Levels of Uninvolved Immunoglobulin Predict Clinical Status and Progression-Free Survival for Multiple Myeloma Patients
Authors: Harutyunyan Nika M , Vardanyan Suzie , Ghermezi Michael , Gottlieb Jillian , Berenson Ariana , Andreu-Vieyra Claudia , Tang George , Sanchez Eric , Li Mingjie , Wang Cathy , Ben-Zvi Joseph , Garzio Gigi , Chen Haiming , Finlay Judith , Berenson James R 
Published: October 2019

Abstract
Introduction: The levels of serum monoclonal immunoglobulins (M-Igs) are used to monitor multiple myeloma (MM) patients. However, these assessments do not discriminate between normal polyclonal immunoglobulins (uninvolved) and M-Igs since they cannot determine the type of light chain associated with each immunoglobulin class (i.e. IgGκ, IgGλ, IgAκ, IgAλ, IgMκ, and IgMλ). The HevyLite® +(HLC) assays are able to accomplish this but the usefulness of these results for MM patients needs to be further established. We evaluated the levels of involved and uninvolved HLC levels, their ratios and differences and their relationship to outcomes among MM patients.
Materials and Methods: Serum samples (n=189) from MM patients were analyzed using the HLC assays. Manufacturer’s HLC normal reference ranges were used. HLC results were correlated with clinical status as determined at the time of sampling and divided into groups according to clinical status (complete response (CR), ≥ partial response (PR) , < partial response, and progressive disease (PD)). Normality was assessed using the D’Agostino-Pearson omnibus normality test. Statistical comparisons were made using t-student’s or Mann-Whitney tests as appropriate as well as Fisher’s test. Progression-free survival (PFS) was calculated using Kaplan--Meier analysis for specific regimens received during the time the samples were taken. All tests were double-tailed and p-values lower than 0.05 were considered to be statistically significant.
Results: All MM serum samples analyzed had IgG (62%) or IgA (38%) isotypes. Results from the involved HLC/uninvolved HLC ratios and their differences demonstrated that samples from patients with PD had significantly both higher ratios and differences (P<0.0001) compared with patients with ≥ PR. Similar results were also observed for the involved HLC values (P<0.0001). The uninvolved HLC values were significantly lower (P<0.0001) for patients with PD compared with patients with ≥ PR. Similar results were obtained when we examined the percentage of patients who were in > PR compared with those with < PR so that patients in > PR were more likely to have normal uninvolved HLC levels than among patient with <PR (P<0.0001). In addition, we evaluated the proportion of patients in CR or PR based on their levels of uninvolved HLC being in the normal or below the normal range. The results showed that patients in CR were much more likely to have normal uninvolved HLC levels than among those with below normal uninvolved HLC levels (P < 0.0001). Similarly, patients in CR also were more likely to have normal uninvolved HLC levels than among those in PR (P=0.0040). Next, PFS was determined for patients with normal and below normal uninvolved HLC values. Patients with normal uninvolved HLC levels showed a much longer PFS (45 months) than among patients with less than normal uninvolved HLC levels (11 months; P=0.0019). Similarly, PFS was calculated for patients with normal and above normal involved HLC levels. Patients with normal involved HLC levels had a much longer PFS (33 months) than among patients with involved HLC levels that were above the normal range (11 months; P=0.0405).
Conclusion: This study shows that involved HLC/uninvolved HLC ratios, differences between the involved and uninvolved HLCs, higher absolute levels of involved HLC, and lower levels of uninvolved HLC correlate with clinical status for MM patients. In addition, MM patients with normal uninvolved HLC levels have a longer PFS whereas those with involved HLC levels above the normal range show a shorter PFS. These results demonstrate the usefulness of the HLC assay for determining outcome for multiple myeloma patients.

Disclosures
No relevant conflicts of interest to declare.