Materiały źródłowe

• #1 Monoclonal Gammopathy of Undetermined Significance – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK507880/

  Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic preneoplastic plasma cell disorder that is characterized by serum M-protein less than 30 g/L, bone marrow clonal plasma cells less than 10 percent, absence of plasma cell myeloma-related end-organ damage (hypercalcemia, renal insufficiency, anemia, or bone lesions) and absence of B-cell lymphoma or other diseases known to produce an M-protein. MGUS is generally considered a preneoplastic disorder that does not always progress to overt malignancy. […] Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant plasma cell disorder that is characterized by the presence of serum M-protein less than 30 g/L or 3 g/dL, bone marrow (BM) clonal plasma cells less than 10%, absence of plasma cell myeloma (PCM) related end-organ damage (CRAB symptoms: hypercalcemia, renal insufficiency, anemia and, bone lesions) and absence of B-cell lymphoma or other disease known to produce an M-protein. MGUS is generally considered a preneoplastic disorder that does not always progress to overt malignancy.

• #2 Pathogenesis of Monoclonal Gammopathy of Undetermined Significance (MGUS) and Progression to Multiple Myeloma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3040450/

  Monoclonal gammopathy of undetermined significance (MGUS) – including immunoglobulin light chain only MGUS – is an age dependent pre-malignant tumor that is present in about 4% of Caucasian individuals over the age of 50, but is comprised of two different kinds of tumors, about 15% lymphoid or lymphoplasmacytoid MGUS and the remainder plasma cell MGUS. […] Most, if not all, MM tumors are preceded by plasma cell MGUS, which shares four partially overlapping oncogenic features with MM. […] However, two models based on clinical laboratory tests indicate that it is possible to stratify MGUS tumors into groups that have average rates of progression as low as 0.26% per year and as high as 12% per year. […] MGUS is present in about 4% of Caucasians over the age of 50, with a 1% average annual risk of progression to malignant MM.

• #3 Pathogenesis of Monoclonal Gammopathy of Undetermined Significance (MGUS) and Progression to Multiple Myeloma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3040450/

  Monoclonal gammopathy of undetermined significance (MGUS) – including immunoglobulin light chain only MGUS – is an age dependent pre-malignant tumor that is present in about 4% of Caucasian individuals over the age of 50, but is comprised of two different kinds of tumors, about 15% lymphoid or lymphoplasmacytoid MGUS and the remainder plasma cell MGUS. […] Most, if not all, MM tumors are preceded by plasma cell MGUS, which shares four partially overlapping oncogenic features with MM. […] However, two models based on clinical laboratory tests indicate that it is possible to stratify MGUS tumors into groups that have average rates of progression as low as 0.26% per year and as high as 12% per year. […] MGUS is present in about 4% of Caucasians over the age of 50, with a 1% average annual risk of progression to malignant MM.

• #4 Pathogenesis and progression of monoclonal gammopathy of undetermined significance | Leukemia

  https://www.nature.com/articles/leu2008203

  In Caucasians, monoclonal gammopathy of undetermined significance (MGUS) is an age-related condition with prevalence as high as 3% in persons older than 50 years. […] On average, the transformation rate to a malignant monoclonal gammopathy is 1% per year, with the mechanisms of progression likely related to bone marrow microenvironment and/or the cytokine network. […] The predictors of malignant transformation are the plasma cell mass (M-protein size and/or proportion of plasma cell in the bone marrow), IgA isotype, serum free light-chain ratio and evolving type and ratio between phenotypically aberrant and normal bone marrow plasma cells. […] It is recommended to follow these patients, particularly those with high risk of progression, annually to detect MM before complications, such as renal failure or extensive skeletal, involvement occur.

• #5 Monoclonal Gammopathies of Undetermined Significance (MGUS): Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/204297-overview

  Monoclonal gammopathy of undetermined significance (MGUS) is the most common of a spectrum of diseases called plasma cell dyscrasias. The cause of MGUS is unknown, though the same theories that apply to the pathogenesis of MM may be valid in MGUS. MM is almost always preceded by MGUS. […] The reason for the monoclonal expansion of a single Ig-secreting plasma cell population in what appears to be a nonmalignant manner is unknown in most cases. […] Most cases of MGUS involve IgG or IgA monoclonal cell populations. About 15-20% are composed of IgM monoclonal cells. […] Several studies have confirmed that characteristic genetic abnormalities of MM are present in patients with MGUS. […] Nagoshi et al identified a possible secondary genetic change involving MGUS; they found transcriptional dysregulation of the deleted in colorectal carcinoma (DCC) gene in 25% of MGUS cases studied, and in 57% of MM.

• #6 Diagnosis of monoclonal gammopathy of undetermined significance – UpToDate

  https://www.uptodate.com/contents/diagnosis-of-monoclonal-gammopathy-of-undetermined-significance

  There are three distinct clinical types of MGUS, each with a risk of progressing through a unique intermediate (more advanced) premalignant stage and then to a malignant plasma cell dyscrasia or lymphoproliferative disorder: Non-IgM MGUS (IgG, IgA, or IgD MGUS) – Non-IgM MGUS is the most common subtype of MGUS and has the potential to progress to smoldering (asymptomatic) multiple myeloma and to symptomatic multiple myeloma. Less frequently, these individuals progress to AL amyloidosis, light chain deposition disease, or another lymphoproliferative disorder. […] IgM MGUS – IgM MGUS accounts for approximately 15 percent of MGUS cases. It is considered separately from the non-IgM MGUS because it has the potential to progress to smoldering Waldenströ m macroglobulinemia and to symptomatic Waldenströ m macroglobulinemia, and less often to lymphoma or AL amyloidosis. Infrequently, IgM MGUS can progress to IgM multiple myeloma.

• #7 Monoclonal gammopathy of undetermined significance | Canadian Cancer Society

  https://cancer.ca/en/cancer-information/cancer-types/multiple-myeloma/what-is-multiple-myeloma/monoclonal-gammopathy-of-undetermined-significance

  Monoclonal gammopathy of undetermined significance (MGUS) is a precancerous condition and the most common plasma cell disorder. Precancerous conditions are not yet cancer, but there is a chance these abnormal changes will eventually become cancer or a related condition. This can take months or years. […] In MGUS, abnormal plasma cells (called myeloma cells) make one type of immunoglobulin( Ig) called an M-protein. There are 3 main types of MGUS depending on which immunoglobulin is involved. […] IgM MGUS involves the IgM immunoglobulin. IgM MGUS may develop into Waldenstrom macroglobulinemia, amyloidosis, lymphoma or multiple myeloma. […] Non-IgM MGUS is the most common type of MGUS. It involves immunoglobulins other than IgM usually IgG or IgA immunoglobulins. Non-IgM MGUS may develop into multiple myeloma, solitary plasmacytoma or amyloidosis.

• #8 Diagnosis of monoclonal gammopathy of undetermined significance – UpToDate

  https://www.uptodate.com/contents/diagnosis-of-monoclonal-gammopathy-of-undetermined-significance

  There are three distinct clinical types of MGUS, each with a risk of progressing through a unique intermediate (more advanced) premalignant stage and then to a malignant plasma cell dyscrasia or lymphoproliferative disorder: Non-IgM MGUS (IgG, IgA, or IgD MGUS) – Non-IgM MGUS is the most common subtype of MGUS and has the potential to progress to smoldering (asymptomatic) multiple myeloma and to symptomatic multiple myeloma. Less frequently, these individuals progress to AL amyloidosis, light chain deposition disease, or another lymphoproliferative disorder. […] IgM MGUS – IgM MGUS accounts for approximately 15 percent of MGUS cases. It is considered separately from the non-IgM MGUS because it has the potential to progress to smoldering Waldenströ m macroglobulinemia and to symptomatic Waldenströ m macroglobulinemia, and less often to lymphoma or AL amyloidosis. Infrequently, IgM MGUS can progress to IgM multiple myeloma.

• #9 Pathogenesis of Monoclonal Gammopathy of Undetermined Significance (MGUS) and Progression to Multiple Myeloma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3040450/

  The remaining PC MGUS tumors only rarely (1%) secrete a monoclonal IgM, but instead usually secrete an intact non-IgM M-Ig (IgGIgA IgDIgE). […] The prevalence of the light chain only MGUS tumors is 0.8%, i.e. about 20% of MGUS tumors, suggesting that light chain only MM is generated from light chain only MGUS, a result that has been confirmed in some studies. […] Two recent studies have confirmed that almost all cases of MM are preceded by MGUS. […] In contrast to MGUS, SMM is much more likely to progress to MM, with an average rate of progression of about 10% per year. […] The first model, proposed by a group at the Mayo Clinic, is based on abnormalities of the serum M-Ig. […] The second model, proposed by a Spanish group, introduces novel prognostic criteria for MGUS and SMM based on the flow cytometry immunophenotypic profile of BM PCs.

• #10 Monoclonal Gammopathies of Undetermined Significance (MGUS): Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/204297-overview

  Monoclonal gammopathy of undetermined significance (MGUS) is the most common of a spectrum of diseases called plasma cell dyscrasias. The cause of MGUS is unknown, though the same theories that apply to the pathogenesis of MM may be valid in MGUS. MM is almost always preceded by MGUS. […] The reason for the monoclonal expansion of a single Ig-secreting plasma cell population in what appears to be a nonmalignant manner is unknown in most cases. […] Most cases of MGUS involve IgG or IgA monoclonal cell populations. About 15-20% are composed of IgM monoclonal cells. […] Several studies have confirmed that characteristic genetic abnormalities of MM are present in patients with MGUS. […] Nagoshi et al identified a possible secondary genetic change involving MGUS; they found transcriptional dysregulation of the deleted in colorectal carcinoma (DCC) gene in 25% of MGUS cases studied, and in 57% of MM.

• #11 Monoclonal gammopathy of undetermined significance | Canadian Cancer Society

  https://cancer.ca/en/cancer-information/cancer-types/multiple-myeloma/what-is-multiple-myeloma/monoclonal-gammopathy-of-undetermined-significance

  Light chain MGUS (LC MGUS) involves a light chain immunoglobulin. LC MGUS may develop into multiple myeloma, solitary plasmacytoma or amyloidosis. […] MGUS usually develops in people 70 years of age or older. Black men (including men of African ancestry) and people with a family history of MGUS or multiple myeloma have a higher chance of developing MGUS. […] In general, the risk of MGUS progressing to multiple myeloma is 1% each year and remains 1% each year you live with the disease. So, even 25 years after a diagnosis, the risk of MGUS progressing to multiple myeloma is still 1%. […] Recently, diagnostic tests have helped to identify which people with MGUS have a low risk and which have a high risk of developing multiple myeloma and other conditions including amyloidosis, solitary plasmacytoma or Waldenstrom macroglobulinemia.

• #12 Monoclonal Gammopathy of Undetermined Significance (MGUS)—Not So Asymptomatic after All

  https://www.mdpi.com/2072-6694/12/6/1554

  Monoclonal Gammopathy of Undetermined Significance (MGUS) is considered to be a benign precursor condition that may progress to a lymphoproliferative disease or multiple myeloma. […] MGUS is characterized by the presence of a serum monoclonal paraprotein derived from immunoglobulin (Ig). MGUS may be classified into IgM and non-IgM MGUS, depending on the cellular clone responsible for the particular paraprotein. […] In a minority of cases, MGUS can be identified as light chain only, which refers to the isolated secretion of κ or λ light chains of immunoglobulin. […] Light chains derived from all variants of MGUS may aggregate in and impair organs such as the kidney and heart. […] Depending on the nature of light chain infiltration, amyloid light chain (AL) amyloidosis or light-chain deposition disease may be the pathophysiological process involved.

• #13 Pathogenesis of Monoclonal Gammopathy of Undetermined Significance (MGUS) and Progression to Multiple Myeloma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3040450/

  There are four very early and partially overlapping molecular pathogenic events that are shared by MGUS and MM tumors: IgH translocations, aneuploidy, chromosome 13 deletion, and dysregulation of a CYCLIN D gene. […] The prevalence of the t(4;14) translocation is substantially lower (ca 3-4%) in MGUS tumors, but has a similar prevalence in SMM and MM, which suggests the unproven possibility that this translocation results in a higher rate of progression of MGUS to SMM or MM. […] It appears that the pathogenesis of PC MGUS and MM involves two pathways defined by chromosome content: hyperdiploid (HRD) and non-hyperdiploid (NHRD). […] Deletion of chromosome 13 – usually the entire chromosome – has been reported to be present in about 25-50% of MGUS tumors by different groups, whereas all groups agree that this abnormality is present in approximately 50% of MM tumors.

• #14 Monoclonal Gammopathy of Undetermined Significance | IntechOpen

  https://www.intechopen.com/chapters/44075?jwsource=cl

  Several authors discuss the very early and partially overlapping molecular pathogenic events that are shared by MGUS, and how they are associated to progression at the MGUS to MM transition. […] The first step in the pathogenesis is likely an abnormal response to antigenic stimulation, mediated possibly by aberrant expression of toll-like receptors and overexpression of interleukin (IL) 6 receptors and IL-1. […] This then results in the development of primary cytogenetic abnormalities, either hyperdiploidy or immunoglobulin heavy chain translocations. […] Hyperdiploid tumors, which include about 50% of MM tumors, often have multiple trisomies involving chromosomes 3, 5, 7, 9, 11, 15, 19, and 21; also, a substantially lower prevalence of immunoglobulin heavy chain translocations and monosomy of chromosome 13 compared with nonhyperdiploid tumors.

• #15 Monoclonal gammopathy of uncertain significance (MGUS)

  https://www.ufrgs.br/imunovet/molecular_immunology/pathohomotissueblood_MGUS.html

  IgH translocated MGUS/SMM (50%): primary translocations in the clonal plasma cells involving the IgH locus on chromosome 14q32. The most common partner chromosome loci and genes dysregulated in these translocations are: 11q13 (CCND1 [cyclin D1 gene]), 4p16.3 (FGFR-3 and MMSET), 6p21 (CCND3 [cyclin D3 gene]), 16q23 (c-maf), 20q11 (mafB). It is felt that these translocations are important pathogenetically in initiating and sustaining clonal proliferation. The precipitating event for these translocations may be related to infection or immune dysregulation, and likely occurs during IgH CSR or SHM. […] IgH non-translocated MGUS/SMM (40-50%): pathogenesis is unclear. Karyotyping is of no value in determining the risk of progression, because cells in metaphase are rare in MGUS. The early results of FISH are abnormal in more than half of patients with MGUS, but the prognostic significance of these findings is under investigation.

• #16 Pathogenesis of Monoclonal Gammopathy of Undetermined Significance (MGUS) and Progression to Multiple Myeloma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3040450/

  There are four very early and partially overlapping molecular pathogenic events that are shared by MGUS and MM tumors: IgH translocations, aneuploidy, chromosome 13 deletion, and dysregulation of a CYCLIN D gene. […] The prevalence of the t(4;14) translocation is substantially lower (ca 3-4%) in MGUS tumors, but has a similar prevalence in SMM and MM, which suggests the unproven possibility that this translocation results in a higher rate of progression of MGUS to SMM or MM. […] It appears that the pathogenesis of PC MGUS and MM involves two pathways defined by chromosome content: hyperdiploid (HRD) and non-hyperdiploid (NHRD). […] Deletion of chromosome 13 – usually the entire chromosome – has been reported to be present in about 25-50% of MGUS tumors by different groups, whereas all groups agree that this abnormality is present in approximately 50% of MM tumors.

• #17 Monoclonal Gammopathy of Undetermined Significance | IntechOpen

  https://www.intechopen.com/chapters/44075

  The biological events related to progression from normal plasma cells to MM precursor disease and to MM involve many overlapping oncogenic steps that differently affect each individual. […] Several authors discuss the very early and partially overlapping molecular pathogenic events that are shared by MGUS, and how they are associated to progression at the MGUS to MM transition. […] The first step in the pathogenesis is likely an abnormal response to antigenic stimulation, mediated possibly by aberrant expression of toll-like receptors and overexpression of interleukin (IL) 6 receptors and IL-1. […] This then results in the development of primary cytogenetic abnormalities, either hyperdiploidy or immunoglobulin heavy chain translocations. […] Hyperdiploid tumors, which include about 50% of MM tumors, often have multiple trisomies involving chromosomes 3, 5, 7, 9, 11, 15, 19, and 21; also, a substantially lower prevalence of immunoglobulin heavy chain translocations and monosomy of chromosome 13 compared with nonhyperdiploid tumors.

• #18 Pathogenesis of Monoclonal Gammopathy of Undetermined Significance (MGUS) and Progression to Multiple Myeloma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3040450/

  There are four very early and partially overlapping molecular pathogenic events that are shared by MGUS and MM tumors: IgH translocations, aneuploidy, chromosome 13 deletion, and dysregulation of a CYCLIN D gene. […] The prevalence of the t(4;14) translocation is substantially lower (ca 3-4%) in MGUS tumors, but has a similar prevalence in SMM and MM, which suggests the unproven possibility that this translocation results in a higher rate of progression of MGUS to SMM or MM. […] It appears that the pathogenesis of PC MGUS and MM involves two pathways defined by chromosome content: hyperdiploid (HRD) and non-hyperdiploid (NHRD). […] Deletion of chromosome 13 – usually the entire chromosome – has been reported to be present in about 25-50% of MGUS tumors by different groups, whereas all groups agree that this abnormality is present in approximately 50% of MM tumors.

• #19 Monoclonal Gammopathy of Undetermined Significance | IntechOpen

  https://www.intechopen.com/chapters/44075

  This data suggests a possible role of delta 13 in the transition from MGUS to MM specifically in cases with t(11;14) or t(6;14). […] In summary, it has been proposed that the pathogenesis of MGUS and MM can be considered as occurring in three phases. First, partially overlapping genetic events common to MGUS and MM include at a minimum primary immunoglobulin heavy chain translocations, hyperdiploidy, and del13 that lead directly or indirectly to dysregulation of a CCND gene; second, the transition from MGUS to MM is associated with increased MYC expression and sometimes K-RAS mutations, but can also include del13 in t(11;14) tumors; third, additional progression of the MM tumor seems to be associated with other events.

• #20 Pathogenesis of Monoclonal Gammopathy of Undetermined Significance (MGUS) and Progression to Multiple Myeloma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3040450/

  Dysregulation of a CYCLIN D gene seems to be a unifying event for virtually all MGUS and MM tumors. […] Many somatic genetic abnormalities that are thought to represent progression events have been identified in MM tumors. […] It is significant that the prevalence of K- or N-RAS activating mutations is approximately 15% each in MM tumors, whereas the prevalence of N-RAS mutations is 7% in MGUS tumors and K-RAS mutations have not been identified in MGUS tumors. […] Importantly, a murine model using MGUS prone mice generates MM tumors that are good phenocopies of human MM tumors when these mice contain a MYC transgene that can be activated by somatic hypermutation as B cells pass through a germinal center.

• #21 Monoclonal Gammopathy of Undetermined Significance | IntechOpen

  https://www.intechopen.com/chapters/44075

  Trisomies of these same chromosomes also occur in premalignant MGUS tumors. […] It has been well established that each translocation subgroup found in MM tumors is associated with deregulation of a D group cyclin either directly, such as occurs with the t(11;14) (cyclin D1) and t(6;14) (cyclin D3) or indirectly, such as occurs with the t(4;14) or in the MAF translocation group. […] All these translocations have also been reported in MGUS. […] The first studies that showed structural chromosomal changes in MGUS and performed fluorescence in situ hybridization experiments (FISH) found 14q32 and 13q14 abnormalities. […] There is evidence of an immunoglobulin light chain- translocation in MGUS associated with a prevalence of 10% in MGUS/SMM. […] The presence and time of occurrence of delta 13 depend on the presence of specific concurrent abnormalities: earlier when t(4;14) or t(14;16) was present, later with t(14;20), and even later with t(11;14) or t(6;14).

• #22 Monoclonal Gammopathy of Undetermined Significance | IntechOpen

  https://www.intechopen.com/chapters/44075?jwsource=cl

  This data suggests a possible role of delta 13 in the transition from MGUS to MM specifically in cases with t(11;14) or t(6;14). […] In summary, it has been proposed that the pathogenesis of MGUS and MM can be considered as occurring in three phases. […] First, partially overlapping genetic events common to MGUS and MM include at a minimum primary immunoglobulin heavy chain translocations, hyperdiploidy, and del13 that lead directly or indirectly to dysregulation of a CCND gene; second, the transition from MGUS to MM is associated with increased MYC expression and sometimes K-RAS mutations, but can also include del13 in t(11;14) tumors; third, additional progression of the MM tumor seems to be associated with other events.

• #23 Monoclonal gammopathy of undetermined significance – Wikipedia

  https://en.wikipedia.org/wiki/Monoclonal_gammopathy_of_undetermined_significance

  Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell dyscrasia in which plasma cells or other types of antibody-producing cells secrete a myeloma protein, i.e. an abnormal antibody, into the blood; this abnormal protein is usually found during standard laboratory blood or urine tests. MGUS resembles multiple myeloma and similar diseases, but the levels of antibodies are lower, the number of plasma cells (white blood cells that secrete antibodies) in the bone marrow is lower, and it rarely has symptoms or major problems. However, since MGUS can progress to multiple myeloma, with a rate ranging from 0.5% to 1.5% per year depending on the risk category, yearly monitoring is recommended. […] The progression from MGUS to multiple myeloma usually involves several steps. […] Pathologically, the lesion in MGUS is in fact very similar to that in multiple myeloma. There is a predominance of clonal plasma cells in the bone marrow with an abnormal immunophenotype (CD38+ CD56+ CD19) mixed in with cells of a normal phenotype (CD38+ CD56 CD19+); in MGUS, on average more than 3% of the clonal plasma cells have the normal phenotype, whereas in multiple myeloma, less than 3% of the cells have the normal phenotype.

• #24

  https://haematologica.org/article/view/7062

  Progression of MGUS to MM or other related malignancies occurs at a rate of approximately 1% per year. […] Presenting features as well as the dynamics of the plasma cell clone during the first years of follow up are helpful in predicting risk of progression of MGUS to symptomatic disease. […] Biological characteristics of the clone also have predictive value in conventional MGUS and these include heavy chain isotype (IgA/IgM IgG); light chain production as determined by abnormal serum FLC ratio or presence of Bence Jones proteinuria; detection of circulating clonal B cells or plasma cells; increased bone resorption in bone biopsy; clonal heterogeneity; DNA aneuploidy assessed by flow cytometry; and abnormal metaphase cytogenetics. […] The risk of progression for light-chain MGUS is lower when compared to conventional MGUS.

• #25 Monoclonal gammopathy of undetermined significance | Canadian Cancer Society

  https://cancer.ca/en/cancer-information/cancer-types/multiple-myeloma/what-is-multiple-myeloma/monoclonal-gammopathy-of-undetermined-significance

  Low-risk MGUS has all of the following features: The M-protein level in the blood is less than 15 g/L. The type of M-protein is IgG. The free light chain ratio is normal. […] High-risk MGUS has any of the following features: The M-protein level in the blood is more than 15 g/L. The type of M-protein is IgA or IgM. The free light chain ratio is abnormal. […] If only one of the above features is present, there is a 21% absolute risk of MGUS progressing to multiple myeloma or a related condition after 20 years. […] If 2 of the above features are present, there is a 37% absolute risk. […] If all 3 of the above features are present, there is a 58% absolute risk.

• #26 Pathogenesis of Monoclonal Gammopathy of Undetermined Significance (MGUS) and Progression to Multiple Myeloma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3040450/

  Monoclonal gammopathy of undetermined significance (MGUS) – including immunoglobulin light chain only MGUS – is an age dependent pre-malignant tumor that is present in about 4% of Caucasian individuals over the age of 50, but is comprised of two different kinds of tumors, about 15% lymphoid or lymphoplasmacytoid MGUS and the remainder plasma cell MGUS. […] Most, if not all, MM tumors are preceded by plasma cell MGUS, which shares four partially overlapping oncogenic features with MM. […] However, two models based on clinical laboratory tests indicate that it is possible to stratify MGUS tumors into groups that have average rates of progression as low as 0.26% per year and as high as 12% per year. […] MGUS is present in about 4% of Caucasians over the age of 50, with a 1% average annual risk of progression to malignant MM.

• #27 Monoclonal gammopathy of uncertain significance (MGUS)

  https://www.ufrgs.br/imunovet/molecular_immunology/pathohomotissueblood_MGUS.html

  The risk of progression with MGUS does not diminish even after 25-35 years, making lifelong follow-up necessary in all persons diagnosed with MGUS. […] The mechanisms by which presence of monoclonal free light chains increase risk of progression in MGUS are not understood, but they may either represent clonal evolution of the neoplastic plasma cell or function as a surrogate marker for cytogenetic subtypes of MGUS that possess an inherently higher tendency progression. […] The initial plasma-cell burden, as reflected by the serum monoclonal protein concentration and the proportion of bone marrow plasma cells, is the critical risk factor for malignant transformation in MGUS.

• #28 Monoclonal gammopathy of undetermined significance – Wikipedia

  https://en.wikipedia.org/wiki/Monoclonal_gammopathy_of_undetermined_significance

  At the Mayo Clinic, MGUS transformed into multiple myeloma or similar lymphoproliferative disorders at the rate of about 0.52% a year depending on risk category. However, because they were elderly, most patients with MGUS died of something else and did not go on to develop multiple myeloma. When this was taken into account, only 11.2% developed lymphoproliferative disorders. […] In 2009, prospective data demonstrated that all or almost all cases of multiple myeloma are preceded by MGUS. […] In addition to multiple myeloma, MGUS may also progress to Waldenstrm’s macroglobulinemia or primary amyloidosis.

• #29 Pathogenesis of Monoclonal Gammopathy of Undetermined Significance (MGUS) and Progression to Multiple Myeloma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3040450/

  Dysregulation of a CYCLIN D gene seems to be a unifying event for virtually all MGUS and MM tumors. […] Many somatic genetic abnormalities that are thought to represent progression events have been identified in MM tumors. […] It is significant that the prevalence of K- or N-RAS activating mutations is approximately 15% each in MM tumors, whereas the prevalence of N-RAS mutations is 7% in MGUS tumors and K-RAS mutations have not been identified in MGUS tumors. […] Importantly, a murine model using MGUS prone mice generates MM tumors that are good phenocopies of human MM tumors when these mice contain a MYC transgene that can be activated by somatic hypermutation as B cells pass through a germinal center.

• #30

  https://www.clinicalcorrelations.org/2011/12/22/what-is-the-significance-of-monoclonal-gammopathy-of-undetermined-significance-mgus/

  Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell dyscrasia that is defined as a serum M protein 30 g/L, clonal plasma cells 10% in the bone marrow, and the absence of end-organ damage that can be attributed to a plasma cell proliferative disorder. […] The pathophysiology of the transition from normal plasma cells to MGUS to multiple myeloma involves many overlapping oncogenic events. […] The first step in the pathogenesis is usually an abnormal response to antigenic stimulation, possibly mediated by overexpression of interleukin (IL)-6 receptors and dysregulation of the cyclin D gene. […] These changes result in the development of primary cytogenetic abnormalities, either hyperdiploidy or immunoglobulin heavy chain translocation. […] The progression of MGUS to multiple myeloma is likely secondary to a random second hit, the manner of which is unknown. […] Mutations with Ras and p53, methylation of p16, myc abnormalities, and induction of angiogenesis have also been associated with progression.

• #31 Progression of monoclonal gammopathy of undetermined significance to multiple myeloma is associated with enhanced translational quality control and overall loss of surface antigens | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-05345-x

  Progression from MGUS to MM is accompanied by upregulated EIF2 signaling, DNA repair, and proteins involved in translational quality control, whereas integrin- and actin cytoskeletal signaling and cell surface markers are downregulated. […] Compared to the premalignant plasma cells in MGUS, malignant MM cells apparently have mobilized several pathways that collectively contribute to ensure translational fidelity and to avoid proteotoxic stress, especially in the ER. […] The overall reduced expression of immunoglobulins and surface antigens contribute to this and may additionally mediate evasion from recognition by the immune apparatus. […] Progression from MGUS to MM is accompanied by enhanced ribosomal biogenesis and epitranscriptomic writers, potentially augmenting translational fidelity. […] Taken together, progression from MGUS to MM is accompanied by an overall reduced expression of surface antigens that may contribute to immune evasion of the malignant cells and modulate interaction with the bone marrow microenvironment.

• #32 Progression of monoclonal gammopathy of undetermined significance to multiple myeloma is associated with enhanced translational quality control and overall loss of surface antigens | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-05345-x

  Progression from MGUS to MM is accompanied by upregulated EIF2 signaling, DNA repair, and proteins involved in translational quality control, whereas integrin- and actin cytoskeletal signaling and cell surface markers are downregulated. […] Compared to the premalignant plasma cells in MGUS, malignant MM cells apparently have mobilized several pathways that collectively contribute to ensure translational fidelity and to avoid proteotoxic stress, especially in the ER. […] The overall reduced expression of immunoglobulins and surface antigens contribute to this and may additionally mediate evasion from recognition by the immune apparatus. […] Progression from MGUS to MM is accompanied by enhanced ribosomal biogenesis and epitranscriptomic writers, potentially augmenting translational fidelity. […] Taken together, progression from MGUS to MM is accompanied by an overall reduced expression of surface antigens that may contribute to immune evasion of the malignant cells and modulate interaction with the bone marrow microenvironment.

• #33 Monoclonal gammopathy of undetermined significance (MGUS) – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/mgus/symptoms-causes/syc-20352362

  Monoclonal gammopathy of undetermined significance (MGUS) is a condition in which an atypical protein is found in the blood. The protein is called monoclonal protein or M protein. […] Experts don’t know what causes MGUS. Changes in genes and being around certain chemicals, such as those used to kill pests, appear to play a role. […] Each year, about 1% of people with MGUS get certain types of blood cancers or other serious diseases, such as: Multiple myeloma. Light chain amyloidosis. Waldenstrom macroglobulinemia. Lymphoma. Other issues linked to MGUS include broken bones, blood clots, kidney problems, and damage to nerves outside of the brain and spinal cord, also known as peripheral neuropathy.

• #34 Monoclonal gammopathy of undetermined significance – Symptoms, diagnosis and treatment | BMJ Best Practice US

  https://bestpractice.bmj.com/topics/en-us/1173

  Monoclonal gammopathy of undetermined significance is an asymptomatic premalignant disorder associated with relatively low risk (on average 0.5% to 1.0% per year) of progression to multiple myeloma or related plasma cell proliferative malignancies. […] No etiologic risk factors have been defined. Male sex, older age, family history of monoclonal gammopathy of undetermined significance, African ancestry, and exposure to radiation or pesticide are associated with a higher prevalence. […] Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic disorder associated with an increased risk of developing multiple myeloma and related plasma cell proliferative malignancies. […] Risk factors include male sex, age 50 years, African ancestry, family history of MGUS or multiple myeloma, immune-mediated conditions, radiation exposure, and pesticide exposure.

• #35 Monoclonal gammopathy of undetermined significance – the role of genetic and infectious agents in the pathogenesis of the disease | Pasiarski | Acta Haematologica Polonica

  https://journals.viamedica.pl/acta_haematologica_polonica/article/view/83534

  Monoclonal gammopathy of undetermined significance (MGUS) is a disorder characterized by an increased concentration of one type of immunoglobulin following a clonal proliferation of plasma cells. The etiology and pathogenesis of MGUS are not fully understood. The risk factors of proven importance include family history and hormonal factors. Recently carried out cohort studies have shown that the molecular abnormalities in this disease are connected with specific loci in the genome, i.e. 2p, 3p and 7p, within which the following genes have been identified: DNMT3A and DTNB (2p), and TRAK1 ULK4 (3p) and CDCA7L (7p). […] Both the invalid responses to auto- and exoantigens are the factors contributing to the formation of cytogenetic and molecular abnormalities. […] So far, little attention had been paid to the role of infections in the development and progression of MGUS to multiple myeloma (MM). Only an increased susceptibility to infections and a significant reduction of specific antibodies against various pathogens (i. e. Streptococcus pneumoniae) were documented in patients with MGUS. This paper aims to explain the role of known and newly discovered genetic factors in the development and progression of MGUS, and an indication of the important role of infections in the course of the disease and to draw attention to the necessity of the immunoprophylaxis.

• #36 Monoclonal Gammopathy of Undetermined Significance (MGUS)

  https://www.healthline.com/health/how-serious-is-mgus

  Each year, the risk of MGUS progressing to multiple myeloma is about 1 percent. MGUS can also progress to other types of blood disorders. The type of conditions that can develop depend on which type of MGUS you have. […] There are three types of MGUS, each associated with an elevated risk of certain health conditions. […] The diseases triggered by MGUS may cause bone fractures, blood clots, and kidney problems over time. These complications can make managing the condition and treating any associated diseases more challenging. […] MGUS is a precancerous condition. Precancerous means that its not cancer, but it has the potential to progress to cancer. Some people with MGUS go on to develop multiple myeloma or other blood cancers, but the majority do not. […] Studies indicate that people with a first-degree relative with MGUS or multiple myeloma have a 2 to 3 times higher risk of developing MGUS. A first-degree relative is a full sibling or biological parent. […] MGUS is a lab finding that may progress into some cancerous conditions. It should be monitored with the help of a physician.

• #37 Monoclonal Gammopathy of Undetermined Significance (MGUS)

  https://www.healthline.com/health/how-serious-is-mgus

  Monoclonal gammopathy of undetermined significance (MGUS) is an abnormal finding of a blood test. It means theres a specific protein present in your blood and is an early sign of certain types of a cancer called myeloma. […] Monoclonal gammopathy of undetermined significance (MGUS) is the name for a laboratory finding of an abnormal protein in the blood. This condition needs to be monitored because sometimes it is an early sign of developing smoldering myeloma or multiple myeloma, which are types of cancer. […] What doctors do know is that MGUS causes abnormal plasma cells in the bone marrow to produce M protein. […] The prevalence of MGUS is twice as high in African Americans when compared with white Americans. This is most likely be due to genetic factors. Environmental factors are possible, but evidence is lacking.

• #38 Monoclonal gammopathy of undetermined significance – the role of genetic and infectious agents in the pathogenesis of the disease | Pasiarski | Acta Haematologica Polonica

  https://journals.viamedica.pl/acta_haematologica_polonica/article/view/83534

  Monoclonal gammopathy of undetermined significance (MGUS) is a disorder characterized by an increased concentration of one type of immunoglobulin following a clonal proliferation of plasma cells. The etiology and pathogenesis of MGUS are not fully understood. The risk factors of proven importance include family history and hormonal factors. Recently carried out cohort studies have shown that the molecular abnormalities in this disease are connected with specific loci in the genome, i.e. 2p, 3p and 7p, within which the following genes have been identified: DNMT3A and DTNB (2p), and TRAK1 ULK4 (3p) and CDCA7L (7p). […] Both the invalid responses to auto- and exoantigens are the factors contributing to the formation of cytogenetic and molecular abnormalities. […] So far, little attention had been paid to the role of infections in the development and progression of MGUS to multiple myeloma (MM). Only an increased susceptibility to infections and a significant reduction of specific antibodies against various pathogens (i. e. Streptococcus pneumoniae) were documented in patients with MGUS. This paper aims to explain the role of known and newly discovered genetic factors in the development and progression of MGUS, and an indication of the important role of infections in the course of the disease and to draw attention to the necessity of the immunoprophylaxis.

• #39 Monoclonal gammopathy of undetermined significance (MGUS) – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/mgus/symptoms-causes/syc-20352362

  Monoclonal gammopathy of undetermined significance (MGUS) is a condition in which an atypical protein is found in the blood. The protein is called monoclonal protein or M protein. […] Experts don’t know what causes MGUS. Changes in genes and being around certain chemicals, such as those used to kill pests, appear to play a role. […] Each year, about 1% of people with MGUS get certain types of blood cancers or other serious diseases, such as: Multiple myeloma. Light chain amyloidosis. Waldenstrom macroglobulinemia. Lymphoma. Other issues linked to MGUS include broken bones, blood clots, kidney problems, and damage to nerves outside of the brain and spinal cord, also known as peripheral neuropathy.

• #40 Monoclonal Gammopathy of Undetermined Significance (MGUS)

  https://my.clevelandclinic.org/health/diseases/17744-monoclonal-gammopathy-of-undetermined-significance-mgus

  Monoclonal gammopathy of undetermined significance happens when your bone marrow produces abnormal plasma cells. […] In MGUS, abnormal plasma cells produce M proteins instead of antibodies. M proteins circulate in your bloodstream. These abnormal proteins may build up in your bloodstream and in your pee (urine), damaging your kidneys, heart and nerves. M proteins in your blood may also reduce your bodys ability to fight infection. […] Healthcare providers arent sure why bone marrow produces abnormal plasma cells that then produce M proteins. The condition is linked to the following: Genetic changes. A history of autoimmune diseases. A history of treatment for autoimmune diseases. Exposure to high levels of radiation. Exposure to pesticides and insecticides. […] No, you cant prevent this condition. It happens when certain genes mutate, creating abnormal plasma cells that produce the abnormal proteins that cause MGUS symptoms.

• #41 Monoclonal Gammopathy of Undetermined Significance (MGUS)

  https://my.clevelandclinic.org/health/diseases/17744-monoclonal-gammopathy-of-undetermined-significance-mgus

  Monoclonal gammopathy of undetermined significance happens when your bone marrow produces abnormal plasma cells. […] In MGUS, abnormal plasma cells produce M proteins instead of antibodies. M proteins circulate in your bloodstream. These abnormal proteins may build up in your bloodstream and in your pee (urine), damaging your kidneys, heart and nerves. M proteins in your blood may also reduce your bodys ability to fight infection. […] Healthcare providers arent sure why bone marrow produces abnormal plasma cells that then produce M proteins. The condition is linked to the following: Genetic changes. A history of autoimmune diseases. A history of treatment for autoimmune diseases. Exposure to high levels of radiation. Exposure to pesticides and insecticides. […] No, you cant prevent this condition. It happens when certain genes mutate, creating abnormal plasma cells that produce the abnormal proteins that cause MGUS symptoms.

• #42 Monoclonal Gammopathies of Undetermined Significance (MGUS): Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/204297-overview

  The risk of progression to MM or other lymphoproliferative disorder is present at a constant rate throughout the remainder of a patient’s life. This observation suggests that the second event responsible for progression is a random event and not cumulative. […] Although autoimmune disease is a well-described risk factor for the development of MGUS, a Swedish population-based study determined that patients with a history of autoimmune disease have a significantly lower risk of progression from MGUS to MM or other lymphoproliferative diseases.

• #43 Monoclonal Gammopathy of Undetermined Significance (MGUS)

  https://my.clevelandclinic.org/health/diseases/17744-monoclonal-gammopathy-of-undetermined-significance-mgus

  Monoclonal gammopathy of undetermined significance happens when your bone marrow produces abnormal plasma cells. […] In MGUS, abnormal plasma cells produce M proteins instead of antibodies. M proteins circulate in your bloodstream. These abnormal proteins may build up in your bloodstream and in your pee (urine), damaging your kidneys, heart and nerves. M proteins in your blood may also reduce your bodys ability to fight infection. […] Healthcare providers arent sure why bone marrow produces abnormal plasma cells that then produce M proteins. The condition is linked to the following: Genetic changes. A history of autoimmune diseases. A history of treatment for autoimmune diseases. Exposure to high levels of radiation. Exposure to pesticides and insecticides. […] No, you cant prevent this condition. It happens when certain genes mutate, creating abnormal plasma cells that produce the abnormal proteins that cause MGUS symptoms.

• #44 Monoclonal Gammopathy of Undetermined Significance | IntechOpen

  https://www.intechopen.com/chapters/44075?jwsource=cl

  Several authors discuss the very early and partially overlapping molecular pathogenic events that are shared by MGUS, and how they are associated to progression at the MGUS to MM transition. […] The first step in the pathogenesis is likely an abnormal response to antigenic stimulation, mediated possibly by aberrant expression of toll-like receptors and overexpression of interleukin (IL) 6 receptors and IL-1. […] This then results in the development of primary cytogenetic abnormalities, either hyperdiploidy or immunoglobulin heavy chain translocations. […] Hyperdiploid tumors, which include about 50% of MM tumors, often have multiple trisomies involving chromosomes 3, 5, 7, 9, 11, 15, 19, and 21; also, a substantially lower prevalence of immunoglobulin heavy chain translocations and monosomy of chromosome 13 compared with nonhyperdiploid tumors.

• #45

  https://www.clinicalcorrelations.org/2011/12/22/what-is-the-significance-of-monoclonal-gammopathy-of-undetermined-significance-mgus/

  Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell dyscrasia that is defined as a serum M protein 30 g/L, clonal plasma cells 10% in the bone marrow, and the absence of end-organ damage that can be attributed to a plasma cell proliferative disorder. […] The pathophysiology of the transition from normal plasma cells to MGUS to multiple myeloma involves many overlapping oncogenic events. […] The first step in the pathogenesis is usually an abnormal response to antigenic stimulation, possibly mediated by overexpression of interleukin (IL)-6 receptors and dysregulation of the cyclin D gene. […] These changes result in the development of primary cytogenetic abnormalities, either hyperdiploidy or immunoglobulin heavy chain translocation. […] The progression of MGUS to multiple myeloma is likely secondary to a random second hit, the manner of which is unknown. […] Mutations with Ras and p53, methylation of p16, myc abnormalities, and induction of angiogenesis have also been associated with progression.

• #46

  https://link.springer.com/article/10.1007/s11914-018-0479-z

  MGUS (monoclonal gammopathy of undetermined significance) is a plasma cell disorder characterized by a moderate increase in serum monoclonal protein (3 g/dL), an increase in bone marrow plasma cell infiltration (10%) and the absence of any end-organ damage. […] Although MGUS is considered a benign condition, evidence for clinical consequences is increasing. […] Data reveals important MGUS-related bone alterations that may contribute to disease pathogenesis. […] However, the exact health implications of MGUS itself and the mechanisms behind them remain unclear. […] It is now evident that the bone microenvironment plays a key role in hematologic cancers and other oncogenic processes leading to bone metastasis. […] The bone microenvironment is an appropriate site to study changes that could possibly drive controlled clonal plasma cells into a more malignant monoclonal gammopathy.

• #47

  https://haematologica.org/article/view/7062

  Monoclonal gammopathy of undetermined significance is one of the most common pre-malignant disorders. […] Clonal burden, as determined by bone marrow plasma cell percentage or M-protein level, as well as biological characteristics, including heavy chain isotype and light chain production, are helpful in predicting risk of progression of monoclonal gammopathy of undetermined significance to symptomatic disease. […] Furthermore, alterations in the bone marrow microenvironment of monoclonal gammopathy of undetermined significance patients result in an increased risk of venous and arterial thrombosis, infections, osteoporosis, and bone fractures. […] The importance of MGUS not only lies in the increased risk of developing a hematologic malignancy, but the small clone may also be responsible for severe organ damage through the production of a toxic M-protein which has autoantibody activity or deposits in tissues.

• #48

  https://link.springer.com/article/10.1007/s11914-018-0479-z

  Altogether, evidence from this and other research fields suggests that osteoblast and other cells within the bone marrow microenvironment could potentially be driving early mutations present in the plasma cells of MGUS patients. […] The future development of models like this will be extremely useful to advance the study of MGUS pathogenesis and to better understand the initial events of malignant transformation that ultimately will help us to develop drugs for targeting the microenvironment and/or its interaction with clonal plasma cells.

• #49 Monoclonal Gammopathy of Undetermined Cardiovascular Significance; Current Evidence and Novel Insights

  https://www.mdpi.com/2308-3425/10/12/484

  Overall, data show that patients with MGUS may have an increased risk of CVD events. Although several hypotheses have been proposed, mechanistic studies examining the association between MGUS and CVD are lacking. The possible pathophysiological mechanisms between MGUS and CVD are presented in Figure 1. […] Emerging data have shown that the pathogenetic mechanisms in hematological malignancies and CVD may have interrelated genetic backgrounds. […] Serum levels of RANKL and RANKL/OPG have been found to be higher in patients with MGUS than in controls, especially in patients with MGUS at high risk for progression to symptomatic MM. Therefore, biomarkers related to bone metabolism are increased in patients with MGUS, whereas they may also promote vascular calcification and, subsequently, may lead to an increased risk for CVD events.

• #50

  https://link.springer.com/article/10.1007/s11914-018-0479-z

  Nonetheless, little is known about how the bone marrow microenvironment affects MGUS pathogenesis. […] More recently, evidence is accumulating to challenge this. […] The etiology behind these results was not clarified. […] The study was performed using a small cohort of 488 MGUS patients, with limited racial and geographical distributions, so generalization of this data presents some limitations. […] However, some controversy is revealed by these population-based studies. […] Despite current conflicting results, the links between MGUS, bone metabolism alterations, and increased risk of fracture are evident. […] The aforementioned data about MGUS and skeletal changes supports this notion. […] Interestingly, RANKL and RANKL/OPG levels are already increased in high-risk MGUS patients suggesting that although no lesions can be detected, osteoclasts might play an important role in MGUS pathogenesis.

• #51 Pathogenesis and progression of monoclonal gammopathy of undetermined significance | Leukemia

  https://www.nature.com/articles/leu2008203

  In Caucasians, monoclonal gammopathy of undetermined significance (MGUS) is an age-related condition with prevalence as high as 3% in persons older than 50 years. […] On average, the transformation rate to a malignant monoclonal gammopathy is 1% per year, with the mechanisms of progression likely related to bone marrow microenvironment and/or the cytokine network. […] The predictors of malignant transformation are the plasma cell mass (M-protein size and/or proportion of plasma cell in the bone marrow), IgA isotype, serum free light-chain ratio and evolving type and ratio between phenotypically aberrant and normal bone marrow plasma cells. […] It is recommended to follow these patients, particularly those with high risk of progression, annually to detect MM before complications, such as renal failure or extensive skeletal, involvement occur.

• #52 Cracking the “MGUS” Code Reveals Monoclonal Gammopathy of Clinical Significance:

  https://www.onclive.com/view/cracking-the-mgus-code-reveals-monoclonal-gammopathy-of-clinical-significance-

  An acquired factor X deficiency can be seen with amyloidosis. This occurs because both factor X and pentraxin-2 (PTX-2) bind to amyloid fibrils. […] Other reported acquired bleeding conditions seen with monoclonal gammopathy driven by auto-antibody formation include Bernard-Soulier with anti-GPIb/IX/V, Glanzmann thrombasthenia with anti-GPIIb/IIIa, and antifibrin antibodies leading to dysfibrinogenemia and hypofibrinogenemia. […] The purposed mechanism driving increased bone turnover is an increase in cytokines CCL3/ MIP-1 (osteoclast-activating factor) and DKK1 (osteoblast-suppressive factor).

• #53 Progression of monoclonal gammopathy of undetermined significance to multiple myeloma is associated with enhanced translational quality control and overall loss of surface antigens | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-05345-x

  Progression from MGUS to MM is accompanied by upregulated EIF2 signaling, DNA repair, and proteins involved in translational quality control, whereas integrin- and actin cytoskeletal signaling and cell surface markers are downregulated. […] Compared to the premalignant plasma cells in MGUS, malignant MM cells apparently have mobilized several pathways that collectively contribute to ensure translational fidelity and to avoid proteotoxic stress, especially in the ER. […] The overall reduced expression of immunoglobulins and surface antigens contribute to this and may additionally mediate evasion from recognition by the immune apparatus. […] Progression from MGUS to MM is accompanied by enhanced ribosomal biogenesis and epitranscriptomic writers, potentially augmenting translational fidelity. […] Taken together, progression from MGUS to MM is accompanied by an overall reduced expression of surface antigens that may contribute to immune evasion of the malignant cells and modulate interaction with the bone marrow microenvironment.

• #54 Monoclonal Gammopathy of Undetermined Significance (MGUS)—Not So Asymptomatic after All

  https://www.mdpi.com/2072-6694/12/6/1554

  Even though the vast majority of the cases of MM arise from a prior state of MGUS, overall, the annual risk of progression from MGUS to symptomatic MM, WM, or other related disorders is only ~1%. […] However, even in the absence of malignancy and when matched by age and sex, MGUS patients experience shorter overall survival from diagnosis than is expected (8.1 vs. 12.4 years) according to a prospective cohort study. […] In addition to progression to lymphoproliferative diseases and amyloidosis, patients with MGUS appear to suffer from a greater prevalence of recurrent infections, ischemic heart disease, peripheral neuropathy, and renal diseases compared to those without MGUS. […] The aim of this review is to examine the most consistently reported co-morbidities associated with MGUS, namely the increased risk of bone fractures, peripheral neuropathy, renal impairment, secondary immunodeficiency, and cardiovascular disease.

• #55 Monoclonal Gammopathy of Undetermined Significance (MGUS)—Not So Asymptomatic after All

  https://www.mdpi.com/2072-6694/12/6/1554

  The term monoclonal gammopathy of renal significance (MGRS) was first introduced in 2012 by the International Kidney and Monoclonal Gammopathy Research Group (IKMG) to describe a set of renal disorders that were characterized by the deposition of monoclonal immunoglobulin in the kidney. […] MGRS currently encompasses all precursor B-cell or plasma cell clonal disorders that secrete a nephrotoxic monoclonal paraprotein. […] The most serious complication of MGRS is end-stage renal disease (ESRD) and the comorbidities it entails. […] The association between monoclonal paraproteinemia and neuropathy has been demonstrated in a population-based screening study, which found a higher than expected prevalence of peripheral neuropathy. […] The absolute prevalence of peripheral neuropathy appears to be under 5% of MGUS patients.

• #56

  https://haematologica.org/article/view/7062

  Interestingly, the quality of response is better among patients with secondary MGUS. […] The M-protein seems to play a role in the development of several skin disorders including plane xanthoma and Schnitzler syndrome. […] Various kidney disorders are the result of toxic M-proteins produced by the MGUS clone, including monoclonal immunoglobulin deposition disease, light-chain proximal tubulopathy, and type 1 and type 2 cryoglobulinemic glomerulonephritis. […] Importantly, M-protein-associated kidney diseases have a high recurrence rate after kidney transplantation. […] Treatment of M-protein-related disorders is dependent on severity. […] In addition, therapy directed at eradication of the MGUS clone is only justified when there is a clear causal relationship between MGUS and the associated disorder. […] The contributing role of the M-protein and/or growth factors secreted by the clonal cells is even less clear for other skin diseases that are associated with MGUS.

• #57 Monoclonal Gammopathy of Undetermined Significance (MGUS)—Not So Asymptomatic after All

  https://www.mdpi.com/2072-6694/12/6/1554

  The term monoclonal gammopathy of renal significance (MGRS) was first introduced in 2012 by the International Kidney and Monoclonal Gammopathy Research Group (IKMG) to describe a set of renal disorders that were characterized by the deposition of monoclonal immunoglobulin in the kidney. […] MGRS currently encompasses all precursor B-cell or plasma cell clonal disorders that secrete a nephrotoxic monoclonal paraprotein. […] The most serious complication of MGRS is end-stage renal disease (ESRD) and the comorbidities it entails. […] The association between monoclonal paraproteinemia and neuropathy has been demonstrated in a population-based screening study, which found a higher than expected prevalence of peripheral neuropathy. […] The absolute prevalence of peripheral neuropathy appears to be under 5% of MGUS patients.

• #58 Monoclonal Gammopathy of Undetermined Significance (MGUS)—Not So Asymptomatic after All

  https://www.mdpi.com/2072-6694/12/6/1554

  IgM is the most commonly associated paraprotein with peripheral neuropathy, compared to IgG and IgA, at a ratio of approximately 6:3:1. […] Peripheral neuropathy affects up to 20% of patients with AL amyloidosis. […] MGUS is a recognized cause of secondary antibody deficiency. […] The prevalence of MGUS increases with age, as does an age-related decline in immune function, or immunosenescence. […] The increase in risk was not influenced by the paraprotein isotype but was positively correlated with the M-protein concentration. […] The majority of patients with MGUS are over the age of 65, and even in healthy individuals, the immune response to vaccination declines with age. […] Cardiovascular Disease (CVD) comprises arterial (coronary, peripheral, and cerebrovascular), venous thromboembolic and structural myocardial disorders.

• #59 How to Diagnose Monoclonal Gammopathy of Undetermined Significance

  https://consultqd.clevelandclinic.org/how-to-diagnose-monoclonal-gammopathy-of-undetermined-significance

  The monoclonal gammopathies encompass a number of disorders characterized by the production of a monoclonal protein (M protein) by an abnormal clone of plasma cells or other lymphoid cells. Monoclonal gammopathy of undetermined significance (MGUS) is the most common of these disorders. Its clinical relevance lies in the inherent risk of progression to hematologic malignancies such as multiple myeloma or other lymphoproliferative disorders, or of organ dysfunction due to the toxic effects of the M protein. […] Misfolded light-chain deposition leading to organ dysfunction is the hallmark of light-chain amyloidosis, which constitutes a subset of MGRS. An abnormal light-chain ratio, especially if skewed toward lambda, should trigger an investigation for light-chain amyloidosis. […] Neuropathy associated with M proteins is a clinical entity related to a multitude of disorders that may necessitate treating the underlying cellular clone responsible for the secretion of the toxic M protein. These disorders include light-chain amyloidosis, POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes or sclerotic bone lesions) syndrome and IgM-related neuropathies with antimyelin-associated glycoprotein antibodies.

• #60 Monoclonal Gammopathy of Undetermined Significance (MGUS)—Not So Asymptomatic after All

  https://www.mdpi.com/2072-6694/12/6/1554

  IgM is the most commonly associated paraprotein with peripheral neuropathy, compared to IgG and IgA, at a ratio of approximately 6:3:1. […] Peripheral neuropathy affects up to 20% of patients with AL amyloidosis. […] MGUS is a recognized cause of secondary antibody deficiency. […] The prevalence of MGUS increases with age, as does an age-related decline in immune function, or immunosenescence. […] The increase in risk was not influenced by the paraprotein isotype but was positively correlated with the M-protein concentration. […] The majority of patients with MGUS are over the age of 65, and even in healthy individuals, the immune response to vaccination declines with age. […] Cardiovascular Disease (CVD) comprises arterial (coronary, peripheral, and cerebrovascular), venous thromboembolic and structural myocardial disorders.

• #61 Monoclonal Gammopathy of Undetermined Cardiovascular Significance; Current Evidence and Novel Insights

  https://www.mdpi.com/2308-3425/10/12/484

  Light chain AL amyloidosis is an MGUS-associated condition with a severe impact on the cardiovascular system due to the deposition of monoclonal light chains. […] The accumulation of immunoglobulin light chain-based amyloid fibrils in cardiac tissue can cause restrictive cardiomyopathy. […] The mechanisms that lead to cardiovascular events include small vessel vasculitis (cryoglobulinemic vasculitis), vascular occlusion by the cryoprecipitate, thrombotic microangiopathy and hyperviscosity syndrome. […] Patients with antiphospholipid syndrome have an increased risk for arterial and venous thromboses, and recommendations for cardiovascular risk management have been published by The European Alliance of Associations for Rheumatology (EULAR). […] Monoclonal gammopathies, including Waldenstrom disease, multiple myeloma and MGUS have been associated with the presence of antiphospholipid antibodies.

• #62 Monoclonal Gammopathy of Undetermined Cardiovascular Significance; Current Evidence and Novel Insights

  https://www.mdpi.com/2308-3425/10/12/484

  Light chain AL amyloidosis is an MGUS-associated condition with a severe impact on the cardiovascular system due to the deposition of monoclonal light chains. […] The accumulation of immunoglobulin light chain-based amyloid fibrils in cardiac tissue can cause restrictive cardiomyopathy. […] The mechanisms that lead to cardiovascular events include small vessel vasculitis (cryoglobulinemic vasculitis), vascular occlusion by the cryoprecipitate, thrombotic microangiopathy and hyperviscosity syndrome. […] Patients with antiphospholipid syndrome have an increased risk for arterial and venous thromboses, and recommendations for cardiovascular risk management have been published by The European Alliance of Associations for Rheumatology (EULAR). […] Monoclonal gammopathies, including Waldenstrom disease, multiple myeloma and MGUS have been associated with the presence of antiphospholipid antibodies.

• #63 Monoclonal Gammopathy of Undetermined Significance | IntechOpen

  https://www.intechopen.com/chapters/44075?jwsource=cl

  This data suggests a possible role of delta 13 in the transition from MGUS to MM specifically in cases with t(11;14) or t(6;14). […] In summary, it has been proposed that the pathogenesis of MGUS and MM can be considered as occurring in three phases. […] First, partially overlapping genetic events common to MGUS and MM include at a minimum primary immunoglobulin heavy chain translocations, hyperdiploidy, and del13 that lead directly or indirectly to dysregulation of a CCND gene; second, the transition from MGUS to MM is associated with increased MYC expression and sometimes K-RAS mutations, but can also include del13 in t(11;14) tumors; third, additional progression of the MM tumor seems to be associated with other events.

• #64 Pathogenesis of Monoclonal Gammopathy of Undetermined Significance (MGUS) and Progression to Multiple Myeloma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3040450/

  Dysregulation of a CYCLIN D gene seems to be a unifying event for virtually all MGUS and MM tumors. […] Many somatic genetic abnormalities that are thought to represent progression events have been identified in MM tumors. […] It is significant that the prevalence of K- or N-RAS activating mutations is approximately 15% each in MM tumors, whereas the prevalence of N-RAS mutations is 7% in MGUS tumors and K-RAS mutations have not been identified in MGUS tumors. […] Importantly, a murine model using MGUS prone mice generates MM tumors that are good phenocopies of human MM tumors when these mice contain a MYC transgene that can be activated by somatic hypermutation as B cells pass through a germinal center.

• #65

  https://haematologica.org/article/view/7062

  Progression of MGUS to MM or other related malignancies occurs at a rate of approximately 1% per year. […] Presenting features as well as the dynamics of the plasma cell clone during the first years of follow up are helpful in predicting risk of progression of MGUS to symptomatic disease. […] Biological characteristics of the clone also have predictive value in conventional MGUS and these include heavy chain isotype (IgA/IgM IgG); light chain production as determined by abnormal serum FLC ratio or presence of Bence Jones proteinuria; detection of circulating clonal B cells or plasma cells; increased bone resorption in bone biopsy; clonal heterogeneity; DNA aneuploidy assessed by flow cytometry; and abnormal metaphase cytogenetics. […] The risk of progression for light-chain MGUS is lower when compared to conventional MGUS.

• #66 Monoclonal gammopathy of undetermined significance | Canadian Cancer Society

  https://cancer.ca/en/cancer-information/cancer-types/multiple-myeloma/what-is-multiple-myeloma/monoclonal-gammopathy-of-undetermined-significance

  Low-risk MGUS has all of the following features: The M-protein level in the blood is less than 15 g/L. The type of M-protein is IgG. The free light chain ratio is normal. […] High-risk MGUS has any of the following features: The M-protein level in the blood is more than 15 g/L. The type of M-protein is IgA or IgM. The free light chain ratio is abnormal. […] If only one of the above features is present, there is a 21% absolute risk of MGUS progressing to multiple myeloma or a related condition after 20 years. […] If 2 of the above features are present, there is a 37% absolute risk. […] If all 3 of the above features are present, there is a 58% absolute risk.

• #67 Monoclonal Gammopathy of Undetermined Significance (MGUS)—Not So Asymptomatic after All

  https://www.mdpi.com/2072-6694/12/6/1554

  Our understanding of the pathogenesis of increased CVD risk in MGUS remains limited. […] Overall, there is a growing appreciation of the increased risk of CVD in MGUS. […] Up to 90% of cases of MGUS are undiagnosed and are considered to predate symptomatic MM or lymphoproliferative disease by up to twenty years. […] Therefore, MGUS as a contributory factor to the risk of fractures, nephropathy, renal impairment, and cardiovascular risk may be under-appreciated.

• #68 Monoclonal Gammopathy of Undetermined Cardiovascular Significance; Current Evidence and Novel Insights

  https://www.mdpi.com/2308-3425/10/12/484

  In conclusion, MGUS is associated with an increased risk of CVD. Data are more evident for CAD than for cerebrovascular events, whereas data on PAD are limited. Studies examining whether MGUS is associated with subclinical atherosclerosis using markers such as CT calcium score, pulse wave velocity and carotid intima-media thickness are needed to elucidate whether MGUS accelerates atherosclerosis. […] Therefore, people with MGUS may benefit from regular cardiovascular risk assessment and management as well as close hematological follow-up to monitor disease progression.

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