Prognostic Impact Of Serum Free Light Chain (sFLC) Assay In Newly Diagnosed Multiple Myeloma (MM) Treated With Bortezomib
Authors: Tacchetti Paola , Rocchi Serena , Pezzi Annalisa , Zamagni Elena , Pantani Lucia , Zannetti Beatrice Anna , Mancuso Katia , Brioli Annamaria , Martinelli Giovanni , Cavo Michele 
Published: October 2019

Abstract

Introduction
sFLC assay is an important advance in the diagnosis and monitoring of MM, however data on prognostic significance are still limited.

Methods
We performed a retrospective analysis aimed to investigate the role of sFLC assay as predictor of outcomes in newly diagnosed MM patients (pts) treated up-front with bortezomib based regimens. sFLC assay (Freelite; The Binding Site, Birmingham, UK) was performed by BN II nephelometer (Date Behring, Deerfield, IL, USA). sFLC-k, sFLC-l and sFLC k/l ratio were serially measured at baseline, during treatment and follow-up. sFLC k/l ratios were classified as normal (0.26-1.65) or abnormal (<0.26 or >1.65) according to the IMWG criteria. An involved sFLC level >=100 mg/L, defined by the IMWG criteria as the level to identify a sFLC evaluable disease, was categorized as high.

Results
We analyzed 110 pts who received first-line bortezomib-based treatments: 67% incorporated into autotransplantation and 33% combined with conventional chemoterapy. The median age was 63 years, 47 pts (43%) were female and 63 (57%) were male. Fifty-eight pts (53%) had IgG heavy chains, 25 (23%) IgA, 1 (1%) IgM and 1 (1%) IgD; 23 pts (21%) had light chain only disease, and 2 pts (2%) had nonsecretory MM. Overall, the involved light chain was kappa in 69 pts (64%), lambda in 36 (33%) and both in 2 (2%), whereas 3 pts (3%) had no detectable light chains. An abnormal sFLC k/l ratio was detected in 91 pts (83%) at baseline, whereas 76 pts (69%) had an involved sFLC >=100 mg/L. The median involved k and l concentrations were 720 and 479 mg/L, respectively. Baseline sFLC >=100 mg/L correlated with higher frequency of Bence Jones isotype (p=0.041), higher beta-2-microglobulin (b2M) (p=0.011), lower hemoglobin concentration (p=0.003) and higher frequency of del(13q) (p=0.016). No correlation was found between high baseline sFLC and other parameters including ISS stage, LDH, bone marrow infiltration, and presence of t(4;14) or del(17p). IMWG response was: 43% stringent complete response (sCR), 11% complete response (CR), 18% very good partial response (VGPR) and 15% partial response (PR). Overall, 83 pts (75%) achieved a normalization of sFLC k/l ratio during treatment. With a median follow-up of 26 months (mos), 36 pts progressed and 17 died. The median time to progression (TTP), progression free survival (PFS) and overall survival (OS) were 46, 46 and 75 mos, respectively. In comparison with a baseline sFLC <100 mg/L, sFLC >=100 mg/L was associated with a reduced rate of sCR/CR (71% vs 48%, p=0.028), a lower probability to normalize sFLC k/l ratio (94% vs 67%, p=0.002) and a shorter median TTP (not reached vs 36 mos, p=0.047) and PFS (not reached vs 35 mos, p=0.034), whereas the OS was similar in the two groups (65 vs 75 mos, p=0.16). By the opposite, pts who achieved a normalization of sFLC k/l ratio during treatment had an extended TTP (53 vs 20 mos, p<0.0001), PFS (53 vs 18 mos, p<0.0001) and OS (not reached vs 75 mos, p=0.0026) in comparison with those who failed this objective. Of the 36 pts who relapsed or progressed, 28 could be assessed for sFLC at relapse. Eleven pts (39%) showed a sFLC escape, defined as an increase of sFLC with no associated increase of intact M protein concentration, that preceded the conventional relapse by a median time of 4 mos. No difference was observed between pts with or without sFLC escape, in terms of time to start second line therapy (1 vs 2 mos, p=0.38) and OS post relapse (p=0.86), whereas sFLC >=100 mg/L at relapse was associated with earlier start of salvage therapy, compared with sFLC <100 mg/L (1 vs 4 mos, p=0.006). A multivariate analysis including age, treatment, b2M, albumin, ISS stage, sFLC and cytogenetic abnormalities identified non-transplant regiments (p<0.001), IIS 3 (p=0.032) and sFLC >=100 mg/L (p=0.047) as variables independently associated with a reduced probability to normalize sFLC k/l ratio. By Cox regression analysis, the normalization of sFLC k/l ratio was an independent factor predicting for extended TTP and PFS (p=0.022 and p=0.001) together with ISS 1-2 (p=0.042 and p=0.007).

Conclusions
High sFLC at baseline was associated with more aggressive disease characterized by a lower probability to achieve sCR/CR and shorter TTP and PFS. Moreover, high sFLC at relapse predicted for short-lasting asymptomatic phase. By opposite, the achievement of normal sFLC k/l ratio during treatment resulted a considerable prognostic indicator of longer TTP and PFS.

Disclosures:
Tacchetti: Janssen: Honoraria; Celgene: Honoraria. Zamagni:Janssen-Cilag: Honoraria; Celgene: Honoraria. Brioli:Celgene: Honoraria. Martinelli:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy; Ariad: Consultancy. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium: 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; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees.