Monoclonal Gammopathy of Undetermined Significance (MGUS)Monoclonal Gammopathy of Undetermined Significance (MGUS)

Česká verzia

Authors: Sandecká Viera ¹; Pour Ludek ¹; Adam Zdeněk ¹; Krejčí Marta ¹; Štork Martin ¹; Ševčíková Sabina ²; Král Zdeněk ¹
Authors place of work: Interní hematologická a onkologická klinika LF MU a FN Brno ¹; Babákova myelomová skupina, Ústav patologické fyziologie, LF MU, Brno ²
Published in the journal: Klin Onkol 2018; 31(4): 270-276
Category: Review
doi: https://doi.org/10.14735/amko2018270

Summary

Background:
Monoclonal gammopathy of undetermined significance (MGUS) is one of the most prevalent premalignant conditions associated with a risk of malignant transformation to multiple myeloma (MM) or other forms of lymphoproliferative disorders with risk of progression of approximately 1% per year. IgG and IgA MGUS are precursor conditions of multiple myeloma (MM), whereas light-chain MGUS is a precursor condition of light chain MM. IgM MGUS is a precursor condition of Waldenström macroglobulinemia (MW) or other lymphoproliferative diseases. Aim: Assessment of the risk of progression of patients with asymptomatic monoclonal gammopathies (MG) is based on various factors, including the serum paraprotein (M protein) concentration, isotype of M protein, serum free light chain ratio, infiltration of bone marrow plasmocytes, reduction of one or two noninvolved immunoglobulin subtype levels (immunoparesis), evolving and non-evolving subtype of MGUS, ratio of normal/abnormal plasma cells in bone marrow identified by multiparametric flow cytometry techniques and number of circulating plasma cells in peripheral blood. Three risk stratification models have been constructed that are useful in daily practice for predicting risk of progression of MGUS into malignant forms of monoclonal gammopathy – MAYO, PETHEMA and CMG model. The goal of all three models is to identify correctly prognostic markers that can divide patients into low-risk MGUS and high-risk MGUS groups.

Conclusion:
This review provides a look at the definition, pathogenesis, diagnostic algorithm, clinical significance and stratification of MGUS patients, followed by recommendations for patient risk dispensarisation intervals.

Keywords:
monoclonal gammopathy of undetermined significance – multiple myeloma – progression – risk factors

This work was supported by grant of Ministry of Health, Czech Republic – Conceptual development of research organization (FNBr, 65269705).

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Submitted: 28. 3. 2018

Accepted: 11. 6. 2018

Zdroje

1. Kyle RA, Rajkumar SV. Monoclonal gammopathies of undetermined significance. Best Pract Res Clin Haenatol 2005 2005; 18 (4): 689–707. doi: 10.1016/j.beha.2005.01.025.

2. Krizalkovicová V, Maisnar V, Pour L et al. Monoclonal gammopathies of undetermined significance. Klin Onkol 2008; 21 (4): 160–164.

3. Landgren O, Kyle RA, Pfeiffer RM et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood 2009; 113 (22): 5412–5417. doi: 10.1182/blood-2008-12-194241.

4. Kyle RA. Monoclonal gammopathy of undetermined significance (MGUS). Baillieres Clin Haematol 1995; 8 (4): 761–781.

5. Korde N, Kristinsson SY, Landgren O. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): novel biological insights and development of early treatment strategies. Blood 2011; 117 (21): 5573–5581. doi: 10.1182/blood-2011-01-270140.

6. Cohen HJ, Crawford J, Rao MK et al. Racial differences in the prevalence of monoclonal gammopathy in a community-based sample of the elderly. Am J Med 1998; 104 (5): 439–444.

7. Therneau TM, Kyle RA, Melton LJ 3rd et al. Incidence of monoclonal gammopathy of undetermined significance and estimation of duration before first clinical recognition. Mayo Clin Proc 2012; 87 (11): 1071–1079. doi: 10.1016/j.mayocp.2012.06.014.

8. Davis FE, Dring AM, Li C et al. Insights into the multistep transformation of MGUS to myeloma using microarray expression analysis. Blood 2003; 102 (13): 4504–4511.

9. Bladé J. Clinical practice. Monoclonal gammopathy of undetermined significance. N Engl J Med 2006; 355 (26): 2765–2770.

10. Malik AA, Ganti AK, Potti A et al. Role of Helicobacter pylori infection in the incidence and clinical course of monoclonal gammopathy of undetermined significance. Am J Gastroenterol 2002; 97 (6): 1371–1374.

11. Rajkumar SV, Kyle RA, Plevak MF et al. Helicobacter pylori infection and monoclonal gammopathy of undetermined significance. Br J Haematol 2002; 119 (3): 706–708.

12. Ross FM, Avet-Loiseau H, Ameye G et al. Report from the European Myeloma Network on interphase FISH in multiple myeloma and related disorders. Haematologica 2012, 97 (8): 1272–1277.

13. Mikhael JR, Dingli D, Roy V et al. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo stratification of myeloma and risk-adapted therapy (mSMART) consensus guidelines 2013. Mayo Clinic Proc 2013, 88 (4): 360–376. doi: 10.1016/j.mayocp.2013.01.019.

14. van de Donk NW, Palumbo A, Johnsen HE 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): 984–996. doi: 10.3324/haematol.2013.100552.

15. Tichý M, Maisnar V. Laboratorní průkaz monoklonálních imunoglobulinů. Vnitř Lék 2006; 52 (Suppl 2): 41–45.

16. Tichý M, Friedecký B, Vávrová J et al. Standardizace biochemických laboratorních vyšetření u mnohočetného myelomu. Klin Biochem Metab 2006; 14 (35): 8–13.

17. Radocha J, Pour L, Pika T et al. Multicentered patient-based evidence of the role of free light chain ratio normalization in multiple myeloma disease relapse. Eur J Haematol 2016; 96 (2): 119–127. doi: 10.1111/ejh.12556.

18. Ščudla V, Minařík J, Schneiderka P et al. Význam sérových hladin volných lehkých řetězců imunoglobulinu v diagnostice a hodnocení aktivity mnohočetného myelomu z vybraných monoklonálních gamapatií. Vnitř Lék 2005; 51 (11): 1249–1259.

19. Pika T, Minařík J, Lochman P et al. Přínos vyšetření sérových hladin volných lehkých řetězců pro subklasifikaci nesekretorické formy mnohočetného myelomu. Klin Biochem Metab 2010; 18 (39): 77–79.

20. Radocha J. HevyLite™ – nová metoda detekce monoklonálních imunoglobulinů – editorial. Vnitř Lék 2015; 61 (1): 13–14.

21. Ščudla V, Pika T, Heřmanová Z. Hevylite – nová analytická metoda v diagnostice a hodnocení průběhu monoklonálních gamapatií. Klin Biochem Metab 2010; 18 (39): 62–68.

22. Jackson N, Ling NR, Ball J et al. An analysis of myeloma plasma cell phenotype using antibodies defined at the III^rd International Workshop on Human Leucocyte Differentiation Antigens. Clin Exp Immunol 1988; 72 (3): 351–356.

23. Lima M, Teixeira Mdos A, Fonseca S et al. Immunophenotypic aberrations, DNA content, and cell cycle analysis of plasma cells in patients with myeloma and monoclonal gammopathies. Blood Cells Mol Dis 2000; 26 (6): 634–645.

24. Maisnar V, Tousková M, Tichý M et al. The significance of soluble CD138 in diagnosis of monoclonal gammopathies. Neoplasma 2006; 53 (1): 26–29.

25. Bataille R, Jégo G, Robillard N et al. The phenotype of normal, reactive and malignant plasma cells. Identification of „many and multiple myelomas“ and of new targets for myeloma therapy. Haematologica 2006; 91 (9): 1234–1240.

26. Miltenyi S, Müller W, Weichel W et al. High gradient magnetic cell separation with MACS. Cytometry 1990; 11 (2): 231–238.

27. Herzenberg LA, Parks D, Sahaf B et al. The history and future of the fluorescence activated cell sorter and flow cytometry: a view from Stanford. Clin Chem 2002; 48 (10): 1819–1827.

28. Buresova I, Cumova J, Kovarova L et al. Bone marrow plasma cell separation – validation of separation algorithm. Clin Chem Lab Med 2012; 50 (6): 1139–1140. doi: 10.1515/cclm-2012-8837.

29. Kovarova L, Buresova I, Buchler T et al. Phenotype of plasma cells in multiple myeloma and monoclonal gammopathy of undetermined significance. Neoplasma 2009; 56 (6): 526–532.

30. Seong C, Delasalle K, Hayes K et al. Prognostic value of cytogenetics in multiple myeloma. Br J Haematol 1998; 101 (1): 189–194.

31. Avet-Loiseau H, Attal M, Moreau P et al. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome. Blood 2007; 109 (8): 3489–3495.

32. Rajkumar SV. Multiple myeloma: 2016 update on diagnosis, risk-stratification and management. Am J Hematol 2016; 91 (7): 719–734. doi: 10.1002/ajh.24402.

33. Kyle RA, Therneau TM, Rajkumar SV et al. A longterm study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 2002; 346 (8): 564–569.

34. Kyle RA, Rajkumar SV. Monoclonal gammopathy of undetermined significance and smouldering multiple myeloma: emphasis on risk factors for progression. Br J Haematol 2007; 139 (5): 730–743.

35. Kyle RA, Rajkumar SV, Therneau TM et al. Prognostic factors and predictors of outcome of immunoglobulin M monoclonal gammopathy of undetermined significance. Clin Lymphoma 2005; 5 (4): 257–260.

36. Cesana C, Klersy C, Barbarano L et al. Prognostic factors for malignant transformation in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. J Clin Oncol 2002; 20 (6): 1625–1634.

37. Kyle RA, Therneau TM, Rajkumar SV et al. Long-term follow-up of 241 patients with monoclonal gammopathy of undetermined significance: the original Mayo Clinic series 25 years later. Mayo Clin Proc 2004; 79 (7): 859–866.

38. Rosiñol L, Cibeira MT, Montoto S 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 (4): 428–434.

39. Rajkumar SV, Kyle RA, Therneau TM et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood 2005; 106 (3): 812–817.

40. Pika T, Lochman P, Sandecka V et al. Immunoparesis in MGUS – Relationship of uninvolved immunoglobulin pair suppression and polyclonal immunoglobuline levels to MGUS risk categories. Neoplasma 2015; 62 (5): 827–832. doi: 10.4149/neo_2015_100.

41. Katzmann JA, Clark R, Kyle RA et al. Suppresion of uninvolved immunoglobulins defined by heavy/light chain pair suppression is a risk factor for progression of MGUS. Leukemia 2013; 27 (1): 208–212. doi: 10.1038/leu.2012.189.

42. Pérez-Persona E, Vidriales MB, Mateo G 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 (7): 2586–2592.

43. Kumar S, Rajkumar SV, Kyle RA et al. Prognostic value of circulating plasma cells in monoclonal gammopathy of undetermined significance. J Clin Oncol 2005; 23 (24): 5668–5674.

44. Hillengass J, Weber MA, Kilk K et al. Prognostic significance of whole-body MRI in patients with monoclonal gammopathy of undetermined significance. Leukemia 2014; 28 (1): 174–178. doi: 10.1038/leu.2013.244.

45. Heuck C, Sexton R, Dhodapkar MV et al. SWOG S0120 observational trial for MGUS and asymptomatic multiple myeloma (AMM): imaging predictors of progression for patients treated at UAMS. Blood 2011; 118: 3955.

46. Pérez-Persona E, Mateo G, García-Sanz R 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): 110–114. doi: 10.1111/j.1365-2141.2009.07929.x.

47. Sandecká V, Hájek R, Pour L et al. A first Czech analysis of 1887 cases with monoclonal gammopathy of undetermined significance. Eur J Haematol 2017; 99 (1): 80–90. doi: 10.1111/ejh.12894.

48. Alexanian R. Monoclonal gammopathy in lymphoma. Arch Intern Med 1975; 135 (1): 62–66.

49. Lamboley V, Zabraniecki L, Sie P et al. Myeloma and monoclonal gammopathy of uncertain significance associated with aqcuired von Willebrand‘s syndrome. Seven new cases with a literature review. Joint Bone Spine 2002; 69 (1): 62–67.

50. Ropper AH, Gorson KC. Neuropathies associated with paraproteinemia. N Engl J Med 1998; 338 (22): 1601–1607.

51. Adam Z, Feit J, Krejčí M et al. IgA pemphigus a monoklonální gamapatie, je zde souvislost? Dermatol praxi 2010; 4 (4): 221–224.

52. Viktorinová M, Ditrichová D. Kožní projevy interních chorob. Int Med 2005; 7 (5) 242–249.

53. Adam Z, Šedivá H, Koukalová R et al. Schnitzlerové syndrom: Diferenciální diagnostika, přehled léčebných možností a popis 5 případů léčených anakinrou. Vnitř Lék 2016; 62 (9): 491–499.

54. Myeloma.cz. Česká myelomové skupina. [online]. Dostupné na: http: //www.myeloma.cz/index.php?pg=registr-rmg-registry-of-monoclonal-gammo-pathies.