Uninvolved Immunoglobulin Suppression Determined By "Hevylite" ASSAY. Strongly Predicts Evolution of Smoldering Myeloma (SMM) to Symptomatic Multiple Myeloma (MM)
Authors: Papaioannou Paraskevi , Gkioka Annita Ioanna , Tsalimalma Kallirroi , Koudouna Aspasia , Kopsaftopoulou Anastasia , Chamoulkou Konstantina , Grafakos Ioannis , Bitsani Aikaterini , Iliakis Theodoros , Dimou Maria , Kafassi Nikolitsa , Sfikakis Petros , Panayiotidis Panayiotis , Kyrtsonis Marie-Christine 
Published: October 2019

Abstract
SMM may have an indolent course and remain stable for years; however, some patients evolve to MM requiring treatment within two years or less. To timely recognize these patients, three biomarkers (FLCR>100, ≥1 osteolysis and ≥60% plasma cell bone marrow infiltration) were recently established to discriminate asymptomatic MM patients at increased risk of rapid evolution and therefore, patients displaying the aforementioned biomarkers are considered symptomatic and receive immediate treatment. Despite the usage of the new IMWG definition criteria, there are still patients evolving rapidly and the notion of High risk SMM remains subjective among scientific groups. We herein studied wherever immunoglobulin (Ig) Heavy/Light Chain (HLC) measurements with the "Hevylite" assay that measures separately HLC-IgA, -G, -M-kappa or lambda, could add prognostic information on SMM evolution, with special attention to the significance of polyclonal Ig suppression. This method allows exact quantification of the amount of pure monoclonal fraction but also the degree of suppression of uninvolved polyclonal Igs.
Patients and Methods: We studied 79 SMM patients of whom 30 were men and 49 women, with median age 65 (31-84) Ig type was IgG in 64 patients (81%) and IgA in the rest (19%). None of the patients had a free light chain ratio (FLCR) of more than 100, bone disease or more than 60% plasma cell bone marrow infiltration, in accordance to the last IMWG definition criteria. Patients were regularly followed (each 3 months) since SMM diagnosis and for a long period of time (median 98 months) during which 15 patients evolved to MM. "HevyLite" assay measurements were performed by nephelometry according to the manufacturer's instructions in frozen sera sample drawn at the time of diagnosis. We then calculated in all patients the ratio of involved/uninvolved Ig (HLCR); we also scored on a 5 points scale the eventuality of uninvolved Ig kappa or lambda below normal limits, that are, according to the manufacturer's testing on healthy individuals, 3608, 2023, 300, 312, 267, and 185 mg/L for IgG-kappa, IgG-lambda, IgA-kappa, IgA-lambda, IgM-kappa and IgM-lambda respectively. Results' relationship with SMM evolution were analyzed by standard methods using the SPSS v22.0. software and p values below 0,05 were considered statistically significant. Survival curved were drawn according to Kaplan-Mayer method.
Results: Monoclonal Ig type was IgG-kappa, IgG-lambda, IgA-kappa, IgA-lambda in 61%, 19%, 11% and 9% of SMM patients respectively. Uninvolved IgG-kappa, IgG-lambda, IgA-kappa, IgA-lambda, IgM-kappa, IgM-lambda ranged from 625 to 14300 mg/L, 495 to 12700 mg/L , 214 to 2930 mg/L, 38 to 2580 mg/L, 19 to 1300 mg/L, 51 to 950 mg/L respectively. Median HLCR was 7 (range 0,24-707). Patients with HLCR above median tended to evolve faster than the others (p=0,1-not reaching statistical significance). Thirty-five patients had no one uninvolved Ig class depressed (score 0), 28 had 1, 9 had 2, 5 had 3 and 2 had 4; No score 5 was observed. Time to evolution strongly correlated to high score uninvolved Ig suppression (p< 0,00001). A simplified score separating 3 groups, the first with 0 Ig suppression, the 2nd with 1 or 2 and the 3rd with 3 or 4 proved to be equally potent in separating 3 risk-groups of SMM patients at risk of evolution to myeloma (p< 0,00001) and the great majority of the patients in the 3rd group evolved within two years (figure).
In conclusion, the presence of decreased uninvolved Ig levels as determined by "Hevylite" constitutes a powerful prognostic marker of SMM evolution to MM.
Figure. Figure.

Disclosures
No relevant conflicts of interest to declare.