Serum Free-Lite Chain (sFLC) Assay in Multiple Myeloma (MM): Clinical Correlates and Prognostic Implications in Newly Diagnosed MM Patients Treated with Total Therapy 2 or 3 (TT2/3).
Authors: Cavallo Federica , Rasmussen Erik , Zangari Maurizio , Tricot Guido , Fender Belinda , Fox Michelle , Burns Michael , Barlogie Bart 
Published: April 2020

Abstract
Background: Most newly diagnosed patients with MM have detectable M-protein in serum or urine; only ~5% have non-secretory MM and another 5% are “low secretors” with serum M &lt; 0.5 g/dL and &lt; 100mg/d of Bence Jones proteinuria despite marked tumor burden detected in the bone marrow and on imaging studies. Serum FLCs are present in the majority of such patients and are useful for response assessment. The aim of this study was to examine sFLC in the context of a comprehensive staging work-up for MM.
Patients and Methods: TT2 protocol consists of intensive induction with VAD, DCEP, CAD and DCEP followed by tandem transplants, while in TT3 Velcade (V) is added to the DT-PACE regimen in 2 cycles as induction prior to MEL 200 tandem transplant and 2 cycles as consolidation, followed by VDT maintenance. 328 patients from these 2 protocols had baseline sFLC along with the other standard variables. The association between baseline sFLC levels and sFCL ratio (FLCr) and standard parameters was evaluated using Spearman’s correlation coefficient and a Kruskal-Wallis test. During the induction therapy, bi-weekly samples were available for TT3 patients while TT2 patients had weekly samples procured.
Results: Significant positive baseline correlations between sFLC and B2M, LDH, creatinine, bone marrow PC% and urine-M excretion (all p&lt;.001); negative correlates were seen with Hb, platelet count and serum-M (p&lt;.001). Both sFCL and FLCr were higher in the presence of cytogenetic abnormalities (CA) than without CA (p=.02 and p=.002); these variables also increased across ISS stage (both p&lt;.001). As expected, 100% of LC only patients had an abnormal free k/l or l/k ratio; surprisingly, also 90% of those with IgA or IgG isotypes and 4/5 patients with non-secretory MM had an abnormal ratio. The median ratio was higher among LC than non-LC MM (487 vs 35; p&lt;0.001). Baseline sFLC were significantly, positively correlated with urine M for only LC MM (R=.34; p=.012) but not with serum IgA (R=−.11, p=.36) or serum IgG (R=.04, p=.56). For the purpose of predicting response or failure to induction therapy, 140 patients with baseline sFLC &gt;=30 mg/dL and serial sFLC measurements were considered: 19% and 23% had normalization of sFLC by 30 days of induction therapy and prior to transplant 1. Normalization of sFLC increased probability of subsequent CR both at 30 days (HR: 3.1; p=0.002) and prior to TX1 (HR=3.9; p=−.001) (Figure 1).
Conclusion: S-FLC and FCLr are both highly correlated with CA and ISS, the 2 most important prognostic factors for both EFS and OS, and can hence be expected to have major independent predictive power with longer follow-up. Importantly, subsequent CR was significantly lower in the absence of sFLC normalization by 30 days and prior to transplant 1.
Fig 1. CR by normalization of sFLC Pre-TX1 Fig 1. CR by normalization of sFLC Pre-TX1