Proposal and Validation of Prognostic Scoring Systems for IgG and IgA Monoclonal Gammopathies of Undetermined Significance

Abstract

Purpose:The presenting clinico-hematologic features of 1,283 patients with IgG and IgA monoclonal gammopathies of undetermined significance (MGUS) were correlated with the frequency of evolution into multiple myeloma (MM). Experimental Design: Two IgG MGUS populations were evaluated: a training sample (553 patients) and a test sample (378 patients); the IgA MGUS population consisted of 352 patients. Results: Forty-seven of the 553 training group patients and 22 of 378 test group IgG patients developed MM after a median follow-up of 6.7 and 3.6 years, respectively. Multivariate analysis showed that serum monoclonal component (MC) levels of V1.5 g/dL, the absence of light-chain proteinuria and normal serum polyclonal immunoglobulin levels defined a prognostically favorable subset of patients, and could be used to stratify the patients into three groups at different 10-year risk of evolution (hazard ratio, 1.0, 5.04, 11.2; P < 0.001). This scoring system was validated in the test sample. Thirty of the 352 IgA patients developed MM after a median follow-up of 4.8 years, and multivariate analysis showed that hemoglobin levels of <12.5 g/dL and reduced serum polyclonal immunoglobulin correlated with progression. A pooled statistical analysis of all of the patients confirmed the validity of Mayo Clinic risk model showing that IgA class, serum MC levels, and light-chain proteinuria are the most important variables correlated with disease progression. Conclusions: Using simple variables, we validated a prognostic model for IgG MGUS. Among the IgA cases, the possible prognostic role of hemoglobin emerged in addition to a decrease in normal immunoglobulin levels.Monoclonal gammopathies of undetermined significance (MGUS) are the most common forms of plasma cell dyscrasia, with a prevalence of 3% in the general adult population ages >50 years. The incidence of MGUS increases with age, and is >5% in patients ages >70 years (1). By definition, serum monoclonal component (MC) concentrations are V3 g/dL and bone marrow plasma cell counts <10%; there is no related organ or tissue impairment and no evidence of multiple myeloma (MM), macroglobulinemia, amyloidosis, or other related plasma cell or lymphoproliferative disorders (2). As MGUS have a rate of malignant evolution of f1% per year (3 -6), it is important to identify the features at diagnosis that are capable of predicting neoplastic transformation. In a previous study of a limited series of IgG MGUS patients, we found that serum MC levels, the presence or absence of light-chain proteinuria, normal or decreased polyclonal immunoglobulin levels, and the percentage of bone marrow plasma cells were the most reliable variables in predicting different clinical outcomes (7). On the basis of these data, we also identified a subset of IgG MGUS patients at low risk of evolution for whom we proposed a noninvasive diagnostic approach, without bone marrow Imaging, Diagnosis, Prognosis

Increased T Regulatory Cells Are Associated with Adverse Clinical Features and Predict Progression in Multiple Myeloma

“…From this finding, we believe that IgA myeloma patients might have stronger immunological suppression than IgG myeloma patients which could also influence survival. To support this hypothesis, several clinical data reported that IgG myeloma patients had better prognosis than IgA myeloma patients but difference between IgG and IgA myeloma patients with regard to immune status/performance and functions are yet to be revealed [42], [43]. There are reports available showing that stage dependent increases of Treg cells in MM and B-CLL and our data also corroborate this finding but lacks statistical significance [23], [44].…”

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

“…Clonal burden as determined by BM plasma cell percentage 10,12-16 and/or M-protein size 4,10,[12][13][14][15][17][18][19][20][21][22][23] is an important risk factor for malignant transformation of MGUS. Furthermore, Rosinol et al showed that a progressive increase of the M-protein (evolving MGUS) is predictive of progression.…”

“…Tumor load • M-protein level 4,10,[12][13][14][15][17][18][19][20][21][22][23]31 • [40][41][42]44 but not in others. [37][38][39]43 Also after allogeneic (allo)-SCT development of secondary MGUS has been described.…”

“…This explains the predictive value of reduction of polyclonal serum immunoglobulins. 10,13,21,23,31 Also several imaging techniques may prove to be useful in predicting progression of MGUS. Detection of focal lesions by MRI at baseline 22,29,32 or development of focal lesions by MRI or PET-CT predicted for progression to active MM.…”

Value of reflex testing based on hypogammaglobulinemia as demonstrated in serum protein electrophoresis

“…Individuals with consistently reduced serum Ig concentrations are more susceptible to infections [4][5][6][7][8], and may be associated with an increased risk of developing cancer, particularly hematological neoplasms, as observed in patients with common variable immunodeficiency [9][10][11]. Moreover, 8-35% patients with monoclonal gammopathy of unknown significance (MGUS) have been reported to have reduced polyclonal (uninvolved, nonparaprotein) Ig [12][13][14], and this reduction in uninvolved Ig is associated with an increased risk of malignant transformation [14][15][16]. Somewhat higher incidences of hypo-Ig have also been reported in other lymphoproliferative diseases such as chronic lymphocytic leukemia (up to 85% at some stages) [18], Waldenstrom's macroglobulinemia (63% and 58% with IgA and IgG reductions respectively) [19] and smoldering multiple myeloma (45-83%) [20][21][22].…”