Early Normalization of Serum Free Light Chain (FLC) Assays Correlates with Profound and Prolonged Responses in Newly Diagnosed Multiple Myeloma (MM)
Authors: Gironella Mercedes , Senín Alicia , Vallejo Karla , Arenas Pamela , Raheja Priyanka , Dieli Romina , Hernández Manuel , Bosch Francesc 
Published: October 2019

Abstract
FLC is a recognized biomarker used for monitoring response and outcome of patients with amyloidosis and oligosecretory and non-secretory MM. Nevertheless, the role of FLC in the early prediction of response to the treatment in patients with gammopathies has not been fully ascertained. Against this background, we have evaluated the relationship between early FLC detection and the achievement of a deep and prolonged response after the end of the treatment in a series of patients diagnosed with MM and homogeneously treated in a single institution.
Eighty-six newly diagnosed patients with MM between 2011 and January 2018 at the University Hospital Vall d'Hebron treated front-line with a bortezomib-based scheme were retrospectively analyzed. All patients had FLC levels measured by the Freelite® nephelometric assay at diagnosis, after the 2nd cycle of therapy, and at the end of treatment. Different parameters related to the FLC measurement were evaluated: normalization of the involved FLC (iFLC), ratio of involved/uninvolved FLCs (R_FLC)<10, reduction of R_FLC>95% compared to the baseline, and normalization of the ratio Kappa/lambda FLC (R_K/L). The predictive value of these parameters on the response after chemotherapy treatment was evaluated by using the Pearson´s exact test, and their impact on outcomes was analyzed by Kaplan Meier method using the long rank test for comparisons.
The median age of the series at diagnosis was 69 years old (45-89). Forty-seven patients (55%) were considered candidate for autologous hematopoietic stem cell transplantation, therefore receiving induction treatment with the VTD combination (bortezomib-talidomide-dexametasone). In contrast, 39 patients (45%) were not candidate for autologous transplantation and were treated with MPV (melfalan-prednisone-bortezomib). The involved Ig was IgG in 54.7% of cases, IgA in 18.6%, IgD in 1.2% and IgM in 1.2%. Twenty-four percent of patients were diagnosed with MM of light chains (12% kappa and 12% lambda), whereas only 3 patients were diagnosed as having a oligosecretory MM. Twenty-nine percent of the cases were ISS III, 33% had increased serum LDH levels, and 79% showed immunoparesis. The kappa FLC mean at diagnosis was 1603.61 mg/dL (0.06 -36100 mg/dL) and lambda FLC was 1104 mg/dL (0.05-26500 mg/dL). Kappa FLC mean after 2nd cicle was of 192.14 mg/dL (1,61-6430 mg/dL) and lambda FLC was 61.41 mg/dL (0.05-1434 mg/dL).
Thrirty-seven percent of patients obtained a profound response (≥VGPR) after the 2nd cycle of therapy, being this percentage increased to 63% of patients at the end of the chemotherapy treatment. Alongside this, the normalization of the iFLC was observed after the 2nd cycle of treatment in 44% of patients, the normalization of the R_K/L in 42%, R_FLC<10 in 70% of patients, and a reduction of R_FLs>95% was observed in 57% of patients. The great majority (80-87%) of patients attaining the normalization of any of these parameters after the 2nd cycle experienced a response ≥VGPR at the end of the treatment (table 1). With a median follow-up of 28.2 months (7-84 months), the overall PFS of the series was of 26.7 months. Of note, median PFS was of 40.3 months for patients who achieved the normalization of the iFLC after the 2nd cycle vs. 24.6 months for those who did not (p=0.047) (figure 1). Moreover, PFS was 27.3 months for those who had R_FLC<10 vs. 23 months for those with R_FLC≥10 (p=0.042). Finally, patients with reduction of R_FLC>95% exhibited a trend for a longer PFS (40.3 vs. 23.5 months) (p=0.09), as those patients with normalization of R_K/L who presented a PFS of 40.3 vs. 26.5 months (p=0.099).
In conclusion, patients with normalization of different parameters related to FLC at 2 months of the onset of treatment exhibit a deeper and prolonged response to bortezomib-based chemotherapies, suggesting that this assessment could be of paramount interest in the early prediction of outcomes in patients with MM receiving treatment. Therefore, early FLC determinations should be incorporated into prospective clinical trials to validate these observations.

Disclosures
No relevant conflicts of interest to declare.