The clinical relevance and management of monoclonal gammopathy of undetermined significance and related disorders: recommendations from the European Myeloma Network

Abstract

Monoclonal gammopathy of undetermined significance is one of the most common pre-malignant disorders. IgG and IgA monoclonal gammopathy of undetermined significance are precursor conditions of multiple myeloma; lightchain monoclonal gammopathy of undetermined significance of light-chain multiple myeloma; and IgM monoclonal gammopathy of undetermined significance of Waldenström's macroglobulinemia and other lymphoproliferative disorders. Clonal burden, as determined by bone marrow plasma cell percentage or M-protein level, as well as biological characteristics, including heavy chain isotype and light chain production, are helpful in predicting risk of progression of monoclonal gammopathy of undetermined significance to symptomatic disease. Furthermore, alterations in the bone marrow microenvironment of monoclonal gammopathy of undetermined significance patients result in an increased risk of venous and arterial thrombosis, infections, osteoporosis, and bone fractures. In addition, the small clone may occasionally be responsible for severe organ damage through the production of a monoclonal protein that has autoantibody activity or deposits in tissues. These disorders are rare and often require therapy directed at eradication of the underlying plasma cell or lymphoplasmacytic clone. In this review, we provide an overview of the clinical relevance of monoclonal gammopathy of undetermined significance. We also give general recommendations of how to diagnose and manage patients with monoclonal gammopathy of undetermined significance. ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o nClinical relevance of MGUS haematologica | 2014; 99(6) 985 Figure 1. Model for the mechanisms that contribute to the development and progression of MGUS. Obesity, exposure to pesticides, radiation exposure, and personal history of autoimmune diseases, inflammatory conditions and infections are associated with an increased risk of MGUS. In addition, there is a genetic predisposition to MGUS. (A) Primary immunoglobulin heavy chain (IgH) translocations with 5 recurrent chromosomal partners (4p16, 6p21, 11q13, 16q23, 20q11) and hyperdiploidy are early events and associated with the initiation of limited clonal plasma cell proliferation in non-IgM MGUS. Acquisition of secondary chromosomal abnormalities (such as deletions of (parts of) chromosomes or secondary chromosomal translocations) and mutations involving individual genes results in the stepwise progression from MGUS to newly diagnosed symptomatic MM, and finally aggressive forms of MM such as sPCL or extramedullary MM. During this process there is a progressive replacement of normal/polyclonal plasma cells (orange) by clonal plasma cells (blue). Progression of the plasma cell disorder is also accompanied by altered interactions of the tumor cells with various components of their microenvironment such as osteoclasts, endothelial cells, and cells of the immune system. Recent evidence suggests the presence of intraclonal heterogeneity in MGUS, adding a further level of genetic compl...

Large registry analysis to accurately define second malignancy rates and risks in a well-characterized cohort of 744 consecutive multiple myeloma patients followed-up for 25 years

“…As this was a registry-based study, treatment decisions were not determined at random, and since the age and stage distribution changes over the course of time, 21 we considered it important to keep all these factors in the multivariate model. We further investigated 'MM diagnosis before 2004' (as a rough adjustment for changes in the course of time [1][2][3][4][5][6][7][8][9][10][11][12] ) and 'prior/synchronous AM' univariately as potential prognostic factors, 12 but did not keep them in the final multivariate model, as they showed no significant effect on SPM. Moreover, we compared our data with the European GEKID cancer registry to capture the age-and sex-matched German population, with the SEER and prior analyses of other cancer registries.…”

“…Nevertheless, one challenge of this extended survival is that myeloma patients may acquire second malignancies, with an estimated incidence ranging between 2%-10%. [1][2][3][4][5] Living longer with the disease, therefore, involves the risk of long-term sequelae, including both solid tumor and hematologic second malignancies. Previous reports on second malignancies have focused on those developing subsequent to myeloma.…”

“…[1][2][3][4] Current attempts in myeloma focus on further improving survival. Nevertheless, one challenge of this extended survival is that myeloma patients may acquire second malignancies, with an estimated incidence ranging between 2%-10%.…”

Secondary monoclonal gammopathy of undetermined significance after allogeneic stem cell transplantation in multiple myeloma

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] Several terms have been used to describe this phenomenon, including abnormal protein band, oligoclonal protein bands, transient mono-or oligoclonal gammopathy, apparent isotype switch, oligoclonal humoral response, atypical serum immunofixation pattern, and in myeloma patients, as we will use in this study, secondary monoclonal gammopathy of undetermined significance MGUS (sMGUS). 18 We consider post-transplant MGUS as a subtype of sMGUS.…”

Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma in Older Adults

“…Risk factors such as radiation or pesticide exposure, 11,12 or history of autoimmune or chronic infectious disease, 13 have been described as risk factors for MM or MGUS, but most patients with MM and MGUS have no identifiable risk factors. Perhaps the most important risk factor for these diseases is advanced age.…”