Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Myeloma

Suppression of uninvolved immunoglobulins defined by heavy/light chain pair suppression is a risk factor for progression of MGUS

Leukemia volume 27, pages 208–212 (2013)Cite this article

Subjects

Abstract

We hypothesized that the suppression of uninvolved immunoglobulin in monoclonal gammopathy of undetermined significance (MGUS) as detected by suppression of the isotype-specific heavy and light chain (HLC-pair suppression) increases the risk of progression to malignancy. This approach required quantitation of individual heavy/light chains (for example, IgGλ in IgGκ MGUS patients). Of 1384 MGUS patients from Southeastern Minnesota seen at the Mayo Clinic from 1960 to 1994, baseline serum samples obtained within 30 days of diagnosis were available in 999 persons. We identified HLC-pair suppression in 27% of MGUS patient samples compared with 11% of patients with suppression of uninvolved IgG, IgA or IgM. HLC-pair suppression was a significant risk factor for progression (hazard ratio (HR), 2.3; 95% confidence interval (CI) 1.5–3.7; P<0.001). On multivariate analysis, HLC-pair suppression was an independent risk factor for progression to malignancy in combination with serum M-spike size, heavy chain isotype and free light chain ratio (HR, 1.8; 95% CI, 1.1–3.00; P=0.018). The finding that HLC-pair suppression predicts progression in MGUS and occurs several years before malignant transformation has implications for myeloma biology.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Offord JR et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med 2006; 354: 1362–1369.

    Article  CAS  Google Scholar 

  2. Landgren O, Kyle RA, Pfeiffer RM, Katzmann JA, Caporaso NE, Hayes RE et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood 2009; 113: 5412–5417.

    Article  CAS  Google Scholar 

  3. Weiss BM, Abadie J, Verma P, Howard RS, Kuehl WM . A monoclonal gammopathy precedes multiple myeloma in most patients. Blood 2009; 113: 5418–5422.

    Article  CAS  Google Scholar 

  4. Kyle RA, Therneau TM, Rajkumar SV, Offord JR, Larson DR, Plevak MF et al. A long-term study of prognosis of monoclonal gammopathy of undetermined significance. N Engl J Med 2002; 346: 564–569.

    Article  Google Scholar 

  5. Cesana C, Klersy C, Barbarano L, Nosari AM, Crugnola M, Pungolino E et al. Prognostic factors for malignant transformation in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. J Clin Oncol 2002; 20: 1625–1634.

    Article  Google Scholar 

  6. Rajkumar SV, Kyle RA, Therneau TM, Melton LJ, Bradwell AR, Clark RJ et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance (MGUS). Blood 2005; 106: 812–817.

    Article  CAS  Google Scholar 

  7. Kyle RA, Rajkumar SV . Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia 2009; 23: 3–9.

    Article  CAS  Google Scholar 

  8. Pérez-Persona E, María-Belén V, Mateo G, Garcia-Sanz R, Mateos M-V, Garcia de Coca A et al. New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells. Blood 2007; 110: 2586–2592.

    Article  Google Scholar 

  9. Bradwell AR, Harding SJ, Fourrier NJ, Wallis GLF, Drayson MT, Carr-Smith HD et al. Assessment of monoclonal gammopathies by nephelometric measurement of individual immunoglobulin kappa/lambda ratios. Clin Chem 2009; 55: 1646–1655.

    Article  CAS  Google Scholar 

  10. Kaplan E, Meier P . Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.

    Article  Google Scholar 

  11. Cox DR . Regression models and life tables. J R Stat Soc 1972; 34: 187–202.

    Google Scholar 

  12. Gooley TA, Leisenring W, Crowley J, Storer BE . Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med 1999; 18: 695–706.

    Article  CAS  Google Scholar 

  13. Kyle RA . Monoclonal gammopathy of undetermined significance. Natural history in 241 cases. Am J Med 1978; 64: 814–826.

    Article  CAS  Google Scholar 

  14. Kyle RA, Durie BGM, Rajkumar SV, Landgren O, Blade J, Merlini G et al. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia 2010; 24: 1121–1127.

    Article  CAS  Google Scholar 

  15. Bianchi G, Kyle RA, Colby CL, Larson DR, Kumar S, Katzmann JA et al. Impact of optimal follow-up of monoclonal gammopathy of undetermined significance (MGUS) on early diagnosis and prevention of myeloma-related complications. Blood 2010; 116: 2019–2025.

    Article  CAS  Google Scholar 

  16. Ward ES, Zhou J, Ghetie V, Ober RJ . Evidence to support the cellular mechanism involved in serum IgG homeostasis in humans. Int Immunol 2003; 15: 187–195.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported in part by the National Cancer Institute (CA107476, CA100707, CA83724), National Institutes of Health, US Public Health Service, Bethesda, MD and in part by the Jabbs Foundation, Birmingham, UK and the Henry J Predolin Foundation, USA.

Author contributions

JAK, SVR, RAK, ARB and AD designed the research. RC generated the data. DRL, TMT, JTB and CLC analyzed the data. JAK, SVR, LJM, OL, JRC, AD, SK and RAK wrote and edited the manuscript. All authors reviewed and approved the final manuscript.

Author information

Authors and Affiliations

  1. Division of Clinical Biochemistry and Immunology, Department of Laboratory Medicine, Mayo Clinic, Rochester, MN, USA

    J A Katzmann & R Clark

  2. Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA

    R A Kyle, A Dispenzieri, S Kumar & S V Rajkumar

  3. Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA

    D R Larson, T M Therneau, J T Benson & C L Colby

  4. Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA

    L J Melton III & J R Cerhan

  5. Multiple Myeloma Section, National Cancer Institute, Bethesda, MD, USA

    O Landgren

  6. The Binding Site, Birmingham, UK

    A R Bradwell

Authors
  1. J A Katzmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R Clark
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R A Kyle
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D R Larson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T M Therneau
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L J Melton III
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J T Benson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C L Colby
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A Dispenzieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. O Landgren
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. S Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. A R Bradwell
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. J R Cerhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. S V Rajkumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J A Katzmann.

Ethics declarations

Competing interests

Dr Bradwell is the founder of the Binding Site, manufacturer of the Hevylite assay and has a financial investment in the company. Dr Kyle has received honoraria from The Binding Site for educational lectures. None of the other authors have conflicts of interest pertinent to this manuscript.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Katzmann, J., Clark, R., Kyle, R. et al. Suppression of uninvolved immunoglobulins defined by heavy/light chain pair suppression is a risk factor for progression of MGUS. Leukemia 27, 208–212 (2013). https://doi.org/10.1038/leu.2012.189

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2012.189

Keywords

This article is cited by

Search

Advanced search

Quick links