Serum Free Light Chain Ratio (FLCR) at Diagnosis Constitute a Powerful Prognostic Factor of Survival in Multiple Myeloma (MM).
Authors: Kyrtsonis Marie-Christine , Vassilakopoulos Theodoros P. , Kafasi Nicoletta , Sachanas Sotirios , Tzenou Tatiana , Papadogiannis Argiroula , Galanis Zacharoula , Kalpadakis Christina , Dimou Maria , Kyriakou Elias , Angelopoulou Maria K. , Dimopoulou Maria N. , Siakantaris Marina P. , Kokoris Styliani I. , Dimitriadou Evangelia M. , Panayiotidis Panayiotis , Pangalis Gerassimos A. 
Published: October 2019

Abstract
MM is characterized by the presence of a monoclonal immunoglobulin (Ig) in the serum, produced by neoplastic plasma cells infiltrating the bone marrow (BM). Small amounts of free light chains (FLC) are secreted in normal individuals. In case of monoclonality, the FLC ratio increased. The detection and quantification of serum FLCs and of their ratio, was recently introduced as a useful method for the diagnosis and monitoring of light chain MM, amyloidosis, non-secretory MM and MGUS. However, the possible role of FLCR as a prognostic variable has not been investigated yet. We therefore studied the relationship of baseline serum FLCR with disease characteristics and prognosis in MM patients. Eighty-six MM patients (55 kappa-, 31 lambda- ), 16 individuals with MGUS (8 kappa-, 8 lambda-) and 29 healthy individuals (HI) were studied. Serum free light chain levels were measured in frozen sera drawn at diagnosis, before treatment, using a latex-enhanced immunoassay (The Binding Site, Birmingham, UK) on a Behring BN II nephelometric analyzer. Then, the FLCR was calculated, accordingly as kappa/lambda or lambda/kappa, depending on the monoclonal light chain type of the patient. Forty-nine percent of MM patients were males and 65% were ≥ 65 years old. The Ig type was IgG in 61%, IgA in 22%, BJ in 16% and IgD in 1%. Thirty-five percent of patients were in stage I, 31% in stage II and 34% in stage III according to Durie and Salmon while 36% were in stage 1, 22% in stage 2 and 42% in stage 3 of the ISS staging system. Twenty-five percent of patients had Hb < 10g/dL, 13% creatinin ≥2 mg/dl, 10% elevated LDH, 19% serum albumin < 3.5 g/dL, 45% CRP ≥4 mg/L, 41% beta-2-microglobulin ≥5.5 mg/L, 17% presented spontaneous bone fractures and 41% had ≥50% plasma cell BM infiltration. The median serum FLCR at diagnosis was 3.68 in the 55 kappa-MM patients, 38.49 in the 31 lambda-MM patients, 1.24 in kappa-MGUS, 2.14 in lambda-MGUS and 0.43 in HI (κ/λ). Differences between MM and HI and MM and MGUS were significant (p < 0.001). Baseline serum FLCR correlated with creatinin (p=0.03), LDH (p=0.003), the percentage of BM infiltration (p=0.001), the presence of spontaneous fractures (p=0.002) and Durie and Salmon staging (p=0.003). In patients with BJ MM, FLCR was higher then in the ones with other Ig types (p=0.001). Serum FLCR did not correlate with age, gender, hemoglobin, CRP, serum albumin, beta-2-microglobulin, paraprotein level nor with the ISS staging. With a median follow-up of 27.2 months (3.2–89.8), MM patients with serum FLCR < median, had a 3- and 5- year survival of 92±6 and 79±10 respectively, while the corresponding 3- and 5-year survival of patients with FLCR ≥ median were 67±8 and 32±13 (p=0.001). In multivariate analysis, serum FLCR above the median provided prognostic information independent of the value of ISS. In conclusion, baseline serum FLCR appears to be a powerful prognostic factor of survival in MM.