CoChat
Sign Up
Cited by 1,127Multiple Myeloma Research and TreatmentsChronic Lymphocytic Leukemia ResearchAmyloidosis: Diagnosis, Treatment, Outcomes

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

Open access
Landgren, Ola, Kyle, Robert A., Pfeiffer, Ruth M., Katzmann, Jerry A., Caporaso, Neil E., Hayes, Richard B., Dispenzieri, Angela, Kumar, Shaji +4 more·2009·Blood
DOI 10.1182/blood-2008-12-194241PMC PMC2689042
Open this paper in CoChat — free account

Abstract

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

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1182/blood-2008-12-194241

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Multiple myeloma does not develop rapidly; symptoms and organ damage may take decades to manifest.

    “This tumor does not develop rapidly; instead, it may take decades for symptoms and organ damage to manifest.4-8”

    From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [6]

    The Discussion (page unavailable) reports a prolonged premalignant stage, with detectable M-protein eight or more years before diagnosis, and notes that MGUS-associated myeloma risk persists after 25–35 years. The Introduction describes MGUS as asymptomatic. These passages support slow development, but the paper does not establish that symptoms and organ damage take decades to manifest. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Monoclonal proteins are present in a significant fraction of healthy individuals, and later studies confirmed their universal presence before the development of multiple myeloma.

    “Interestingly, these proteins were found in a significant fraction of healthy individuals and later studies confirmed their universal presence before the development of MM.6”

    From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [6]

    The Introduction reports MGUS in 3.2% of the white general population aged 50 or older, supporting the claim that monoclonal proteins occur in a significant fraction of otherwise healthy people. The Results and Discussion say an asymptomatic MGUS stage consistently preceded multiple myeloma in this study, but they do not establish universal presence of detectable M-proteins: only 64 of 71 subjects (90.1%) were ever found to have one before diagnosis. The paper's MGUS definition also includes an abnormal free-light-chain ratio without a detected M-protein. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Patients with MGUS and SMM might experience progression to multiple myeloma over an extremely variable timeframe, with some progressing within 2 years, others after 10 to 20 years, or never.

    “Several epidemiological studies have shown that patients with MGUS and SMM might experience progression to MM over an extremely variable timeframe. Some patients progressed to MM within 2 years of diagnosis, while others may progress after 10 to 20 years or might never progress at all.4-6,75”

    From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [6]

    The Discussion (page unavailable) says MGUS progression risk varies greatly, that most people with MGUS never develop MM, and that risk persists over decades. It does not address SMM or establish progression within 2 years of diagnosis; its 2-year figure refers to serum samples collected before MM diagnosis, not time since MGUS diagnosis. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 21

  1. [1]Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med. 2004;351:1860–1873. doi: 10.1056/NEJMra041875. [DOI] [PubMed] [Google Scholar] · DOI
  2. [2]Anonymous. Atlanta, GA: American Cancer Society; 2008. Cancer Facts & Figures 2008. [Google Scholar]
  3. [4]Anonymous. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003;121:749–757. [PubMed] [Google Scholar]
  4. [5]Kyle RA. Monoclonal gammopathy of undetermined significance: natural history in 241 cases. Am J Med. 1978;64:814–826. doi: 10.1016/0002-9343(78)90522-3. [DOI] [PubMed] [Google Scholar] · DOI
  5. [6]Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. 2002;346:564–569. doi: 10.1056/NEJMoa01133202. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  6. [7]Prorok PC, Andriole GL, Bresalier RS, et al. Design of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Control Clin Trials. 2000;21:273S–309S. doi: 10.1016/s0197-2456(00)00098-2. [DOI] [PubMed] [Google Scholar] · DOI
  7. [8]Hayes RB, Sigurdson A, Moore L, et al. Methods for etiologic and early marker investigations in the PLCO trial. Mutat Res. 2005;592:147–154. doi: 10.1016/j.mrfmmm.2005.06.013. [DOI] [PubMed] [Google Scholar] · DOI
  8. [9]Katzmann JA, Clark RJ, Abraham RS, et al. Serum reference intervals and diagnostic ranges for free kappa and free lambda immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains. Clin Chem. 2002;48:1437–1444. [PubMed] [Google Scholar]
  9. [10]Drayson M, Tang LX, Drew R, Mead GP, Carr-Smith H, Bradwell AR. Serum free light-chain measurements for identifying and monitoring patients with nonsecretory multiple myeloma. Blood. 2001;97:2900–2902. doi: 10.1182/blood.v97.9.2900. [DOI] [PubMed] [Google Scholar] · DOI
  10. [11]Kyle RA, Katzmann JA, Lust JA, Dispenzieri A. Immunochemical characterization of immunoglobulins. In: Rose NR, Hamilton RG, Detrik B, editors. Manual of Clinical Laboratory Immunology. Washington, DC: ASM Press; 2002. pp. 71–91. [Google Scholar]
  11. [12]Rajkumar SV, Kyle RA, Therneau TM, et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood. 2005;106:812–817. doi: 10.1182/blood-2005-03-1038. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  12. [13]Zeger SL, Liang KY. Longitudinal data analysis for discrete and continuous outcomes. Biometrics. 1986;42:121–130. [PubMed] [Google Scholar]
  13. [14]Kyle RA, Therneau TM, Rajkumar SV, et al. Long-term follow-up of IgM monoclonal gammopathy of undetermined significance. Blood. 2003;102:3759–3764. doi: 10.1182/blood-2003-03-0801. [DOI] [PubMed] [Google Scholar] · DOI
  14. [15]Landgren O, Gridley G, Turesson I, et al. Risk of monoclonal gammopathy of undetermined significance (MGUS) and subsequent multiple myeloma among African American and white veterans in the United States. Blood. 2006;107:904–906. doi: 10.1182/blood-2005-08-3449. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  15. [16]Landgren O, Kyle RA. Multiple myeloma, chronic lymphocytic leukaemia and associated precursor diseases. Br J Haematol. 2007;139:717–723. doi: 10.1111/j.1365-2141.2007.06866.x. [DOI] [PubMed] [Google Scholar] · DOI
  16. [17]Bergsagel PL, Kuehl WM, Zhan F, Sawyer J, Barlogie B, Shaughnessy J., Jr Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood. 2005;106:296–303. doi: 10.1182/blood-2005-01-0034. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  17. [18]Kuehl WM, Bergsagel PL. Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer. 2002;2:175–187. doi: 10.1038/nrc746. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  18. [19]Zhan F, Barlogie B, Arzoumanian V, et al. Gene-expression signature of benign monoclonal gammopathy evident in multiple myeloma is linked to good prognosis. Blood. 2007;109:1692–1700. doi: 10.1182/blood-2006-07-037077. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  19. [20]Bladé J, Rosinol L, Cibeira MT, de Larrea CF. Pathogenesis and progression of monoclonal gammopathy of undetermined significance. Leukemia. 2008;22:1651–1657. doi: 10.1038/leu.2008.203. [DOI] [PubMed] [Google Scholar] · DOI
  20. [21]Rosiñol L, Cibeira MT, Montoto S, et al. Monoclonal gammopathy of undetermined significance: predictors of malignant transformation and recognition of an evolving type characterized by a progressive increase in M protein size. Mayo Clin Proc. 2007;82:428–434. doi: 10.4065/82.4.428. [DOI] [PubMed] [Google Scholar] · DOI
  21. [22]Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC. Advances in biology of multiple myeloma: clinical applications. Blood. 2004;104:607–618. doi: 10.1182/blood-2004-01-0037. [DOI] [PubMed] [Google Scholar] · DOI

Cited by

Sorted by citations

Authors
Landgren, O., Kyle, R. A., Pfeiffer, R. M., Katzmann, J. A., Caporaso, N. E., Hayes, R. B., Dispenzieri, A., Kumar, S., Clark, R. J., Baris, D., Hoover, R., & Rajkumar, S. V.
Affiliations
  • National Institutes of Health (US)
  • Mayo Clinic (US)
  • Division of Cancer Epidemiology and Genetics (US)
  • Division of Hematology and Internal Medicine, and
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2009-05-28
Volume
113
Issue
22
Pages
5412-5417
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood-2008-12-194241
PMC
PMC2689042
OpenAlex
W2031157863
Cited by
1,127
References
1
Citations by year
2026: 38 · 2025: 54 · 2024: 84 · 2023: 49 · 2022: 78 · 2021: 93 · 2020: 79 · 2019: 74 · 2018: 70 · 2017: 68 · 2016: 60 · 2015: 61 · 2014: 66 · 2013: 64 · 2012: 55
FWCI
41.32
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute (CA6 2242, CA 107476 03, P01CA062242)
Topics
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Amyloidosis: Diagnosis, Treatment, Outcomes
Keywords
monoclonal gammopathy of undetermined significance, multiple myeloma, progression to multiple myeloma, monoclonal protein, free light chains, long-term monitoring, PLCO Cancer Screening Trial, progression markers
MeSH terms
Adult, Aged, Aged, 80 and over, Diagnosis, Differential, Female, Humans, Immunoglobulins, Male, Middle Aged, Multiple Myeloma, Paraproteinemias, Precancerous Conditions, Time Factors, Prevalence, Early Detection of Cancer

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review