THE SPECTRUM OF PLASMA CELL DYSCRASIAS
Differential diagnosis of monoclonal gammopathy of undetermined signiﬁcance
Giampaolo Merlini1,2 and Giovanni Palladini1,2
Research and Treatment Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientiﬁco Policlinico San Matteo, Pavia, Italy; and 2Department of Molecular Medicine, University of Pavia, Pavia, Italy
Monoclonalgammopathy of undetermined signiﬁcance (MGUS) is an asymptomatic plasma cell disorder occurring in 4.2% of adults 50 years of age, which can progress into symptomatic diseases either through proliferation of the plasma cell clone, giving rise to multiple myeloma and other lymphoplasmacellular neoplasms, or through organ damage caused by the monoclonal protein, as seen in light-chain amyloidosis andrelated conditions. Differential diagnosis of asymptomatic and symptomatic monoclonal gammopathies is the determinant for starting therapy. The criteria for determining end-organ damage should include markers of organ injury caused by the monoclonal protein. Patient assessment and optimal follow-up are now performed using risk stratiﬁcation models that should also take into account the risk ofdeveloping AL amyloidosis. Patients with low-risk MGUS (approximately 40% of all MGUS patients) need limited assessment and very infrequent follow-up. The ongoing development of novel molecular biomarkers and advanced imaging techniques will improve the identiﬁcation of high-risk patients who may beneﬁt from early therapeutic intervention through innovative clinical trials.
Robert Kylecoined the term monoclonal gammopathy of undetermined signiﬁcance (MGUS) in 1978 after the observation that asymptomatic patients with a monoclonal protein (M-protein) had higher risk of developing multiple myeloma (MM), Waldenstrom ¨ macroglobulinemia (WM), light-chain amyloidosis (AL), or related conditions. MGUS is a premalignant clonal disorder that is present in more than 4% of the general whitepopulation older than 50 years of age1,2 and is associated with a 1%/y risk of progression to MM or related malignancies. Because the transition from MGUS into a malignant, symptomatic condition is an evolving process,3 the differential diagnosis between MGUS and these diseases is frequently challenging. MGUS may progress toward symptomatic conditions, requiring the initiation of treatment, through2 general mechanisms (Figure 1): (1) progression of the proliferative characteristics toward smoldering MM (SMM), MM, and other lymphoplasmacellular disorders, which account for approximately 90% of the progression; or (2) the development of end-organ damage caused by the M-protein such as AL amyloidosis, light chain deposition disease (LCDD), and other rarer conditions, which account forapproximately 10% of the progression. Because most MGUS progression occurs toward MM, little attention has been dedicated to the development of other disorders caused by the M-protein.
required to achieve the best diagnostic sensitivity for other serious conditions such as AL amyloidosis or LCDD.4,5
Prevalence and risk factors
Using the serum FLC assay and immunoﬁxation electrophoresis, Mayo Clinicinvestigators determined the overall age- and sexadjusted prevalence of conventional MGUS in persons 50 years of age or older in Olmsted County to be 3.4%.1,6 Considering that the prevalence of light-chain MGUS is 0.8%, the overall MGUS prevalence is 4.2% (95% conﬁdence interval, 3.9-4.5).6 Studies in both white and Japanese populations demonstrate a clear increase in prevalence with age. Theprevalence is also affected by sex: 3.7% and 2.9% in white men and women, respectively, and 2.8% and 1.6% in Japanese men and women, respectively. MGUS is twice as prevalent in black adults (5.9%-8.4%).7 The etiology of MGUS is unknown, and previous studies support a role of both genetic and environmental factors. A family history of MGUS or MM increases the risk of MGUS by approximately 3.3- and...
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