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benign monoclonal gammopathy; monoclonal gammopathy of undetermined significance (MGUS)

Etiology: 1) idiopathic 2) 25% of patients with Gaucher's disease have MGUS 3) 15% of AIDS patients have MGUS 4) Schnitzler syndrome (1% of patients with MGUS) Epidemiology: 1) prevalence is 6.6% of elderly > 80 years of age, - 1.7% of population age 50-59 years - 3.2% of population > 50 years [5,10] - 10% of population > > 50 years [14] - 0.15% of the general population 2) prevalence is higher in African Americans than the general US population, 17% in blacks > 50 years [14] Pathology: 1) limited proliferation of immunoglobulin-secreting cells 2) < 10% bone marrow plasma cells 3) no myeloma-related organ pathology Genetics: - MICA plays role in progression of MGUS Clinical manifestations: 1) most patients are asymptomatic 2) 10% have an associated polyneuropathy Laboratory: 1) complete blood count (CBC): no anemia 2) serum chemistries a) serum calcium: no hypercalcemia b) serum creatinine: no renal insufficiency 3) serum protein electrophoresis a) "M" spike, IgG or IgA, (most IgG) b) monoclonal IgA, IgG or IgM > 0.2 g/dL & < 3 g/dL [1,14] c) if M spike > 1.5 g/dL, obtain bone marrow biopsy [6] 4) serum free light chains* - kappa/lambda free light chains in serum - more sensitive than free light chains in urine - < 0.26 or > 1.65 associated with increased risk of progression to multiple myeloma [6] 5) urinalysis - may show hematuria 6) urine protein electrophoresis: - light chains in urine < 500 mg/24 hours [1] 7) serum beta-2 microglobulin < 0.3 mg/dL - useful for prognosis in multiple myeloma - not routinely measured in MGUS [1] 8) serum IL-6 generally normal in MGUS, but not helpful 9) erythrocyte sedimentation rate (< 40 mm/hr) 10) cytogenetics: a) generally normal because of low proliferative rate & low number of plasma cells in bone marrow b) more sensitive methods frequently demonstrate chromosomal aberrations - chromosomal translocations involving heavy chain on chromosome 14q32 in 50% 11) annual testing with serum protein electrophoresis & serum free light chains [12] 12) see ARUP consult [7] * a newly described disorder monoclonal gammopathy of renal significance requires renal biopsy for diagnosis, thus serum free light chains not indicated prior to renal biopsy if MGUS with active urine sediment & increase in serum creatinine [1] * another diagnosis monoclonal gammopathy of indeterminate potential with M spike of 0.015-0.2 g/dL [14] (not associated with development of hematologic malignancy) Special laboratory: - bone marrow biopsy & bone marrow aspirate - obtain if M spike > 1.5 g/dL - < 10% plasma cells in the bone marrow - renal biopsy - obtain if active urine sediment & increase in serum creatinine [1] * a prediction model for which patients should be considered for bone marrow sampling is available as online calculator [16] Radiology: 1) MRI of skull, spine, pelvis may be useful 2) radiographic survey, including long bones - no osteolytic bone lesions 3) bone mineral density to assess osteoporosis [1] Complications: 1) 27% evolve into plasma-cell dyscrasia within 25 years [4] a) multiple myeloma b) Waldenstrom's macroglobulinemia c) AL-amyloidosis d) B-cell lymphoma 2) multiple myeloma may evolve from MGUS more than 30 years since initial presentation (mean of 8-10 years); many of these cases may be considered "smoldering myeloma" 3) concentration of monoclonal protein is most important risk factor for progression to plasma-cell dyscrasia [3]; 4) M-spike > 1.5 g/dL & abnormal serum free light chains are predictive of progression to plasma cell dyscrasia over 20 years 5) IgA or IgM M protein increases risk of progression to multiple myeloma [1,10] 6) low-risk MGUS can progress to multiple myeloma within 5 years [12] 7) increased risk of vertebral fractures 8) end-stage renal disease with high rates of recurrence after renal transplantation [9] 9) risk of progression: 1% annual risk [15]; 10% at 10 years, 18% at 20 years, 28% at 30 years, 36% at 35 years, & 36% at 40 years [10] 10) benign monoclonal gammopathy of renal significance (see Management:) 11) 20% higher risk of all-cause mortality compared with the general US population [15] * without accounting for death due to competing causes Management: 1) watchful waiting: monitor all patients indefinitely [6] - clinically monitor patients every 6-12 months [1] - routine follow-up laboratory testing unnecessary [1] 2) plasma exchange may be useful in patients with IgA-associated neuropathy 3) prognosis a) low risk of progression when - M-protein < 1.5 g/dL - bone marrow plasma cells < 5% - polyclonal immunoglobulin levels are normal - no detectable free light chain - ESR < 40 mm/hr b) idiopathic Bence Jones proteinuria or abnormal kappa/lambda free light chain in serum associated with increased of progression to multiple myeloma (RR = 2.5) - requires multiple myeloma-like therapy [1] 4) bisphosphonates normalize bone turnover markers & may reduce risk of vertebral fractures [6]

Related

monoclonal gammopathy of renal significance multiple myeloma; plasmacytoma/plasma cell myeloma protein electrophoresis Schnitzler syndrome

General

lymphoproliferative disorder paraproteinemia (monoclonal gammopathy) plasma cell dyscrasia

References

  1. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018, 2022. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  2. Bataille R, Harousseau JL. Multiple myeloma. N Engl J Med. 1997 Jun 5;336(23):1657-64. Review. PMID: 9171069
  3. Journal Watch 22(6):44-45, 2002 Kyle RA et al, Monoclonal gammopathies of undetermined significance. N Engl J Med 2002, 346:564 PMID: 12616697
  4. Journal Watch 24(16):129, 2004 Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Melton LJ 3rd. 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 Jul;79(7):859-66. PMID: 15244381
  5. Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Offord JR, Dispenzieri A, Katzmann JA, Melton LJ 3rd. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006 Mar 30;354(13):1362-9. PMID: 16571879
  6. Geriatrics at your Fingertips, 13th edition, 2011 Reuben DB et al (eds) American Geriatric Society
  7. ARUP Consult: Plasma Cell Dyscrasias The Physician's Guide to Laboratory Test Selection & Interpretation https://arupconsult.com/content/plasma-cell-dyscrasias - Plasma Cell Dyscrasias Testing Algorithm https://arupconsult.com/algorithm/plasma-cell-dyscrasias-testing-algorithm
  8. Kyle RA, Durie BG, Rajkumar SV et al 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 Jun;24(6):1121-7. PMID: 20410922
  9. Leung N, Bridoux F, Hutchison CA et al Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant. Blood. 2012 Nov 22;120(22):4292-5 PMID: 23047823
  10. Kyle RA, Larson DR, Therneau TM et al Long-Term Follow-up of Monoclonal Gammopathy of Undetermined Significance. N Engl J Med 2018; 378:241-249. January 18, 2018 PMID: 29342381 http://www.nejm.org/doi/full/10.1056/NEJMoa1709974
  11. 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 Jun;99(6):984-96. Review. PMID: 24658815 Free PMC Article
  12. Landgren O, Hofmann JN, McShane CM et al Association of Immune Marker Changes With Progression of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma. JAMA Oncol. Published online July 18, 2019. PMID: 31318385 https://jamanetwork.com/journals/jamaoncology/fullarticle/2738419 - Munshi NC, Jagannath S; Avet-Loiseau H. Monoclonal Gammopathy May Be of Unpredictable Significance. JAMA Oncol. Published online July 18, 2019. PMID: 31318381 https://jamanetwork.com/journals/jamaoncology/fullarticle/2738413
  13. Ravindran A, Lackore KA, Glasgow AE, et al. Monoclonal gammopathy of undetermined significance: Indications for prediagnostic testing, subsequent diagnoses, and follow-up practice at Mayo Clinic. Mayo Clin Proc 2020 May; 95:944 PMID: 32370855 https://www.mayoclinicproceedings.org/article/S0025-6196(20)30084-7/pdf
  14. El-Khoury H et al. Prevalence of monoclonal gammopathies and clinical outcomes in a high-risk US population screened by mass spectrometry: A multicentre cohort study. Lancet Haematol 2022 May; 9:e340.
  15. Ji M, Huber JH, Schoen MW et al Mortality in the US Populations With Monoclonal Gammopathy of Undetermined Significance. JAMA Oncol. Published online July 27, 2023 PMID: 37498610 https://jamanetwork.com/journals/jamaoncology/fullarticle/2807732
  16. Eythorsson E, Rognvaldsson S, Thorsteinsdottir S et al. Development of a multivariable model to predict the need for bone marrow sampling in persons with monoclonal gammopathy of undetermined significance: A cohort study nested in a clinical trial. Ann Intern Med 2024 Apr; 177:449. PMID: 38560901 https://www.acpjournals.org/doi/10.7326/M23-2540 - Predicting the need for bone marrow sampling in MGUS (Online calculator) https://istopmm.com/riskmodel/