MULTIPLE MYELOMA AND OTHER PLASMA CELL DISEASES

multiplemyelomawos

SMOLDERING MULTIPLE MYELOMA, DIAGNOSIS AND MANAGEMENT

Mesut Tığlıoğlu1 Ahmet Kürşad Güneş2

1Göztepe Prof. Dr. Süleyman Yalçın City Hospital, Department of Hematology, İstanbul, Türkiye
2Ankara Etlik City Hospital, Department of Hematology, Ankara, Türkiye

Tığlıoğlu M, Güneş AK. Smoldering Multiple Myeloma, Diagnosis and Management. In: Sevindik ÖG, editor. Multiple Myeloma and Other Plasma Cell Dyscrasias. 1st ed. Ankara: Türkiye Klinikleri; 2025. p.9-19.

ABSTRACT

Smoldering multiple myeloma (SMM) is a clinical entity that is frequently asymptomatic and heterogeneous, positioned between monoclonal gammopathy of undetermined significance (MGUS), whose implications remainunclear, and symptomatic multiple myeloma (MM), which is marked by myeloma defining events (MDEs) such as hypercalcemia, renal failure, anemia, or bone lesions (CRAB), within the categorization of plasma cell disorders. The diagnostic criteria and differential diagnosis for MGUS, SMM, and MM, revised in 2014 by the International Myeloma Working Group (IMWG), have been enhanced with the clonal bone marrow plasma cell ratio, the affected free light chain ratio, and pathological findings identified through imaging techniques. The objective has been to identify patients with an 80% likelihood of advancement within two years, assess the risk of end-organ damage within the diverse clinic, and establish the frequency of follow up and potential therapeutic options. The American National Cancer Database Study reported the median age at diagnosis as 67, with an incidence rate of 0.9 per 100,000 individuals. SMM occurs in roughly 0.5% of individuals over 40 years of age. The probability of progression from SMM to MM is reported to be 10% annually over the initial 5 years, 3% annually in the subsequent 5 years, and 1% annually over the final 10 years, with an overall progression rate of 73% within 15 years of diagnosis. The Mayo 2018 criteria and the IMWG 2020 risk scoring methodology are being utilized as realistic and successful risk classification frameworks and scoring methodologies. The management and treatment of high-risk SMM patients remain debatable. In conjunction with these ideas, numerous contemporary combinations, algorithms, and continuing research pertain to the treatment of high-risk SMM. The patient’s comorbidities, age, and preferences must be assessed in treatment and strategies focused on illness management should be employed in suitable patients. Despite the challenges in identifying a therapeutic method that significantly enhances overall survival in the treatment of SMM, new researches reveal promising results.

Keywords: Smoldering multiple myeloma; Diagnosis; Risk score; Treatment

Referanslar

  1. Rajkumar Sv, Kumar S. Multiple myeloma current treatment algorithms. Blood Cancer J. 2020;28;10(9):94. [Crossref]  [PubMed]  [PMC]
  2. Kyle RA, Greipp PR. Smoldering multiple myeloma. N Engl J Med. 1980;302(24): 1322-1330. [Crossref]  [PubMed]
  3. Tageja N, Manasanch EE, Korde N, Kwok M, Mailankody S, Bhutani M, et al. Smoldering multiple myeloma: present position and potential promises. Eur J Haematol. 2014;92(1):1-12. [Crossref]  [PubMed]
  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. Journal of clinical oncology. 2010;28(4):690. [Crossref]  [PubMed]  [PMC]
  5. 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(12):e538-48. [Crossref]  [PubMed]
  6. Kyle RA, Durie BG, Rajkumar Sv, landgren O, Blade J, Merlini G, Kröger N, et al. Monoclonal gammopathy of un determined significance (MGuS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. leukemia. 2010;24(6):1121-7. [Crossref]  [PubMed]  [PMC]
  7. 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. 2016:21;6(10):e486. [Crossref]  [PubMed]  [PMC]
  8. Kristinsson SY, Holmberg E, Blimark C. Treatment for high-risk smoldering myeloma. N Engl J Med. 2013 Oct 31;369(18):1762-3. [Crossref]
  9. Thorsteinsdottir S, Gislason GK, Aspelund T, et al. Prevalence of smoldering multiple myeloma: results from the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study. Blood. 2021;138(Supplement 1):151-151. [Crossref]
  10. van de Donk NW, Palumbo A, Johnsen HE, Engelhardt M, Gay F, Gregersen H, Hajek R, et al. The clinical relevance and management of monoclonal gammopathy of undetermined significance and related disorders: recommendations from the European Myeloma Network. Haematologica. 2014;99(6):984-96. [Crossref]  [PubMed]  [PMC]
  11. Kyle RA, Remstein ED, Therneau TM, Dispenzieri A, Kurtin PJ, Hodnefield JM, et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med. 2007:21;356(25):2582-90. [Crossref]  [PubMed]
  12. Madhira BR, Konala vM, Adapa S, et al. Recent advances in the management of smoldering multiple myeloma. World J Oncol. 2020;11(2):45-50. [Crossref]  [PubMed]  [PMC]
  13. 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. 2008:15;111(2):785-9. [Crossref]  [PubMed]  [PMC]
  14. 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. 2007:1;110(7):2586-92. [Crossref]  [PubMed]
  15. 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 monoclonal component and multiparameter flow cytometry of bone marrow plasma cells. Br J Haematol. 2010;148(1):110-4. [Crossref]  [PubMed]
  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. 2016:29;6(7):e454. [Crossref]  [PubMed]  [PMC]
  17. Merz M, Hielscher T, Wagner B, Sauer S, Shah S, Raab MS, et al. Predictive value of longitudinal whole-body magnetic resonance imaging in patients with smoldering multiple myeloma. leukemia. 2014;28(9):1902-8. [Crossref]  [PubMed]
  18. zamagni E, Nanni C, Gay F, Pezzi A, Patriarca F, Bellò M, et al. 18F-FDG PET/CT focal, but not osteolytic, lesions predict the progression of smoldering myeloma to active disease. leukemia. 2016;30(2):417-22. [Crossref]  [PubMed]
  19. Neben K, Jauch A, Hielscher T, et al. Progression in smoldering myeloma is independently determined by the chromosomal abnormalities del (17p), t (4; 14), gain 1q, hyperdiploidy, and tumor load. Journal of clinical oncology. 2013;31(34):4325-4332. [Crossref]  [PubMed]
  20. Bustoros M, Sklavenitis-Pistofidis R, Park J, Redd R, zhitomirsky B, Dunford AJ, et al. Genomic Profiling of Smoldering Multiple Myeloma Identifies Patients at a High Risk of Disease Progression. J Clin Oncol. 2020:20;38(21):23802389.
  21. Garcés JJ, Puig N, Termini R, Cedena MT, Moreno C, Pérez JJ, et al. Circulating Tumor Cells (CTCs) in Smoldering and Active Multiple Myeloma (MM): Mechanism of Egression, Clinical Significance and Therapeutic Endpoints. Blood. 2021:138(1);76. [Crossref]
  22. San Miguel J, Mateos M-v, Gonzalez v, et al. updated risk stratification model for smoldering multiple myeloma (SMM) incorporating the revised IMWG diagnostic criteria. American Society of Clinical Oncology; 2019. [Crossref]
  23. Hill E, Dew A, Morrison C, et al. Assessment of Discordance Among Smoldering Multiple Myeloma Risk Models. JAMA Oncol. 2021;7(1):132-134. [Crossref]  [PubMed]  [PMC]
  24. Mateos Mv, Kumar S, Dimopoulos MA, et al. International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM). Blood Cancer J. 2020;10:102. [Crossref]  [PubMed]  [PMC]
  25. Chabrun F, Schwartz D, Gentile S, Gupta TR, Gisbert NC, Martín-Sánchez E, et al. Improved Risk Stratification of Smoldering Multiple Myeloma (SMM) using Trajectory Data in the Pangea 2.0 Model: A Multicenter Study in 1,431 Participants. Blood 2024;144(Supplement 1):1017. [Crossref]
  26. Mellgard G, Gilligan M, Cliff ERS, Bhutani D, Mohyuddin GR, Eisenberger A, et al. Risk stratification models overestimate progression risk in contemporary patients with smoldering multiple myeloma. Hemasphere. 2024:20;8(3):e61. [Crossref]  [PubMed]  [PMC]
  27. lakshman A, Rajkumar Sv, Buadi FK, et al. Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer Journal. 2018;8:59. [Crossref]  [PubMed]  [PMC]
  28. Rajkumar Sv, Kumar S, lonial S, et al. Smoldering multiple myeloma current treatment algorithms. Blood Cancer J. 2022;12:129. [Crossref]  [PubMed]  [PMC]
  29. Costa lJ, Bal S, Chhabra S. Population-level trends in early mortality and overall survival of patients with multiple myeloma. Are we facing stagnation? Blood. 2019;134:4760. [Crossref]
  30. Mateos Mv, Hernández MT, Salvador C, Rubia J, de Arriba F, lópez-Corral l, et al. lenalidomide-dexamethasone versus observation in high-risk smoldering myeloma after 12 years of median follow-up time: A randomized, open-label study. Eur J Cancer. 2022;174:243-250. [Crossref]  [PubMed]
  31. lonial S, Jacobus S, Fonseca R, et al. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. Journal of Clinical Oncology. 2020;38(11):1126. [Crossref]  [PubMed]  [PMC]
  32. Mateos Mv, et al. Curative Strategy for High-Risk Smoldering Myeloma: Carfilzomib, lenalidomide, and Dexamethasone (KRd) Followed by Transplant, KRd Consolidation, and Rd Maintenance. JCO. 2024;42:3247-3256. [Crossref]  [PubMed]  [PMC]
  33. Dimopoulos MA, voorhees PM, Schjesvold F, Cohen YC, Hungria v, Sandhu I, et al. Daratumumab or Active Moni toring for High-Risk Smoldering Multiple Myeloma. N Engl J Med. 2024 Dec 9.
  34. Musto P, Petrucci MT, Bringhen S, Guglielmelli T, Caravita T, Bongarzoni v, et al. A multicenter, randomized clinical trial comparing zoledronic acid versus observation in patients with asymptomatic myeloma. Cancer. 2008:1;113(7):1588-95. [Crossref]  [PubMed]
  35. Bustoros M, liu C, Reyes K, Hornburg K, Guimond K, Styles R, et al. Phase II Trial of the Combination of Ixazomib, lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma. Blood. 2018;132(Supplement 1):804. [Crossref]
  36. Joseph NS, Dhodapkar Mv, lonial S. The role of early intervention in high-risk smoldering myeloma. American Society of Clinical Oncology Educational Book. 2020;40:355-363. [Crossref]  [PubMed]
  37. Visram A, Cook J, Warsame R. Smoldering multiple myeloma: evolving diagnostic criteria and treatment strategies. Hematology Am Soc Hematol Educ Program. 2021:10;2021(1):673-681 gy.2021000304 [Crossref]  [PubMed]  [PMC]
  38. Turk Hematoloji Derneği. Multipl Myelom Tanı ve Tedavi Kılavuzu (Sürüm 1.03). İstanbul: Türk Hematoloji Derneği; Mart 2020.