Screening panels for detection of monoclonal gammopathies.
01 Aug 2009-Clinical Chemistry (American Association for Clinical Chemistry)-Vol. 55, Iss: 8, pp 1517-1522
TL;DR: The major impact of using a simplified screening panel of serum PEL plus FLC rather than PEL, IFE, and FLC is an 8% reduction in sensitivity for MGUS, 23% for POEMS (7 patients), 4% for plasmacytoma (1 patient), 1% for AL, and 0.5% for SMM.
Abstract: Background: The repertoire of serologic tests for identifying a monoclonal gammopathy includes serum and urine protein electrophoresis (PEL), serum and urine immunofixation electrophoresis (IFE), and quantitative serum free light chain (FLC). Although there are several reports on the relative diagnostic contribution of these assays, none has looked at the tests singly and in combination for the various plasma cell proliferative disorders (PCPDs).
Methods: Patients with a PCPD and all 5 assays performed within 30 days of diagnosis were included (n = 1877). The diagnoses were multiple myeloma (MM) (n = 467), smoldering multiple myeloma (SMM) (n = 191), monoclonal gammopathy of undetermined significance (MGUS) (n = 524), plasmacytoma (n = 29), extramedullary plasmacytoma (n = 10), Waldenstrom macroglobulinemia (WM) (n = 26), primary amyloidosis (AL) (n = 581), light chain deposition disease (LCDD) (n = 18), and POEMS syndrome (n = 31).
Results: Of the 1877 patients, 26 were negative in all assays. Omitting urine from the panel lost an additional 23 patients (15 MGUS, 6 AL, 1 plasmacytoma, 1 LCDD), whereas the omission of FLC lost 30 patients (6 MM, 23 AL, and 1 LCDD). The omission of serum IFE as well as urine lost an additional 58 patients (44 MGUS, 7 POEMS, 5 AL, 1 SMM, and 1 plasmacytoma).
Conclusions: The major impact of using a simplified screening panel of serum PEL plus FLC rather than PEL, IFE, and FLC is an 8% reduction in sensitivity for MGUS, 23% for POEMS (7 patients), 4% for plasmacytoma (1 patient), 1% for AL, and 0.5% for SMM. There is no diminution in sensitivity for detecting MM, macroglobulinemia, and LCDD.
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TL;DR: The term monoclonal gammopathy of renal significance is thought to be most helpful to indicate a causal relationship between the monoconal gamsopathy and the renal damage and because the significance of the mon Coclonal Gammopathy is no longer undetermined.
449 citations
TL;DR: This review addresses the pathologic and clinical features of MGRS lesions, indications of renal biopsy, and a proposed algorithm for the hematologic workup.
330 citations
Mayo Clinic1, University of Poitiers2, Tulane University3, Imperial College Healthcare4, University Hospitals Birmingham NHS Foundation Trust5, Columbia University6, Monash University7, University College London8, LSU Health Sciences Center Shreveport9, National and Kapodistrian University of Athens10, Princess Margaret Cancer Centre11, University of Pavia12, University of Queensland13, Loyola University Medical Center14, Hôpital Maisonneuve-Rosemont15, University of Alabama at Birmingham16, University of Alberta17, University of Pennsylvania18
TL;DR: The IKMG redefines MGRS as a clonal proliferative disorder that produces a nephrotoxic monoclonal immunoglobulin and does not meet previously defined haematological criteria for treatment of a specific malignancy.
Abstract: The term monoclonal gammopathy of renal significance (MGRS) was introduced by the International Kidney and Monoclonal Gammopathy Research Group (IKMG) in 2012. The IKMG met in April 2017 to refine the definition of MGRS and to update the diagnostic criteria for MGRS-related diseases. Accordingly, in this Expert Consensus Document, the IKMG redefines MGRS as a clonal proliferative disorder that produces a nephrotoxic monoclonal immunoglobulin and does not meet previously defined haematological criteria for treatment of a specific malignancy. The diagnosis of MGRS-related disease is established by kidney biopsy and immunofluorescence studies to identify the monotypic immunoglobulin deposits (although these deposits are minimal in patients with either C3 glomerulopathy or thrombotic microangiopathy). Accordingly, the IKMG recommends a kidney biopsy in patients suspected of having MGRS to maximize the chance of correct diagnosis. Serum and urine protein electrophoresis and immunofixation, as well as analyses of serum free light chains, should also be performed to identify the monoclonal immunoglobulin, which helps to establish the diagnosis of MGRS and might also be useful for assessing responses to treatment. Finally, bone marrow aspiration and biopsy should be conducted to identify the lymphoproliferative clone. Flow cytometry can be helpful in identifying small clones. Additional genetic tests and fluorescent in situ hybridization studies are helpful for clonal identification and for generating treatment recommendations. Treatment of MGRS was not addressed at the 2017 IKMG meeting; consequently, this Expert Consensus Document does not include any recommendations for the treatment of patients with MGRS.
299 citations
TL;DR: Age-specific and sex-specific prevalence and rates of progression to lymphoproliferative disorders for light-chain and conventional MGUS and assessed incidence of renal disorders in patients with light- chain MGUS are calculated.
292 citations
TL;DR: The mechanisms of disease and diagnostic approaches to patients with acute kidney injury complicating multiple myeloma are discussed.
Abstract: Renal failure remains a principal cause of morbidity for patients with multiple myeloma. Once reversible factors such as hypercalcemia have been corrected, the most common cause of severe renal failure in these patients is a tubulointerstitial pathology that results from the very high circulating concentrations of monoclonal immunoglobulin free light chains. These endogenous proteins can result in isolated proximal tubule cell cytotoxicity, tubulointerstitial nephritis and cast nephropathy (myeloma kidney). Less frequently, high levels of free light chains can lead to immunoglobulin light chain amyloidosis and light chain deposition disease, although these conditions are usually associated with insidious progression of renal failure rather than acute kidney injury. Unless there is rapid intervention, progressive and irreversible damage occurs, particularly interstitial fibrosis and tubular atrophy. Despite advances in our understanding of the pathogenesis of these processes there has been a gap in translating these achievements into improved patient outcomes. The International Kidney and Monoclonal Gammopathy Research Group was formed to address this need. In this Review, we discuss the mechanisms of disease and diagnostic approaches to patients with acute kidney injury complicating multiple myeloma.
226 citations
References
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Mayo Clinic1, Leeds Teaching Hospitals NHS Trust2, University of Arkansas3, University of Nantes4, University of Turin5, University of South Florida6, National and Kapodistrian University of Athens7, University of Birmingham8, Lille University of Science and Technology9, Harvard University10, Cleveland Clinic11, University of Pittsburgh12, University of Salamanca13, Nagoya University14, McGill University15, Erasmus University Rotterdam16, Lund University17, University of Minnesota18, Medical College of Wisconsin19
TL;DR: The International Myeloma Working Group has reviewed the criteria for diagnosis and classification with the aim of producing simple, easily used definitions based on routinely available investigations to facilitate comparison of therapeutic trial data.
Abstract: The monoclonal gammopathies are a group of disorders associated with monoclonal proliferation of plasma cells. The characterization of specific entities is an area of difficulty in clinical practice. The International Myeloma Working Group has reviewed the criteria for diagnosis and classification with the aim of producing simple, easily used definitions based on routinely available investigations. In monoclonal gammopathy of undetermined significance (MGUS) or monoclonal gammopathy, unattributed/unassociated (MG[u]), the monoclonal protein is < 30 g/l and the bone marrow clonal cells < 10% with no evidence of multiple myeloma, other B-cell proliferative disorders or amyloidosis. In asymptomatic (smouldering) myeloma the M-protein is greater than or equal to 30 g/l and/or bone marrow clonal cells greater than or equal to 10% but no related organ or tissue impairment (ROTI)(end-organ damage), which is typically manifested by increased calcium, renal insufficiency, anaemia, or bone lesions (CRAB) attributed to the plasma cell proliferative process. Symptomatic myeloma requires evidence of ROTI. Non-secretory myeloma is characterized by the absence of an M-protein in the serum and urine, bone marrow plasmacytosis and ROTI. Solitary plasmacytoma of bone, extramedullary plasmacytoma and multiple solitary plasmacytomas (+/- recurrent) are also defined as distinct entities. The use of these criteria will facilitate comparison of therapeutic trial data. Evaluation of currently available prognostic factors may allow better definition of prognosis in multiple myeloma.
2,066 citations
TL;DR: The risk of progression of MGUS to multiple myeloma or related disorders is about 1 percent per year, and the initial concentration of serum monoclonal protein was a significant predictor of progression at 20 years.
Abstract: Background A monoclonal gammopathy of undetermined significance (MGUS) occurs in up to 2 percent of persons 50 years of age or older. Reliable predictors of progression have not been identified, and information on prognosis is limited. Methods We identified 1384 patients residing in southeastern Minnesota in whom MGUS was diagnosed at the Mayo Clinic from 1960 through 1994. The primary end point was progression to multiple myeloma or another plasma-cell cancer. Results During 11,009 person-years of follow-up, MGUS progressed in 115 of the 1384 patients to multiple myeloma, IgM lymphoma, primary amyloidosis, macroglobulinemia, chronic lymphocytic leukemia, or plasmacytoma (relative risk of progression, 25.0, 2.4, 8.4, 46.0, 0.9, and 8.5, respectively). The overall relative risk of progression was 7.3 in these patients as compared with the white population of the Iowa Surveillance, Epidemiology, and End Results program. In 32 additional patients, the monoclonal protein concentration increased to more than 3...
1,260 citations
TL;DR: Among residents of Olmsted County, Minnesota, MGUS was found in 3.2% of persons 50 years of age or older and 5.3 percent of persons 70 years ofAge or older, which are higher in men than in women.
Abstract: BACKGROUND The prevalence of monoclonal gammopathy of undetermined significance (MGUS), a premalignant plasma-cell disorder, among persons 50 years of age or older has not been accurately determined. We used sensitive laboratory techniques to ascertain the prevalence of MGUS in a large population in a well-defined geographic area. METHODS We identified all living residents of Olmsted County, Minnesota, as of January 1, 1995. We obtained serum that remained after the performance of routine clinical tests at Mayo Clinic or asked subjects for whom such serum was unavailable to provide a sample. Agarose-gel electrophoresis was performed on all serum samples, and any serum sample with a discrete band of monoclonal protein or thought to have a localized band was subjected to immunofixation. RESULTS Serum samples were obtained from 21,463 of the 28,038 enumerated residents 50 years of age or older (76.6 percent). MGUS was identified in 694 (3.2 percent) of these persons. Age-adjusted rates were higher in men than in women (4.0 percent vs. 2.7 percent, P<0.001). The prevalence of MGUS was 5.3 percent among persons 70 years of age or older and 7.5 percent among those 85 years of age or older. The concentration of monoclonal immunoglobulin was less than 1.0 g per deciliter in 63.5 percent and at least 2.0 g per deciliter in only 4.5 percent of 694 persons. The concentration of uninvolved immunoglobulins was reduced in 27.7 percent of 447 persons tested, and 21.5 percent of 79 tested had a monoclonal urinary light chain. CONCLUSIONS Among residents of Olmsted County, Minnesota, MGUS was found in 3.2 percent of persons 50 years of age or older and 5.3 percent of persons 70 years of age or older.
1,161 citations
Mayo Clinic1, Spanish National Research Council2, Masaryk University3, University of Turin4, Catholic Medical Center5, Emory University6, Alexandra Hospital7, Memorial Sloan Kettering Cancer Center8, University of Würzburg9, University of Arkansas for Medical Sciences10, University of Bologna11, Free University of Berlin12, Royal Prince Alfred Hospital13, Lund University14, Cedars-Sinai Medical Center15
TL;DR: Consensus guidelines for the use of the serum immunoglobulin-free light chain assay are provided, in the diagnosis and management of clonal PCD.
Abstract: The serum immunoglobulin-free light chain (FLC) assay measures levels of free κ and λ immunoglobulin light chains. There are three major indications for the FLC assay in the evaluation and management of multiple myeloma and related plasma cell disorders (PCD). In the context of screening, the serum FLC assay in combination with serum protein electrophoresis (PEL) and immunofixation yields high sensitivity, and negates the need for 24-h urine studies for diagnoses other than light chain amyloidosis (AL). Second, the baseline FLC measurement is of major prognostic value in virtually every PCD. Third, the FLC assay allows for quantitative monitoring of patients with oligosecretory PCD, including AL, oligosecretory myeloma and nearly two-thirds of patients who had previously been deemed to have non-secretory myeloma. In AL patients, serial FLC measurements outperform PEL and immunofixation. In oligosecretory myeloma patients, although not formally validated, serial FLC measurements reduce the need for frequent bone marrow biopsies. In contrast, there are no data to support using FLC assay in place of 24-h urine PEL for monitoring or for serial measurements in PCD with measurable disease by serum or urine PEL. This paper provides consensus guidelines for the use of this important assay, in the diagnosis and management of clonal PCD.
699 citations
TL;DR: Reference and diagnostic intervals for serum FLCs have been developed for use with a new, automated immunoassay that makes the detection and quantification of monoclonal F LCs easier and more sensitive than with current methods.
Abstract: Background: The detection of monoclonal free light chains (FLCs) is an important diagnostic aid for a variety of monoclonal gammopathies and is especially important in light-chain diseases, such as light-chain myeloma, primary systemic amyloidosis, and light-chain-deposition disease. These diseases are more prevalent in the elderly, and assays to detect and quantify abnormal amounts of FLCs require reference intervals that include elderly donors. Methods: We used an automated immunoassay for FLCs and sera from a population 21–90 years of age. We used the calculated reference and diagnostic intervals to compare FLC results with those obtained by immunofixation (IFE) to detect low concentrations of monoclonal κ and λ FLCs in the sera of patients with monoclonal gammopathies. Results: Serum κ and λ FLCs increased with population age, with an apparent change for those >80 years. This trend was lost when the FLC concentration was normalized to cystatin C concentration. The ratio of κ FLC to λ FLC (FLC K/L) did not exhibit an age-dependent trend. The diagnostic interval for FLC K/L was 0.26–1.65. The 95% reference interval for κ FLC was 3.3–19.4 mg/L, and that for λ FLC was 5.7–26.3 mg/L. Detection and quantification of monoclonal FLCs by nephelometry were more sensitive than IFE in serum samples from patients with primary systemic amyloidosis and light-chain-deposition disease. Conclusions: Reference and diagnostic intervals for serum FLCs have been developed for use with a new, automated immunoassay that makes the detection and quantification of monoclonal FLCs easier and more sensitive than with current methods. The serum FLC assay complements IFE and allows quantification of FLCs in light-chain-disease patients who have no detectable serum or urine M-spike.
614 citations