Advances in the Diagnosis, Classification, Risk Stratification, and Management of Monoclonal Gammopathy of Undetermined Significance: Implications for Recategorizing Disease Entities in the Presence of Evolving Scientific Evidence

Rajkumar, S. Vincent; Kyle, Robert A.; Buadi, Francis K.

doi:10.4065/mcp.2010.0520

Cited by 103 publications

(62 citation statements)

References 37 publications

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“…13 Each subtype seems to follow its own biologic dictums while displaying individualistic clinical tendencies. A number of studies have allowed researchers to investigate the natural history of each MGUS subtype on an individual categorical basis.…”

Section: Distinct Clinical Subtypes Of Mgus and Smmmentioning

confidence: 99%

“…3 The equivalent of SMM found in IgM and light-chain monoclonal gammopathies is smoldering Waldenström macroglobulinemia and idiopathic Bence Jones proteinuria, respectively (Table 1). 13 …”

Section: Distinct Clinical Subtypes Of Mgus and Smmmentioning

confidence: 99%

“…(Reprinted with permission. 13 ) for MGUS or SMM. Aggressive disease monitoring is based on whether patients fit into MGUS or SMM precursor disease and the above-outlined risk factors in the Mayo Clinic model and Spanish study group model (Table 2).…”

Section: Light-chain Mgusmentioning

confidence: 99%

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Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): novel biological insights and development of early treatment strategies

Korde

Kristinsson

Landgren

2011

Blood

174

144

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Monoclonal gammopathy of unknown significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic plasma cell dyscrasias, with a propensity to progress to symptomatic MM. In recent years there have been improvements in risk stratification models (involving molecular markers) of both disorders, which have led to better understanding of the biology and probability of progression of MGUS and SMM. In the context of numerous molecular events and heterogeneous risk of progression, developing individualized risk profiles for patients with MGUS and SMM represents an ongoing challenge that has to be addressed by prospective clinical monitoring and extensive correlative science. In this review we discuss the current standard of care of patients with MGUS and SMM, the use of risk models, including flow cytometry and free-light chain analyses, for predicting risk of progression. Emerging evidence from molecular studies on MGUS and SMM, involving cytogenetics, geneexpression profiling, and microRNA as well as molecular imaging is described. IntroductionMultiple myeloma is a malignant neoplasm of plasma cells in the bone marrow associated with an overproduction of monoclonal (M)-protein often causing characteristic osteolytic lesions, anemia, renal failure, and hypercalcemia. 1 In contrast, monoclonal gammopathy of unknown significance (MGUS) is an asymptomatic plasma cell dyscrasia that is present in more than 3% of the general white population older than age 50 and has an average multiple myeloma progression risk of 1% per year. 2 Smoldering multiple myeloma (SMM) is another asymptomatic plasma cell disorder but carries a higher risk of progression to frank multiple myeloma (10% per year the first 5 years) compared with MGUS. 3 Indeed, both MGUS and SMM represent the quintessential model for studying multiple myeloma precursor disease, and to develop early intervention strategies.The etiology of MGUS remains unclear and it is a current topic of investigation. Race seems to play a role given the observation that prevalence of MGUS is 2-to 3-fold higher in AfricanAmericans and blacks from Africa compared with whites. 4,5 Other identified risk factors for MGUS include older age, male sex, exposure to pesticides, and family history of MGUS or MM. 2,6,7 Thus, previous studies support a role for both genetic and environmental factors in the development of multiple myeloma and its precursor states. 8 Two independent studies have demonstrated that most cases of multiple myeloma are preceded by MGUS. In the Prostate, Colorectal, Lung and Ovarian Cancer Screening Trial, annual serum samples were collected from 77 469 healthy donors prospectively. Among 71 patients who during a 10-year follow-up time developed multiple myeloma, serum samples consistently demonstrated MGUS in the years before the malignant diagnosis. 9 Another study, based on the Department of Defense Serum Repository, showed a very similar finding. 10 Current clinical practice relies on careful surveillance as the cornerstone for management of multiple myel...

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Section: Distinct Clinical Subtypes Of Mgus and Smmmentioning

confidence: 99%

Section: Distinct Clinical Subtypes Of Mgus and Smmmentioning

confidence: 99%

See 1 more Smart Citation

Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): novel biological insights and development of early treatment strategies

Korde

Kristinsson

Landgren

2011

Blood

174

144

View full text Add to dashboard Cite

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“…4 There are 3 types of MGUS with distinct natural histories: nonIgM-(IgG or IgA)-MGUS, IgM-MGUS, and light-chain-MGUS. 5,6 Although IgG and IgA-and light-chain-MGUS typically progress to MM or develop light chain amyloidosis, IgM-MGUS cases more often progress to WM or other NHLs.…”

Section: Introductionmentioning

confidence: 99%

Monoclonal gammopathy of undetermined significance and risk of lymphoid and myeloid malignancies: 728 cases followed up to 30 years in Sweden

Turesson

Kovalchik

Pfeiffer

et al. 2014

Blood

120

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• Free light chain ratio, M-protein concentration, and immunosuppression predict progression of MGUS to lymphoid malignancies.In 728 Swedish cases of monoclonal gammopathy of undetermined significance (MGUS), followed up to 30 years (median, 10 years), we estimated the cumulative risk of hematologic disorders originating from lymphoid and myeloid lineages. Using Cox regression models, we examined associations of demographic and laboratory factors with progression and determined the discriminatory power of 3 prediction models for progression. Eighty-four MGUS cases developed a lymphoid disorder, representing a cumulative risk of 15.4%. Multiple myeloma (MM) occurred in 53 patients, and the 30-year cumulative risk was 10.6%; an ∼0.5% annual risk. Three factors were significantly associated with progression: abnormal free light-chain (FLC) ratio (<0.26 or >1.65), M-protein concentration ( ‡1.5 g/dL), and reduction of 1 or 2 noninvolved immunoglobulin isotype levels (immunoparesis). A prediction model with separate effects for these 3 factors and the M-protein isotype had higher discriminatory power than other models, although the differences were not statistically significant. The 30-year cumulative risk for myeloid malignancies was <2%. Our study confirms that abnormal FLC ratio and M-protein concentration >1.5 g/dL, factors previously considered by Mayo Clinic researchers, are predictors for MM progression and suggests that separate consideration of immunoparesis and the Mayo Clinic risk factors could improve identification of MGUS patients at high risk for progression. (Blood. 2014;123(3):338-345) Continuing Medical Education online This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and the American Society of Hematology. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians. Medscape, LLC designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at http://www.medscape.org/journal/blood; and (4) view/print certificate. For CME questions, see page 457. Disclosures The authors, Associate Editor A. Keith Stewart, and CME questions author Laurie Barclay, freelance writer and reviewer, Medscape, LLC, declare no competing financial interests. Learning objectives 1. Describe the risk for hematologic disorders originating from lymphoid and myeloid lineages in patients with monoclonal gammopathy of undetermined significance (MGUS), based on a long-term follow-up study.2. ...

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“…The isotype affects the likelihood of an MGUS progressing; individuals with non-IgG M-proteins have a greater likelihood of developing MM than those with IgG M-proteins [5,6]. Further, information about isotype and electrophoretic migration position is needed when following response to therapy so that one may distinguish relapse of the original clone from the development of oligoclonal bands and/or a second (usually reactive) M-protein.…”

Section: Introductionmentioning

confidence: 99%

Challenges of measuring monoclonal proteins in serum

Keren

Schroeder

2016

Clinical Chemistry and Laboratory Medicine (CCLM)

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Abstract:The measurement of monoclonal protein (M-protein) is vital for stratifying risk and following individuals with a variety of monoclonal gammopathies. Direct measurement of the M-protein spike by electrophoresis and immunochemical measurements of specific isotypes or free light chains pairs has provided useful information about the quantity of M-protein. Nonetheless, both traditional electrophoresis and immunochemical methods give poor quantification with M-proteins smaller than 10 g/L (1 g/dL) when in the presence of polyclonal immunoglobulins that co-migrate with the M-protein. In addition, measurements by electrophoresis of M-proteins migrating in the β-and α-regions are contaminated by normal serum proteins in those regions. The most precise electrophoretic method to date for quantification involves exclusion of the polyclonal immunoglobulins by using the tangent skimming method on electropherograms, which provides a 10-fold improvement in precision. So far, however, tangent measurements are limited to γ migrating M-proteins. Another way to improve M-protein measurements is the use of capillary electrophoresis (CE). With CE, one can employ immunosubtraction to select a region of interest in the β region thereby excluding much of the normal proteins from the M-protein measurement. Recent development of an immunochemical method distinguishing heavy/light chain pairs (separately measuring IgGK and IgGL, IgAK and IgAL, and IgMK and IgML) provides measurements that could exclude polyclonal contaminants of the same heavy chain with the uninvolved light chain type. Yet, even heavy/light results contain an immeasurable quantity of polyclonal heavy/ light chains of the involved isotype. Finally, use of liquid chromatography-tandem mass spectrometry (LC-MS/MS) looms on the horizon as a means to provide more consistent and sensitive measurements of M-proteins.

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Advances in the Diagnosis, Classification, Risk Stratification, and Management of Monoclonal Gammopathy of Undetermined Significance: Implications for Recategorizing Disease Entities in the Presence of Evolving Scientific Evidence

Cited by 103 publications

References 37 publications

Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): novel biological insights and development of early treatment strategies

Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): novel biological insights and development of early treatment strategies

Monoclonal gammopathy of undetermined significance and risk of lymphoid and myeloid malignancies: 728 cases followed up to 30 years in Sweden

Challenges of measuring monoclonal proteins in serum

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