Prognostic Value of the Hevylite Chain in MGUS Patients in a Population Study
Authors: García Mateo Aránzazu , Mateos Maria-Victoria , Orfao Alberto , Contreras Sanfeliciano Teresa , Contreras Sanfeliciano Luzalba del Carmen , Caro Narros Mª Del Rosario , Puig Noemi , Queizan José Antonio , Olivier Carmen 
Published: October 2019

Abstract
Introduction:
Studies have shown that a large monoclonal protein (MP) and immunoparesis in MGUS/SMM have predictive value of progression since they may be indirectly related to the degree of clonal expansion of bone marrow plasma cells (BMPC). A recently available assay, the Hevylite® (HLC), has allowed a more precise determination of MP and the quantification of isotype-matched immunosuppression (i.e. suppression of the monoclonal isotype but of the alternative light chain) which has shown prognostic value in some studies. In this study, we aim to evaluate the association between the alteration of the HLC parameters in MGUS patients with already known prognostic factors, but also, with less studied biomarkers such as circulating clonal plasma cells (cCPC) by Next Generation Flow (NGF) (Flores-Montero et al., Leukemia, 2017).
Methods:
A total of 175 MGUS patients diagnosed between October 2008 and September 2015 were included in the study. The median follow-up was 64 months (range: 1-100 months). MGUS and MGUS progression were defined according to the International Myeloma Working Group (IMWG) criteria. Clinical records were retrieved for all patients. HLC determinations were carried on a SPA+ turbidimeter analyzer and using specific reagents (Binding Site®, UK). The 6 HLCs pairs (IgGk, IgGl, IgAk, IgAl, IgMk and IgMl) were analyzed in all samples. HLC normal ranges were defined by the laboratory based on normal sera. Statistical analysis was done using IBM-SPSS-22.
Results:
HLC ratio was altered in 56.3% of the 111 patients with available sera (47.5% for IgG MGUS and 73.9% and 87.5% for IgA and IgM), respectively (p = 0.026). Patients with altered HLC ratio presented an MP significantly higher (Table 1) than those with normal ratio (0.62 g/dL vs 0.33 g/dL, p<0.0001; HR: 53.23 with 95% CI (2.82 / 1005.54), p=0.008); 100% of the patients had MP>1.5 g/dL (p = 0.044)). Interestingly, it also correlated with a greater frequency and a greater amount of cCPC by NGF (68.29%, p=0.001; 0.2864 /mL vs 0.0139 /mL p=0.0001). Regarding BMPC infiltration, there was a correlation between altered HLC ratios and greater percentages of infiltration of BMPC (3.72% vs. 2.43%, p = 0.001) and higher percentage of BMPC measured by multiparameter flow cytometry (MFC) (54.42% vs 24.42%, p <0.001; HR: 1.02 with 95% CI (1.01 / 1.03), p = 0.007). Patients with altered HLC ratio presented MP> 1.5 mg/dL (100%, p = 0.044), non-IgG (78,12%, p = 0.003) and ratio of altered CLL (77,77%, p = 0.011). Patients with normal HLC ratios correlated with other low risk of progression to MM parameters, such as a MP <1 g/dL (100%, p=0.0001) or <0,5 g/dL (87.8%, p=0.0001) or less than 5% of BMPC (91.3%, p=0.007).Considering the IMWG risk stratification model, 100% of the patients classified as intermediate risk (p = 0.0001) had an altered HLC ratio, while in the low risk group, ratios were evenly distributed. When considering the Spanish (GEM) model, 92% of the patients in the low risk group had normal HLC ratios (p = 0.010). Uninvolved HLC suppression >25% was observed in 15.2% of the patients. These patients presented significantly higher MP (0.91 g/dL vs 0.42 g/dL, p<0.0001; HR: 7.22 with 95% CI (1.11 / 46.83), p=0.038), greater infiltration of BMPC by MFC (70.54% vs 35.52%, p<0.0001; HR: 1.02 with 95% CI (1 / 1.04), p=0.040) and a greater amount of cCPC (0.8905 /mL vs 0.0256 /mL, p=0.030) compared to those without HLC suppression. Patients with moderate (<25%) or no suppression correlated with less aggressive parameters, such as the lower MP, <1 g/dL (95.8%, p = 0.0001) or < 0.5 g/dL (70.5%, p = 0.005). However, no significant correlation was found between the IMWG or the Spanish risk stratification models, and the frequency of HLC suppression.
Conclusions:
HLC abnormalities have been associated with negative prognostic factors previously established, reinforcing the idea that the HLC parameters are directly related to a greater propensity of clonal expansion, or a greater tumor load. However, the short follow-up time did not allow the confirmation of the prognostic value of HLC alterations regarding greater risk of progression to MM. A re-evaluation of the results at 10 years is foreseen. We expect to be able to access whether an evolving pattern exists for the HLC parameters mainly to investigate if the immune suppression by HLC progressively intensifies in patients closest to progressing to MM.

Disclosures
García Mateo: Celgene: Honoraria; Amgen: Honoraria; Binding Site: Research Funding. Mateos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Puig:Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Queizan:Janssen: Consultancy. Olivier:Celgene: Honoraria; Jassen: Honoraria.