Can Assessment of Patient Monoclonal Immunoglobulins By Heavy/Light Analysis be Used to Assign Patient Responses Analogous to IMWG Response Criteria?
Authors: Boyle Eileen , Fouquet Guillemette , Lejeune Julie , Manier Salomon , Musset Lucile , Bories Claire , Dulery Remy , Guidez Stéphanie , Bonnet Sarah , Onraed Brigitte , Faucompre Jean-Luc , Tricot Sabine , Poulain Stephanie , Leblond Veronique , Snell Kym , Leleu Xavier 
Published: October 2019

Abstract
Background
Quantification of monoclonal immunoglobulins in serum is the foundation of IMWG multiple myeloma (MM) response criteria for patients with intact immunoglobulin disease. However, electrophoretic methods for quantifying M-Ig in serum are subject to well documented limitations including inaccuracy at high concentrations (due to dye saturation) and poor sensitivity at low concentrations. Moreover, the methods require skilled interpretation and can be time consuming; however their clinical utility is well established. Recently heavy/light chain (HLC) assays, which quantify kappa and lambda isotypes of intact immunoglobulins have become available. Here we compare responses assigned by the immunoassays to IMWG criteria and evaluate the clinical impact of discordance.
Methods
Sequential sera, from enrolment to progression, were available for 107 MM patients (59 IgGκ, 29 IgGλ, 12 IgAκ, 7 IgAλ) enrolled onto either the IFM 2009-02 end-stage relapsed or refractory MM or the IFM 2010-02 in del17p and t(4;14) relapsed or refractory MM trials. The inclusion criterion was a measurable intact immunoglobulin MM according to IMWG criteria (M spike ≥ 10 g/L), using serum and/or urine protein electrophoresis. IgA HLC (IgAκ and IgAλ) and IgG HLC (IgGκ and IgGλ) analysis was compared to historic SPEP, IFE, UPEP, uIFE and serum free light chain (sFLC) results (measured using polyclonal antisera based assays). Responses were assigned at approximately 90 days (median 90, range 61-107 days) and at maximum response (if different) according to IMWG criteria using changes in monoclonal protein concentrations measured either by SPEP or dHLC (clonal - non clonal). Complete response was assigned either by the absence of monoclonal protein on IFE or by a normal HLC ratio.
Results
At the time of enrolment, 87/88 IgG and 17/17 IgA patients had abnormal HLC ratios which were concordant with IFE results, and quantification of the monoclonal protein by dHLC was similar (median (range): 29.2 (2.5-77.5) g/L) and SPEP (30.7 (1.8-66.9) g/L). After 3 months of treatment, responses assigned by HLC/FLC assays showed near-perfect agreement with responses assigned using SPEP and IFE (Weighted Kappa >0.81, p<0.001). Analysing patients with ≥ partial response (PR) or <PR by either method showed 93% concordance. However, univariant Cox regression modelling suggested that the HLC assigned responses were significantly associated with PFS (p=0.05), whereas the IMWG assigned responses were not (p=0.345). Similarly, HLC assigned responses had a slightly better model fit using AIC statistics compared to IMWG assigned response (AIC 374 vs. 378).
At maximum response there was near-perfect agreement between the responses assigned using HLC/FLC or SPEP, IFE, UPEP, uIFE (Weighted Kappa >0.81, p<0.001). Changes in dHLC predicted response in 16/39 patients (15 IgG and 1 IgA), achieving ≥PR up to 224 days earlier than SPEP (median 52 days, range 22-224 days). In addition, in 10/79 patients, changes in dHLC indicated relapse up to 77 days (median 56 days range 28-77 days) earlier than standard methods.
Conclusion
Changes in dHLC can be used in place of SPEP quantification to assign IMWG responses in patients with intact immunoglobulin MM. Minor discordances had an impact on the model fit favouring the HLC assigned response over response assigned using SPE/IFE. Changes in dHLC identified response and relapse earlier than clinically assigned in a number of patients. Considering the small number of patients, we suggest that larger prospective trials be conducted to validate these findings.

Disclosures
Leblond: GSK: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Mundipharma: Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau. Snell:The Binding Site Group Ltd: Research Funding. Leleu:Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria; BMS: Honoraria; Amgen: Honoraria.