medicine; Pr EL OKBI Public Hospital, Guelma 24000, Algeria 3Department of Hematology, IBN ZOHR Public Hospital, Guelma 24000, Algeria 4Laboratory of Pharmaceutical Chemistry, College of Medicine, Annaba 2300, Algeria 5Department of Pneumology, IBN ZOHR Public Hospital, Guelma 24000, Algeria 6Department of Biochemistry, College of Pharmacy, Kafrelsheikh University, Egypt

Differential diagnosis of monoclonal gammopathy of undetermined significance.

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic plasma cell disorder occurring in 4.2% of adults > 50 years of age, which can progress into symptomatic diseases either through proliferation of the plasma cell clone, giving rise to multiple myeloma and other lymphoplasmacellular neoplasms, or through organ damage caused by the monoclonal protein, as seen in light-chain amyloidosis and related conditions. Differential diagnosis of asymptomatic and symptomatic monoclonal gammopathies is the determinant for starting therapy. The criteria for determining end-organ damage should include markers of organ injury caused by the monoclonal protein. Patient assessment and optimal follow-up are now performed using risk stratification models that should also take into account the risk of developing AL amyloidosis. Patients with low-risk MGUS (approximately 40% of all MGUS patients) need limited assessment and very infrequent follow-up. The ongoing development of novel molecular biomarkers and advanced imaging techniques will improve the identification of high-risk patients who may benefit from early therapeutic intervention through innovative clinical trials.

Monoclonal gammopathies presenting as inflammatory arthritis: uncommon but important - a case series

To review the clinical profile of patients with plasma cell dyscrasias presenting with inflammatory arthritis. Retrospective analysis was performed on clinical, laboratory and imaging data of patients who presented with inflammatory arthritis between May 2009 and April 2010 and were subsequently diagnosed as having plasma cell dyscrasias. Six out of 630 patients presenting with inflammatory arthritis were identified. The demographic, clinical and laboratory characteristics of these patients were analyzed. The diagnosis of monoclonal gammopathy was based on protein electrophoresis, immunoelectrophoresis and bone marrow biopsy. The outcomes of the treatments were analyzed. Four patients had monoclonal gammopathy of unknown significance and two patients had multiple myeloma. Mean age of the patients was 65years (range 59-74). Three patients presented with oligoarticular arthritis, two with symmetrical polyarticular joint pains and one with fleeting periarticular pains. Wrist and shoulder were the most commonly involved joints. Three patients had carpal tunnel syndrome. Five patients were seronegative for both rheumatoid factor and anti-cyclic citrullinated peptide antibodies. Mean erythrocyte sedimentation rate (ESR) was high in all patients (range: 82-120mm/h with a mean of 99.6mm/h). Arthritis improved with chemotherapy in patients with multiple myeloma. Occurrence of inflammatory arthritis with plasma dyscrasias is more than a chance association. Plasma cell dyscrasias should be ruled out in any elderly patient presenting with atypical arthritis with disproportionately high ESR, high creatinine and hyperglobulinemia.

Recommendations for the management of monoclonal gammopathies in biochemistry

Multiple myeloma (MM) is a hematologic malignancy most frequently preceded by a transient state called "pre-myeloma", whose main representatives are the Monoclonal Gammopathy of Undetermined Significance (MGUS) and asymptomatic MM. The biologist has an important role in the diagnosis of monoclonal gammopathy, from initial diagnosis to monitoring. Many national and international recommendations have been published in recent years, particularly that of the National Health Authority (HAS) and of the International Myeloma Working Group (IMWG). The HAS published a guide detailing all of the management of patients with MM. These recommendations are currently restricted to France. The IMWG made recommendations for early screening of these diseases, aiming to diagnose almost all of the monoclonal gammopathies. This is not without problems, with a significant cost to the patient, particularly for the expensive serum-free light chain measurement, not recommended by the HAS. In France, there are no national guidelines for the detection of pre-myeloma pathologies. In the absence of specific recommendations for these cases, the dialogue between clinician and biologist is even more crucial for the optimal management of patients with monoclonal gammopathy, particularly for establishing a difficult diagnosis.