Immunoglobulin Type M Monoclonal Gammopathy of Undetermined Significance (IgM-MGUS)

  • Mary L. McMaster
  • Helga M. Ögmundsdóttir
  • Sigurdur Y. Kristinsson
  • Robert A. Kyle
Chapter

Abstract

The term monoclonal gammopathy pertains to the expansion of a single clone of B lymphocytes that produce an excess of a homogeneous immunoglobulin. Monoclonal gammopathy of undetermined significance (MGUS) is diagnosed in a patient who presents with a monoclonal gammopathy in the absence of histologic evidence, signs, or symptoms of a malignant lymphoproliferative or plasmacytic disorder. MGUS is among the most common premalignant conditions in Western populations, having a prevalence of about 4 % in white adults older than age 50. The immunoglobulin type M (IgM) subtype of MGUS (IgM-MGUS) exhibits unique features that distinguish it from non-IgM MGUS, including a distinctive racial prevalence pattern and spectrum of malignant outcomes. Putative risk factors predisposing to development of IgM-MGUS have been identified, but most await confirmation. The MYD88 L265P mutation that is characteristic of Waldenström macroglobulinemia (WM) is found in about half of IgM-MGUS patients. The most common malignant outcome is WM, but patients can develop other lymphoproliferative B-cell diseases. Patients progress to WM at a rate of 1.5 % per year, and they continue to be at risk of progression more than 20 years following diagnosis. Size of the monoclonal component at diagnosis has been the most consistent predictor of prognosis. IgM MGUS is also associated with other nonmalignant comorbidities, and patients diagnosed with it have inferior survival compared to the general population. Thus, there is growing consensus that IgM monoclonal gammopathy may indeed have clinical significance. Further, while routine screening for IgM-MGUS is not widely advocated, it is recommended that, when discovered, IgM-MGUS patients should be followed for life.

Keywords

Multiple Myeloma Chronic Lymphocytic Leukemia Monoclonal Gammopathy Undetermined Significance Class Switch Recombination 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Owen RG, Treon SP, Al-Katib A, Fonseca R, Greipp PR, McMaster ML, Morra E, Pangalis GA, San Miguel JF, Branagan AR, Dimopoulos MA. Clinicopathological definition of Waldenstrom’s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom’s Macroglobulinemia. Semin Oncol. 2003;30(2):110–5.CrossRefPubMedGoogle Scholar
  2. 2.
    Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos M-V, 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 BGM, San Miguel JF. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538–48.CrossRefPubMedGoogle Scholar
  3. 3.
    Keren DE. Procedures for the evaluation of monoclonal immunoglobulins. Arch Pathol Lab Med. 1999;123:126–32.PubMedGoogle Scholar
  4. 4.
    Guinan JE, Kenny DF, Gatenby PA. Detection and typing of paraproteins: comparison of different methods in a routine diagnostic laboratory. Pathology. 1989;21:35–41.CrossRefPubMedGoogle Scholar
  5. 5.
    Aguzzi E, Bergami MR, Gasparro C, Bellotti V, Merlini G. Occurrence of monoclonal components in general practice: clinical implications. Eur J Haematol. 1992;48:192–5.CrossRefPubMedGoogle Scholar
  6. 6.
    Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Offord JR, Dispenzieri A, Katzmann JA, Melton III LJ. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006;354(13):1362–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Murray DL, Seningen JL, Dispenzieri A, Snyder MR, Kyle RA, Rajkumar SV, Katzmann JA. Laboratory persistence and clinical progression of small monoclonal abnormalities. Am J Clin Pathol. 2012;138(4):609–13.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Strobel SL. Transient paraproteinemia: an intriguing immunological anomaly. Ann Clin Lab Sci. 2003;33(3):265–70.PubMedGoogle Scholar
  9. 9.
    Morra E, Cesana C, Kiersy C, Varettoni M, Cavanna L, Canesi B, Tresoldi E, Barbarano L, Lazzarino M. Predictive variables for malignant transformation in 452 patients with asymptomatic IgM monoclonal gammopathy. Semin Oncol. 2003;30(2):172–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Dispenzieri A, Katzmann JA, Kyle RA, Larson DR, Melton III LJ, Colby CL, Therneau TM, Clark R, Kumar SK, Bradwell A, Fonseca R, Jelinek DF, Rajkumar SV. Prevalence and risk of progression of light-chain monoclonal gammopathy of undetermined significance: a retrospective population-based cohort study. Lancet. 2010;375(9727):1721–8.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Drayson M, Tang L, Drew R, Mead G, Carr-Smith H, Bradwell A. Serum free light-chain measurements for identifying and monitoring patients with nonsecretory multiple myeloma. Blood. 2001;97:2900–2.CrossRefPubMedGoogle Scholar
  12. 12.
    Wood PB, McElroy YG, Stone MJ. Comparison of serum immunofixation electrophoresis and free light chain assays in the detection of monoclonal gammopathies. Clin Lymphoma Myeloma Leuk. 2010;10(4):278–80.CrossRefPubMedGoogle Scholar
  13. 13.
    McMaster ML, Landgren O. Prevalence, clinical aspects and natural history of IgM MGUS. Cytometry B Clin Cytom. 2010;78 Suppl 1:S91–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Landgren O, Graubard BI, Katzmann JA, Kyle RA, Ahmadizadeh I, Clark R, Kumar SK, Dispenzieri A, Greenberg AJ, Therneau TM, Melton III LJ, Caporaso N, Korde N, Roschewski M, Costello R, McQuillan GM, Rajkumar SV. Racial disparities in the prevalence of monoclonal gammopathies: a population-based study of 12 482 persons from the National Health and Nutritional Examination Survey. Leukemia. 2014;28:1537–42.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA, editors. SEER Cancer Statistics Review, 1975–2011. National Cancer Institute, Bethesda, MD. http://seer.cancer.gov/csr/1975_2011/, based on November 2013 SEER data submission, posted to the SEER website, April, 2014.
  16. 16.
    Landgren O, Gridley G, Turesson I, Caporaso NE, Goldin LR, Baris D, Fears TR, Hoover RN, Linet MS. Risk of monoclonal gammopathy of undetermined significance (MGUS) and subsequent multiple myeloma among African American and white veterans in the United States. Blood. 2006;107(3):904–6.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Landgren O, Katzmann JA, Hsing AW, Pfeiffer RM, Kyle RA, Yeboah ED, Biritwum RB, Tettey Y, Adjei AA, Larson DR, Dispenzieri A, Melton III LJ, Goldin LR, McMaster ML, Caporaso NE, Rajkumar SV. Prevalence of monoclonal gammopathy of undetermined significance among men in Ghana. Mayo Clin Proc. 2007;82(12):1468–73.CrossRefPubMedGoogle Scholar
  18. 18.
    Landgren O, Rajkumar SV, Pfeiffer RM, Kyle RA, Katzmann JA, Dispenzieri A, Cai Q, Goldin LR, Caporaso NE, Fraumeni JF, Blot WJ, Signorello LB. Obesity is associated with an increased risk of monoclonal gammopathy of undetermined significance (MGUS) among African-American and Caucasian women. Blood. 2010;116(7):1056–9.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Wang H, Chen Y, Li F, Delasalle K, Wang J, Alexanian R, Kwak L, Rustveld L, Du XL, Wang M. Temporal and geographic variations of Waldenstrom macroglobulinemia incidence: a large population-based study. Cancer. 2012;118(15):3793–800.CrossRefPubMedGoogle Scholar
  20. 20.
    Iwanaga M, Tagawa M, Tsukasaki K, Kamihira S, Tomonaga M. Prevalence of monoclonal gammopathy of undetermined significance: a study of 52,802 persons in Nagasaki City, Japan. Mayo Clin Proc. 2007;82(12):1474–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Wu SP, Minter A, Costello R, Zingone A, Lee C-K, Au W-Y, Landgren O. MGUS prevalence in an ethnically Chinese population in Hong Kong. Blood. 2013;121(12):2363–4.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Watanaboonyongcharoen P, Nakorn TN, Rojnuckarin P, Lawasut P, Intragumtornchai T. Prevalence of monoclonal gammopathy of undetermined significance in Thailand. Int J Hematol. 2012;95(2):176–81.CrossRefPubMedGoogle Scholar
  23. 23.
    Park HK, Lee KR, Kim YJ, Cho HI, Eun Kim J, Woong Kim K, Jung Kim Y, Lee KW, Hyun Kim J, Bang SM, Lee JS. Prevalence of monoclonal gammopathy of undetermined significance in an elderly urban Korean population. Am J Hematol. 2011;86(9):752–5.CrossRefPubMedGoogle Scholar
  24. 24.
    Ruiz-Argüelles GJ, Ruiz-Delgado GJ. On the prevalence and genetic predisposition of monoclonal gammopathy of undetermined significance (MGUS). Int J Hematol. 2012;96:144–5.CrossRefPubMedGoogle Scholar
  25. 25.
    Cabrera Q, Macro M, Hebert B, Cornet E, Collignon A, Troussard X. Epidemiology of monoclonal gammopathy of undetermined significance (MGUS): the experience from the specialized registry of hematologic malignancies of Basse-Normandie (France). Cancer Epidemiol. 2014;38:354–6.CrossRefPubMedGoogle Scholar
  26. 26.
    Saleun JP, Vicariot M, Deroff P, Morin JF. Monoclonal gammopathies in the adult population of Finistère, France. J Clin Pathol. 1982;35(1):63–8.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Anagnostopoulos A, Evangelopoulou A, Sotou D, Gika D, Mitsibounas D, Dimopoulos MA. Incidence and evolution of monoclonal gammopathy of undetermined significance (MGUS) in Greece. Ann Hematol. 2002;81(7):357–61.CrossRefPubMedGoogle Scholar
  28. 28.
    Axelsson U, Bachmann R, Hällén J. Frequency of pathological proteins (M-components) in 6,995 sera from an adult population. Acta Med Scand. 1966;179:235–47.CrossRefPubMedGoogle Scholar
  29. 29.
    Fine JM, Lambin P, Leroux P. Frequency of monoclonal gammopathy (‘M components’) in 13,400 sera from blood donors. Vox Sang. 1972;23:336–43.CrossRefPubMedGoogle Scholar
  30. 30.
    Lindqvist EK, Goldin LR, Landgren O, Blimark C, Mellqvist UH, Turesson I, Wahlin A, Björkholm M, Kristinsson SY. Personal and family history of immune-related conditions increase the risk of plasma cell disorders: a population-based study. Blood. 2011;118(24):6284–91.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Landgren O, Kristinsson SY, Goldin LR, Caporaso NE, Blimark C, Meliqvist UH, Wahlin A, Bjorkholm M, Turesson I. 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):791–5.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Vachon CM, Kyle RA, Therneau TM, Foreman BJ, Larson DR, Colby CL, Phelps TK, Dispenzieri A, Kumar SK, Katzmann JA, Rajkumar SV. Increased risk of monoclonal gammopathy in first-degree relatives of patients with multiple myeloma or monoclonal gammopathy of undetermined significance. Blood. 2009;114(4):785–90.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Grass S, Preuss K-D, Wikowicz A, Terpos E, Ziepert M, Nikolaus D, Yang Y, Fadle N, Regitz E, Dimopoulos MA, Treon SP, Hunter ZR, Pfreundschuh M. Hyperphosphorylated paratarg-7: a new molecularly defined risk factor for monoclonal gammopathy of undetermined significance of the IgM type and Waldenström macroglobulinemia. Blood. 2011;117(10):2918–23.CrossRefPubMedGoogle Scholar
  34. 34.
    Preuss K-D, Pfreundschuh M, Fadle N, Regitz E, Kubuschok B. Sumoylated HSP90 is a dominantly inherited plasma cell dyscrasias risk factor. J Clin Invest. 2015;125(1):316–23.CrossRefPubMedGoogle Scholar
  35. 35.
    Kriangkum J, Taylor BJ, Reiman T, Belch AR, Pilarski LM. Origins of Waldenström’s macroglobulinemia: does it arise from an unusual B-cell precursor? Clin Lymphoma. 2005;5(4):217–9.CrossRefPubMedGoogle Scholar
  36. 36.
    Sahota SS, Forconi F, Ottensmeier CH, Provan D, Oscier DG, Hamblin TJ, Stevenson FK. Typical Waldenstrom macroglobulinemia is derived from a B-cell arrested after cessation of somatic mutation but prior to isotype switch events. Blood. 2002;100(4):1505–7.PubMedGoogle Scholar
  37. 37.
    Martín-Jiménez P, García-Sanz R, Balanzategui A, Alcoceba M, Ocio E, Sanchez ML, González M, San Miguel J. Molecular characterization of heavy chain immunoglobulin gene rearrangements in Waldenström’s macroglobulinemia and IgM monoclonal gammopathy of undetermined significance. Haematologica. 2007;92:635–42.CrossRefPubMedGoogle Scholar
  38. 38.
    Rollett RA, Wilkinson EJ, Gonzalez D, Fenton JAL, Short MA, Evans PAS, Rawstron AC, Owen RG. Immunoglobulin heavy chain sequence analysis in Waldenström’s macroglobulinemia and immunoglobulin M monoclonal gammopathy of undetermined significance. Clin Lymphoma Myeloma. 2006;7(1):70–2.CrossRefPubMedGoogle Scholar
  39. 39.
    McMaster ML, Giambarresi T, Vasquez L, Goldstein AM, Tucker MA. Cytogenetics of familial Waldenström’s macroglobulinemia: in pursuit of an understanding of genetic predisposition. Clin Lymphoma. 2005;5(4):230–4.CrossRefPubMedGoogle Scholar
  40. 40.
    Bergsagel PL, Kuehl WM. Molecular pathogenesis and a consequent classification of multiple myeloma. J Clin Oncol. 2005;23(26):6333–8.CrossRefPubMedGoogle Scholar
  41. 41.
    Schop RFJ, Van Wier SA, Xu R, Ghobrial I, Ahmann GJ, Greipp PR, Kyle RA, Dispenzieri A, Lacy MQ, Rajkumar SV, Gertz MA, Fonseca R. 6q deletion discriminates Waldenström macroglobulinemia from IgM monoclonal gammopathy of undetermined significance. Cancer Genet Cytogenet. 2006;169:150–3.CrossRefPubMedGoogle Scholar
  42. 42.
    Treon SP, Xu L, Yang G, Zhou Y, Liu X, Cao Y, Sheehy P, Manning RJ, Patterson CJ, Tripsas C, Arcaini L, Pinkus GS, Rodig SJ, Sohani AR, Harris NL, Laramie JM, Skifter DA, Lincoln SE, Hunter ZR. MYD88 L265P somatic mutation in Waldenström’s macroglobulinemia. N Engl J Med. 2012;367(9):826–33.CrossRefPubMedGoogle Scholar
  43. 43.
    Landgren O, Staudt L. MYD88 L265P somatic mutation in IgM MGUS. N Engl J Med. 2012;367(23):2255–6.CrossRefPubMedGoogle Scholar
  44. 44.
    Varettoni M, Arcaini L, Zibellini S, Boveri E, Rattotti S, Riboni R, Corso A, Orlandi E, Bonfichi M, Gotti M, Pascutto C, Mangiacavalli S, Croci G, Fiaccadori V, Morello L, Guerrera ML, Paulli M, Cazzola M. Prevalence and clinical significance of the MYD88 (L265P) somatic mutation in Waldenström’s macroglobulinemia and related lymphoid neoplasms. Blood. 2013;121(13):2522–8.CrossRefPubMedGoogle Scholar
  45. 45.
    Xu L, Hunter ZR, Yang G, Zhou Y, Cao Y, Liu X, Morra E, Trojani A, Greco A, Arcaini L, Varettoni M, Brown JR, Tai Y-T, Anderson KC, Munshi NC, Patterson CJ, Manning RJ, Tripsas CK, Lindeman NI, Treon SP. MYD88 L265P in Waldenström macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction. Blood. 2013;121(11):2051–8.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Jiménez C, Sebastián E, Chillón MC, Giraldo P, Mariano Hernández J, Escalante F, González-López TJ, Aguilera C, de Coca AG, Murillo I, Alcoceba M, Balanzategui A, Sarasquete ME, Corral R, Marín LA, Paiva B, Ocio EM, Gutiérrez NC, San Miguel JF, Garcia-Sanz R. MYD88 L265P is a marker highly characteristic of, but not restricted to, Waldenström’s macroglobulinemia. Leukemia. 2013;27(8):1722–8.CrossRefPubMedGoogle Scholar
  47. 47.
    McMaster ML, Goldin LR, Bai Y, Ter-Minassian M, Boehringer S, Giambarresi TR, Vasquez LG, Tucker MA. Genome wide linkage screen for Waldenström macroglobulinemia susceptibility loci in high-risk families. Am J Hum Genet. 2006;79(4):695–701.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Braggio E, Fonseca R. Genomic abnormalities of Waldenström macroglobulinemia and related low-grade B-cell lymphomas. Clin Lymph Myeloma Leukemia. 2013;13(2):198–201.CrossRefGoogle Scholar
  49. 49.
    Baldini L, Guffanti A, Cesana BM, Colombi M, Chiorboli O, Damilano I, Maiolo AT. Role of different hematologic variables in defining the risk of malignant transformation in monoclonal gammopathy. Blood. 1996;87(3):912–8.PubMedGoogle Scholar
  50. 50.
    Blade J, Lopez-Guillermo A, Rozman C, Cervantes F, Salgado C, Aguilar J-L, Vives-Corrons J-L, Montserrat E. Malignant transformation and life expectancy in monoclonal gammopathy of undetermined significance. Br J Haematol. 1992;81:391–4.CrossRefPubMedGoogle Scholar
  51. 51.
    Colls BM. Monoclonal gammopathy of undetermined significance (MGUS) – 31 year follow up of a community study. Aust NZ J Med. 1999;29(4):500–4.CrossRefGoogle Scholar
  52. 52.
    Pasqualetti P, Casale R. Risk of malignant transformation in patients with monoclonal gammopathy of undetermined significance. Biomed Pharmacother. 1997;51:74–8.CrossRefPubMedGoogle Scholar
  53. 53.
    van de Donk N, de Weerdt O, Eurelings M, Bloem A, Lokhorst H. Malignant transformation of monoclonal gammopathy of undetermined significance: cumulative incidence and prognostic factors. Leuk Lymphoma. 2001;42(4):609–18.CrossRefGoogle Scholar
  54. 54.
    van de Poel MHW, Coebergh JWW, Hillen HFP. Malignant transformation of monoclonal gammopathy of undetermined significance among out-patients of a community hospital in Southeastern Netherlands. Br J Haematol. 1995;91:121–5.CrossRefPubMedGoogle Scholar
  55. 55.
    Ögmundsdóttir HM, Haraldsdóttir V, Gudmundur MJ, Ólafsdótir G, Bjarnadóttir K, Sigvaldason H, Tulinius H. Monoclonal gammopathy in Iceland: a population-based registry and follow-up. Br J Haematol. 2002;118:166–73.CrossRefPubMedGoogle Scholar
  56. 56.
    Gregersen H, Mellemkjaer L, Ibsen JS, Dahlerup JF, Thomassen L, Sørensen HT. 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):1172–9.PubMedGoogle Scholar
  57. 57.
    Cesana C, Klersy C, Barbarano L, Nosari AM, Crugnola M, Pungolino E, Gargantini L, Granata S, Valentini M, Morra E. Prognostic factors for malignant transformation in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. J Clin Oncol. 2002;20(6):1625–34.CrossRefPubMedGoogle Scholar
  58. 58.
    Turreson I, Kovalchik SA, Pfeiffer RM, Kristinsson SY, Goldin LR, Drayson MT, Landgren O. Monoclonal gammopathy of undetermined significance and risk of lymphoid and myeloid malignancies: 728 cases followed up to 30 years in Sweden. Blood. 2014;123(3):338–45.CrossRefGoogle Scholar
  59. 59.
    Waldmann TA, Strober W. Metabolism of immunoglobulins. Prog Allergy. 1969;13:1–110.PubMedGoogle Scholar
  60. 60.
    Rajkumar SV, Kyle RA, Therneau TM, Melton III LJ, Bradwell AR, Clark RJ, Larson DR, Plevak MF, Dispenzieri A, Katzmann JA. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood. 2005;106(3):812–7.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Kyle RA, Therneau TM, Rajkumar SV, Remstein ED, Offord JR, Larson DR, Plevak MF, Melton III LJ. Long-term follow-up of IgM monoclonal gammopathy of undetermined significance. Blood. 2003;102(10):3759–64.CrossRefPubMedGoogle Scholar
  62. 62.
    Montoto S, Rozman M, Rosiñol L, Nadal E, Giné E, Aymerich M, Ferrer A, Esteve J, Bosch F, López-Guillermo A, Bladé J, Montserrat E. Malignant transformation in IgM monoclonal gammopathy of undetermined significance. Semin Oncol. 2003;30(2):178–81.CrossRefPubMedGoogle Scholar
  63. 63.
    Morra E, Cesana C, Klersy C, Barbarano L, Miqueleiz S, Varettoni M, Lucchesini C, Ricci F, Lazzarino M. Prognostic factors for transformation on asymptomatic immunoglobulin M monoclonal gammopathies. Clin Lymphoma. 2005;5(4):265–9.CrossRefPubMedGoogle Scholar
  64. 64.
    Baldini L, Goldaniga M, Guffanti A, Broglia C, Cortelazzo S, Rossi A, Morra E, Columbi M, Callea V, Pogliani E, Ilariucci F, Luminari S, Morel P, Merlini G, Gobbi P. Immunoglobulin M monoclonal gammopathies of undetermined significance and indolent Waldenström’s macroglobulinemia recognize the same determinants of evolution into symptomatic lymphoid disorders: proposal for a common prognostic scoring system. J Clin Oncol. 2005;23(21):4662–8.CrossRefPubMedGoogle Scholar
  65. 65.
    Morra E, Cesana C, Klersy C, Barbarano L, Varettoni M, Cavanna L, Canesi B, Tresoldi E, Miqueleiz S, Bernuzzi P, Nosari AM, Lazzarino M. Clinical characteristics and factors predicting evolution of asymptomatic IgM monoclonal gammopathies and IgM-related disorders. Leukemia. 2004;18:1512–7.CrossRefPubMedGoogle Scholar
  66. 66.
    Kyle RA, Benson JT, Larson DR, Therneau TM, Dispenzieri A, Kumar S, Melton III JM, Rajkumar SV. Progression in smoldering Waldenström macroglobulinemia: long-term results. Blood. 2012;119(19):4462–6.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Steingrimsdottir H, Haraldsdottir V, Olafsson Í, Gudnason V, Ogmundsdottir H. Monoclonal gammopathy: natural history studied with a retrospective approach. Haematologica. 2007;92(8):1131–4.CrossRefPubMedGoogle Scholar
  68. 68.
    Landgren O, Kyle RA, Pfeiffer RM, Katzmann JA, Caporaso NE, Hayes RB, Dispenzieri A, Kumar S, Clark RJ, Baris D, Hoover R, Rajkumar SV. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood. 2009;113(22):5412–7.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Weiss BM, Abadie J, Verma P, Howard RS, Kuehl WM. A monoclonal gammopathy precedes multiple myeloma in most patients. Blood. 2009;113(22):5418–22.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    McMaster ML, Csako G. Protein electrophoresis, immunoelectrophoresis and immunofixation electrophoresis as predictors for high-risk phenotype in familial Waldenström macroglobulinemia. Int J Cancer. 2008;122(5):1183–8.CrossRefPubMedGoogle Scholar
  71. 71.
    Kristinsson SY, Björkholm M, Goldin LR, McMaster ML, Turesson I, Landgren O. Risk of lymphoproliferative disorders among first-degree relatives of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia patients: a population-based study in Sweden. Blood. 2008;112(8):3052–6.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Steingrímsson V, Lund SH, Turesson I, Goldin LR, Björkholm M, Landgren O, Kristinsson SY. Population-based study on the impact of the familial form of Waldenström macroglobulinemia on overall survival. Blood. 2015;125(13):2174–5.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Kyle RA. ‘Benign’ monoclonal gammopathy – after 20-35 years of follow-up. Mayo Clin Proc. 1993;68:26–36.CrossRefPubMedGoogle Scholar
  74. 74.
    Gregersen H, Ibsen JS, Mellemkjœr L, Dahlerup JF, Olsen JH, Sørensen HT. Mortality and causes of death in patients with monoclonal gammopathy of undetermined significance. Br J Haematol. 2001;112:353–7.CrossRefPubMedGoogle Scholar
  75. 75.
    Schaar CG, le Cessie S, Snijder S, Franck PFH, Wijermans PW, Ong C, Kluin-Nelemans H. Long-term follow-up of a population based cohort with monoclonal proteinaemia. Br J Haematol. 2008;144:176–84.CrossRefPubMedGoogle Scholar
  76. 76.
    Kristinsson SY, Björkholm M, Andersson TM-L, Eloranta S, Dickman PW, Goldin LR, Blimark C, Mellqvist U-H, Wahlin A, Turesson I, Landgren O. Patterns of survival and causes of death following a diagnosis of monoclonal gammopathy of undetermined significance: a population-based study. Haematologica. 2009;94(12):1714–20.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Gobbi PG, Baldini L, Broglia C, Goldaniga M, Comelli M, Morel P, Morra E, Cortelazzo S, Bettini R, Merlini G. Prognostic validation of the international classification of immunoglobulin M gammopathies: a survival advantage for patients with immunoglobulin M monoclonal gammopathy of undetermined significance? Clin Cancer Res. 2005;11(5):1786–90.CrossRefPubMedGoogle Scholar
  78. 78.
    Bida JP, Kyle RA, Therneau TM, Melton III LJ, Plevak MF, Larson DR, Dispenzieri A, Katzmann JA, Rajkumar SV. Disease associations with monoclonal gammopathy of undetermined significance: a population-based study of 17,398 patients. Mayo Con Proc. 2009;84(8):685–93.CrossRefGoogle Scholar
  79. 79.
    Gregersen H, Madsen KM, Sørensen HT, Schønheyder HC, Ibsen JS, Dahlerup JF. The risk of bacteremia in patients with monoclonal gammopathy of undetermined significance. Eur J Haematol. 1998;61(2):140–2.CrossRefPubMedGoogle Scholar
  80. 80.
    Kristinsson SY, Tang M, Pfeiffer RM, Björkholm M, Goldin LR, Blimark C, Mellqvist U-H, Wahlin A, Turesson I, Landgren O. Monoclonal gammopathy of undetermined significance and risk of infections: a population-based study. Haematologica. 2012;97(6):854–8.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Tete SM, Kipling D, Westra J, de Haan A, Bijl M, Dunn-Walters DK, Sahota SS, Bos NA. Monoclonal paraprotein influences baseline B-cell repertoire diversity and perturbates influenza vaccination-induced B-cell response. Exp Hematol. 2015;43:439–47.CrossRefPubMedGoogle Scholar
  82. 82.
    Bataille R, Chappard D, Alexandre C, Dessauw P, Sany J. Importance of quantitative histology of bone changes in monoclonal gammopathy. Br J Cancer. 1986;53:805–10.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Vejlgaard T, Abildgaard N, Jans H, Nielsen JL, Heickendorff L. Abnormal bone turnover in monoclonal gammopathy of undetermined significance: analyses of type I collagen telopeptide, osteocalcin, bone-specific alkaline phosphatase and propeptides of type I and type III procollagens. Eur J Haematol. 1997;58:104–8.CrossRefPubMedGoogle Scholar
  84. 84.
    Pepe J, Petrucci MT, Nofornoi I, Fassino V, Diacinti D, Romagnoli E, Minisola S. Lumbar bone mineral density as the major factor determining increased prevalence of vertebral fractures in monoclonal gammopathy of undetermined significance. Br J Haematol. 2006;134:485–90.CrossRefPubMedGoogle Scholar
  85. 85.
    Melton III LJ, Rajkumar SV, Khosla S, Achenbach SJ, Oberg AL, Kyle RA. Fracture risk in monoclonal gammopathy of undetermined significance. J Bone Miner Res. 2004;19:25–30.CrossRefPubMedGoogle Scholar
  86. 86.
    Gregersen H, Jensen P, Gislum M, Jørgensen B, Sørensen HT, Nørgaard M. Fracture risk in patients with monoclonal gammopathy of undetermined significance. Br J Haematol. 2006;135:62–7.CrossRefPubMedGoogle Scholar
  87. 87.
    Kristinsson SY, Tang M, Pfeiffer RM, Björkholm M, Blimark C, Mellqvist U-H, Wahlin A, Turesson I, Landgren O. Monoclonal gammopathy of undetermined significance and risk of skeletal fractures: a population-based study. Blood. 2010;116(15):2651–5.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Piot JM, Royer M, Schmidt-Tanguy A, Hoppé E, Gardembas M, Bourrée T, Hunault M, François S, Boyer F, Ifrah N, Renier G, Chevailler A, Audran M, Chappard D, Libouban H, Mabilleau G, Legrand E, Bouvard B. Factors associated with an increased risk of vertebral fracture in monoclonal gammopathies of undetermined significance. Blood Cancer J. 2016;5:e345. doi: 10.1038/bcj.2015.71.CrossRefGoogle Scholar
  89. 89.
    Kristinsson SY, Pfeiffer RM, Björkholm M, Goldin LR, Schulman S, Blimark C, Mellqvist U-H, Wahlin A, Turesson I, Landgren O. Arterial and venous thrombosis in monoclonal gammopathy of undetermined significance and multiple myeloma: a population-based study. Blood. 2010;115(24):4991–8.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Treon SP, Soumerai JD, Branagan AR, Hunter ZR, Patterson CJ, Ioakimidis L, Chu L, Musto P, Baron AD, Nunnink JC, Kash JJ, Terjanian TO, Hyman PM, Nawfel EL, Sharon DJ, Munshi NC, Anderson KC. Lenalidomide and rituximab in Waldenstrom's macroglobulinemia. Clin Cancer Res. 2009;15(1):355–60.CrossRefPubMedGoogle Scholar
  91. 91.
    Hultcrantz M, Pfeiffer RM, Björkholm M, Goldin LR, Turesson I, Schulman S, Landgren O, Kristinsson SY. Elevated risk of venous but not arterial thrombosis in Waldenström macroglobulinemia/lymphoplasmacytic lymphoma. J Thromb Haemost. 2014;12(11):1816–21.CrossRefPubMedGoogle Scholar
  92. 92.
    Cao XX, Meng Q, Mao YY, Su W, Zhen JF, Shen KN, Zhang CL, Huang XF, Duan MH, Zhang W, Zhu TN, Cai HC, Chen M, Zhou DB, Li J. The clinical spectrum of IgM monoclonal gammopathy: a single center retrospective study of 377 patients. Leukemia Res. 2016;46:85–8.CrossRefGoogle Scholar
  93. 93.
    Go R, Doyle LM. A monoclonal gammopathy in search of clinical significance: 57 years later. Blood. 2009;114(11):2355–6.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  • Mary L. McMaster
    • 1
    • 2
  • Helga M. Ögmundsdóttir
    • 3
  • Sigurdur Y. Kristinsson
    • 3
    • 4
  • Robert A. Kyle
    • 5
  1. 1.Division of Cancer Epidemiology and Genetics, Department of Health and Human ServicesNational Cancer Institute, National Institutes of HealthBethesdaUSA
  2. 2.Commissioned Corps, Department of Health and Human ServicesUnited States Public Health ServiceWashington, DCUSA
  3. 3.Faculty of MedicineUniversity of IcelandReykjavikIceland
  4. 4.Department of MedicineKarolinska University Hospital and Karolinska InstituteStockholmSweden
  5. 5.Division of Hematology and internal MedicineMayo Clinic College of MedicineRochesterUSA

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