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.

Prevalence of smoldering multiple myeloma based on nationwide screening

An Author Correction to this article was published on 20 March 2023

This article has been updated

Abstract

Smoldering multiple myeloma (SMM) is an asymptomatic precursor to multiple myeloma. Here we define the epidemiological characteristics of SMM in the general population in Iceland. The iStopMM study (ClinicalTrials.gov ID: NCT03327597) is a nationwide screening study for multiple myeloma precursors where all residents in Iceland 40 years or older were invited to participate. SMM was defined as 10–60% bone marrow plasma cells and/or monoclonal (M) protein concentration ≥3 g dl−1, in the absence of myeloma-defining events. Of the 80,759 who gave informed consent to participate, 75,422 (93%) were screened. The prevalence of SMM in the total population was 0.53% (95% confidence interval (CI) = 0.49–0.57%) in individuals 40 years or older. In men and women, the prevalence of SMM was 0.67% (95% CI = 0.62–0.73%) and 0.39% (95% CI = 0.35–0.43%), respectively; it increased with age in both sexes. For the 193 individuals with SMM, median age was 70 years (range 44–92 years) and 60% were males. The mean M protein concentration of individuals with SMM was 0.62 g dl−1 (range 0.01–3.5 g dl−1) and 73% had 11–20% bone marrow plasma cell infiltration. The high prevalence of SMM has implications for future treatment policies in multiple myeloma as the evidence supporting treatment initiation at the SMM stage is emerging.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Fig. 1: The iStopMM study design.
Fig. 2: Estimated prevalence of SMM by age in the population over 40 years old, using fitted values stratified by sex.

Data availability

EuroFlow developed and validated a multiple myeloma MRD database containing representative flow cytometry datasets from normal healthy bone marrow samples processed in different standardized centers. The database (available through Infinicyt), when used with files that follow standardized operating procedures, allows for an automated analysis of the complete bone marrow sample (https://www.cytognos.com/euroflow-databases/resources/multiple-myeloma/). Due to Icelandic law on ethics in research, data privacy regulations and per informed consent from participants in this study, the patient-level data used for this study cannot be shared. We encourage researchers or parties interested in collaboration for noncommercial use to apply to the corresponding author. The request will be reviewed by the iStopMM team to verify whether data sharing is within the restrictions of the study’s ethical approval.

Code availability

The code used to generate the main results in this paper is publicly available on GitHub (https://github.com/blodskimun/SMM_prevalence).

Change history

References

  1. Kyle, R. A. & Greipp, P. R. Smoldering multiple myeloma. N. Engl. J. Med. 302, 1347–1349 (1980).

    Article  CAS  PubMed  Google Scholar 

  2. Rajkumar, S. V. et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 15, e538–e548 (2014).

    Article  PubMed  Google Scholar 

  3. Kyle, R. A. et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N. Engl. J. Med. 356, 2582–2590 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Kristinsson, S. Y., Holmberg, E. & Blimark, C. Treatment for high-risk smoldering myeloma. N. Engl. J. Med. 369, 1762–1763 (2013).

    Article  CAS  PubMed  Google Scholar 

  5. Cowan, A. J. et al. Global burden of multiple myeloma: a systematic analysis for the global burden of disease study 2016. JAMA Oncol. 4, 1221–1227 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Kyle, R. A. 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 24, 1121–1127 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Pérez-Persona, E. 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 110, 2586–2592 (2007).

    Article  PubMed  Google Scholar 

  8. Dispenzieri, A. et al. Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. Blood 111, 785–789 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mateos, M.-V. et al. International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM). Blood Cancer J. 10, 102 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Rajkumar, S. V., Landgren, O. & Mateos, M.-V. Smoldering multiple myeloma. Blood 125, 3069–3075 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lakshman, A. et al. Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer J. 8, 59 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Mateos, M.-V. et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N. Engl. J. Med. 369, 438–447 (2013).

    Article  CAS  PubMed  Google Scholar 

  13. Mateos, M.-V. et al. Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): long-term follow-up of a randomised, controlled, phase 3 trial. Lancet Oncol. 17, 1127–1136 (2016).

    Article  CAS  PubMed  Google Scholar 

  14. Lonial, S. et al. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J. Clin. Oncol. 38, 1126–1137 (2020).

    Article  CAS  PubMed  Google Scholar 

  15. Kumar, S. K. et al. Multiple Myeloma, Version 3.2021, NCCN Clinical Practice Guidelines in Oncology. J. Natl Compr. Canc. Netw. 18, 1685–1717 (2020).

    Article  CAS  PubMed  Google Scholar 

  16. Lonial, S., Rajkumar, S. V. & Mateos, M. V. Risk stratified management approaches for smouldering multiple myeloma: clinical research becomes clinical practice. Lancet Haematol. 9, e162–e165 (2022).

    Article  CAS  PubMed  Google Scholar 

  17. Sigurdardottir, E. E. et al. The role of diagnosis and clinical follow-up of monoclonal gammopathy of undetermined significance on survival in multiple myeloma. JAMA Oncol. 1, 168–174 (2015).

    Article  PubMed  Google Scholar 

  18. Go, R. S., Gundrum, J. D. & Neuner, J. M. Determining the clinical significance of monoclonal gammopathy of undetermined significance: a SEER-Medicare population analysis.Clin. Lymphoma Myeloma Leuk. 15, 177–186.e4 (2015).

    Article  PubMed  Google Scholar 

  19. Rögnvaldsson, S. et al. 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. Blood Cancer J. 11, 94 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Sørrig, R. et al. Smoldering multiple myeloma risk factors for progression: a Danish population-based cohort study. Eur. J. Haematol. 97, 303–309 (2016).

    Article  PubMed  Google Scholar 

  21. Kyle, R. A. et al. Long-term follow-up of monoclonal gammopathy of undetermined significance. N. Engl. J. Med. 378, 241–249 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Miguel, J. S. et al. Updated risk stratification model for smoldering multiple myeloma (SMM) incorporating the revised IMWG diagnostic criteria. J. Clin. Oncol. 37, 8000 (2019).

    Article  Google Scholar 

  23. Hill, E. et al. Assessment of discordance among smoldering multiple myeloma risk models. JAMA Oncol. 7, 132–134 (2021).

    Article  PubMed  Google Scholar 

  24. Maura, F. et al. Moving from cancer burden to cancer genomics for smoldering myeloma: a review. JAMA Oncol. 6, 425–432 (2019).

    Article  Google Scholar 

  25. Maura, F., Landgren, O. & Morgan, G. J. Designing evolutionary based interception strategies to block the transition from precursor phases to multiple myeloma. Clin. Cancer Res. 27, 15–23 (2021).

    Article  CAS  PubMed  Google Scholar 

  26. Landgren, O. Advances in MGUS diagnosis, risk stratification, and management: introducing myeloma-defining genomic events. Hematology Am. Soc. Hematol. Educ. Program 2021, 662–672 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Landgren, O. et al. Prevalence of monoclonal gammopathy of undetermined significance among men in Ghana. Mayo Clin. Proc. 82, 1468–1473 (2007).

    Article  PubMed  Google Scholar 

  28. Iwanaga, M., Tagawa, M., Tsukasaki, K., Kamihira, S. & Tomonaga, M. Prevalence of monoclonal gammopathy of undetermined significance: study of 52,802 persons in Nagasaki City, Japan. Mayo Clin. Proc. 82, 1474–1479 (2007).

    Article  PubMed  Google Scholar 

  29. Dimopoulos, M. A., Kastritis, E. & Terpos, E. Non-secretory myeloma: one, two, or more entities? Oncology 27, 930–932 (2013).

    PubMed  Google Scholar 

  30. Mohyuddin, G. R., Ouchveridze, E., Goodman, A. & Prasad, V. The landscape of trials for smoldering multiple myeloma: endpoints, trial design, and lessons learnt. Leuk. Lymphoma 62, 2793–2795 (2021).

    Article  PubMed  Google Scholar 

  31. Musto, P. et al. 2021 European Myeloma Network review and consensus statement on smoldering multiple myeloma: how to distinguish (and manage) Dr. Jekyll and Mr. Hyde. Haematologica 106, 2799–2812 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kapoor, P. & Rajkumar, S. V. Smoldering multiple myeloma: to treat or not to treat. Cancer J. 25, 65–71 (2019).

    Article  PubMed  Google Scholar 

  33. Flores-Montero, J. et al. Next generation flow for highly sensitive and standardized detection of minimal residual disease in multiple myeloma. Leukemia 31, 2094–2103 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The iStopMM study is funded by the Black Swan Research Initiative by the International Myeloma Foundation and the Icelandic Centre for Research (grant no. 173857). This project also received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant no. 716677), the International Myeloma Society, the Paula and Rodger Riney Foundation Translational Research Award and the Leukemia & Lymphoma Society Career Development Program Scholar in Clinical Research Award. Screening tests were performed by The Binding Site. Additional funding was provided by the University of Iceland, Landspítali University Hospital and the Icelandic Cancer Society. The funders had no role in study design, data collection, data analysis, data interpretation or manuscript writing. We thank all the participants in the iStopMM study.

Author information

Authors and Affiliations

Authors

Contributions

S.Y.K., O.L. and S.H. developed the iStopMM study. S.T., G.K.G. and T.A. performed the statistical analysis. J.Þ.Ó. performed the flow cytometry analysis. S.T., S.R., G.A.S., T.J.L. and Á.Þ. contributed to the practical design of the iStopMM study. B.V., P.T.Ö., B.A.A. and M.S. assessed the biopsy material from patients with SMM. I.Þ. and Í.Ó. performed the SPEP analysis. E.E. and Á.J. assessed the WBLDCT images. O.B. and S.H. participated in the initial screening analysis. M.H., B.G.M.D., T.J.L., S.H., O.L., S.Y.K. and S.T. contributed to the scientific design of the study. S.T. wrote the original manuscript. S.Y.K. supervised the work. All authors reviewed and approved the manuscript.

Corresponding author

Correspondence to Sigurður Y. Kristinsson.

Ethics declarations

Competing interests

O.B. and S.H. are currently employed by The Binding Site. The other authors declare no competing interests.

Peer review

Peer review information

Nature Medicine thanks Dickran Kazandjian, Roberto Mina, Niels Abildgaard and Ingemar Turesson for their contribution to the peer review of this work. Primary Handling Editor: Ming Yang, in collaboration with the Nature Medicine team.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Thorsteinsdóttir, S., Gíslason, G.K., Aspelund, T. et al. Prevalence of smoldering multiple myeloma based on nationwide screening. Nat Med 29, 467–472 (2023). https://doi.org/10.1038/s41591-022-02183-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41591-022-02183-6

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing