Advertisement

Risk Stratification in Newly Diagnosed Smoldering Multiple Myeloma

  • María-Victoria MateosEmail author
  • Jesús San-Miguel
Chapter

Abstract

Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by the presence of ≥3 g/dL serum M-protein and/or 10–60% bone marrow plasma cell infiltration with no myeloma-defining event. The risk of progression to active MM is not uniform, and several markers are useful for identifying patients at high risk of progression. The definition of the disease has recently been revisited, and asymptomatic MMs at 80–90% of progression risk at 2 years are now considered to be active MMs candidates for treatment. Although the current standard of care is not to treat, a randomized trial in high-risk SMM patients comparing early treatment versus observation has shown a significant benefit in terms of time to progression and overall survival for early intervention. These findings highlight the need for both more precise biomarkers for accurate risk stratification in order to plan an optimized follow-up according to the risk of progression, as well as confirmatory clinical trials in order to establish whether or not early treatment should become standard of care in high-risk SMM.

Keywords

Smoldering myeloma MGUS Risk stratification Lenalidomide Thalidomide Bisphosphonates Flow cytometry Positron emission tomography-computed tomography (PET-CT) Magnetic resonance imaging (MRI) 

References

  1. 1.
    Kyle RA, Greipp PR. Smoldering multiple myeloma. N Engl J Med. 1980;302(24):1347–9. doi: 10.1056/NEJM198006123022405.CrossRefPubMedGoogle Scholar
  2. 2.
    Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, Kumar S, Hillengass J, Kastritis E, Richardson P, Landgren O, Paiva B, Dispenzieri A, Weiss B, LeLeu X, Zweegman S, Lonial S, Rosinol L, Zamagni E, Jagannath S, Sezer O, Kristinsson SY, Caers J, Usmani SZ, Lahuerta JJ, Johnsen HE, Beksac M, Cavo M, Goldschmidt H, Terpos E, Kyle RA, Anderson KC, Durie BG, Miguel JF. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014b;15(12):e538–48. doi: 10.1016/s1470-2045(14)70442-5.CrossRefPubMedGoogle Scholar
  3. 3.
    Kristinsson SY, Holmberg E, Blimark C. Treatment for high-risk smoldering myeloma. N Engl J Med. 2013;369(18):1762–3. doi: 10.1056/NEJMc1310911#SA1.CrossRefPubMedGoogle Scholar
  4. 4.
    Blade J, Dimopoulos M, Rosinol 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(4):690–7. doi: 10.1200/JCO.2009.22.2257.CrossRefPubMedGoogle Scholar
  5. 5.
    Hillengass J, Fechtner K, Weber MA, Bauerle T, Ayyaz S, Heiss C, Hielscher T, Moehler TM, Egerer G, Neben K, Ho AD, Kauczor HU, Delorme S, Goldschmidt H. Prognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic multiple myeloma. J Clin Oncol. 2010;28(9):1606–10. doi: 10.1200/JCO.2009.25.5356.CrossRefPubMedGoogle Scholar
  6. 6.
    Kastritis E, Moulopoulos LA, Terpos E, Koutoulidis V, Dimopoulos MA. The prognostic importance of the presence of more than one focal lesion in spine MRI of patients with asymptomatic (smoldering) multiple myeloma. Leukemia. 2014;28(12):2402–3. doi: 10.1038/leu.2014.230.CrossRefPubMedGoogle Scholar
  7. 7.
    Rajkumar SV, Larson D, Kyle RA. Diagnosis of smoldering multiple myeloma. N Engl J Med. 2011;365(5):474–5. doi: 10.1056/NEJMc1106428.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Kastritis E, Terpos E, Moulopoulos L, Spyropoulou-Vlachou M, Kanellias N, Eleftherakis-Papaiakovou E, Gkotzamanidou M, Migkou M, Gavriatopoulou M, Roussou M, Tasidou A, Dimopoulos MA. Extensive bone marrow infiltration and abnormal free light chain ratio identifies patients with asymptomatic myeloma at high risk for progression to symptomatic disease. Leukemia. 2012;27(4):947–53.CrossRefPubMedGoogle Scholar
  9. 9.
    Waxman AJ, Mick R, Garfall AL, Cohen A, Vogl DT, Stadtmauer EA, Weiss BM. Classifying ultra-high risk smoldering myeloma. Leukemia. 2014. doi: 10.1038/leu.2014.313.
  10. 10.
    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(4):941–6. doi: 10.1038/leu.2012.296.CrossRefPubMedGoogle Scholar
  11. 11.
    Kyle RA, Remstein ED, Therneau TM, Dispenzieri A, Kurtin PJ, Hodnefield JM, Larson DR, Plevak MF, Jelinek DF, Fonseca R, Melton LJ 3rd, Rajkumar SV. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med. 2007;356(25):2582–90. doi: 10.1056/NEJMoa070389.CrossRefPubMedGoogle Scholar
  12. 12.
    Dispenzieri A, Kyle RA, Katzmann JA, Therneau TM, Larson D, Benson J, Clark RJ, Melton LJ 3rd, Gertz MA, Kumar SK, Fonseca R, Jelinek DF, Rajkumar SV. Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. Blood. 2008;111(2):785–9. doi: 10.1182/blood-2007-08-108357.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Sorrig R, Klausen TW, Salomo M, Vangsted AJ, Ostergaard B, Gregersen H, Frolund UC, Andersen NF, Helleberg C, Andersen KT, Pedersen RS, Pedersen P, Abildgaard N, Gimsing P. Smoldering multiple myeloma risk factors for progression: a Danish population-based cohort study. Eur J Haematol. 2015. doi: 10.1111/ejh.12728.
  14. 14.
    Perez-Persona E, Vidriales MB, Mateo G, Garcia-Sanz R, Mateos MV, de Coca AG, Galende J, Martin-Nunez G, Alonso JM, de Las HN, Hernandez JM, Martin A, Lopez-Berges C, Orfao A, San Miguel JF. 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(7):2586–92.CrossRefPubMedGoogle Scholar
  15. 15.
    Perez-Persona E, Mateo G, Garcia-Sanz R, Mateos MV, de Las HN, de Coca AG, Hernandez JM, Galende J, Martin-Nunez G, Barez A, Alonso JM, Martin A, Lopez-Berges C, Orfao A, San Miguel JF, Vidriales MB. Risk of progression in smouldering myeloma and monoclonal gammopathies of unknown significance: comparative analysis of the evolution of monoclonal component and multiparameter flow cytometry of bone marrow plasma cells. Br J Haematol. 2010;148(1):110–4. doi: 10.1111/j.1365-2141.2009.07929.x.CrossRefPubMedGoogle Scholar
  16. 16.
    Bianchi G, Kyle RA, Larson DR, Witzig TE, Kumar S, Dispenzieri A, Morice WG, Rajkumar SV. High levels of peripheral blood circulating plasma cells as a specific risk factor for progression of smoldering multiple myeloma. Leukemia. 2013;27(3):680–5. doi: 10.1038/leu.2012.237.CrossRefPubMedGoogle Scholar
  17. 17.
    Fernández de Larrea C, Isola I, Cibeira MT, Rosiñol L, Calvo X, Tovar N, Elena M, Magnano L, Aróstegui JI, Rozman M, Yagüe J, Bladé J. Smoldering multiple myeloma: impact of the evolving pattern on early progression. Blood. 2014;124(21):3363–3.Google Scholar
  18. 18.
    Rosinol L, Blade J, Esteve J, Aymerich M, Rozman M, Montoto S, Gine E, Nadal E, Filella X, Queralt R, Carrio A, Montserrat E. Smoldering multiple myeloma: natural history and recognition of an evolving type. Br J Haematol. 2003;123(4):631–6.CrossRefPubMedGoogle Scholar
  19. 19.
    Dhodapkar MV, Sexton R, Waheed S, Usmani S, Papanikolaou X, Nair B, Petty N, Shaughnessy JD Jr, Hoering A, Crowley J, Orlowski RZ, Barlogie B. Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120). Blood. 2014;123(1):78–85. doi: 10.1182/blood-2013-07-515239.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Gonzalez de la Calle V, Garcia-Sanz R, Sobejano E, Ocio EM, Puig N, Gutierrez NC, Melón A, Gonzalez J, Garcia de Coca A, Hernandez JM, Hernandez R, Barez A, Alonso JM, Aguilera C, Escalante F, Martin G, Lopez R, de la Fuente P, Mateos M-V. Bence Jones proteinuria in smoldering multiple myeloma as predictor marker of progression to symptomatic multiple myeloma. Blood. 2014;124(21):3369–9.Google Scholar
  21. 21.
    Merz M, Hielscher T, Wagner B, Sauer S, Shah S, Raab MS, Jauch A, Neben K, Hose D, Egerer G, Weber MA, Delorme S, Goldschmidt H, Hillengass J. Predictive value of longitudinal whole-body magnetic resonance imaging in patients with smoldering multiple myeloma. Leukemia. 2014. doi: 10.1038/leu.2014.75.
  22. 22.
    Zamagni E, Nanni C, Gay F, Pezzi A, Patriarca F, Bello M, Rambaldi I, Tacchetti P, Hillengass J, Gamberi B, Pantani L, Magarotto V, Versari A, Offidani M, Zannetti B, Carobolante F, Balma M, Musto P, Rensi M, Mancuso K, Dimitrakopoulou-Strauss A, Chauvie S, Rocchi S, Fard N, Marzocchi G, Storto G, Ghedini P, Palumbo A, Fanti S, Cavo M. 18F-FDG PET/CT focal, but not osteolytic, lesions predict the progression of smoldering myeloma to active disease. Leukemia. 2016;30(2):417–22. doi: 10.1038/leu.2015.291.CrossRefPubMedGoogle Scholar
  23. 23.
    Siontis B, Kumar S, Dispenzieri A, Drake MT, Lacy MQ, Buadi F, Dingli D, Kapoor P, Gonsalves W, Gertz MA, Rajkumar SV. Positron emission tomography-computed tomography in the diagnostic evaluation of smoldering multiple myeloma: identification of patients needing therapy. Blood cancer journal. 2015;5:e364. doi: 10.1038/bcj.2015.87.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Rajkumar SV, Gupta V, Fonseca R, Dispenzieri A, Gonsalves WI, Larson D, Ketterling RP, Lust JA, Kyle RA, Kumar SK. Impact of primary molecular cytogenetic abnormalities and risk of progression in smoldering multiple myeloma. Leukemia. 2013. doi: 10.1038/leu.2013.86.
  25. 25.
    Neben K, Jauch A, Hielscher T, Hillengass J, Lehners N, Seckinger A, Granzow M, Raab MS, Ho AD, Goldschmidt H, Hose D. Progression in smoldering myeloma is independently determined by the chromosomal abnormalities del(17p), t(4;14), gain 1q, hyperdiploidy, and tumor load. J Clin Oncol. 2013;31(34):4325–32. doi: 10.1200/jco.2012.48.4923.CrossRefPubMedGoogle Scholar
  26. 26.
    Khan R, Dhodapkar M, Rosenthal A, Heuck C, Papanikolaou X, Qu P, van Rhee F, Zangari M, Jethava Y, Epstein J, Yaccoby S, Hoering A, Crowley J, Petty N, Bailey C, Morgan G, Barlogie B. Four genes predict high risk of progression from smoldering to symptomatic multiple myeloma (SWOG S0120). Haematologica. 2015;100(9):1214–21. doi: 10.3324/haematol.2015.124651.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Hajek R, Sandecka V, Seckinger A, Spicka I, Scudla V, Gregora E, Radocha J, Brozova L, Jarkovsky J, Rihova L, Mikulasova A, Starostka D, Walterova L, Adamova D, Kessler P, Brejcha M, Vonke I, Obernauerova J, Valentova K, Adam Z, Minarik J, Straub J, Gumulec J, Ho AD, Hillengass J, Goldschmidt H, Maisnar V, Hose D. Prediction of progression of smouldering into therapy requiring multiple myeloma by easily accessible clinical factors [in 527 patients]. Blood. 2014;124(21):2071–1.Google Scholar
  28. 28.
    Muta T, Iida S, Matsue K, Sunami K, Isoda J, Harada N, Saburi Y, Okamura S, Kumagae K, Watanabe J, Kuroda J, Aoki K, Ogawa R, Miyamoto T, Akashi K, Takamatsu Y. Predictive significance of serum beta 2-microglobulin levels and M-protein velocity for symptomatic progression of smoldering multiple myeloma. Blood. 2014;124(21):3379–9.Google Scholar
  29. 29.
    Mateos MV, San Miguel JF. New approaches to smoldering myeloma. Curr Hematol Malig Rep. 2013. doi: 10.1007/s11899-013-0174-1.
  30. 30.
    Mateos MV, Hernandez MT, Giraldo P, de la Rubia J, de Arriba F, Lopez Corral L, Rosinol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, Lopez J, Olavarria E, Quintana N, Garcia JL, Blade J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013;369(5):438–47. doi: 10.1056/NEJMoa1300439.CrossRefPubMedGoogle Scholar
  31. 31.
    Landgren O, Roschewski M, Mailankody S, Kwok M, Manasanch EE, Bhutani M, Tageja N, Kazandjian D, Zingone A, Costello R, Burton D, Zhang Y, Wu P, Carter G, Mulquin M, Zuchlinski D, Carpenter A, Gounden V, Morrison C, Maric I, Calvo KR, Braylan RC, Yuan C, Stetler-Stevenson M, Arthur DC, Lindenberg L, Karen K, Choyke P, Steinberg SM, Figg WD, Korde N. Carfilzomib, lenalidomide, and dexamethasone in high-risk smoldering multiple myeloma: final results from the NCI phase 2 pilot study. Blood. 2014;124(21):4746–6.Google Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Hematology DepartmentComplejo Asistencial Universitario de Salamanca/Instituto Biosanitario de Salamanca (CAUSA/IBSAL)SalamancaSpain
  2. 2.Clinica Universidad de NavarraPamplonaSpain

Personalised recommendations