Materiały źródłowe

• #1 The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group | Nature Reviews Nephrology

  https://www.nature.com/articles/s41581-018-0077-4

  The concept of monoclonal gammopathy of undetermined significance (MGUS) was first introduced in 1978 by Robert Kyle. This premalignant condition is characterized by the presence of a serum monoclonal immunoglobulin 30g/l and 10% monoclonal bone marrow plasma cells in a patient who does not have any organ damage attributable to the monoclonal immunoglobulin. Conversion of MGUS to malignancy, which mandates the initiation of appropriate treatment, is indicated by the development of disease-specific features. For example, conversion to multiple myeloma (MM) is indicated by the occurrence of one or more myeloma-defining events, such as hypercalcaemia, renal impairment, anaemia, lytic bone lesions or an event suggestive of impending myeloma (such as a serum involved:uninvolved free light-chain ratio 100, 60% bone marrow plasma cells or 1 bone lesions on MRI). Patients with MGUS who do not yet exhibit any of these disease-specific features do not require treatment but should undergo careful monitoring.

• #2 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 annual risk of progression to multiple myeloma (MM), Waldenstrm macroglobulinemia (WM), amyloidosis (AL), or other lymphoproliferative disorders is approximately 1%. However, the mode and risk of progression vary between IgM MGUS and those with non-IgM MGUS. […] An abnormal serum free light-chain ratio (ratio of kappa to lambda free light chains) and a high serum monoclonal protein (M protein) level (1.5 g per deciliter) are risk factors for progression. In IgM MGUS, Kyle et al reported a risk of progression at 20 years of 55% in patients with both risk factors, compared with 41% in those with one risk factor and 19% in patients with neither risk factor. In patients with non-IgM MGUS, the risk of progression at 20 years was 30% in those with both risk factors, 20% in those with one risk factor, and 7% in those with neither risk factor. […] The following factors were significantly associated with progression: An abnormal FLC ratio of less than 0.26 or more than 1.65, an M-protein concentration of 1.5 g/dL or more, and reduction of one or two noninvolved immunoglobulin isotype levels.

• #3

  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. […] It is important to clinicians because it is associated with a 1% annual risk of progression to multiple myeloma or related malignancy. […] The cumulative probability of progression was 12% at 10 years, 25% at 20 years, and 30% at 25 years. The overall risk of progression was about 1% per year. […] Predicting which patients with MGUS will remain stable compared to those who will progress is very difficult at the time of diagnosis. […] Those patients with non-IgG type, high serum M protein level (15 g/L), and an abnormal serum free light chain ratio are associated with increased risk for progression to smoldering myeloma and then to multiple myeloma.

• #4

  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. […] It is important to clinicians because it is associated with a 1% annual risk of progression to multiple myeloma or related malignancy. […] The cumulative probability of progression was 12% at 10 years, 25% at 20 years, and 30% at 25 years. The overall risk of progression was about 1% per year. […] Predicting which patients with MGUS will remain stable compared to those who will progress is very difficult at the time of diagnosis. […] Those patients with non-IgG type, high serum M protein level (15 g/L), and an abnormal serum free light chain ratio are associated with increased risk for progression to smoldering myeloma and then to multiple myeloma.

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

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

  Monoclonal gammopathy of undetermined significance (MGUS) is considered a preneoplastic condition with an annual risk of progression of approximately 1%. The risk of progression is increased when M protein greater than or equal to 15 g/L and with an abnormal free light chain ratio. Non-IgM MGUS does not require treatment. However, the management of patients with non-IgM MGUS requires an understanding of the risk of progression of the disease. Generally, close follow-up is recommended for these patients. Most providers believe that all non-IgM MGUS patients should undergo a clinical examination and laboratory evaluation for disease progression annually. […] The patients with MGUS who are at risk for progressing to advanced disease can be risk-stratified based on the following criteria: Serum monoclonal protein level greater than or equal to 15 g/L (1.5 g/dL), Non-IgG MGUS (i.e., IgA, IgM, and IgD MGUS), Abnormal serum free light chain ratio. Patients with three risk factors are categorized as high-risk MGUS; patients with two risk factors are categorized as high-intermediate risk MGUS. Patients with one risk factor are categorized as low-intermediate risk MGUS. Patients with no risk factors are categorized as low-risk MGUS. Despite close observation, some non-IgM MGUS patients may show progression to PCM abruptly.

• #6 Monoclonal gammopathy of undetermined significance and Smoldering Multiple Myeloma: A review of the current understanding of epidemiology, biology, risk stratification and management of myeloma precursor disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3593941/

  The term monoclonal gammopathy of undetermined significance (MGUS) was coined in 1978. […] Clinical features that are prognostic of rapid transformation have been identified but no specific molecular markers have been identified. […] A limitation is that a vast majority of patients with precursor disease especially low risk MGUS will never progress to myeloma in their lifetime and treating these patients is not only unnecessary but may be potentially harmful. […] The challenge is to identify a subset of patients with the precursor state that would definitely progress to myeloma and in whom interventions will have a meaningful impact. […] In 1384 MGUS patients, the risk of progression to MM or a related disorder after 20 years was 14% with an initial protein level of 0.5 g/dL or less, 25% for 1.5 g/dL, 41% for 2 g/dL, 49% for 2.5 g/dL, and 64% with 3 g/dL.

• #7 Prognosis of young patients with monoclonal gammopathy of undetermined significance (MGUS) | Blood Cancer Journal

  https://www.nature.com/articles/s41408-021-00406-6

  Monoclonal gammopathy of undetermined significance (MGUS) is rare in young patients (age 40 years at diagnosis), with a prevalence of 0.3%, representing ~2% of all patients with MGUS. […] We hypothesized that MGUS detected in young patients may be associated with a higher risk of progression. […] The risk of progression to multiple myeloma or a related disorder at 5 years and 10 years was 6.0% and 13.8%, respectively. […] The size of M protein was a significant risk factor for progression (HR 4.2, 95% CI 2.27.9). […] Young patients with MGUS have a similar risk of progression as older patients, 1.4% per year. […] Patients with immune-related disorders may have a lower risk of progression. […] The risk of progression to plasma cell or lymphoid disorders in young patients was predicted by the size of the serum M protein, a potent risk factor with a 3 fold higher risk of progression per unit increase.

• #8 Monoclonal gammopathy of undetermined significance and Smoldering Multiple Myeloma: A review of the current understanding of epidemiology, biology, risk stratification and management of myeloma precursor disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3593941/

  MGUS patients with IgM or IgA monoclonal protein have an increased risk of progression to disease as compared to patients with IgG protein. […] An abnormal FLC assay was an independent risk factor for progression from MGUS to MM. […] The presence of 0, 1 or 2 of these factors was associated with a progression risk of 2, 10 and 46% respectively in MGUS. […] Other studies have identified various factors that are prognostic for progression to symptomatic disease. […] Age, sex, race, chromosomal translocations are not prognostic factors for progression from precursor disease to symptomatic myeloma. […] The recent advances in our knowledge about MGUS and SMM have helped us better understand the pathogenesis of myeloma. […] Intervening at the precursor state provides a unique opportunity to alter the natural history of the disease.

• #9

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

  There are currently no data available on extrinsic factors that promote progression. […] The absolute risk of progression at 20 years was 5% for patients without risk factors (low-risk), but the risk increased to 21%, 37%, and 58% for patients with 1 (low-intermediate risk), 2 (high-intermediate risk), or 3 (high risk) of these risk factors, respectively. […] The recommendations were circulated among the panel members and also discussed in the 2013 EMN Trialist meeting.

• #10 Risk of MGUS Progression to Myeloma Can Change – NCI

  https://www.cancer.gov/news-events/cancer-currents-blog/2019/mgus-multiple-myeloma-progression-risk

  A new study suggests that a persons risk of progressing from a benign condition called monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma, a type of blood cancer, can change over time. […] On average, about 1% of people with MGUS go on to develop multiple myeloma each year. […] But according to the new findings, published July 18 in JAMA Oncology, the levels of those blood markers and the risk of developing cancer can change over time. […] The study shows that most of the high-risk patients were low risk at some earlier point, explained lead investigator Ola Landgren, M.D., Ph.D., professor of medicine and chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center. […] Currently, only people who have a high- or intermediate-risk MGUS are recommended to receive annual follow-up tests to check for signs of progression. However, the study investigators said that their findings support annual blood tests for all individuals with MGUS, regardless of their initial risk assessment.

• #11 Risk of MGUS Progression to Myeloma Can Change – NCI

  https://www.cancer.gov/news-events/cancer-currents-blog/2019/mgus-multiple-myeloma-progression-risk

  The findings that low- and intermediate-risk MGUS could convert to high-risk MGUS within a few years, the study authors wrote, supports annual blood testing for all individuals diagnosed with MGUS or light-chain MGUS, as well as yearly assessment of a patients clinical risk status. […] A potential benefit of annual blood testing is that it could lead to earlier detection of multiple myeloma, which could lessen or prevent severe myeloma-related complications like a bone fracture or kidney failure, Dr. Landgren said. […] Three retrospective studies have shown that people who had MGUS and received annual checkups prior to being diagnosed with multiple myeloma were far less likely to have a severe complication than those who didn’t get checkups. […] Drs. Landgren and Hofmann are exploring other markers that may be more predictive of progression to myeloma.

• #12 Prognosis of young patients with monoclonal gammopathy of undetermined significance (MGUS) | Blood Cancer Journal

  https://www.nature.com/articles/s41408-021-00406-6

  Our study did not find a statistically significant difference in the risk of progression between patients with immune-related conditions and patients without immune-related conditions, although there was a trend towards higher risk of progression in those without a coexisting immune disorder (HR 2.36, 95% CI 0.856.52, p=0.088). […] The cumulative risk of progression at 5 years and 10 years for patients with immune-related conditions concurrently present when MGUS was first diagnosed was 1.5% and 10.1% respectively; the corresponding rate in patients without immune-related conditions at the time of diagnosis tend to be higher at 12.3% and 18.9%, respectively (HR 2.36, 95% CI 0.856.52, p=0.088). […] Young patients with MGUS have a similar risk of progression as in older patients, 1.4% per year. Approximately 50% are diagnosed in the setting of immune-related disorders. When occurring in the setting of immune-related disorders, the M protein is smaller, more likely to resolve, and may have a lower risk of progression than in patients in whom MGUS is detected without concurrent immune-related disorder.

• #13 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. Most patients do not progress to an overt condition, but nevertheless, MGUS is associated with a shortened life expectancy and, in a minority of cases, a number of co-morbid conditions that include an increased fracture risk, renal impairment, peripheral neuropathy, secondary immunodeficiency, and cardiovascular disease. […] 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%. Therefore, most patients with MGUS do not progress to symptomatic MM or other lymphoproliferative disorders. 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.

• #14

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

  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. […] MGUS patients have a poorer survival than the general population. […] This indicates that after exclusion of MM and other lymphoproliferative disorders, attention should also be paid to the presence of coexisting diseases that may contribute to the increased mortality in MGUS. […] MGUS patients have an approximately 2-fold increased risk of developing bacterial and viral infections compared to controls. […] There is an approximately 28-fold increased risk of developing myeloid malignancies including myelodysplastic syndrome, acute myeloid leukemia, and polycythemia vera in MGUS.

• #15

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

  MGUS patients have an increased risk of osteoporosis and fractures. […] The risk of thrombosis did not vary by M-protein level in one study, whereas in two studies risk of venous thrombosis was increased in patients with higher M-protein levels. […] 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. […] The M-protein seems to play a role in the development of several skin disorders including plane xanthoma and Schnitzler syndrome. […] The small clone may occasionally be responsible for severe organ damage through the production of a monoclonal protein that has autoantibody activity or deposits in tissues. […] The average risk of progression is approximately 1% per year.

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

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

  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. […] The occurrence of a non-traumatic fracture in the context of MGUS requires careful assessment by a hematologist with access to cross-sectional imaging and a bone marrow biopsy to exclude a myeloma-defining event. Furthermore, the occurrence of these fractures in the context of MGUS does not herald progression to MM. […] The most serious complication of MGRS is end-stage renal disease (ESRD) and the comorbidities it entails. In a retrospective study of 37 patients with MGRS, it was found that 22% of patients eventually progressed to ESRD at a mean follow-up of 30.3 months.

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

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

  The wide spectrum of MGRS combined with the high prevalence of MGUS and chronic kidney disease, which in turn may be due to other medical conditions such as hypertension and diabetes mellitus, may complicate and delay the accurate diagnosis of MGRS. Thus, it is imperative that a concurrent hematologic and renal evaluation be performed in those who are suspected of having MGRS. […] The increase in risk was not influenced by the paraprotein isotype but was positively correlated with the M-protein concentration. […] The current standard of care for patients with MGUS or SMM is observation, and during this time, it is important to remember routine vaccination against common infectious diseases during routine follow-up care, so-called ‘watch, wait, and vaccinate’.

• #18

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

  In June 2010, the IMWG released consensus guidelines for monitoring and managing patients with MGUS and smoldering myeloma. […] If the serum monoclonal protein is 15 g/L, IgG type, and the free light chain ratio is normal, then the risk of eventual progression to multiple myeloma or related malignancy is low. […] However, patients that fall in the intermediate and high risk MGUS category are managed differently. […] An estimated 20,580 new cases of multiple myeloma were diagnosed in the United States in 2009. Median survival is about 3 to 4 years following diagnosis, although survival has improved with newer therapies such as autologous stem cell transplantation, immunomodulatory drugs, and proteosome inhibitors. […] According to the current IMWG guidelines, MGUS and smoldering myeloma should not be treated outside of clinical trials. […] Patients with smoldering myeloma have a relatively high rate of progression to multiple myeloma at 10% yearly.

• #19 The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group | Nature Reviews Nephrology

  https://www.nature.com/articles/s41581-018-0077-4

  The occurrence of kidney diseases associated with a monoclonal gammopathy in the absence of symptomatic MM, WM or CLL is increasingly recognized. Most of these patients have a small, low-grade clonal disorder that is similar to MGUS, although (unlike MGUS) these clones do cause vital organ damage including neuropathy, cardiomyopathy, hepatic dysfunction and dermopathy mediated by the monoclonal immunoglobulin. The clonal aetiology of these diseases results in clinical features that differ from those of non-monoclonal gammopathies, such as membranous nephropathy or IgA nephropathy. For example, monoclonal immunoglobulin-related diseases tend to be progressive and are unlikely to undergo spontaneous remission. Monoclonal immunoglobulin-related diseases also show higher rates of recurrence after kidney transplantation (often 80%) than their non-monoclonal counterparts.

• #20 The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group | Nature Reviews Nephrology

  https://www.nature.com/articles/s41581-018-0077-4

  The new IKMG consensus definition of MGRS includes all B cell or plasma cell proliferative disorders (such as SMM, SWM and monoclonal B cell lymphocytosis (MBL; a diagnosis that is the equivalent of MGUS for clones of the CLL lineage)) that produce a nephrotoxic monoclonal immunoglobulin. Low-grade CLL and low-grade B cell non-Hodgkin lymphomas, such as marginal zone lymphoma, mantle-cell lymphoma or mucosa-associated lymphoid tissue (MALT) lymphoma are also considered to be MGRS when they are associated with renal lesions. These low-grade proliferative disorders would be classified as MGUS, and affected patients would be monitored for progression but not offered treatment if not for the renal injury. In patients who develop renal lesions as a result of the monoclonal immunoglobulin, therapeutic intervention is required to prevent further damage resulting in end-stage renal disease.

• #21 The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group | Nature Reviews Nephrology

  https://www.nature.com/articles/s41581-018-0077-4

  MGRS is a new classification of pathogenic clonal proliferative disorders that produce a nephrotoxic protein. The term MGRS was needed to improve the classification of these diseases for research purposes, and to accurately categorize them as pathological, so that government agencies could allocate the resources necessary for their treatment. The diagnosis of MGRS can be established only by performing a kidney biopsy that either demonstrates the presence of monotypic immunoglobulin deposits or infers their involvement in the case of C3 glomerulonephritis or thrombotic microangiopathy with a circulating monoclonal immunoglobulin. Detection of a monoclonal immunoglobulin, in addition to helping to establish the diagnosis of MGRS, has diagnostic and prognostic value and is also used to predict treatment responses.

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