Free Light Chain Escape in Multiple Myeloma : an Exceptional Phenomenon

Background : Free Light Chain (FLC) escape has been described for the first time in 1971 by Hobbs, who reported biochemical relapses of multiple myeloma (MM) with only Bence Jones proteinuria, in patients followed for an intact monoclonal immunoglobulin (Ig) MM. Indeed, FLC escape is defined as an increase of FLC without corresponding increase of the intact monoclonal Ig. In the era of novel-agent based therapy and autologous stem cell transplantation (ASCT), the patterns of disease progression may change, including a potential increased rate of FLC escape. Brioli and al (Blood 2014;123(22):3414-9) reported that 10% of the cases at relapse presented with FLC escape, and that FLC evaluation at relapse could represent an interesting marker of impact from intraclonal heterogeneity on myeloma outcome. We analysed the relapse patterns of patients treated according to the IFM 2009 clinical trial.

Methods: Patients treated according to the IFM 2009 clinical trial (Lenalidomide bortezomib dexamethasone RVD + / - ASCT, Attal and al, ASH 2015) were analyzed. In patients presenting with an intact monoclonal Ig at diagnosis, serum and urine electrophoresis + FLC were compared in a central lab at the time of diagnosis and at the time of progression, in order to identify FLC escape.

Results: 700 patients with symptomatic de novo MM were enrolled in the IFM DFCI 2009 clinical trial. Among them, 318 had a progressive disease, assessed with a centralized biochemistry analysis and 267 patients of them with an intact monoclonal Ig were included in this study. A vast majority (250 patients, 94%) showed an increase of the initial serum monoclonal component up to 5 g/L or up to 25% from the NADIR (IMWG criteria for progressive disease). 8 patients progressed with new bone lesions or plasmocytoma (3%) without any biological markers of progressive disease... Finally, 9 patients (3%) were identified as FLC escape as they did not exhibit an increased intact monoclonal Ig but they had an increased serum FLC and/or an increased Bence Jones proteinuria. Three of them had a serum and urinary measurable disease on diagnosis and they relapsed with both an increase of FLC and an increase of Bence Jones proteinuria. The six other patients presented at diagnosis only with an urinary measurable disease: 3 of them relapsed with an increase of FLC, without any Bence Jones proteinuria, the three others relapsed both on FLC and urines. Isotype of monoclonal component was IgG (6 patients), IgA (2) or IgD (1); light chain was Kappa for 6 patients and Lambda for the three others. Four patients were treated with RVD alone, and 5 patients with RVD + ASCT. The relapse occurred in a median of 2 years after diagnosis (5 months - 3.5 years).

Conclusion: Based on a very large study of patients treated into a phase 3 clinical trial with centralized assessment of response and relapse, we are showing that FLC escape in a very rare phenomenom, observed in 3% of the cases. The low frequency of FLC escape does not lead to a systematic monitoring of intact Ig MM by FLC.