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Haematologica Dec 2023Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic precursor condition that precedes multiple myeloma and related disorders but has also been...
Disease associations with monoclonal gammopathy of undetermined significance can only be evaluated using screened cohorts: results from the population-based iStopMM study.
Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic precursor condition that precedes multiple myeloma and related disorders but has also been associated with other medical conditions. Since systematic screening is not recommended, MGUS is typically diagnosed due to underlying diseases and most cases are not diagnosed. Most previous studies on MGUS disease associations have been based on clinical cohorts, possibly resulting in selection bias. Here we estimate this selection bias by comparing clinically diagnosed and screened individuals with MGUS with regards to demographics, laboratory features, and comorbidities. A total of 75,422 participants in the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study were screened for MGUS by serum protein electrophoresis, immunofixation and free light chain assay (clinicaltrials gov. Identifier: NCT03327597). We identified 3,352 individuals with MGUS, whereof 240 had previously been clinically diagnosed (clinical MGUS), and crosslinked our data with large, nationwide registries for information on comorbidities. Those with clinical MGUS were more likely to have at least one comorbidity (odds ratio=2.24; 95% confidence interval: 1.30-4.19), and on average had more comorbidities than the screened MGUS group (3.23 vs. 2.36, mean difference 0.68; 95% confidence interval: 0.46-0.90). They were also more likely to have rheumatological disease, neurological disease, chronic kidney disease, liver disease, heart failure, or endocrine disorders. These findings indicate that individuals with clinical MGUS have more comorbidities than the general MGUS population and that previous studies have been affected by significant selection bias. Our findings highlight the importance of screening data when studying biological and epidemiological implications of MGUS.
Topics: Humans; Multiple Myeloma; Monoclonal Gammopathy of Undetermined Significance; Iceland; Paraproteinemias; Comorbidity; Disease Progression
PubMed: 37439374
DOI: 10.3324/haematol.2023.283191 -
Frontiers in Immunology 2022Various epidemiological studies, including case reports and -series in addition to larger, population-based studies, have reported an increased prevalence of monoclonal... (Review)
Review
Various epidemiological studies, including case reports and -series in addition to larger, population-based studies, have reported an increased prevalence of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma in individuals with a prior history of immune-related conditions. This is believed to support the role of chronic antigen stimulation in the pathogenesis of these conditions. In this short review, we summarize some of the largest population-based studies researching autoimmune diseases, infections, and the subsequent risk of MGUS, and discuss our understanding on its etiology and pathogenesis. Furthermore, we highlight important methodological limitations of previous studies in the field, but almost all studies on MGUS have been based on clinical, possibly biased, cohorts. Finally, we discuss future directions in researching the associations of MGUS and other disorders, including immune-related conditions, where screening studies play an important role.
Topics: Autoimmune Diseases; Autoimmunity; Humans; Immune System Diseases; Monoclonal Gammopathy of Undetermined Significance; Multiple Myeloma; Paraproteinemias
PubMed: 35572590
DOI: 10.3389/fimmu.2022.876271 -
Veterinary Clinical Pathology Dec 2022Hyperglobulinemia is reported in 26% of canine chronic B-cell lymphocytic leukemia (B-CLL) cases. However, few cases have been characterized by protein electrophoresis...
BACKGROUND
Hyperglobulinemia is reported in 26% of canine chronic B-cell lymphocytic leukemia (B-CLL) cases. However, few cases have been characterized by protein electrophoresis and immunofixation (IF), and the incidence of a monoclonal protein (M-protein) is unknown using these techniques.
OBJECTIVE
To characterize and determine the proportion of canine B-CLL cases with an M-protein using plasma protein electrophoresis (PPE), routine and free light chain (fLC) IF, and to assess if productive B-CLL cases express MUM1/IRF4 by cell tube block (CTB).
METHODS
PPE, routine (targeting IgG, IgA, IgM, IgG4, and light chain) and fLC IF were performed using 48 dog B-CLL plasma samples from patients diagnosed via peripheral blood flow cytometry. CTB was performed on a separate cohort of 15 patients.
RESULTS
Hyperproteinemia (>7.5 g/dL) was present in 17/48 cases (35%). An M-protein was detected in 32/48 cases (67%). Of these, 19/32 cases (59%) had only complete (monoclonal heavy and light chain) M-proteins detected, 10/32 cases (31%) had both complete and fLC M-proteins detected, and 3/32 cases (9%) had only an fLC M-protein detected. IgM was the most common clonal immunoglobulin isotype detected (23 cases). CD21 cell counts were higher in cases with detectable M-protein. Plasma fLC IF suggested β-γ region interference, likely caused by clotting proteins. All B-CLL cases consistently expressed PAX5 and did not express MUM1/IRF4.
CONCLUSIONS
Most B-CLL cases had an M-protein and were not hyperproteinemic. Most cases with paraproteins had a complete IgM monoclonal gammopathy; a subset had documented fLCs. The prognostic significance of heavy and fLC presence should be evaluated.
Topics: Dogs; Animals; Leukemia, Lymphocytic, Chronic, B-Cell; Immunoglobulin Light Chains; Immunoelectrophoresis; Paraproteinemias; Immunoglobulin M; Dog Diseases
PubMed: 35883213
DOI: 10.1111/vcp.13156 -
European Journal of Medical Research Jul 2021This study aimed to analyze the clinicopathological characteristics of patients with paraproteinemia and renal damage.
BACKGROUND
This study aimed to analyze the clinicopathological characteristics of patients with paraproteinemia and renal damage.
METHODS
Ninety-six patients from 2014 to 2018 with paraproteinemia and renal damage were enrolled and the clinical data, renal pathology, treatment and prognosis data were collected.
RESULTS
A total of 96 patients (54 male and 42 female), accounting for 2.7% of all renal biopsies, were enrolled in this study. Among them, 42 were monoclonal gammopathy of renal significance (MGRS), 21 were renal monotypic immunoglobulin alone (renal monoIg), and 19 were monoclonal gammopathy of undetermined significance (MGUS). Individuals with multiple myeloma (MM) accounted for the fewest number of patients (n = 14). In the MGRS group, the main diseases were amyloidosis (n = 25) and cryoglobulinemic glomerulonephritis (n = 7), while in the MM group, the main diseases were cast nephropathy (n = 9) and light chain deposit disease (n = 3). In the MGUS group, it was mainly IgA nephropathy (IgAN, n = 10) and idiopathic membranous nephropathy (n = 5); while in the renal monoIg group, most of the cases were IgAN (n = 19). Chemotherapy was mainly administered to patients in the MM group, while immunosuppression therapy was mostly administered to patients in the renal monoIg group. Most patients with renal monoIg exhibited a major response, followed by the patients with MGUS and MGRS, while most of the patients with MM had a partial response but none had a major response. Approximately more than half (57.1%) of the patients with MM progressed to end-stage renal disease (ESRD), followed by MGRS (33.3%); however, the mortality rate was low in both the MGRS and MM groups. The survival analysis reviewed that serum creatinine, hemoglobin levels, and the serum κ/λ ratio were independent risk factors for ESRD in patients with MGRS.
CONCLUSIONS
The clinicopathological changes in patients with MGRS were between those in patients with MM and MGUS. The treatment for MGRS and MM was more intensive, and the overall mortality rate was low. Both MGUS and renal monoIg alone exhibited slighter clinicopathological features than MGRS and MM, and the treatment was focused mostly on primary renal diseases.
Topics: Adult; Biopsy; China; Female; Humans; Incidence; Kidney; Kidney Diseases; Male; Middle Aged; Paraproteinemias; Prognosis
PubMed: 34217367
DOI: 10.1186/s40001-021-00538-2 -
Frontiers in Immunology 2023Subsets of patients diagnosed with a monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) or multiple myeloma (MM), present with... (Review)
Review
Determination of the target of monoclonal immunoglobulins: a novel diagnostic tool for individualized MGUS therapy, and prevention and therapy of smoldering and multiple myeloma.
Subsets of patients diagnosed with a monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) or multiple myeloma (MM), present with a monoclonal immunoglobulin (Ig) specific for an infectious pathogen, including hepatitis C and B viruses (HCV, HBV), and several . Such cases are likely initiated by infection, since in the context of HCV- or HBV-infected patients, antiviral therapy can lead to the disappearance of antigenic stimulation, control of clonal plasma cells, and reduced or suppressed monoclonal Ig production. Complete remission has been obtained with anti-HCV therapy in refractory MM with a HCV-specific monoclonal Ig, and antiviral treatments significantly improved the probability of survival of MM patients infected with HCV or HBV prior to the diagnosis of MM. Monoclonal Igs may also target glucolipids, particularly glucosylsphingosine (GlcSph), and GlcSph-reducing therapy can lead to complete remission in SMM and MM patients presenting with a GlcSph-specific monoclonal Ig. The present review describes the importance of determining the target of the monoclonal Ig of MGUS, SMM and MM patients, and discusses the efficacy of target-reducing treatments in the management of MGUS, SMM and MM cases who present with a monoclonal Ig reactive against a treatable infectious pathogen or GlcSph.
Topics: Humans; Multiple Myeloma; Monoclonal Gammopathy of Undetermined Significance; Smoldering Multiple Myeloma; Paraproteins; Antibodies, Monoclonal; Hepatitis C
PubMed: 38022528
DOI: 10.3389/fimmu.2023.1253363 -
Journal of Proteome Research Sep 2023Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell disorder characterized by the presence of a predominant monoclonal antibody (i.e., M-protein)...
Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell disorder characterized by the presence of a predominant monoclonal antibody (i.e., M-protein) in serum, without clinical symptoms. Here we present a case study in which we detect MGUS by liquid-chromatography coupled with mass spectrometry (LC-MS) profiling of IgG1 in human serum. We detected a Fab-glycosylated M-protein and determined the full heavy and light chain sequences by bottom-up proteomics techniques using multiple proteases, further validated by top-down LC-MS. Moreover, the composition and location of the Fab-glycan could be determined in CDR1 of the heavy chain. The outlined approach adds to an expanding mass spectrometry-based toolkit to characterize monoclonal gammopathies such as MGUS and multiple myeloma, with fine molecular detail. The ability to detect monoclonal gammopathies and determine M-protein sequences straight from blood samples by mass spectrometry provides new opportunities to understand the molecular mechanisms of such diseases.
Topics: Humans; Monoclonal Gammopathy of Undetermined Significance; Paraproteinemias; Multiple Myeloma; Mass Spectrometry; Immunoglobulin G
PubMed: 37499263
DOI: 10.1021/acs.jproteome.3c00330 -
Clinical Journal of the American... Dec 2016Disorders of plasma and B cells leading to paraproteinemias are associated with a variety of renal diseases. Understanding the mechanisms of injury and associated... (Review)
Review
Disorders of plasma and B cells leading to paraproteinemias are associated with a variety of renal diseases. Understanding the mechanisms of injury and associated nephropathies provides a framework that aids clinicians in prompt diagnosis and appropriate adjunctive treatment of these disorders. Glomerular diseases that may be associated with paraproteinemias include amyloid deposition, monoclonal Ig deposition disease, proliferative GN with monoclonal Ig deposits, C3 glomerulopathy caused by alterations in the complement pathway, immunotactoid glomerulopathy, fibrillary GN, and cryoglobulinemia. Tubular lesions include the classic Fanconi syndrome, light-chain proximal tubulopathy, interstitial fibrosis, and cast nephropathy. These paraproteinemic renal diseases are distinct in their pathogenesis as well as their urinary and kidney biopsy findings. Renal pathology is usually initiated by deposition and direct involvement of the intact monoclonal Ig or Ig fragments with resident cells of the nephron. Our review summarizes current insights into the underlying molecular pathogenesis of these interesting kidney lesions.
Topics: Amyloidosis; Glomerulonephritis; Humans; Immunoglobulin Heavy Chains; Immunoglobulin Light Chains; Kidney Diseases; Kidney Glomerulus; Kidney Tubules, Distal; Kidney Tubules, Proximal; Paraproteinemias; Paraproteins
PubMed: 27526707
DOI: 10.2215/CJN.02560316 -
BMC Neurology Jan 2016The term paraproteinemic neuropathy describes a heterogeneous set of neuropathies characterized by the presence of homogeneous immunoglobulin in the serum. An abnormal... (Review)
Review
The term paraproteinemic neuropathy describes a heterogeneous set of neuropathies characterized by the presence of homogeneous immunoglobulin in the serum. An abnormal clonal proliferation of B-lymphocytes or plasma cells, which may or may not occur in the context of a hematologic malignancy, produces the immunoglobulins in excess. If malignancy is identified, treatment should be targeted to the neoplasm. Most cases, however, occur as monoclonal gammopathy of undetermined significance. Few prospective, randomized, placebo-controlled trials are available to inform the management of paraproteinemic neuropathies. Clinical experience combined with data from smaller, uncontrolled studies provide a basis for recommendations, which depend on the specific clinical setting in which the paraprotein occurs. In this review, we provide a clinically practical approach to diagnosis and management of such patients.
Topics: Analgesics; Antineoplastic Agents; Excitatory Amino Acid Antagonists; Glucocorticoids; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Life Style; Paraproteinemias; Peripheral Nervous System Diseases; Plasmapheresis; Stem Cell Transplantation; Vascular Endothelial Growth Factor A
PubMed: 26821540
DOI: 10.1186/s12883-016-0532-4 -
Annales de Biologie Clinique Oct 2016The diagnostics and follow-up of monoclonal gammopathies such as multiple myeloma require precise analysis of the monoclonal component as well as the other... (Review)
Review
The diagnostics and follow-up of monoclonal gammopathies such as multiple myeloma require precise analysis of the monoclonal component as well as the other immunoglobulins isotypes, which might be limited by the sensitivity of standard laboratory methods. New serum biomarkers were developed for routine practice in the last decades, such as the free light chain assays and more recently the heavy/light chain assay
s. Studies have shown that serum free light chain measurement was useful in the identification and follow-up of pauci or nonsecretory myeloma, free light-chain multiple myeloma and AL amyloidosis. It is also an important prognostic marker for monoclonal gammopathy of undetermined significance and AL amyloidosis progression. Hevylite method enables quantitative analysis of heavy/light chain pairs of IgG, IgA and IgM immunoglobulins. This technique has a promising potential to enrich the standard analytic tools as it enables to assess the concentration and ratio of the levels of both tumor and physiological immunoglobulins (heavy/light chain pair suppression), which is not possible with serum protein electrophoresis or global quantitative analysis of immunoglobulin isotypes. This review includes the latest International myeloma working group recommendations and key data presented at the Euromedlab convention in June 2015 Paris regarding serum free light chain and heavy/light chain assays in the biological monitoring of dysglobulinemia.Topics: Amyloidosis; Biomarkers; Follow-Up Studies; Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Immunoglobulins; Monitoring, Physiologic; Multiple Myeloma; Paraproteinemias; Practice Guidelines as Topic; Prognosis
PubMed: 27707674
DOI: 10.1684/abc.2016.1180 -
Clinical Journal of the American... Apr 2022Patients with monoclonal gammopathy and concomitant kidney diseases are frequently found in clinical practice. Some of them are diagnosed with monoclonal gammopathy of...
BACKGROUND AND OBJECTIVES
Patients with monoclonal gammopathy and concomitant kidney diseases are frequently found in clinical practice. Some of them are diagnosed with monoclonal gammopathy of renal significance (MGRS) due to the presence of monoclonal Ig-related kidney injuries. This study aimed to investigate the histopathologic spectrum and clinical characteristics associated with MGRS in a large cohort of patients with monoclonal gammopathy and biopsy-proven kidney diseases from a single Chinese nephrology referral center.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
Patients who presented with monoclonal gammopathy (monoclonal spike on serum and/or urine immunofixation tests) and underwent kidney biopsy in the Peking University First Hospital from January 1, 1999 to December 31, 2020 were enrolled in this retrospective study. Patients with malignant hematologic diseases were excluded. Clinical and laboratory data were collected from the electronic medical record system. Comparisons of patients with and without MGRS and with and without amyloidosis were performed. The clinical characteristics associated with MGRS were identified using multivariable logistic regression.
RESULTS
A total of 700 patients with monoclonal gammopathy and kidney biopsy were identified. Thirteen patients with repeat kidney biopsies were analyzed separately. For the remaining 687 patients with one kidney biopsy, 261 patients (38%) had MGRS lesions, and the rest (426 patients, 62%) had non-MGRS kidney diseases. Ig-related amyloidosis accounted for the most MGRS cases (=164, 63%), followed by monoclonal Ig deposition disease (=23, 9%) and thrombotic microangiopathy (=22, 8%). In the non-MGRS group, membranous nephropathy was the most common diagnosis (=171, 40%). In the multivariable logistic regression model, the presence of abnormal serum free light chain ratio, older age, and greater proteinuria were independently associated with MGRS.
CONCLUSIONS
Monoclonal Ig amyloidosis is the leading cause of MGRS in Chinese patients with monoclonal gammopathy. The presence of abnormal free light chain ratio, older age, and greater proteinuria were associated with MGRS.
Topics: Amyloidosis; Humans; Immunoglobulin Light Chains; Kidney; Kidney Diseases; Monoclonal Gammopathy of Undetermined Significance; Paraproteinemias; Proteinuria; Retrospective Studies
PubMed: 35210280
DOI: 10.2215/CJN.12890921