Serum free light chain escape before IMWG progression: A predictive marker and a therapeutic opportunity

Abstract

Abstract Background Serum free light chains (sFLC) exhibit greater sensitivity than protein electrophoresis (PEP) and immunofixation electrophoresis (IFE), playing a vital role in diagnosis and treatment evaluation for multiple myeloma (MM). In patients without measurable serum and urine M-protein, a ≥25% increase (with an absolute rise ≥10 mg/dL) in the difference of involved and uninvolved sFLC from nadir indicates disease progression (PD). However, in some patients with measurable M-protein, the above-mentioned “FLC escape, FLCe”—occurs before meeting the International Myeloma Working Group (IMWG) criteria for PD. Additionally, a subset exhibits FLCe during progression without fulfilling IMWG-defined PD criteria. This suggests that rising sFLC may earlier reflect disease progression. Method We conducted a single-center retrospective study of newly diagnosed MM (NDMM) patients between September 2018 and May 2025. Baseline characteristics, treatments, and survival data were collected. During follow-up, patients underwent regular SPEP, UPEP, SIFE, UIFE, and sFLC testing, with response assessed per IMWG criteria. We evaluated FLCe free survival (ePFS, defined from treatment start to FLCe), PFS, second time to progression or FLCe (2nd TTPe, from first PD or FLCe to second PD or FLCe) and OS. Result Totally 750 NDMM patients'data were collected. 645 had measurable M-protein at baseline, in which, 633 patients had complete and continuous sFLC monitoring data. By the last follow-up date (median 60.12 months follow-up), PD was observed in 246 patients, among whom 23 develped FLCe prior to PD. Additionally, 12 patients only exhibited FLCe. In total, 258 patients were included in the final analysis, among which FLCe was observed in 35(13.6%) patients. Compared with patients without FLCe (PD group, n=223), patients with FLCe (FLCe group) exhibited higher frequencies of end-organ damage (anemia: 68.6% vs 46.7%, P=0.026; renal impairment: 20% vs 5.8%, P=0.0097; hypercalcemia: 14.3% vs 4.5%,P=0.038) and ISS stage III (68.6% vs 40.8%, P=0.011),and was also associated with significantly higher dFLC, rFLC (both P<0.001), and urine M-protein (P=0.0015) at baseline. Of the FLCe group, 23 (65.7%) progressed to IMWG-defined PD (FLCe→PD group) with a median interval of 4.13 months (95% CI: 2.57–7.63). While 12 (34.3%) observed isolated sFLCe without progression, in which 8 received prompt intensification of therapy following FLCe onset (early intervention group), the remaining 4 were lost to follow-up. Median 32.47 months follow up after FLCe, no second progression or death occurred in 8 early intervention patients. By contrast, 2-year cumulative rates of second progression and mortality were 37.8% and 14.4% in the FLCe→PD group, 44.1% and 5.8% in the PD group, and 44.4% and 6.6% in the combined cohort (n=232). Kaplan-Meier analysis revealed prolonged 2nd TTPe and OS in the 8 early intervention patients relative to both FLCe→PD and PD groups. Compared with sFLCe→PD patients, early intervention FLCe patients had longer median 2nd TTPe (27.3 months vs.not reached (NR)) and median superior OS (both NR). Comparable trends were observed when early intervention group compared with the PD group (2nd TTPe and OS were 28.8 months and NR, respectively.) and the overall cohort (2nd TTPe and OS were 28.8 months and NR, respectively).Due to the very small number of the early intervention group, the differences were not statistically significant till now. However, the early intervention FLCe patients consistently exhibited favorable trends in 2nd TTPe and OS. Notably, the OS curve of the sFLCe→PD group separated early and remained inferior to the PD group throughout follow-up. Although not significant (p=0.081), a hazard ratio of 2.3 (95% CI: 0.897–6.04) suggested a trend toward worse survival in patients with FLCe, underscoring the value of early recognition and intervention. Conclusion FLCe was significantly associated with higher end-organ damage, higher ISS stage, and elevated dFLC/rFLC levels at baseline. The median interval from FLCe to IMWG-PD was 4.13 months. Early therapeutic adjustment post FLCe correlated with improved survival, while delaying treatment adjustment until after IMWG-PD showed a poorer prognostic trend. These findings suggest FLCe may also used as a more sensitive preclinical marker of progression for MM patients with measurable M protein, with timely intervention potentially improve disease control and prognosis.