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.

  • Article
  • Published:

Evolving M-protein pattern in patients with smoldering multiple myeloma: impact on early progression

Leukemia volume 32, pages 1427–1434 (2018)Cite this article

Subjects

Abstract

Smoldering multiple myeloma (SMM) is a biologically heterogeneous, clinically defined entity with a variable rate of progression to symptomatic multiple myeloma (MM). Reliable markers for progression are critical for the development of potential therapeutic interventions. We retrospectively evaluated the predictive value of the evolving pattern of serum M-protein among other progression risk factors in 206 patients with SMM diagnosed between 1973 and 2012. Median time from recognition of evolving type to progression into symptomatic MM was 1.1 years (95% CI 0.5–2.0) and progression rate at 3 years was 71%. Development of the evolving type drastically worsened the prognostic estimation made at diagnosis for every covariate predictive of progression (serum M-protein size, bone marrow plasma cell infiltration, immunoparesis and Mayo Clinic risk). On average, the hazard ratio for progression to symptomatic MM increased to 5.1 (95% CI 3.4–7.6) after recognition of the evolving type. In conclusion, in patients with SMM the evolving pattern accurately predicts the risk of early progression to symptomatic disease, thereby allowing the identification of ultra-high risk patients who would be candidates for immediate therapy.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Kyle RA, Durie BG, 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;24:1121–27.

    Article  PubMed  CAS  Google Scholar 

  2. Ravindran A, Bartley AC, Holton SJ, Gonsalves WI, Kapoor P, Siddiqui MA, et al. Prevalence, incidence and survival of smoldering multiple myeloma in the United States. Blood Cancer J. 2016;6:e486.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003;121:749–57.

    Article  Google Scholar 

  4. Bladé J, Dimopoulos M, Rosiñol L, Rajkumar SV, Kyle RA. Smoldering (asymptomatic) multiple myeloma: current diagnostic criteria, new predictors of outcome, and follow-up recommendations. J Clin Oncol. 2010;28:690–97.

    Article  PubMed  CAS  Google Scholar 

  5. Kyle RA, Remstein ED, Therneau TM, Dispenzieri A, Kurtin P, Hodnefield J, et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med. 2007;356:2582–90.

    Article  PubMed  CAS  Google Scholar 

  6. Dispenzieri A, Kyle RA, Katzmann JA, Therneau TM, Larson D, Benson J, et al. Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. Blood. 2008;111:785–89.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Pérez-Persona E, Vidriales MB, Mateo G, García-Sanz R, Mateos MV, de Coca AG, 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;110:2586–92.

    Article  PubMed  CAS  Google Scholar 

  8. Pérez-Persona E, Mateo G, García-Sanz R, Mateos MV, de Las Heras N, de Coca AG, et al. Risk of progression in smouldering myeloma and monoclonal gammopathies of unknown significance: comparative analysis of the evolution of the monoclonal component and multiparameter flow cytometry of bone marrow plasma cells. Br J Haematol. 2010;148:110–14.

    Article  PubMed  Google Scholar 

  9. Cherry BM, Korde N, Kwok M, Manasanch EE, Bhutani M, Mulquin M, et al. Modeling progression risk for smoldering multiple myeloma: results from a prospective clinical study. Leuk Lymphoma. 2013;54:2215–18.

    Article  PubMed  Google Scholar 

  10. Rosiñol L, Bladé J, Esteve J, Aymerich M, Rozman M, Montoto S, et al. Smoldering multiple myeloma: natural history and recognition of an evolving type. Br J Haematol. 2003;123:631–36.

    Article  PubMed  Google Scholar 

  11. Rosiñol L, Cibeira MT, Montoto S, Rozman M, Esteve J, Filella X, 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;82:428–34.

    Article  PubMed  Google Scholar 

  12. Grambsch PM, Therneau TM. Proportional Hazards Tests and Diagnostics based on Weighted Residuals. Biometrika. 1994;81:515–26.

    Article  Google Scholar 

  13. Schultz LR, Peterson EL, Breslau N. Graphing survival curve estimates for time-dependent covariates. Int J Methods Psychiatr Res. 2002;11:68–74.

    Article  PubMed  Google Scholar 

  14. Kyle RA, Greipp PR. Smoldering multiple myeloma. N Engl J Med. 1980;302:1347–49.

    Article  PubMed  CAS  Google Scholar 

  15. Rosiñol L, Carrió A, Bladé J, Queralt R, Aymerich M, Cibeira MT, et al. Comparative genomic hybridization identifies two variants of smoldering multiple myeloma. Br J Haematol. 2005;130:729–32.

    Article  PubMed  CAS  Google Scholar 

  16. Ravi P, Kumar S, Larsen JT, Gonsalves W, Buadi F, Lacy MQ, et al. Evolving changes in disease biomarkers and risk of early progression in smoldering multiple myeloma. Blood Cancer J. 2016;6:e454.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Kyle RA, Therneau TM, Rajkumar SV, Offord JR, Larson DR, Plevak MF, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. 2002;346:564–69.

    Article  PubMed  Google Scholar 

  18. Rajkumar SV, Landgren O, Mateos MV. Smoldering multiple myeloma. Blood. 2015;125:3069–75.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013;369:438–47.

    Article  PubMed  CAS  Google Scholar 

  20. Caers J, Fernández de Larrea C, Leleu X, Heusschen R, Zojer N, Decaux O, et al. The Changing landscape of smoldering multiple myeloma: a European perspective. Oncologist. 2016;21:333–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Dhodapkar MV, Sexton R, Waheed S, Usmani S, Papanikolaou X, Nair B, et al. Clinical, genomic, and imaging predictors of mieloma progression from asymptomatic monoclonal gammopathies (SWOG S0120). Blood. 2014;123:78–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Gonsalves WI, Rajkumar SV, Dispenzieri A, Dingli D, Timm MM, Morice WG, et al. Quantification of circulating clonal plasma cells via multiparametric flow cytometry identifies patients with smoldering multiple myeloma at high risk of progression. Leukemia. 2016;31:130–35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Katzmann JA, Rajkumar SV. A window into immunoglobulin quantitation and plasma cell disease: antigen epitopes defined by the junction of immunoglobulin heavy and light chains. Leukemia. 2013;27:1–2.

    Article  PubMed  CAS  Google Scholar 

  24. Magnano L, Fernández de Larrea C, Elena M, Cibeira MT, Tovar N, Aróstegui JI, Pedrosa F, et al. Prognostic impact of serum heavy/light chain pairs in patients with monoclonal gammopathy of undetermined significance and smoldering myeloma: long-term results from a single institution. Clin Lymphoma Myeloma Leuk. 2016;16:e71–7.

    Article  PubMed  Google Scholar 

  25. Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538–48.

    Article  PubMed  Google Scholar 

  26. Rajkumar SV, Larson D, Kyle RA. Diagnosis of smoldering multiple myeloma. N Engl J Med. 2011;365:474–75.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Larsen JT, Kumar SK, Dispenzieri A, Kyle RA, Katzmann JA, Rajkumar SV. Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma. Leukemia. 2013;27:941–46.

    Article  PubMed  CAS  Google Scholar 

  28. Hillengass J, Fechtner K, Weber MA, Bäuerle T, Ayyaz S, Heiss C, et al. Prognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic multiple myeloma. J Clin Oncol. 2010;28:1606–10.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Esther Bladé for her technical support in this research. This work has been supported in part by grants PI16/0423 and PI12/1093 from Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa” and 2014SGR-552 from Agència de Gestió d’Ajuts Universitaris i de Recerca (Generalitat de Catalunya).

Author contributions

C.F.L. and I.I. designed the study, collected and analyzed data, performed statistical analysis, wrote and reviewed the paper; A.P. analyzed data, performed statistical analysis, wrote and reviewed the paper; M.C., L.G.L.R., and N.T. collected data and reviewed the paper; X.C. and L.M. collected data, reviewed bone marrow aspirates and reviewed the paper; M.R. reviewed bone marrow aspirates and reviewed the paper; J.I.A., E.L., T.D., and J.Y. collected data, performed laboratory assays and reviewed the paper; L.R. and J.B. analyzed data and reviewed the paper.

Author information

Author notes

    Authors and Affiliations

    1. Department of Hematology, Amyloidosis and Myeloma Unit, Hospital Clínic, IDIBAPS, University of Barcelona, Villarroel 170, 08036, Barcelona, Spain

      Carlos Fernández de Larrea, Ignacio Isola, Ma Teresa Cibeira, Natalia Tovar, Luis-Gerardo Rodríguez-Lobato, Tania Díaz, Ester Lozano, Joan Bladé & Laura Rosiñol

    2. Department of Hemotherapy and Hemostasis, Hospital Clínic, IDIBAPS, University of Barcelona, Villarroel 170, 08036, Barcelona, Spain

      Arturo Pereira

    3. Department of Hematopathology, Hospital Clínic, IDIBAPS, University of Barcelona, Villarroel 170, 08036, Barcelona, Spain

      Laura Magnano, Xavier Calvo & María Rozman

    4. Department of Immunology, Amyloidosis and Myeloma Unit, Hospital Clínic, IDIBAPS, University of Barcelona, Villarroel 170, 08036, Barcelona, Spain

      Juan I. Aróstegui & Jordi Yagüe

    Authors
    1. Carlos Fernández de Larrea
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Ignacio Isola
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Arturo Pereira
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Ma Teresa Cibeira
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Laura Magnano
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Natalia Tovar
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Luis-Gerardo Rodríguez-Lobato
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Xavier Calvo
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Juan I. Aróstegui
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Tania Díaz
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Ester Lozano
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. María Rozman
      View author publications

      You can also search for this author in PubMed Google Scholar

    13. Jordi Yagüe
      View author publications

      You can also search for this author in PubMed Google Scholar

    14. Joan Bladé
      View author publications

      You can also search for this author in PubMed Google Scholar

    15. Laura Rosiñol
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Joan Bladé.

    Ethics declarations

    Conflict of interest

    The authors declare that they have no conflict of interest.

    Additional information

    Carlos Fernández de Larrea and Ignacio Isola contributed equally to this work

    Electronic supplementary material

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Fernández de Larrea, C., Isola, I., Pereira, A. et al. Evolving M-protein pattern in patients with smoldering multiple myeloma: impact on early progression. Leukemia 32, 1427–1434 (2018). https://doi.org/10.1038/s41375-018-0013-4

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1038/s41375-018-0013-4

    This article is cited by

    Search

    Advanced search

    Quick links