Paraproteins of familial MGUS/multiple myeloma target family-typical antigens: hyperphosphorylation of autoantigens is a consistent finding in familial and sporadic MGUS/MM

Blood ◽  
2011 ◽  
Vol 118 (3) ◽  
pp. 635-637 ◽  
Author(s):  
Sandra Grass ◽  
Klaus-Dieter Preuss ◽  
Stephan Thome ◽  
Dennis D. Weisenburger ◽  
Vinetta Witt ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Gammopathy ◽  
Family Members ◽  
Carrier State ◽  
General Mechanism ◽  
Consistent Finding ◽  
Waldenstrom Macroglobulinemia ◽  
Target Family ◽  
Normal Controls ◽  
Undetermined Significance

Abstract Paratarg-7 (P-7) is a frequent paraprotein target in monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), and Waldenström macroglobulinemia. Patients with P-7-specific paraproteins carry a hyperphosphorylated paratarg-7 (pP-7). Because pP-7 carrier state is dominantly inherited, we determined the paraprotein targets in 4 families with familial MGUS/MM. No antigenic target was identified for the paraproteins from 2 members of one family. Paraproteins from affected members of 2 other families targeted P-7, and paraproteins from 4 affected members of a fourth family targeted P-8, which is encoded by the ATG13 gene. P-8 was hyperphosphorylated in the affected family members (pP-8) and pP-8 carrier state is inherited in a dominant fashion. Six additional autoantigenic nonfamilial paraprotein targets were also hyperphosphorylated in the respective patients compared with normal controls. We conclude that paraproteins of affected members with familial MGUS/MM share family-typical hyperphosphorylated antigens and hyperphosphorylation of paraprotein targets might be a general mechanism underlying the pathogenesis of MGUS/MM.

Hyperphosphorylated paratarg-7: a new molecularly defined risk factor for monoclonal gammopathy of undetermined significance of the IgM type and Waldenström macroglobulinemia

Blood ◽  
2011 ◽  
Vol 117 (10) ◽  
pp. 2918-2923 ◽  
Author(s):  
Sandra Grass ◽  
Klaus-Dieter Preuss ◽  
Alexandra Wikowicz ◽  
Evangelos Terpos ◽  
Marita Ziepert ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Gammopathy ◽  
Immunoglobulin A ◽  
Cell Receptor ◽  
Carrier State ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Phosphatase Treatment ◽  
Increased Risk ◽  
Undetermined Significance

Abstract We recently described paratarg-7 (P-7), a protein of unknown function, as the target of 15% of immunoglobulin A (IgA) and IgG paraproteins in monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma. To determine the frequency of P-7 as a paraprotein target in IgM-MGUS and Waldenström macroglobulinemia (WM), sera from patients with IgM-MGUS/WM were tested for reactivity with recombinant P-7 by enzyme-linked immunoabsorbent assay. The specificity of the paraprotein-mediated reaction was shown by absorption studies and cloning of the respective B-cell receptor. The paraproteins of 18 (9 WM and 9 IgM-MGUS) of 161 patients (11%) reacted with P-7. Isoelectric focusing and phosphatase treatment showed that P-7 was hyperphosphorylated (pP-7) in all patients with an anti–P-7-specific IgM paraprotein tested. Because only 4 of 200 healthy controls (2%) were carriers of pP-7, pP-7 carrier state is associated with a significantly increased risk (odds ratio = 6.2; P = .001) for developing IgM-MGUS/MW. Family analyses showed that the pP-7 carrier state is inherited as a dominant trait. After IgA/IgG-MGUS and multiple myeloma, IgM-MGUS/WM is the second neoplasia associated with pP-7 carrier state. The dominant inheritance of pP-7 explains cases of familial IgM-MGUS/WM and enables the identification of family members at increased risk.

scholarly journals Comparison of Monoclonal Gammopathies Linked to Poliovirus or Coxsackievirus vs. Other Infectious Pathogens

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 438
Author(s):  
Jean Harb ◽  
Nicolas Mennesson ◽  
Cassandra Lepetit ◽  
Maeva Fourny ◽  
Margaux Louvois ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
B Cell ◽  
Monoclonal Gammopathy ◽  
Coat Proteins ◽  
Chronic Stimulation ◽  
B Cell Epitopes ◽  
Monoclonal Immunoglobulins ◽  
Self Antigen ◽  
Coxsackievirus B1 ◽  
Undetermined Significance

Chronic stimulation by infectious pathogens or self-antigen glucosylsphingosine (GlcSph) can lead to monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). Novel assays such as the multiplex infectious antigen microarray (MIAA) and GlcSph assays, permit identification of targets for >60% purified monoclonal immunoglobulins (Igs). Searching for additional targets, we selected 28 purified monoclonal Igs whose antigen was not represented on the MIAA and GlcSph assays; their specificity of recognition was then analyzed using microarrays consisting of 3760 B-cell epitopes from 196 pathogens. The peptide sequences PALTAVETG and PALTAAETG of the VP1 coat proteins of human poliovirus 1/3 and coxsackievirus B1/B3, respectively, were specifically recognized by 6/28 monoclonal Igs. Re-analysis of patient cohorts showed that purified monoclonal Igs from 10/155 MGUS/SM (6.5%) and 3/147 MM (2.0%) bound to the PALTAVETG or PALTAAETG epitopes. Altogether, PALTAV/AETG-initiated MGUS are not rare and few seem to evolve toward myeloma.

scholarly journals Iceland screens, treats, or prevents multiple myeloma (iStopMM): a population-based screening study for monoclonal gammopathy of undetermined significance and randomized controlled trial of follow-up strategies

2021 ◽  
Vol 11 (5) ◽  
Author(s):  
Sæmundur Rögnvaldsson ◽  
Thorvardur Jon Love ◽  
Sigrun Thorsteinsdottir ◽  
Elín Ruth Reed ◽  
Jón Þórir Óskarsson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Early Treatment ◽  
Monoclonal Gammopathy ◽  
Controlled Trial ◽  
Participation Rate ◽  
Population Based ◽  
Early Therapy ◽  
Screening Study ◽  
Undetermined Significance

AbstractMonoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM). Population-based screening for MGUS could identify candidates for early treatment in MM. Here we describe the Iceland Screens, Treats, or Prevents Multiple Myeloma study (iStopMM), the first population-based screening study for MGUS including a randomized trial of follow-up strategies. Icelandic residents born before 1976 were offered participation. Blood samples are collected alongside blood sampling in the Icelandic healthcare system. Participants with MGUS are randomized to three study arms. Arm 1 is not contacted, arm 2 follows current guidelines, and arm 3 follows a more intensive strategy. Participants who progress are offered early treatment. Samples are collected longitudinally from arms 2 and 3 for the study biobank. All participants repeatedly answer questionnaires on various exposures and outcomes including quality of life and psychiatric health. National registries on health are cross-linked to all participants. Of the 148,704 individuals in the target population, 80 759 (54.3%) provided informed consent for participation. With a very high participation rate, the data from the iStopMM study will answer important questions on MGUS, including potentials harms and benefits of screening. The study can lead to a paradigm shift in MM therapy towards screening and early therapy.

Interleukin‐6 is expressed by plasma cells from patients with multiple myeloma and monoclonal gammopathy of undetermined significance

1998 ◽  
Vol 101 (2) ◽  
pp. 287-295 ◽  
Author(s):  
Hamdi I. A. Sati ◽  
Jane F. Apperley ◽  
Mike Greaves ◽  
John Lawry ◽  
Roger Gooding ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Interleukin 6 ◽  
Monoclonal Gammopathy ◽  
Plasma Cells ◽  
Undetermined Significance

scholarly journals Deep vein thrombosis after monoclonal gammopathy of undetermined significance and multiple myeloma

Blood ◽  
2008 ◽  
Vol 112 (9) ◽  
pp. 3582-3586 ◽  
Author(s):  
Sigurdur Y. Kristinsson ◽  
Thomas R. Fears ◽  
Gloria Gridley ◽  
Ingemar Turesson ◽  
Ulf-Henrik Mellqvist ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Gammopathy ◽  
First Year ◽  
Small Hospital ◽  
Entire Study ◽  
Crude Incidence ◽  
Vein Thrombosis ◽  
Increased Risk ◽  
Underlying Mechanisms ◽  
Undetermined Significance

Patients with multiple myeloma (MM) have an increased risk of deep venous thrombosis (DVT), particularly when treated with immunomodulatory drugs. Recently, 2 small hospital-based studies observed persons with the MM precursor condition, monoclonal gammopathy of undetermined significance (MGUS), to be at increased risk of developing DVT. Among 4 196 197 veterans hospitalized at least once at US Veterans Affairs hospitals, we identified a total of 2374 cases of MGUS, and 39 272 persons were diagnosed with DVT (crude incidence 0.9 per 1000 person-years). A total of 31 and 151 DVTs occurred among MGUS and MM patients, respectively (crude incidence 3.1 and 8.7 per 1000 person-years, respectively; P < .01). Compared with the entire study population, the relative risk (RR) of DVT after a diagnosis of MGUS and MM was 3.3 (95% confidence interval [CI], 2.3-4.7) and 9.2 (95% CI, 7.9-10.8), respectively. The most prominent excess risk of DVT was found during the first year after diagnosis of MGUS (RR = 8.4; 95% CI, 5.7-12.2) and MM (RR = 11.6; 95% CI, 9.2-14.5). Among 229 MGUS cases (9.5%) that progressed to MM, only one person had a DVT diagnosis before transformation. Our findings suggest the operation of shared underlying mechanisms causing coagulation abnormalities among patients with MGUS and MM.

scholarly journals Association of Immune Marker Changes With Progression of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma

JAMA Oncology ◽  
2019 ◽  
Vol 5 (9) ◽  
pp. 1293 ◽  
Author(s):  
Ola Landgren ◽  
Jonathan N. Hofmann ◽  
Charlene M. McShane ◽  
Loredana Santo ◽  
Malin Hultcrantz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Gammopathy ◽  
Immune Marker ◽  
Undetermined Significance

scholarly journals Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study

Blood ◽  
2009 ◽  
Vol 113 (22) ◽  
pp. 5412-5417 ◽  
Author(s):  
Ola Landgren ◽  
Robert A. Kyle ◽  
Ruth M. Pfeiffer ◽  
Jerry A. Katzmann ◽  
Neil E. Caporaso ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Gammopathy ◽  
Population Based ◽  
Serum Samples ◽  
M Proteins ◽  
Cancer Screening Trial ◽  
Risk Of Progression ◽  
Study Population ◽  
A Prospective Study ◽  
Undetermined Significance

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma-cell proliferative disorder associated with a life-long risk of progression to multiple myeloma (MM). It is not known whether MM is always preceded by a premalignant asymptomatic MGUS stage. Among 77 469 healthy adults enrolled in the nationwide population-based prospective Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, we identified 71 subjects who developed MM during the course of the study in whom serially collected (up to 6) prediagnostic serum samples obtained 2 to 9.8 years prior to MM diagnosis were available. Using assays for monoclonal (M)–proteins (electrophoresis/immunofixation) and kappa-lambda free light chains (FLCs), we determined longitudinally the prevalence of MGUS and characterized patterns of monoclonal immunoglobulin abnormalities prior to MM diagnosis. MGUS was present in 100.0% (87.2%-100.0%), 98.3% (90.8%-100.0%), 97.9% (88.9%-100.0%), 94.6% (81.8%-99.3%), 100.0% (86.3%-100.0%), 93.3% (68.1%-99.8%), and 82.4% (56.6%-96.2%) at 2, 3, 4, 5, 6, 7, and 8+ years prior to MM diagnosis, respectively. In approximately half the study population, the M-protein concentration and involved FLC-ratio levels showed a yearly increase prior to MM diagnosis. In the present study, an asymptomatic MGUS stage consistently preceded MM. Novel molecular markers are needed to better predict progression to MM in patients with MGUS.

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