Light Chain Escape in Multiple Myeloma
Authors: Dejoie Thomas , Fouquet Guillemette , Hulin Cyrille , Roussel Murielle , Hebraud Benjamin , Karlin Lionel , Kolb Brigitte , Araujo Carla , Meuleman Nathalie , Tiab Mourad , Malfuson Jean Valère , Bourquard Pascal , Lenain Pascal , Jaccard Arnaud , Belhadj Karim , Lepeu Gérard , Chretien Marie Lorraine , Caillot Denis , Fontan Jean , Rodon Philippe , Schmitt Anna , Voillat Laurent , Cereja Sophie , Pegourie Brigitte , Kuhnowski Frederique , Rigaudeau Sophie , Decaux Olivier , Humbrecht-Kraut Catherine , Frayfer Jamilé , Garderet Laurent , Roos-Weil Damien , Eisenmann Jean Claude , Dorvaux Veronique , Voog Eric G. , Mathiot Claire , Fermand Jean-Paul , Facon Thierry , Avet-Loiseau Hervé , Harousseau Jean Luc , Moreau Philippe , Attal Michel , Leleu Xavier 
Published: October 2019

Abstract

Background. Progression by serum free light chain (sFLC) test without or preceding progression with intact immunoglobulin (Ig) is called light chain escape. This event alone is not considered a progression for patients with Multiple Myeloma (MM) according to International guidelines, although it is often considered a progression in real life and by clinical trials' investigators. We therefore sought to determine whether light chain escape would be a predictor of relapse and thus question a possible need to modify the current criteria for progression according to the International Myeloma Working Group (IMWG).
Material and method. We have reviewed 325 (323 for analysis) patients that presented with a progression in the IFM/DFCI2009 phase 3 study (Attal et al. NEJM 2017). Among these 323 patients, 260 had initial tumor bulk measurement with intact Ig by serum protein electrophoresis test (SPEP; Ig ≥ 10 g/L) and 63 light chain MM (Ig < 10 g/L) measured using urine protein electrophoresis (UPEP). All progressions were validated in the central laboratory of CHU de Nantes (Dr T. Dejoie) and followed IMWG recommendations. sFLC increase was determined by absolute increase ≥ 100 mg/L and ≥ 25% from nadir value of the difference between involved and uninvolved FLC (ΔiFLC). Light chain escape was defined as sFLC increase without progression by SPEP (Ig increase ≥ 5 g/L and ≥ 25%) or UPEP (increase ≥ 200 mg/24h and ≥ 25%).
Results. Among the 260 patients with intact Ig at diagnosis, 3 (1.15%) patients presented a light chain escape: progression by sFLC test without progression by SPEP. In parallel, 228 patients (87.7%) progressed by SPEP, of whom 18/228 (6.25%) showed a sFLC increase preceding the increase of intact Ig, with a median delay of 63 days.
Among the 63 light chain MM, 6 (9.5%) patients presented a light chain escape: progression by sFLC test without progression by UPEP. Interestingly, 6 other patients (9.5%) progressed by SPEP even though Ig was < 10 g/L at diagnosis. Of the remaining 46 patients, 38 (60.3%) showed sFLC increase before progression by UPEP. Finally, 8 patients (12.7%) progressed but with intact Ig pauci-secreting MM meeting none of the M spike based progression criteria.
Median time from iFLC nadir to ΔiFLC ≥ 100 mg/L was 280 days for light chain MM, 496 days for intact Ig MM, and 651 days for light chain escape. Median time from ΔiFLC ≥ 100 mg/L to follow-up visit to assess progression was 402 days light chain MM, 536 days for intact Ig MM, and 713 days for light chain escape.
Overall, 9 (3%) patients had true light chain escape with progression by sFLC test without any other progression criteria. In parallel, in 56 (17%) patients, sFLC increase preceded progression to MM by standard test (SPEP or UPEP). Still the vast majority of patients had a regular relapse using the standard markers for progression.
Conclusion. Based on a large study of patients treated into a phase 3 clinical trial with centralized assessment of response and progression, we showed that 20% of patients had progression by sFLC without meeting standard progression markers, of whom 3% had true light chain escape and 17% early light chain increase. Even though true light chain escape seems to be a rare phenomenon, analysis of sFLC test could help to avoid delayed or missed diagnosis of progression in 20% of patients in this clinical trial. This data should be confirmed in another database to assess whether a modification in the progression criteria in MM International guidelines should be proposed.

Disclosures
Hulin: Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Roussel:Amgen: Consultancy; Celgene: Consultancy; Takeda: Consultancy. Hebraud:Amgen: Consultancy; Janssen: Consultancy, Other: Lecture fees; travel and accommodation for congress, Research Funding; Sanofi: Consultancy; Takeda: Consultancy; Celgene: Consultancy, Other: Lecture fees, Research Funding. Karlin:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support. Belhadj:Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Decaux:Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Garderet:Amgen: Consultancy; Takeda: Consultancy; Celgene: Consultancy. Facon:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Avet-Loiseau:Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Moreau:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Attal:Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janseen: Consultancy, Research Funding; Sanofi: Consultancy. Leleu:Karyopharm: Honoraria; Gilead: Honoraria; Incyte: Honoraria, Other: steering committee membership ; Roche: Honoraria; Sanofi: Honoraria, Other: steering committee membership steering committee membership ; Novartis: Honoraria, Other: steering committee membership ; Amgen: Honoraria, Other: steering committee membership ; Merk: Honoraria, Other: steering committee membership ; Takeda: Honoraria, Other: steering committee membership ; BMS: Honoraria, Other: steering committee membership ; Celgene: Honoraria, Other: steering committee membership ; Janssen: Honoraria, Other.