Association Between Immunoparesis and a Skewed Free Light Chain (FLC) Ratio: A New Prognostic Factor Of Progression from MGUS To Multiple Myeloma?

Monoclonal gammopathy of undetermined significance (MGUS) occurs in 3% of people older than 50 years and up to 10% in those older than 70; it is associated with a 1%/year risk of progression to Multiple Myeloma (MM). In recent years there have been improvements in risk stratification models (involving molecular markers) of this disorder, which have led to better understanding of the biology and probability of progression of MGUS. In the context of numerous molecular events and heterogeneous risk of progression, developing individualized risk profiles for patients with MGUS represents an ongoing challenge that has to be addressed by prospective clinical monitoring and extensive correlative science. Free Lights Chains (FLC) ratio, plasma cells immunophenotype and DNA aneuplody are now important parameters of progression, in addition to the already known prognostic factors (immunoparesis, type and amount of the monoclonal component (MC). Recent data report immunoparesis and a skewed FLC ratio in 25% and 30%, respectively, of patients (pts) at diagnosis.

In this study we evaluated the incidence of these two parameters in a cohort of 114 pts with MGUS, if they are associated and if their incidence is influenced by other parameters (time from diagnosis, type of Immunoglobulin (Ig) and/or light chains). The patients screened were 56 males and 58 females with a median age of 67 years (45-91). Median time from diagnosis to the time of observation was 3 years (0-21). The MC was IgA in 13 pts, IgG in 88, IgM in 13; 74 had a clonal Kappa (K) and 40 a lambda (L) light chain. K/L ratio was abnormal in 57 pts (50%). Immunoparesis was present in 60 pts (52,6%): 22 with a normal K/L ratio (38,5%) and 38 with an abnormal K/L ratio (66,6%) (p-0.004). In 18 pts two classes of Ig were involved. An association between the two parameters occurred in 39 pts (34,2%); it was more frequent in IgA MGUS (61,5%) than in IgG (31,8%) and IgM (23%); we did not observe any differences about immunoparesis between K MGUS (33,7%) and L MGUS (32,5%). The association between a skewed K/L ratio and immunoparesis was present in 25.4% of pts with time from diagnosis of less than 3 years and in 48,8% of pts with a longer time from diagnosis (p-0.04). Our new data confirm that immunoparesis is more frequent in pts with an abnormal K/L ratio. The association seems to be more frequent in case of IgA gammopathy; there are no differences between the two types of light chain. Our data also confirm that the longer is the time elapsed from diagnosis, the higher are the frequency of an abnormal K/L ratio and the incidence of immunoparesis, with a greater probability of association. We need still a larger number of pts with an adequate follow up to evaluate if the association between immunoparesis and abnormal K/L ratio has a prognostic value, although the higher frequency of association in the subset of pts with a longer time from diagnosis seems to contradict this hypothesis.