Long-Term Follow-up of Monoclonal Gammopathy of Undetermined Significance
Open accessAbstract
BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) occurs in approximately 3% of persons 50 years of age or older. METHODS: We studied 1384 patients who were residing in southeastern Minnesota and in whom MGUS was diagnosed at the Mayo Clinic in the period from 1960 through 1994; the median follow-up was 34.1 years (range, 0.0 to 43.6). The primary end point was progression to multiple myeloma or another plasma-cell or lymphoid disorder. RESULTS: During 14,130 person-years of follow-up, MGUS progressed in 147 patients (11%), a rate that was 6.5 times (95% confidence interval [CI], 5.5 to 7.7) as high as the rate in the control population. The risk of progression without accounting for death due to competing causes was 10% at 10 years, 18% at 20 years, 28% at 30 years, 36% at 35 years, and 36% at 40 years. Among patients with IgM MGUS, the presence of two adverse risk factors - namely, 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) - was associated with a risk of progression at 20 years of 55%, as compared with 41% among patients who had one adverse risk factor and 19% among patients who had neither risk factor. Among patients with non-IgM MGUS, the risk of progression at 20 years was 30% among those who had the two risk factors, 20% among those who had one risk factor, and 7% among those who had neither risk factor. Patients with MGUS had shorter survival than was expected in the control population of Minnesota residents of matched age and sex (median, 8.1 vs. 12.4 years; P<0.001). CONCLUSIONS: Significant differences were noted in the risk of progression between patients with IgM MGUS and those with non-IgM MGUS. Overall survival was shorter among patients with MGUS than was expected in a matched control population. (Funded by the National Cancer Institute.).
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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 [4]
The Results section (page not provided) shows that MGUS can progress to multiple myeloma or related disorders over decades, supporting a slow-development interpretation. It does not measure how long symptoms or organ damage take to appear, and its progression rates concern MGUS rather than the growth of an established myeloma tumor. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAll cases of multiple myeloma are preceded by precursor conditions such as smoldering multiple myeloma and monoclonal gammopathy of undetermined significance, often decades before diagnosis.
“MM is well-described to be universally preceded by precursor states, often decades before it is even diagnosed.”
From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [4]
The Discussion identifies non-IgM MGUS as a condition that can progress to multiple myeloma, and the Results document progression during long-term follow-up. But this study followed people already diagnosed with MGUS; it does not establish that every myeloma case had a precursor state or that precursor states often existed decades before myeloma diagnosis. No page numbers were provided in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPatients 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 [4]
The Results section (page unavailable) reports MGUS progression over decades: cumulative risks of 10% at 10 years and 18% at 20 years, with many patients not progressing during follow-up. The Discussion says the duration-related pattern for IgM MGUS is analogous to a previous report on smoldering multiple myeloma (SMM), but this paper does not establish the claimed two-year timeframe for either group. Its reported progression outcomes also include disorders other than multiple myeloma. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMGUS advances to multiple myeloma or a related malignancy at roughly 1% per year.
“MGUS progresses to multiple myeloma or related malignancy a rate of 1% per year.16,17”
From Multiple myeloma: 2024 update on diagnosis, risk-stratification, and management (2024) · cites this paper as [17]
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- Authors
- Kyle, R. A., Larson, D. R., Therneau, T. M., Dispenzieri, A., Kumar, S., Cerhan, J. R., & Rajkumar, S. V.
- Affiliations
- Mayo Clinic (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2018-01-18
- Volume
- 378
- Issue
- 3
- Pages
- 241-249
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC5852672
- OpenAlex
- W2785817645
- Cited by
- 647
- References
- 30
- Citations by year
- 2026: 62 · 2025: 90 · 2024: 101 · 2023: 81 · 2022: 75 · 2021: 76 · 2020: 80 · 2019: 47 · 2018: 33 · 2017: 1 · 2016: 1
- FWCI
- 42.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA107476, CA168762, CA186781)
- 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, progression to multiple myeloma, plasma cell dyscrasia, free light chain ratio, risk factors, survival, long-term follow-up
- MeSH terms
- Adult, Aged, Bone Marrow Examination, Female, Follow-Up Studies, Glycoproteins, Humans, Immunoglobulin M, Immunoglobulin Light Chains, Male, Middle Aged, Monoclonal Gammopathy of Undetermined Significance, Multiple Myeloma, Prognosis, Risk Factors, Proportional Hazards Models, Disease Progression
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