Abstract
Introduction
Guidelines for monitoring light chain multiple myeloma (LCMM) patients currently rely on measurements of the monoclonal protein in urine (Bence Jones proteinuria). However, the presence of light chains in the urine is highly influenced by the individual free light chain, production rate and renal function, which may make accurate monitoring challenging. Serum free light chain measurements are recommended as diagnostic aid for identifying patients with monoclonal gammopathies and as tools to monitor patients with AL amyloidosis and oligo-secretory MM. The correlation between 24hr urine and serum free light chain (sFLC) measurements is insufficient to consider the tests interchangeable, which has prevented recommendations for replacing urine with serum assessment. Here we compare the performance of serum and urine measurements for monitoring 113 newly diagnosed LCMM patients enrolled onto the IFM-2009 trial; and assess the impact of monitoring by either method with clinical outcome.
Methods
The IFM-2009 trial randomised patients into either arm A (8xRVD) or arm B (3xRVD followed by high-dose Melphalan with autologous stem cell rescue, and 2 further RVD treatments). All patients received one year of Lenalidomide maintenance therapy. Urine protein electrophoresis (UPEP) and immunofixation electrophoresis (uIFE) were performed prospectively using standard laboratory procedures. sFLC concentrations were measured nephellometrically using κ sFLC and λ sFLC Freelite®assays (The Binding Site Group Ltd, UK). Minimal residual disease (MRD) was assessed by 7-color flow cytometry at the end of consolidation therapy.
Results
At diagnosis, clonal disease was identified in 100% of patients either by an abnormal κ/λ sFLC ratio or by uIFE. However, whilst all patients had measurable disease by the sFLC assay only 64% had measurable disease using UPEP. The discordance in sensitivity was replicated throughout monitoring and monoclonal light chains were quantifiable after cycle 1 and cycle 3 in 71% vs. 37% patients, and 46% vs. 18%, using sFLC vs. 24hr urine measurements, respectively; in keeping with previous reports.
To understand the clinical significance of these discordant findings we compared the depth of response determined by sFLC measurement to those determined by urine electrophoresis after 3 cycles of therapy. Patients with quantifiable disease by sFLC or an abnormal κ/λ sFLC ratio had dismal PFS (median PFS: 36 months vs. not reached, p=0.006; 33 months vs. not reached, p<0.0001, respectively). Whereas quantifiable disease by UPEP was uninformative for PFS (36 vs. 47 months, p=0.260), and abnormal vs. normal uIFE only tended towards significance (36 vs. 47 months, p=0.072); suggesting that monitoring with the sFLC assay is more clinically relevant than with 24hr urine after 3 cycles of therapy.
Separating the population into patients with negative UPEP at cycle 3 (n=82), patients with a normal sFLC levels had longer PFS than those with abnormal concentrations (not reached vs. 34 months, p=0.015). Concordant with these results, in 78 patients with negative uIFE, an abnormal κ/λ sFLC ratio still heralded a poorer PFS (34 months vs. not reached, p<0.0001) and importantly overall survival (75% OS: 44 months vs. not reached, p=0.016). In contrast, separating the patients into those with identifiable disease by sFLC or an abnormal κ/λ sFLC ratio, the addition of the urine assessment provided no further discriminatory value.
The absence of malignant plasma cells in the bone marrow has been proposed as an important end-point for clinical studies, and therefore we assessed the relationship between early monoclonal light chain removal, as determined by serum and urine assessment, and subsequent elimination of malignant plasma cells. Normalisation of κ/λ sFLC ratio after both 1 and 3 treatment cycles had 100% positive predictive value (PPV) for the prediction of MRD negativity post-consolidation, i.e. all patients whose serum FLC ratio normalised during induction went on to achieve MRD negative status post-consolidation; by contrast patients becoming urine IFE negative at cycles 1 and 3 had PPVs of 81% and 78%, respectively.
Conclusions
Serum FLC measurements offer improved sensitivity and better correlation with clinical outcome than urine assessments, hence providing a strong basis for recommending the former for monitoring LCMM patients.
Disclosures
Attal: amgen: Consultancy, Research Funding; celgene: Consultancy, Research Funding; janssen: Consultancy, Research Funding; sanofi: Consultancy. Moreau:Amgen: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria. Avet-Loiseau:amgen: Consultancy; celgene: Consultancy; sanofi: Consultancy; janssen: Consultancy.
Immunoglobulin Free Light Chain Dimers in Human Diseases