Monoclonal gammopathy of undetermined significance and asymptomatic multiple myelom in the year 2014

Česká verzia

Authors: Zdeněk Adam ¹; Marta Krejčí ¹; Luděk Pour ¹; Eva Ševčíková ¹; Andrea Křivanová ¹; Zdeněk Řehák ²; Renata Koukalová ²; Zdeňka Čermáková ³; Jiří Vaníček ⁴; Sabina Ševčíková ⁵
Authors place of work: Interní hematologická a onkologická klinika LF MU a FN Brno, pracoviště Bohunice, přednosta prof. MUDr. Jiří Mayer, CSc. ¹; Oddělení nukleární medicíny, pracoviště PET Masarykova onkologického ústavu Brno, primář MUDr. Zdeněk Řehák, Ph. D. ²; Oddělení klinické biochemie FN Brno, pracoviště Bohunice, a Katedra laboratorních metod LF MU, přednosta doc. MUDr. Milan Dastych, CSc., MBA ³; Klinika zobrazovacích metod LF MU a FN u sv. Anny Brno, přednosta as. MUDr. Jiří Vaníček, Ph. D. ⁴; Katedra patologické fyziologie LF MU Brno, přednostka prof. MUDr. Anna Vašků, CSc. ⁵
Published in the journal: Vnitř Lék 2014; 60(10): 861-879
Category: Reviews

Summary

Presence of monoclonal immunoglobulin in serum or urine is a relatively common event affecting about 3.2 % of people over 50. Isolated increase of only one type of free light chain, either κ or λ, is detected in 0.7–0.8 % of people over 50. Most people with monoclonal immunoglobulin meet the criteria of the so-called “monoclonal gammopathy of undetermined significance (MGUS)”. MGUS is defined by concentration of monoclonal immunoglobulin in serum < 30 g/l, number of plasma cells in the bone marrow < 10 % and the absence of symptoms of multiple myeloma and other lymphoproliferative diseases. A proportion of people with MGUS gradually progresses from asymptomatic into symptomatic myeloma or other malignant lymphoproliferative disease requiring treatment. Therefore, MGUS is considered to be one of the most common premalignant conditions with an average risk of transformation into malignant disease of 1 % per year. Monoclonal gammopathy of IgG and IgA subtype can develop into multiple myeloma. Light chain monoclonal gammopathy can develop not only into light chain multiple myeloma but also into AL-amyloidosis and light chain deposition disease (amorphous deposits of light chains damaging organs). IgM monoclonal gammopathy may develop into Waldenstrom macroglobulinemia or other lymphoproliferative disorder, or into rare IgM subtype of multiple myeloma. Unfortunately, people with MGUS are threatened by more than an increased risk of transformation into multiple myeloma or other severe hematologic disease. Pre-malignant clone of plasma cells in the bone marrow causes changes in the bone marrow that directly affect the person. For people with MGUS, there is an increased incidence of osteoporosis and increased fracture risk when compared to the general population. People with MGUS also have an increased risk of bacterial infections and thromboembolic complications compared with the same age population without MGUS. Clonal plasma cells, which are the basis of MGUS, may in some cases produce toxic monoclonal immunoglobulin which can damage the body’s own antibody activity by binding to specific antigens (such as cold agglutinin disease), or their deposits in organs (e.g. kidney damage) or physical properties (e.g. cryoglobulinemia). Therefore, it is recommended that this group of people is regularly checked with the aim to capture not only transformation into symptomatic multiple myeloma or another malignant disease, but also the formation of the above-mentioned complications. Moreover, it is recommended to monitor patients with asymptomatic myeloma and to initiate treatment only after symptoms of multiple myeloma are observed. In 2014, discussion of subdivision of subgroups of patients with asymptomatic myeloma with high (≥ 80 %) probability of early (within 2 years) transformation in multiple myeloma which would be beneficial for early initiation of treatment is ongoing. According to first proposals, patients with asymptomatic myeloma that meet at least one of the three conditions: more than 60 % of plasma cells in the bone marrow, ratio of free light kappa and lambda chains is greater than 100 or less than 0.01, or multiple focal lesions on whole-body MRI of the skelet. The review contains current opinions on prognostic classification and appropriate intervals and extent of control examinations.

Key words:
asymptomatic myeloma – monoclonal gammopathy of undetermined significance – PET/CT – symptomatic multiple myeloma – Waldenström macroglobulinemia

Zdroje

1. Sčudla V, Pika T, Budíkova M et al. The relationship between some soluble osteogenic markers, angiogenic cytokines/other biological parameters and the stages of multiple myeloma evaluated according to the Durie-Salmon and International Prognostic Indexstratification systems. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2009; 153(4): 275–282.

2. Ščudla V, Petrová P, Minařík J et al. Příspěvek k hodnocení sérových hladin vybraných biologických působků u monoklonální gamapatie nejistého významu a v jednotlivých klinických stadiích mnohočetného myelomu. Vnitř Lék 2010; 56(6): 591–601.

3. Ščudla V, Budíková M, Petrová P et al. Česká myelomová skupina. Analýza hladin vybraných sérových markerů u monoklonální gamapatie nejistého významu a u mnohočetného myelomu. Klin Onkol 2010; 23(3): 171–181.

4. Ščudla V, Budíková M, Pika T et al. Srovnání hladin vybraných biomarkerů u monoklonální gamapatie nejistého významu a u mnohočetného myelomu. Čas Lék Česk 2009; 148(7): 315–322.

5. Kyle RA. Monoclonal gammopathy of undetermined significance. Natural history in 241 cases. Am J Med 1978; 64(5): 814–826.

6. Kyle RA. Monoclonal gammopathy of uncertain significance; natural history in 241 cases. Mayo Clinic Proceedings 1978; 64(5): 814–826.

7. Landgren O, Kyle RA, Pfeiffer R et al. Monoclonal gammopathy of undetermines significance consistently precedens multiple myeloma: a prospective study. Blood 2009; 113(22): 5412–5417.

8. Weiss BM, Abadie J, Verma P et al. A monoclonal gammopathy precedens multiple myeloma in most patients. Blood 2009; 113(22): 5418–5422.

9. Axelsson U, Bachmann R,Hällén J. Frequency of pathological proteins (M-components) in 6,995 sera from an adult population. Acta Med Scand 1966; 179(2): 235–247.

10. Saleun JP, Vicariot M, Deroff P et al. Monoclonal gammopathies in the adult population of Finistère, France. J Clin Pathol 1982; 35(1): 63–68.

11. Kyle RA, Therneau TM, Rajkumar SV et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med 2006; 354(13): 1362–1369.

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

13. Dispensieri A, Katzman JA, Kyle RA et al. Prevalence and risk of progression of light-chain monoclonal gammopathy of undetermined significance: a retrospective population based cohort study. Lancet 2010; 375(9727): 1721–1728.

14. Tichý M, Maisnar V. Laboratorní průkaz monoklonálního imunoglobulinu. Vnitř Lék 2006; 52(Suppl 2): S41-S45.

15. Ščudla V, Herman M, Minařík J et al. Přínos celotělové magnetické resonance pro diagnózu monoklonální gamapatie nejistého významu, mnohočetého myelomu a stanovení Durie-Salmon Plus. Vnitř Lék 2011; 57(1): 52–60.

16. Mysliveček M, Bačovský J, Ščudla V et al. 18F-FDG PET/CT a 99mTc-MIBI scintigrafie při hodnocení pacientů s mnohočetným myelomem a monoklonální gamapatií nejistého významu: srovnání metod. Klin Onkol 2010; 23(5): 325–331.

17. Mecl J, Benáková H, Nohejlová A et al. Detekce lehkých řetězců, nová metoda diagnostiky krevních chorob. Čas Lék Česk 2007; 146(2): 159–162.

18. Ščudla V, Budíková M, Pika T et al. Česká myelomová skupina. Srovnání sérových hladin vybraných biologických parametrů u monoklonální gamapatie nejistého významu a mnohočetného myelomu. Vnitř Lék 2006; 52(3): 232–240.

19. Tichý M, Rehácek V, Maisnar V et al. Monoklonální gamapatie v sérii 1683 dárců plazmy. Čas Lék Česk 2004; 143(6): 401–404.

20. Maisnar V, Tousková M, Malý J et al. Význam vybraných laboratorních ukazatelů pro diferenciální diagnostiku a sledování aktivity mnohočetného myelomu. Vnitř Lék 2002; 48(4): 290–297.

21. Mian M, Franz I, Wasle I et al. “Idiopathic Bence-Jones proteinuria”: a new characterization of an old entity. Ann Hematol 2013; 92(9): 1263–1270.

22. Maisnar V, Tichy M, Stulik J et al. The problems of proteinuria measurement in urine with presence of Bence Jones protein. Clin Biochem 2011; 44(5–6): 403–405.

23. Vachon CM, Kyle RA Therneau TM et al. Increased risk of monoclonal gammopathy in first degree relatives of patients with multiple myeloma or monoclonal gammopathy of undetermined significance Blood 2009; 114: 785–790.

24. Langren P. Kristinsson SY, Goldin LR et al. Risk of plasma cell and lymphoproliferative disorders among 14621 first-degree relatives of 4458 patients with monoclonal gammopathy of undetermined significance in Sweden. Blood 2009; 114(4): 791–795.

25. Greenberg AJ, Rajkumar SV, Larson DR et al. Increased prevalence of light chain monoclonal gammopathy of undetermined significance in first degrese relativem of individuals with multiple myeloma. Brit J Haematol 2012; 157(4): 472–475.

26. Landgren O, Kyle RA, Hoppin JA et al. Pesticide exposure and risk of monoclonal gammopathy on undetermined significance in the Agricultural Health Study. Blood 2009; 113(25): 6386–6391.

27. McShane CM, Murray LJ, Landgren O et al. Prior autoimmune disease and risk of monoclonal gammopathy of undetermined significance and multiple myeloma: a systematic review. Cancer Epidemiol Biomarkers Prev 2014; 23(2): 332–342.

28. 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(5): 749–757.

29. Kyle RA, Durie BG, Rajkumar SV et al. International Myeloma Working Group. 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(6): 1121–1127.

30. Rajkumar SV, Kyle RA, Baudi FK. Advances in the diagnosis, classification, risk stratification, and management of monoclonal gammopathy of undetermined significance: implications for recategorizing disease entities in the presence of evolving scientific evidence. Mayo Clin Proc 2010; 85(10): 945–948.

31. Mian M, Franz I, Wasle I et al. “Idiopathic Bence-Jones proteinuria”: a new characterization of an old entity. Ann Hematol 2013; 92(9): 1263–1270.

32. Fernández de Larrea C, Kyle RA, Durie BG et al. International Myeloma Working Group. Plasma cell leukemia: consensus statement on diagnostic requirements, response criteria and treatment recommendations by the International Myeloma Working Group. Leukemia 2013; 27(4): 780–791.

33. Ščudla V. Diagnostický význam a úskalí hodnocení roztěrového preparátu kostní dřeni u mnohočetného myelomu. Vnitř Lék 2006; 52(Suppl 2): S55-S65.

34. Banwait R, O’Regan K, Campigotto F et al. The role of 18F-FDG PET/CT imaging in Waldenstrom macroglobulinemia. Am J Hematol 2011; 86(7): 567–572.

35. Gertz MA. Waldenström macroglobulinemia: 2013 update on diagnosis, risk stratification, and management. Am J Hematol 2013; 88(8): 703–711.

36. Shaheen SP, Talwalkar SS, Lin P et al. Waldenström macroglobulinemia: a review of the entity and its differential diagnosis. Adv Anat Pathol 2012; 19(1): 11–27.

37. Owen RG, Pratt G, Auer RL et al. Guidelines on the diagnosis and manageěent of Waldenström macroglobulinaemia. Br J Haematol 2014; 165(3): 316–333.

38. Kyle RA, Therneau TM, Dispenzieri A et al. Immunoglobulin m monoclonal gammopathy of undetermined significance and smoldering Waldenström macroglobulinemia. Clin Lymphoma Myeloma Leuk 2013; 13(2): 184–186.

39. Lin P, Hao S, Handy BC et al. Lymphoid neoplasms associated with IgM paraprotein: a study of 382 patients. Amer J Clin Pathol 2005; 123(2): 200–205.

40. Adam Z, Štěpánková S, Sirotková A et al. Selhání ledvin u pacientky s chronickou B-lymfoctární leukémií (B-CLL) vzniklé na podkladě tvorby odlitkových válců v tubulech ledvin z monoklonálních lehkých řetězců (casth nephropathy). Přínos stanovení volných lehkých řetězců imunoglobulinů pro časnou diagnostiku této komplikace. Vnitř Lék 2011; 57(2): 214–221.

41. Merlini G, Stone MJ. Dangerous small B-cell clones. Blood 2006; 108(8): 2520–2530.

42. Hardiman KL, Horn S, Manoharan A et al. Rheumatic autoantibodies in the sera of patients with paraproteins. Clin Exp Rheumatol 1994; 12(4): 363–368.

43. Daoud MS, Lust JA, Kyle RA et al. Monoclonal gammopathies and associated skin disorders. J Amer Acad Dermatos 1999; 40(4): 507–535.

44. Idilman R, Colantoni A, De Maria N et al. Lymphoproliferative disorders in chronic hepatitis C. J Viral Hepat 2004; 11(4): 302–309.

45. Amara S, Dezube BJ, Cooley TP et al. HIV-associated monoclonal gammopathy: a retrospective analysis of 25 patients. Clin Infect Dis 2006; 43(9): 1198–1205.

46. Caforio AL, Gambino A, Belloni Fortina A et al. Monoclonal gammopathy in heart transplantation: risk factor analysis and relevance of immunosuppressive load. Transplant Proc 2001; 33(1–2): 1583–1584.

47. Kyle RA, Rajkumar SV et al. Monoclonal gammopathy of undetermined significance. Brit J Haematol 2006; 134(6): 573–589.

48. 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.

49. Kyle RA, Thernau 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.

50. 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.

51. Blade J, Lopez-Guillermo A, Rozman C et al. Malignant transformation and life expectancy in monoclonal gammopathy of undetermined significance. Brit J Haematol 1992; 81(3): 391–394.

52. Gregersen H, Mellemkjær L, Ibsen JS et al. The impact of M-component type and immunoglobulin concentration on the risk of malignant transformation in patients with monoclonal gammopathy of undetermined significance. Haematologica 2001; 86(11): 1172–1179.

53. 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 Clinic Proc 2007; 82(4): 428–834.

54. Rajkumar SV, Mesa AM, Fonseca R et al. P.R. Bone marrow angiogenesis in 400 patients with monoclonal gammopathy of undetermined significance multiple myeloma and primary amyloidosis. Clin Cancer Res 2002; 8(7): 2210–2216.

55. 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.

56. 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.

57. Rajkumar SV, Lacy MQ, Kyle RA. Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Blood Rev 2007; 21(5): 255–265.

58. Hillengass HJ, Weber MA, Kilk K et al. Prognostic significance or whole body MRI in patients with monoclonal gammopathy of undetermined significance. Leukemia 2014; 28(1):174–178.

59. 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.

60. Baldini L, Guffanti A, Cesana BM et al. Role of different hematologic variables in defining the risk of malignant transformation in monoclonal gammopathy. Blood1996; 87(3): 912–918.

61. Kyle RA, Gertz MA, Witzig TE et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clinic Proc 2003; 78(1): 21–33.

62. Pika T, Lochman P, Klencová M et al. Suprese alternativního páru imunoglobulinu koreluje s mírou rizikovosti MGUS výraznějši nežli suprese hladin polyklonálních imunoglobulinů – dílčí výsledky vyšetření HevyLite u MGUS. Klin Biochem Metab 2012; 20(41): 63–71.

63. Katzman JA, Clark R, Kyle RA et al. Suppression of uninvolved imunoglobulin defined by haevy/light chain pair suppression is a risk factor for progression of MGUS. Leukemia 2013; 27(1): 208–212.

64. Espiño M, Medina S, Blanchard MJ et al. Involved/uninvolved immunoglobulin ratio identifies monoclonal gammopathy of undetermined significance patients at high risk of progression to multiple myeloma. Br J Haematol 2014; 164(5): 752–755.

65. Rosinol L, Cibeira MG, 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.

66. Perez Persona E, Vidriales MG, et al. New criteria to identify risk of progression in monoclonal gammopathy of undetermined significance and smoldering myeloma based on multiparameter flow cytometriy analysis of bone marrow plasma cells. Blood 2007; 110(7): 2586–2592.

67. Bladé J, Dimopoulos M, Rosiñol L et al. Smoldering (asymptomatic) multiple myeloma: current diagnostic criteria, new predictors of outcome, and follow-up recommendations. J Clin Oncol 2010; 28(4): 690–697.

68. Dizdar O, Erman M, Cankurtaran M at al. Lower bone mineral density in geriatric patients with monoclonal gammopathy of undetermined significance. Ann Hematol 2008; 87(1): 57–60.

69. Pepe J, Petrucci MT, Nofroni I et al. Lumbar bone mineral density as the major factor determining increased prevalence of vertebral fractures in monoclonal gammopathy of uncertain significance. Brit J Haematol 2006; 134(5): 485–490.

70. Melton LJ, Rajkumar SV, Khosla S et al. Fracture risk in monoclonal gammopathy of undetermined significance. J Bone Miner Res 2004; 19(1): 25–30.

71. Gregersen H, Jensen P, Gislum M et al. Fracture risk in patients with monoclonal gammopathy of undetermined significance. Brit J Haematol 2006; 135(1): 62–67.

72. Pepe J, Petrucci MT, Mascia ML et al. The effects of alendronate treatment in osteoporotic patients affected by monoclonal gammopathy of undetermined significance. Calcif Tissue Int 2008; 82(6): 418–426.

73. Jakob C, Zavrsky I, Heider U et al. Bone resorption parameters [carboxy-terminal telopeptide of type-I collagen (ICTP), amino-terminal collagen type-I telopeptide (NTx), and deoxypyridinoline (Dpd)] in MGUS and multiple myeloma. Eur J Haematol 2002; 69(1): 37–42.

74. Politou M, Termos E, Anagnostopoulos A et al. Role of receptor activator of nuclear factor-kappa B ligand (RANKL), osteoprotegerin and macrophage protein 1-alpha (MIP-1a) in monoclonal gammopathy of undetermined significance (MGUS). Brit J Haematol 2004; 126(5): 686- 689.

75. Bida JP, Kyle RA, Therneau TM et al. Disease association with monoclonal gammopathy of undetermined significance. A population based study of 17398 patients. Mayo Clin Proc 2009; 84(8): 685–693.

76. Farr JN, Zhang W, Kumar SK et al. Altered cortical microarchitecture in patients with monoclonal gammopathy of undetermined significance. Blood 2014; 123(5): 647–649.

77. Kristinsson SY, Tang M, Pfeiffer RM et al. Monoclonal gammopathy of undetermined significance and risk of skeletal fractures: a population-based study. Blood 2010; 116(15): 2651–2655.

78. Abrahamsen B, Andersen J, Christensen SS et al. Utility of testing for monoclonal bands in serum of patients with suspected osteoporosis. Brit Med J 2005; 330(7495): 818.

79. Golombic T, Diamond T et al. Prevalence of monoclonal gammopathy of undetermined significance /myeloma in patients with ace osteoporotic vertebral fracture. Annal Haematol 2008; 120(2): 87–90.

80. Srkalovic G, Cameron M, Rybicki L et al. Monoclonal gammopathy of undetermined significance and multiple myeloma are associated with an increased incidence of venothromboembolic disease. Cancer 2004; 101(3): 558–566.

81. Sallah S, Husain A, Wan J et al. The risk of venous thromboembolic disease in patients with monoclonal gammopathy of undetermined significance. Annals of Oncology 2004; 15(10): 1490–1494.

82. Kristinsson SA, Fars TR, Grindley G et al. Deep vein trombosis after monoclonal gammopathy of undetermined significance and multiple myeloma. Blood 2008; 112(9): 3582–3586.

83. Gregersen H, Norgaard M, Severinsen MT at al. Monoclonal gammopathy of undetermined significance and risk of venous trombembolism. Eur J Haematol 2011; 86(2): 129–134.

84. Kristinsson SY, Tang M, Phfeiffer RM et al. Monoclonal gammopathy of undetermined significance and risk of infections. A population based study. Haematologica 2012; 97(6): 854–858.

85. Roeker LE, Larson DR, Kyle RA et al. Risk of acute leukemia and myelodysplastic syndromes in patients with monoclonal gammopathy of undetermined significance (MGUS). A population-based study of 17315 patients. Leukemia 2013; 27(6): 1391–1393.

86. Jimenez-Zepeda VH, Heilman RL, Engel RA et al. Monoclonal gammopathy of undetermined significance does not affect outcomes in patients undergoing solid organ transplants. Transplantation 2011; 92(5): 570–574.

87. Redfield RR, Naji A. Progression of monoclonal gammopathy of undetermined significance to multiple myeloma in a solid organ transplant. Transplantation 2011; 92(12): e65-e66.

88. Rostaing L, Modesto A, Abbal M et al. Long-term follow-up of monoclonal gammopathy of undetermined significance in transplant patients. Am J Nephrol 1994; 14(3): 187–191.

89. Chakalarovski C, Lang P, Buisson C et al. Monoclonal immunoglobulins in patients with renal transplants: characterization, evolution and risk factors. Transpl Int 1992; 5(Suppl 1): S23-S25.

90. Hadden RD, Nobile-Orazio E, Sommer C et al. European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of paraproteinaemic demyelinating neuropathies: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur J Neurol 2006; 13(8): 809–818.

91. Berenson JR, Anderson KC, Aureol RA et al. Monoclonal gammopathy of undetermined significance: a consensus statement. Brit J Haematol 2010; 150(1): 28–38.

92. Brioli A, Giles H, Pawlyn C et al. Serum free immunoglobulin light chain evaluation as a marker of impact from intraclonal heterogeneity on myeloma outcome. Blood 2014; 123(22): 3414–3419.

93. 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.

94. 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.

95. Dimopoulos M, Termos E, Comenzo RL et al. International myeloma working group consensus statement and guidelines regarding the current role of imaging techniques and monitoring multiple myeloma. Leukemia 2009; 23(9): 1549–1556.

96. Moulopoulos LA, Dimopoulos MA, Smith TL et al. Prognostic significance of magnetic resonance imaging in patients with asymptomatic myeloma. J Clin Oncol 1995; 13(1): 251–256.

97. Mariette X, Zagdanski AM, Guermazi A et al. Prognostic value of vertebral lesions detected by magnetic resonance imaging stage I multiple myeloma. Br J Haematol 1999; 104(4): 723–729.

98. 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.

99. Minařík J, Hrbek J, Pika T et al. Srovnání přínosu konvenčního RTG, celotělové magnetické rezonance a celotělového nízkodávkového CT v diagnostice myelomové kostní nemoci. Osteol Bulletin 2013; 18(4): 143–147.

100. Minařík J, Hrbek J, Pika T et al. Pilotní hodnocení nízkodávkovné výpočetní tomografie (LD CT) u nemocných s mnohočetným myelomem, srovnání s konvenční radiografií a celotělovou magnetickou rezonancí. Olomoucké hematologické dny 2014. Sborník abstrakt. Dostupné z WWW: <http://www.olhemdny.cz/files/2014/abstrakta_2014.pdf>.

101. Caers J, Withofs N, Hillengass J et al. The role of positron emission tomography-computed tomography and magnetic resonance imaging in diagnosis and follow up of multiple myeloma. Haematologica2014; 99(4): 629–637.

102. Adam Z, Bolcak K, Stanicek J et al. Fluorodeoxyglucose positron emission tomography in multiple myeloma, solitary plasmocytoma and monoclonal gammapathy of unknown significance. Neoplasma 2007; 54(6): 536–640.

103. Sigurdardottir EE, Turesson I, Lund SH et al. Multiple Myeloma Patients With Prior Knowledge Of MGUS Have a Better Survival Compared To Multiple Myeloma Patients Without Prior Knowledge Of MGUS. Blood 2013; 122(21): 1984.

104. Bianchi G, Kyle RA, Colin L et al. Impact of optimal follow up of monoclonal gammopathy of undetermined significance, on early diagnosis and prevention of myeloma related complications. Blood 2010; 116(12): 2019–2025.

105. Dispenzieri A, Kyle RA, Katzmann JA et al. Immunoglobulin free light chain ratio is and independent riskt factor for progression of smoldering myeloma (asymptomatic) multiple myeloma. Blood 2008; 111(2): 758–789.

106. Rajkumar SV, Larson D, Kyle RA et al. Diagnosis of smoldering multiple myeloma. N Engl J Med 2011; 365(5): 474–475.

107. Rajkumar SV, Kyle RA. Haematological cancer: Treatment of smoldering multiple myeloma. Nat Rev Clin Oncol 2013; 10(10): 554–555.

108. Bladé J, Dimopoulos M, Rosinol L et al. Smoldering (asymptomatic) multiple myeloma. Current diagnostic kriteria new predictors of outcome and follow up recommendation. J Clin Oncol 2010; 28(4): 690–697.

109. Dispenzieri A, Stewart AK, Chanan-Khan A et al. Smoldering multiple myeloma requiring treatment: time for a new definition? Blood 2013; 122(26): 4172–4181.

110. Talamo G, Farroq U, Zangar M et al. Beyond the CRAB symptoms: a study of presenting clinical manifestations of multiple myeloma. Clin Lymphoma Myeloma Leuk 2010; 10(6): 464–468.

111. Mangiacavalli S, Cocito F, Pochintesta L et al. Monoclonal gammopathy of undetermined significance: a new proposal of work up. Eur J Haematol 2013; 91(4): 356–360.