Isotype-Specific Heavy/Light Chain (HLC) Suppression as a Predictor of Myeloma Development in Monoclonal Gammopathy of Undetermined Significance (MGUS).

Clinically available prognostic factors for progression of MGUS to myeloma include the size of the M-spike, heavy chain isotype, and free light chain (FLC) K/L ratio. The combined use of these variables provides approximately a 10-fold difference in risk for progression. The highest risk group, however, still has only a 27% twenty year risk of progression. Therefore, additional predictors of progression are needed. Suppression of uninvolved immunoglobulins has been an inconsistent predictor of progression. The novel Hevylite” assay measures concentrations of each isotype-specific immunoglobulin heavy light chain (HLC) pair (i.e., IgG kappa, IgG lambda, IgA kappa, IgA lambda) and enables us for the first time to determine if suppression of isotype-specific Ig of the opposite HLC is occurring and if it is predictive of progression of MGUS to myeloma. We studied the prognostic value of isotype specific HLC suppression of uninvolved immunoglobins as a predictor of progression in MGUS. Methods: Total immunoglobulins were quantitated by immunonephelometry, and suppression was defined as concentrations less than the lower limit of the reference range. HLC concentrations were quantitated with Hevylite reagents (The Binding Site, Ltd). The antibodies used in this investigational nephelometric assay span epitopes in the junctional areas between the HLC constant regions. Based on reference ranges for GK (407-1130 mg/dL), GL (188-583 mg/dL), AK (55-292 mg/dL), and AL (39-249 mg/dL) that we derived from 276 normal samples, we compared the proportion of patients who had isotype specific suppression of the opposite HLC pair among 30 patients with MGUS who progressed to myeloma versus 36 patients who had not progressed over a similar follow-up period. To confirm the relationship of isotype specific HLC pair suppression compared to suppression of uninvolved immunoglobulins of other heavy chain classes, we tested a second cohort of stored samples from 50 IgG and 14 IgA MGUS patients prior to the development of MM.

In the initial samples from 36 IgG MGUS patients who had stable disease, 6% had suppression of uninvolved intact immunoglobulins of IgA and/or IgM, while 22% had isotype specific suppression of the opposite HLC pair (i.e., IgG lambda suppressed in IgG kappa MGUS, and vice versa). In contrast, in baseline samples from 30 IgG MGUS patients who eventually progressed to myeloma or related malignancy, 7% had suppression of IgA and/or IgM, while 40% had isotype specific suppression of the opposite IgG HLC pair. Thus, HLC pair suppression was more frequent than suppression of Igs from other heavy chain classes, and MGUS patients who eventually progressed had a 2-fold higher rate of isotype specific HLC pair suppression than stable MGUS patients. These findings were confirmed independently on a second cohort of patients who progressed to myeloma 5-10 years after blood collection. In samples from 50 IgG MGUS patients, 42% had suppression of Igs of other heavy chain classes, while 80% had suppression of the isotype specific HLC by the Hevylite assay. In the last samples prior to progression, the suppression of heavy chain classes increased to 60%, while isotype specific HLC suppression rose to 90%. Interestingly, the 14 IgA patients had equivalent suppression of gamma or mu heavy chain classes as compared to the HLC pairs, with 50% of the patients having suppression in the initial sample and 79% in the last sample prior to MM.

Our data suggest that suppression of the opposite IgG HLC pair is a predictor of patients destined for progression. Isotype specific HLC pair suppression of this nature is more frequent in these patients (more sensitive) than suppression of other heavy chain classes. We were not able to demonstrate a similar effect in IgA MGUS. Larger studies are underway to determine if HLC pair suppression is independent of M-spike quantitation, heavy chain isotype, and FLC ratio. Biologically, our findings suggest that clonal IgG plasma cells are able to suppress other IgG producing non-clonal plasma cells far more effectively than IgA or IgM secreting cells, and this occurs more frequently with cells that will eventually undergo malignant transformation.

Bradwell:The Binding Site Group Ltd: Equity Ownership.