Risk Factors For Progression

Identifying patients with MGUS who are at high risk of progression is important; both from the standpoint of prognostication as well as for design and implementation of trials aimed at preventing progression. At the time of diagnosis, it is difficult to predict the disease

Table 89.1 Factors associated with increased risk of progression

1. Higher M-protein levels at diagnosis

3. Higher percentage of plasma cells in bone marrow

4. Suppression of un-involved immunoglobulins

5. Presence of circulating plasma cells or clonal B cells

6. Bone density abnormalities

7. Advanced age

8. Bence Jones Proteinuria

9. Elevated ESR

10. Abnormal free light chain ratio ESR, erythrocyte sedimentation rate.

course for an individual, even though several clinical and laboratory markers have been suggested based on results from large groups of prospectively followed patients with MGUS (Table 89.1). In the Mayo Clinic study of 1384 patients with MGUS, factors associated with a higher risk of progression included higher M-protein levels and non-IgG (IgA or IgM) subgroups.13 The risk of progression to MM or a related disorder at 10 years after diagnosis of MGUS was 6% for an initial M-protein level of 0.5 g/dL or less, 7% for a level of 1 g/dL, 11% for 1.5 g/dL, 20% for 2 g/dL, 24% for 2.5 g/dL, and 34% for 3.0 g/dL. The initial concentration of the M protein appears to be one of the most important risk factors, and similar results have been observed in other large studies. In the Italian series reported by Cesana et al., patients with MGUS who had more than 1.9 g/dL of M protein had twice the rate of progression compared to those with less than 0.95 g/dL.12 In a Danish study reported by Gregersen et al., the risk of progression increased with increasing M-protein concentration.14 The type of immunoglobulin also appears to have predictive value, with those having an IgG paraprotein being at lower risk of progression compared to those with an IgA or IgM M protein. In the Italian study, patients with an IgA or IgM M protein had nearly twice the rate of progression compared to those with IgG. In a series of 128 persons with MGUS reported by Blade et al., the IgA type of MGUS was the only variable associated with a higher probability of progression.22 In the Danish study, the relative risk of progression for IgA and IgM were 1.8 and 1.1, respectively, compared to IgG type paraprotein.14 The proportion of plasma cells in the bone marrow may help predict the risk of progression. Cesana et al. noted an event rate of 0.64/100 person-years among those with 0-5% plasma cells in the marrow, compared to 1.35 and 5.96/100 person-years for those with 6-9% and >10% plasma cells, respectively.12 Baldini et al. reported a transformation rate of 6.8% among those with a plasma cell percentage of <10%, which increased to over 30% in those with 10-30% plasma cells in their marrow. Similar results have been seen in other studies.32 Suppression of uninvolved immunoglobulins (immunoglobulin classes other than the M protein), characteristically seen in myeloma, can also be seen in patients with MGUS. In the Mayo study, nearly 38% of the patients with MGUS had reduction in the uninvolved immunoglobulin.13 Baldini et al. reported a 3.6 fold elevated risk of progression with suppression of one uninvolved immunoglobulin and a 13.1 fold increased risk when two of the polyclonal immunoglobulins were decreased.26 Cesana et al. reported a relative risk of 1.6 for reduction in one normal immunoglobulin, and 7.6 for reduction in two normal immunoglobulins. Similar predictive values for suppression of polyclonal immunoglobulins have been reported by others.14 Clonal plasma cells can be detected in the peripheral blood in up to 20% of the patients with MGUS using immunofluorescence microscopy. Presence of circulating clonal plasma cells in these patients appears to predict for an increased risk of progression. In one study, patients who had circulating plasma cells were twice as likely (relative risk of 2.2) to progress, most commonly to myeloma, compared to those without circulating plasma cells.33 Increased numbers of clonal B cells in the circulation has also been associated with a higher risk of progression.34 Quantification of free light chains (FLCs) in the serum offers a new method for disease assessment in patients with paraproteinemias. The presence of an abnormal kappa/lambda FLC ratio (kappa/lambda ratio <0.26 or >1.65) in the serum may help identify those at a higher risk of progression of their underlying MGUS.35 In a study of 1384 patients with MGUS, an abnormal ratio was detected in 379 patients (33%). The risk of progression in these patients was significantly higher (hazard ratio 3.5, 95% CI 2.3-5.5; p < 0.001) compared to those with a normal ratio. The presence of Bence Jones pro-teinuria nearly tripled the rate of progression in two large studies, and may help predict risk of progres-sion.12 26 Increased rates of bone resorption have been reported in MGUS patients who are at high risk of pro-gression.36 Modern imaging techniques, such as whole-body positron emission tomography (18F-FDG PET), may predict patients with stable disease, though further studies are needed to validate these findings.37 Increased age has been reported as a risk factor in a few studies. Baldini et al. reported a 3.6 fold higher risk of progression for those older than 70 years.26 In one study, a low sCD16 (soluble Fc gamma receptor type III) level in patients with MGUS indicated a high likelihood of rapid progression to MM.38

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