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Prevalence of smoldering multiple myeloma based on nationwide screening

Nature Medicine volume 29, pages 467–472 (2023)Cite this article

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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.

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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

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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.

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Authors and Affiliations

  1. Faculty of Medicine, University of Iceland, Reykjavík, Iceland

    Sigrún Thorsteinsdóttir, Gauti K. Gíslason, Sæmundur Rögnvaldsson, Jón Þórir Óskarsson, Guðrún Á Sigurðardóttir, Ásdís R. Þórðardóttir, Thorvardur J. Löve & Sigurður Y. Kristinsson

  2. Department of Hematology, Rigshospitalet, Copenhagen, Denmark

    Sigrún Thorsteinsdóttir

  3. Public Health Sciences, University of Iceland, Reykjavík, Iceland

    Thor Aspelund

  4. Landspítali University Hospital, Reykjavík, Iceland

    Brynjar Viðarsson, Páll T. Önundarson, Bjarni A. Agnarsson, Margrét Sigurðardóttir, Ingunn Þorsteinsdóttir, Ísleifur Ólafsson, Elías Eyþórsson, Ásbjörn Jónsson & Sigurður Y. Kristinsson

  5. The Binding Site, Birmingham, UK

    Oscar Berlanga & Stephen Harding

  6. Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Malin Hultcrantz

  7. Cedars-Sinai Samual Oschin Cancer Center, Los Angeles, CA, USA

    Brian G. M. Durie

  8. Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA

    Ola Landgren

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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.

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Competing interests

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

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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.

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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

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