{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T23:12:57Z","timestamp":1792624377896,"version":"4.5.0"},"reference-count":48,"publisher":"American Medical Association (AMA)","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Intern Med"],"published-print":{"date-parts":[[2025,4,1]]},"abstract":"<jats:sec id=\"ab-irv240001-1\"><jats:title>Importance<\/jats:title><jats:p>Nearly 5% of adults have the precursor malignant condition monoclonal gammopathy of unknown significance (MGUS). Management centers on differentiating MGUS from more serious conditions to determine additional diagnostic testing, monitoring, and potential therapy.<\/jats:p><\/jats:sec><jats:sec id=\"ab-irv240001-2\"><jats:title>Observations<\/jats:title><jats:p>MGUS is defined by the absence of end-organ damage or symptoms, a small amount of monoclonal immunoglobulin (M protein), and low volume of plasma cells. MGUS must be distinguished from overt malignant diseases like multiple myeloma (MM), immunoglobulin light-chain (AL) amyloidosis, and monoclonal gammopathy of clinical significance (MGCS), all of which cause organ damage or symptoms. Although testing for M proteins is often prompted by clinical findings (eg, osteoporosis or autoimmune disease), recent evidence from screened populations suggests that previous MGUS disease associations were likely overestimated and that testing for M proteins should be reserved for when malignant disease or MGCS is suspected. Risk of progression to malignant disease ranges from 0.5% to 1%, meaning most patients have indolent disease. Guideline-concordant management of MGUS is determined by predicted risk of progression to malignant disease, which depends on subtype of immunoglobulin, M protein concentration, and free light chain ratio. Patients with low-risk MGUS can safely defer bone marrow biopsy and advanced imaging, and should undergo periodic laboratory monitoring. Intermediate- and high-risk MGUS should trigger bone marrow biopsy and bone imaging to detect overt MM and shorter monitoring intervals. Advanced molecular testing may improve on current risk stratification to target monitoring and treatment to those with highest risk of malignant progression and avoid overtreatment of those with low-risk disease. Management will also be informed by results of several clinical trials to clarify the risks and benefits of screening, optimal monitoring strategy, predictors of progression, and potential preventive or curative therapies.<\/jats:p><\/jats:sec><jats:sec id=\"ab-irv240001-3\"><jats:title>Conclusions and Relevance<\/jats:title><jats:p>Evidence-based management of MGUS currently rests on separating clinically indolent from high-risk precursor disease. Research using novel detection methods, incorporating molecular testing into risk stratification, and evaluating screening, monitoring, and therapeutic or lifestyle interventions has the potential to improve outcomes.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamainternmed.2024.8124","type":"journal-article","created":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T16:33:07Z","timestamp":1739809987000},"page":"450","source":"Crossref","is-referenced-by-count":40,"title":["Diagnosis and Management of Monoclonal Gammopathy of Undetermined Significance"],"prefix":"10.1001","volume":"185","author":[{"given":"Yuxin","family":"Liu","sequence":"first","affiliation":[{"name":"Division of Hematologic Oncology, Dana Farber Cancer Institute, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna L.","family":"Parks","sequence":"additional","affiliation":[{"name":"Division of Hematology & Hematologic Malignancies, University of Utah, Salt Lake City"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"issue":"3","key":"irv240001r1","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1056\/NEJMoa1709974","article-title":"Long-term follow-up of monoclonal gammopathy of undetermined significance.","volume":"378","author":"Kyle","year":"2018","journal-title":"N Engl J Med"},{"issue":"9727","key":"irv240001r2","doi-asserted-by":"publisher","first-page":"1721","DOI":"10.1016\/S0140-6736(10)60482-5","article-title":"Prevalence and risk of progression of light-chain monoclonal gammopathy of undetermined significance: a retrospective population-based cohort study.","volume":"375","author":"Dispenzieri","year":"2010","journal-title":"Lancet"},{"issue":"12","key":"irv240001r3","doi-asserted-by":"publisher","first-page":"e538","DOI":"10.1016\/S1470-2045(14)70442-5","article-title":"International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma.","volume":"15","author":"Rajkumar","year":"2014","journal-title":"Lancet Oncol"},{"issue":"2","key":"irv240001r4","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1002\/ajh.26796","article-title":"Waldenstr\u00f6m macroglobulinemia: 2023 update on diagnosis, risk stratification, and management.","volume":"98","author":"Gertz","year":"2023","journal-title":"Am J Hematol"},{"issue":"6","key":"irv240001r5","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1038\/leu.2010.60","article-title":"Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management.","volume":"24","author":"Kyle","year":"2010","journal-title":"Leukemia"},{"issue":"1","key":"irv240001r6","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1001\/jama.2020.5493","article-title":"Systemic amyloidosis recognition, prognosis, and therapy: a systematic review.","volume":"324","author":"Gertz","year":"2020","journal-title":"JAMA"},{"issue":"14","key":"irv240001r7","doi-asserted-by":"publisher","first-page":"1478","DOI":"10.1182\/blood-2018-04-839480","article-title":"Monoclonal gammopathy of clinical significance: a novel concept with therapeutic implications.","volume":"132","author":"Fermand","year":"2018","journal-title":"Blood"},{"key":"irv240001r8","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1111\/j.0954-6820.1963.tb17460.x","article-title":"Frequency of \u201cabnormal\u201d serum globulins (M-components) in the aged.","volume":"173","author":"Hallen","year":"1963","journal-title":"Acta Med Scand"},{"issue":"2","key":"irv240001r9","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1111\/j.0954-6820.1966.tb05453.x","article-title":"Frequency of pathological proteins (M-components) om 6,995 sera from an adult population.","volume":"179","author":"Axelsson","year":"1966","journal-title":"Acta Med Scand"},{"issue":"5","key":"irv240001r10","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1182\/blood.V40.5.719.719","article-title":"Incidence of monoclonal proteins in a Minnesota community with a cluster of multiple myeloma.","volume":"40","author":"Kyle","year":"1972","journal-title":"Blood"},{"issue":"13","key":"irv240001r11","doi-asserted-by":"publisher","first-page":"1362","DOI":"10.1056\/NEJMoa054494","article-title":"Prevalence of monoclonal gammopathy of undetermined significance.","volume":"354","author":"Kyle","year":"2006","journal-title":"N Engl J Med"},{"issue":"4","key":"irv240001r12","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1111\/j.1600-0609.1992.tb01584.x","article-title":"Occurrence of monoclonal components in general practice: clinical implications.","volume":"48","author":"Aguzzi","year":"1992","journal-title":"Eur J Haematol"},{"issue":"1","key":"irv240001r13","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1136\/jcp.35.1.63","article-title":"Monoclonal gammopathies in the adult population of Finist\u00e8re, France.","volume":"35","author":"Saleun","year":"1982","journal-title":"J Clin Pathol"},{"issue":"12","key":"irv240001r14","doi-asserted-by":"publisher","first-page":"1474","DOI":"10.1016\/S0025-6196(11)61090-2","article-title":"Prevalence of monoclonal gammopathy of undetermined significance: study of 52,802 persons in Nagasaki City, Japan.","volume":"82","author":"Iwanaga","year":"2007","journal-title":"Mayo Clin Proc"},{"issue":"12","key":"irv240001r15","doi-asserted-by":"publisher","first-page":"1468","DOI":"10.1016\/S0025-6196(11)61089-6","article-title":"Prevalence of monoclonal gammopathy of undetermined significance among men in Ghana.","volume":"82","author":"Landgren","year":"2007","journal-title":"Mayo Clin Proc"},{"issue":"7","key":"irv240001r16","doi-asserted-by":"publisher","first-page":"1537","DOI":"10.1038\/leu.2014.34","article-title":"Racial disparities in the prevalence of monoclonal gammopathies: a population-based study of 12,482 persons from the National Health and Nutritional Examination Survey.","volume":"28","author":"Landgren","year":"2014","journal-title":"Leukemia"},{"issue":"3","key":"irv240001r17","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1182\/blood-2005-08-3449","article-title":"Risk of monoclonal gammopathy of undetermined significance (MGUS) and subsequent multiple myeloma among African American and white veterans in the United States.","volume":"107","author":"Landgren","year":"2006","journal-title":"Blood"},{"issue":"2","key":"irv240001r18","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1056\/NEJMoa0708704","article-title":"Familial myeloma.","volume":"359","author":"Lynch","year":"2008","journal-title":"N Engl J Med"},{"issue":"4","key":"irv240001r19","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1182\/blood-2008-12-191676","article-title":"Risk of plasma cell and lymphoproliferative disorders among 14621 first-degree relatives of 4458 patients with monoclonal gammopathy of undetermined significance in Sweden.","volume":"114","author":"Landgren","year":"2009","journal-title":"Blood"},{"issue":"16","key":"irv240001r20","doi-asserted-by":"publisher","first-page":"2513","DOI":"10.1182\/blood-2013-10-532283","article-title":"Inherited genetic susceptibility to monoclonal gammopathy of unknown significance.","volume":"123","author":"Weinhold","year":"2014","journal-title":"Blood"},{"issue":"8","key":"irv240001r21","doi-asserted-by":"publisher","first-page":"1517","DOI":"10.1373\/clinchem.2009.126664","article-title":"Screening panels for detection of monoclonal gammopathies.","volume":"55","author":"Katzmann","year":"2009","journal-title":"Clin Chem"},{"issue":"4","key":"irv240001r22","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1093\/clinchem\/47.4.673","article-title":"Highly sensitive, automated immunoassay for immunoglobulin free light chains in serum and urine.","volume":"47","author":"Bradwell","year":"2001","journal-title":"Clin Chem"},{"issue":"4","key":"irv240001r23","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1309\/AJCPT6OWWMHITA1Y","article-title":"Laboratory persistence and clinical progression of small monoclonal abnormalities.","volume":"138","author":"Murray","year":"2012","journal-title":"Am J Clin Pathol"},{"issue":"5","key":"irv240001r24","doi-asserted-by":"publisher","first-page":"e340","DOI":"10.1016\/S2352-3026(22)00069-2","article-title":"Prevalence of monoclonal gammopathies and clinical outcomes in a high-risk US population screened by mass spectrometry: a multicentre cohort study.","volume":"9","author":"El-Khoury","year":"2022","journal-title":"Lancet Haematol"},{"issue":"6","key":"irv240001r25","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1515\/cclm-2015-1023","article-title":"Monoclonal antibody therapeutics as potential interferences on protein electrophoresis and immunofixation.","volume":"54","author":"Willrich","year":"2016","journal-title":"Clin Chem Lab Med"},{"key":"irv240001r26","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1182\/blood-2023-188547","article-title":"Revised definition of free light chains in serum and light chain monoclonal gammopathy of undetermined significance: results of the Istopmm Study.","volume":"142","author":"Einarsson Long","year":"2023","journal-title":"Blood"},{"issue":"9","key":"irv240001r27","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1038\/s41408-022-00732-3","article-title":"Defining new reference intervals for serum free light chains in individuals with chronic kidney disease: Results of the iStopMM study.","volume":"12","author":"Long","year":"2022","journal-title":"Blood Cancer J"},{"issue":"6","key":"irv240001r28","doi-asserted-by":"publisher","first-page":"711","DOI":"10.7326\/M23-2867","article-title":"Association between autoimmune diseases and monoclonal gammopathy of undetermined significance.","volume":"177","author":"Sverrisdottir","year":"2024","journal-title":"Ann Intern Med"},{"issue":"24","key":"irv240001r29","doi-asserted-by":"publisher","first-page":"4991","DOI":"10.1182\/blood-2009-11-252072","article-title":"Arterial and venous thrombosis in monoclonal gammopathy of undetermined significance and multiple myeloma: a population-based study.","volume":"115","author":"Kristinsson","year":"2010","journal-title":"Blood"},{"issue":"15","key":"irv240001r30","doi-asserted-by":"publisher","first-page":"2651","DOI":"10.1182\/blood-2010-04-282848","article-title":"Monoclonal gammopathy of undetermined significance and risk of skeletal fractures: a population-based study.","volume":"116","author":"Kristinsson","year":"2010","journal-title":"Blood"},{"issue":"9","key":"irv240001r31","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1001\/jamaoncol.2023.2278","article-title":"Mortality in the US populations with monoclonal gammopathy of undetermined significance.","volume":"9","author":"Ji","year":"2023","journal-title":"JAMA Oncol"},{"issue":"4S","key":"irv240001r32","first-page":"S1","article-title":"KDIGO 2021 clinical practice guideline for the management of glomerular diseases.","volume":"100","author":"Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group","year":"2021","journal-title":"Kidney Int"},{"issue":"12","key":"irv240001r33","doi-asserted-by":"crossref","first-page":"3392","DOI":"10.3324\/haematol.2023.283191","article-title":"Disease associations with monoclonal gammopathy of undetermined significance can only be evaluated using screened cohorts: results from the population-based iStopMM study.","volume":"108","author":"Sigurbergsd\u00f3ttir","year":"2023","journal-title":"Haematologica"},{"issue":"13","key":"irv240001r34","doi-asserted-by":"crossref","first-page":"2620","DOI":"10.1182\/blood-2011-04-347484","article-title":"Multiple myeloma-related deregulation of bone marrow-derived CD34(+) hematopoietic stem and progenitor cells.","volume":"120","author":"Bruns","year":"2012","journal-title":"Blood"},{"issue":"8","key":"irv240001r35","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1002\/(SICI)1097-0142(19971015)80:8+<1546::AID-CNCR4>3.0.CO;2-I","article-title":"Mechanisms of bone metastasis.","volume":"80","author":"Mundy","year":"1997","journal-title":"Cancer"},{"issue":"3","key":"irv240001r36","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1182\/blood-2005-03-1038","article-title":"Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance.","volume":"106","author":"Rajkumar","year":"2005","journal-title":"Blood"},{"issue":"12","key":"irv240001r37","doi-asserted-by":"crossref","first-page":"ITC177","DOI":"10.7326\/AITC202212200","article-title":"Monoclonal gammopathy of undetermined significance.","volume":"175","author":"Gonsalves","year":"2022","journal-title":"Ann Intern Med"},{"issue":"23","key":"irv240001r38","doi-asserted-by":"crossref","first-page":"2484","DOI":"10.1182\/blood.2019846782","article-title":"Monoclonal gammopathy of undetermined significance.","volume":"133","author":"Mouhieddine","year":"2019","journal-title":"Blood"},{"issue":"2","key":"irv240001r39","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1182\/blood-2017-09-807560","article-title":"How I manage monoclonal gammopathy of undetermined significance.","volume":"131","author":"Go","year":"2018","journal-title":"Blood"},{"issue":"3","key":"irv240001r40","doi-asserted-by":"crossref","first-page":"e203","DOI":"10.1016\/S2352-3026(22)00386-6","article-title":"Personalised progression prediction in patients with monoclonal gammopathy of undetermined significance or smouldering multiple myeloma (PANGEA): a retrospective, multicohort study.","volume":"10","author":"Cowan","year":"2023","journal-title":"Lancet Haematol"},{"issue":"4","key":"irv240001r41","doi-asserted-by":"crossref","first-page":"449","DOI":"10.7326\/M23-2540","article-title":"Development of a multivariable model to predict the need for bone marrow sampling in persons with monoclonal gammopathy of undetermined significance.","volume":"177","author":"Eythorsson","year":"2024","journal-title":"Ann Intern Med"},{"issue":"1","key":"irv240001r42","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1182\/hematology.2021000303","article-title":"Advances in MGUS diagnosis, risk stratification, and management: introducing myeloma-defining genomic events.","volume":"2021","author":"Landgren","year":"2021","journal-title":"Hematology Am Soc Hematol Educ Program"},{"key":"irv240001r43","doi-asserted-by":"crossref","DOI":"10.1016\/j.blre.2024.101242","article-title":"From MGUS to multiple myeloma: Unraveling the unknown of precursor states.","volume":"68","author":"Hevroni","year":"2024","journal-title":"Blood Rev"},{"issue":"1","key":"irv240001r44","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1111\/j.1365-2141.2009.07807.x","article-title":"UK Myeloma Forum (UKMF) and Nordic Myeloma Study Group (NMSG): guidelines for the investigation of newly detected M-proteins and the management of monoclonal gammopathy of undetermined significance (MGUS).","volume":"147","author":"Bird","year":"2009","journal-title":"Br J Haematol"},{"issue":"6","key":"irv240001r45","doi-asserted-by":"crossref","first-page":"984","DOI":"10.3324\/haematol.2013.100552","article-title":"The clinical relevance and management of monoclonal gammopathy of undetermined significance and related disorders: recommendations from the European Myeloma Network.","volume":"99","author":"van de Donk","year":"2014","journal-title":"Haematologica"},{"issue":"5","key":"irv240001r46","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1038\/s41408-021-00480-w","article-title":"Iceland screens, treats, or prevents multiple myeloma (iStopMM): a population-based screening study for monoclonal gammopathy of undetermined significance and randomized controlled trial of follow-up strategies.","volume":"11","author":"R\u00f6gnvaldsson","year":"2021","journal-title":"Blood Cancer J"},{"issue":"3","key":"irv240001r47","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.clml.2014.09.004","article-title":"Determining the clinical significance of monoclonal gammopathy of undetermined significance: a SEER-Medicare population analysis.","volume":"15","author":"Go","year":"2015","journal-title":"Clin Lymphoma Myeloma Leuk"},{"issue":"12","key":"irv240001r48","doi-asserted-by":"crossref","first-page":"2019","DOI":"10.1182\/blood-2010-04-277566","article-title":"Impact of optimal follow-up of monoclonal gammopathy of undetermined significance on early diagnosis and prevention of myeloma-related complications.","volume":"116","author":"Bianchi","year":"2010","journal-title":"Blood"}],"container-title":["JAMA Internal Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamainternalmedicine\/articlepdf\/2830017\/jamainternal_liu_2025_rv_240001_1743791950.63974.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T19:50:10Z","timestamp":1744055410000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamainternalmedicine\/fullarticle\/2830017"}},"subtitle":["A Review"],"short-title":[],"issued":{"date-parts":[[2025,4,1]]},"references-count":48,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,4,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamainternmed.2024.8124","relation":{},"ISSN":["2168-6106"],"issn-type":[{"value":"2168-6106","type":"print"}],"subject":[],"published":{"date-parts":[[2025,4,1]]}}}