Free Light Chains, Monoclonal Proteins, and Chronic Lymphocytic Leukemia.
Authors: Ruchlemer Rosa , Reinus Constantine , Paz Esther , Cohen Ahuva , Melnikov Natalia , Ronson Aharon , Rudensky Bernard 
Published: October 2019

Abstract
Monoclonal proteins(MPs) can frequently be detected in the serum/urine of chronic lymphocytic leukemia(CLL) patients. Serum free light chains(FLC) assays can detect MPs in the absence of M bands on immunofixation(IMF).An abnormal FLC ratio indicates excess of one light chain type suggesting clonality.We evaluated fresh serum/urine samples from 34 CLL patients at various stages of disease by quantitative nephelometric assay,IMF and FLC assay.Median age was 66 yrs(43–87),M:F 1.9:1 and median time from diagnosis 41.5 mos(5–288). 45% had advanced stage and 39% prior treatment with 1–7 therapies.Only 2 patients had mild renal failure.Serum immunoglobulins were normal/low in 94% of patients:IgG (171–1580 mg/l, median 803 mg/l), IgA(<25–310 mg/l, median 88 mg/l),IgM(<18–290 mg/l, median 38 mg/l), irrespective of the presence of a monoclonal protein. 71% of patients had evidence of abnormal immunoglobulin synthesis: by IMF alone (8),IMF and FLC(10) or FLC alone(8).Abnormal FLC ratios were more frequently associated with advanced stage disease and increased κ chains(see table 1). Abnormal FLC ratios(< 0.26 or >1.65) were measured in 18(53%) patients, 8 of whom did not have MPs by IMF. Two advanced stage patients had abnormal FLC ratios due to very low levels of a single light chain, most probably reflecting secondary hypogammaglobulinemia due to CLL and/or chemotherapy.Abnormal FLC ratios reverted to normal after 1 course of chemotherapy(FC+/−R) in 3 patients despite persistence of minimal residual disease(MRD).FLC were of the same type as expressed on the surface of CLL cells, with discrepancies observed in 5 patients.BM biopsy staining for light chains revealed IgAκ MGUS in addition to λ chain restricted CLL in one patient, but was noncontributory in the other 4.
Conclusions: Neither IMF nor the FLC assay alone could detect all MPs. Normal FLC ratios do not exclude the presence of MPs. The FLC ratio should be interpreted with caution in CLL patients with advanced disease and hypogammaglobulinemia. Monoclonal bands and abnormal FLC ratios can be detected despite normal or low levels of serum immunoglobulins in CLL patients. The significance of these monoclonal gammopathies in CLL is not clear and warrants further study in a larger group of patients. Discrepancies between surface immunoglobulins and serum/urine MPs might suggest the presence of an additional condition:ex. MGUS. FLC may not be a sensitive measure of MRD.
Normal FLC ratio Abnormal FLC ratio P value *median No. patients 16(47%) 18(53%) M:F 1.3:1 3.5:1 NS Age* 62.5 yrs(49–73) 68 yrs(43–87) NS Time from CLL diagnosis* 25.3 mos(0–282) 59 mos(0–210) NS Adv stage(Rai III/IV-Binet C) 25% 66.7% 0.018 Untreated 62% 50% NS CLL:κ:λ restriction 7:8(0.88:1) 11:6(1.8:1) NS Monoclonal protein 8(50%) 10(56%) NS Increased freeκ no. 8 15 0.043 Freeκ level* 19.6(4.5–200) 39.2(2.9–386) 0.0064 Increased freeλ no 4 3 NS Free λ level* 19.3(12.4–146) 15.4(0.1–517) NS Serum β 2m* 3.1(1.8–6.7) 4.3(2.2–10.2) NS Zap70≥20 86% 36% 0.002 CD38≥30 44% 44% NS 17pdel/11qdel 40% 44% NS