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Monoclonal gammopathies of unknown significance and smoldering myeloma: Assessment and management of the elderly patients

      Highlights

      • The prevalence of monoclonal gammopathies increases with age.
      • In the elderly, some comorbidities can mimic myeloma-related symptomatology.
      • It is crucial to establish the differential diagnosis to not overtreat MGUS/SMM.
      • Geriatric assessment may improve the management of MGUS/SMM elderly patients.
      • Further investigation is required to define the optimal treatment in high-risk SMM.

      Abstract

      Monoclonal gammopathy of unknown significance (MGUS) is the most frequent plasma cell disorder that commonly affects elderly patients. Although it is an asymptomatic condition, as well as smoldering myeloma (SMM), the risk of progression to multiple myeloma requiring therapy or other B-cell disorders varies greatly for individual patients, remaining low for MGUS (1% per year), while higher and not uniform for SMM patients (10% per year). This scenario implies some special considerations regarding assessment and follow-up, especially in the elderly. In this review, we provide the updated diagnostic criteria of monoclonal gammopathies proposed by the International Myeloma Working Group (IMGW); the current recommendations for the assessment of asymptomatic plasma cell disorders, with some concerns about the need of geriatric evaluation in the elderly population, the importance of distinguishing myeloma-related symptomatology from signs or symptoms caused by multiple chronic conditions typically found in the elderly. Finally, the identification of predictor markers of progression has enabled a proposal of risk-adapted follow-up strategies in MGUS and SMM that should be implemented in clinical practice. Although the standard of care is observation for MGUS and SMM patients as well, a recent randomized trial targeting high-risk SMM showed the clinical benefit of early intervention. The change of the treatment paradigm is also very promising and feasible for elderly patients, as long as a comprehensive geriatric assessment is conducted to optimize early treatment and reach maximum benefit with minimum toxicity, in other words, to ensure a better quality of life for these patients.

      Abbreviations:

      MGUS (Monoclonal gammopathy of unknown significance), SMM (smoldering multiple myeloma), IMWG (International Myeloma Working Group (IMWG)), MDE (myeloma-defining event term), sFLC (serum free light chain), MRI (magnetic resonance imaging), BMPCs (bone marrow plasma cells), GA (geriatric assessment), VTD (venous thromboembolic disease), MGAPN (Monoclonal gammopathy-associated peripheral neuropathy), MGRS (Monoclonal gammopathy of renal significance), WM (Waldënstrom's macroglobulinemia), PN (peripheral neuropathy)

      Keywords

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      References

        • Kyle R.A.
        • Therneau T.M.
        • Rajkumar S.V.
        • Larson D.R.
        • Plevak M.F.
        • Offord J.R.
        • et al.
        Prevalence of monoclonal gammopathy of undetermined significance.
        N Engl J Med. 2006; 354: 1362-1369
        • Therneau T.M.
        • Kyle R.A.
        • Melton 3rd, L.J.
        • Larson D.R.
        • Benson J.T.
        • Colby C.L.
        • et al.
        Incidence of monoclonal gammopathy of undetermined significance and estimation of duration before first clinical recognition.
        Mayo Clin Proc. 2012; 87: 1071-1079
        • Landgren O.
        • Graubard B.I.
        • Katzmann J.A.
        • Kyle R.A.
        • Ahmadizadeh I.
        • Clark R.
        • et al.
        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: 1537-1542
        • Landgren O.
        • Rajkumar S.V.
        • Pfeiffer R.M.
        • Kyle R.A.
        • Katzmann J.A.
        • Dispenzieri A.
        • et al.
        Obesity is associated with an increased risk of monoclonal gammopathy of undetermined significance among black and white women.
        Blood. 2010; 116: 1056-1059
        • Kristinsson S.Y.
        • Holmberg E.
        • Blimark C.
        Treatment for high-risk smoldering myeloma. The New England journal of medicine.
        369. 2013: 1762-1763
        • Rajkumar S.V.
        • Dimopoulos M.A.
        • Palumbo A.
        • Blade J.
        • Merlini G.
        • Mateos M.V.
        • et al.
        International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma.
        Lancet Oncol. 2014; 15: e538-e548
        • Mangiacavalli S.
        • Cocito F.
        • Pochintesta L.
        • Pascutto C.
        • Ferretti V.
        • Varettoni M.
        • et al.
        Monoclonal gammopathy of undetermined significance: a new proposal of workup.
        Eur J Haematol. 2013; 91: 356-360
      1. Go RS, Rajkumar SV. How I manage monoclonal gammopathy of undetermined significance. 2018;131:163–73.

        • Bida J.P.
        • Kyle R.A.
        • Therneau T.M.
        • Melton 3rd, L.J.
        • Plevak M.F.
        • Larson D.R.
        • et al.
        Disease associations with monoclonal gammopathy of undetermined significance: a population-based study of 17,398 patients.
        Mayo Clin Proc. 2009; 84: 685-693
        • Kristinsson S.Y.
        • Tang M.
        • Pfeiffer R.M.
        • Bjorkholm M.
        • Blimark C.
        • Mellqvist U.H.
        • et al.
        Monoclonal gammopathy of undetermined significance and risk of skeletal fractures: a population-based study.
        Blood. 2010; 116: 2651-2655
        • Piot J.M.
        • Royer M.
        • Schmidt-Tanguy A.
        • Hoppe E.
        • Gardembas M.
        • Bourree T.
        • et al.
        Factors associated with an increased risk of vertebral fracture in monoclonal gammopathies of undetermined significance.
        Blood Cancer J. 2015; 5e345
        • Rautiainen S.
        • Manson J.E.
        • Lichtenstein A.H.
        • Sesso H.D.
        Dietary supplements and disease prevention - a global overview.
        Nat Rev Endocrinol. 2016; 12: 407-420
        • Kristinsson S.Y.
        • Bjorkholm M.
        • Schulman S.
        • Landgren O.
        Hypercoagulability in multiple myeloma and its precursor state, monoclonal gammopathy of undetermined significance.
        Semin Hematol. 2011; 48: 46-54
        • Cohen A.L.
        • Sarid R.
        The relationship between monoclonal gammopathy of undetermined significance and venous thromboembolic disease.
        Thromb Res. 2010; 125: 216-219
        • Za T.
        • De Stefano V.
        • Rossi E.
        • Petrucci M.T.
        • Andriani A.
        • Annino L.
        • et al.
        Arterial and venous thrombosis in patients with monoclonal gammopathy of undetermined significance: incidence and risk factors in a cohort of 1491 patients.
        Br J Haematol. 2013; 160: 673-679
        • Roeker L.E.
        • Larson D.R.
        • Kyle R.A.
        • Kumar S.
        • Dispenzieri A.
        • Rajkumar S.V.
        Risk of acute leukemia and myelodysplastic syndromes in patients with monoclonal gammopathy of undetermined significance (MGUS): a population-based study of 17 315 patients.
        Leukemia. 2013; 27: 1391-1393
        • Cho S.Y.
        • Yang H.S.
        • Jeon Y.L.
        • You E.
        • Lee H.J.
        • Yoon H.J.
        • et al.
        A case series of autoimmune diseases accompanied by incidentally diagnosed monoclonal gammopathy: is there a link between the two diseases?.
        Int J Rheum Dis. 2014; 17: 635-639
        • Lindqvist E.K.
        • Goldin L.R.
        • Landgren O.
        • Blimark C.
        • Mellqvist U.H.
        • Turesson I.
        • et al.
        Personal and family history of immune-related conditions increase the risk of plasma cell disorders: a population-based study.
        Blood. 2011; 118: 6284-6291
        • Brown L.M.
        • Gridley G.
        • Check D.
        • Landgren O.
        Risk of multiple myeloma and monoclonal gammopathy of undetermined significance among white and black male United States veterans with prior autoimmune, infectious, inflammatory, and allergic disorders.
        Blood. 2008; 111: 3388-3394
        • Lindqvist E.K.
        • Landgren O.
        • Lund S.H.
        • Turesson I.
        • Hultcrantz M.
        • Goldin L.
        • et al.
        History of autoimmune disease is associated with impaired survival in multiple myeloma and monoclonal gammopathy of undetermined significance: a population-based study.
        Ann Hematol. 2017; 96: 261-269
        • McShane C.M.
        • Murray L.J.
        • Landgren O.
        • O'Rorke M.A.
        • Korde N.
        • Kunzmann A.T.
        • et al.
        Prior autoimmune disease and risk of monoclonal gammopathy of undetermined significance and multiple myeloma: a systematic review.
        in: Cancer Epidemiology, Biomarkers & Prevention: A Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. vol. 23. 2014: 332-342
        • Chaudhry H.M.
        • Mauermann M.L.
        • Rajkumar S.V.
        Monoclonal Gammopathy-associated peripheral neuropathy: diagnosis and management.
        Mayo Clin Proc. 2017; 92: 838-850
        • Bridoux F.
        • Leung N.
        • Hutchison C.A.
        • Touchard G.
        • Sethi S.
        • Fermand J.P.
        • et al.
        Diagnosis of monoclonal gammopathy of renal significance.
        Kidney Int. 2015; 87: 698-711
        • Leung N.
        • Bridoux F.
        • Hutchison C.A.
        • Nasr S.H.
        • Cockwell P.
        • Fermand J.-P.
        • et al.
        Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant.
        Blood. 2012; 120: 4292-4295
        • Hillengass J.
        • Moulopoulos L.A.
        • Delorme S.
        • Koutoulidis V.
        • Mosebach J.
        • Hielscher T.
        • et al.
        Whole-body computed tomography versus conventional skeletal survey in patients with multiple myeloma: a study of the international myeloma working group.
        Blood Cancer J. 2017; 7e599
        • Hillengass J.
        • Fechtner K.
        • Weber M.A.
        • Bauerle T.
        • Ayyaz S.
        • Heiss C.
        • et al.
        Prognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic multiple myeloma.
        J. Clin. Oncol. 2010; 28: 1606-1610
        • Kastritis E.
        • Moulopoulos L.A.
        • Terpos E.
        • Koutoulidis V.
        • Dimopoulos M.A.
        The prognostic importance of the presence of more than one focal lesion in spine MRI of patients with asymptomatic (smoldering) multiple myeloma.
        Leukemia. 2014; 28: 2402-2403
        • Rajkumar S.V.
        • Larson D.
        • Kyle R.A.
        Diagnosis of smoldering multiple myeloma.
        New Engl. J. Med. 2011; 365: 474-475
        • Kastritis E.
        • Terpos E.
        • Moulopoulos L.
        • Spyropoulou-Vlachou M.
        • Kanellias N.
        • Eleftherakis-Papaiakovou E.
        • et al.
        Extensive bone marrow infiltration and abnormal free light chain ratio identifies patients with asymptomatic myeloma at high risk for progression to symptomatic disease.
        Leukemia. 2013; 27: 947-953
        • Larsen J.T.
        • Kumar S.K.
        • Dispenzieri A.
        • Kyle R.A.
        • Katzmann J.A.
        • Rajkumar S.V.
        Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma.
        Leukemia. 2013; 27: 941-946
        • Mateos M.-V.
        • San Miguel J.F.
        How Should We Treat Newly Diagnosed Multiple Myeloma Patients? ASH Education Program Book.
        2013. 2013: 488-495
        • Palumbo A.
        • Bringhen S.
        • Mateos M.-V.
        • Larocca A.
        • Facon T.
        • Kumar S.K.
        • et al.
        Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report.
        Blood. 2015; 125: 2068-2074
        • Kenis C.
        • Decoster L.
        • Puyvelde K.V.
        • Grève J.D.
        • Conings G.
        • Milisen K.
        • et al.
        Performance of two geriatric screening tools in older patients with cancer.
        J Clin Oncol. 2014; 32: 19-26
        • Guerard E.J.
        • Tuchman S.A.
        Monoclonal Gammopathy of undetermined significance and multiple myeloma in older adults.
        Clin Geriatr Med. 2016; 32: 191-205
        • Kyle R.A.
        • Therneau T.M.
        • Rajkumar S.V.
        • Offord J.R.
        • Larson D.R.
        • Plevak M.F.
        • et al.
        A long-term study of prognosis in monoclonal gammopathy of undetermined significance.
        New Engl. J. Med. 2002; 346: 564-569
        • Dispenzieri A.
        • Katzmann J.A.
        • Kyle R.A.
        • Larson D.R.
        • Melton 3rd, L.J.
        • Colby C.L.
        • et al.
        Prevalence and risk of progression of light-chain monoclonal gammopathy of undetermined significance: a retrospective population-based cohort study.
        Lancet (London, England). 2010; 375: 1721-1728
        • Eisele L.
        • Durig J.
        • Huttmann A.
        • Duhrsen U.
        • Assert R.
        • Bokhof B.
        • et al.
        Prevalence and progression of monoclonal gammopathy of undetermined significance and light-chain MGUS in Germany.
        Ann Hematol. 2012; 91: 243-248
        • Cesana C.
        • Klersy C.
        • Barbarano L.
        • Nosari A.M.
        • Crugnola M.
        • Pungolino E.
        • et al.
        Prognostic factors for malignant transformation in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma.
        J. Clin. Oncol. 2002; 20: 1625-1634
        • Blade J.
        • Rosinol L.
        • Cibeira M.T.
        • de Larrea C.F.
        Pathogenesis and progression of monoclonal gammopathy of undetermined significance.
        Leukemia. 2008; 22: 1651-1657
        • Rajkumar S.V.
        • Kyle R.A.
        • Therneau T.M.
        • Melton 3rd, L.J.
        • Bradwell A.R.
        • Clark R.J.
        • et al.
        Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance.
        Blood. 2005; 106: 812-817
        • Rosinol L.
        • Cibeira M.T.
        • Montoto S.
        • Rozman M.
        • Esteve J.
        • Filella X.
        • 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: 428-434
        • Perez-Persona E.
        • Mateo G.
        • Garcia-Sanz R.
        • Mateos M.V.
        • de Las Heras N.
        • de Coca A.G.
        • 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: 110-114
        • Turesson I.
        • Kovalchik S.A.
        • Pfeiffer R.M.
        • Kristinsson S.Y.
        • Goldin L.R.
        • Drayson M.T.
        • et al.
        Monoclonal gammopathy of undetermined significance and risk of lymphoid and myeloid malignancies: 728 cases followed up to 30 years in Sweden.
        Blood. 2014; 123: 338-345
        • Perez-Persona E.
        • Vidriales M.B.
        • Mateo G.
        • Garcia-Sanz R.
        • Mateos M.V.
        • de Coca A.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: 2586-2592
        • Kyle R.A.
        • Durie B.G.
        • Rajkumar S.V.
        • Landgren O.
        • Blade J.
        • Merlini G.
        • 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; 24: 1121-1127
        • Kyle R.A.
        • Remstein E.D.
        • Therneau T.M.
        • Dispenzieri A.
        • Kurtin P.J.
        • Hodnefield J.M.
        • et al.
        Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. The New England journal of medicine.
        356. 2007: 2582-2590
        • González-Calle V.
        • Dávila J.
        • Escalante F.
        • de Coca A.
        • Aguilera C.
        • López R.
        • et al.
        Bence Jones proteinuria in smoldering multiple myeloma as a predictor marker of progression to symptomatic multiple myeloma.
        Leukemia. 2016; 30: 2026-2031
        • Bianchi G.
        • Kyle R.A.
        • Larson D.R.
        • Witzig T.E.
        • Kumar S.
        • Dispenzieri A.
        • et al.
        High levels of peripheral blood circulating plasma cells as a specific risk factor for progression of smoldering multiple myeloma.
        Leukemia. 2013; 27: 680-685
        • Gonsalves W.I.
        • Rajkumar S.V.
        • Dispenzieri A.
        • Dingli D.
        • Timm M.M.
        • Morice W.G.
        • et al.
        Quantification of circulating clonal plasma cells via multiparametric flow cytometry identifies patients with smoldering multiple myeloma at high risk of progression.
        Leukemia. 2017; 31: 130-135
        • Rosinol L.
        • Blade J.
        • Esteve J.
        • Aymerich M.
        • Rozman M.
        • Montoto S.
        • et al.
        Smoldering multiple myeloma: natural history and recognition of an evolving type.
        Br J Haematol. 2003; 123: 631-636
        • Rajkumar S.V.
        • Gupta V.
        • Fonseca R.
        • Dispenzieri A.
        • Gonsalves W.I.
        • Larson D.
        • et al.
        Impact of primary molecular cytogenetic abnormalities and risk of progression in smoldering multiple myeloma.
        Leukemia. 2013; 27: 1738-1744
        • Fouquet G.
        • Amouzou K.
        • Renaud L.
        • Carpentier B.
        • Simonnet A.
        • Van de Wyngaert Z.
        • et al.
        Monoclonal gammopathies of undetermined significance do not systematically require a specialized consultation.
        La Revue de Med. Int. 2015; 36: 444-449
        • Mateos M.V.
        • Hernandez M.T.
        • Giraldo P.
        • de la Rubia J.
        • de Arriba F.
        • Lopez Corral L.
        • et al.
        Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma.
        N Engl J Med. 2013; 369: 438-447
        • Mateos M.V.
        • Hernandez M.T.
        • Giraldo P.
        • de la Rubia J.
        • de Arriba F.
        • Corral L.L.
        • et al.
        Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): long-term follow-up of a randomised, controlled, phase 3 trial.
        Lancet Oncol. 2016; 17: 1127-1136