Multiple Myeloma (MM): Impact of Immunoglobulin Isotype on the Speed of Response
Authors: Caillon Helene , Attal Michel , Moreau Philippe , Dejoie Thomas 
Published: October 2019

Abstract
Background: Detection and/or measurement of monoclonal components by serum protein electrophoresis (SPE) is essential for evaluation of response in multiple myeloma according to the International Myeloma Working Group (IMWG) criteria. Patient peak on SPE has a single presentation due to the extreme heterogeneity of monoclonal components based on isotype of immunoglobulin (Ig), charge, polymerization, viscosity, precipitation … Regarding the Ig isotype, distribution of myelomas has been known for a long time with about 55 % of IgG myelomas, 25 % of IgA myelomas, and 15% of light chain multiple myelomas (LCMM). Therefore differences in terms of various physical and chemical characteristics are observed according to isotype such as half-lives (IgG : 7-21 days ; IgA : 6 days ; only a few hours for light chains of Ig). Considering both differences about frequency and clearance according to Ig isotype, we addressed the question of the impact of isotype on the speed of response in multiple myeloma.
Objective: The aim of this study was to assess if the different isotypes of monoclonal components involved in multiple myeloma have an impact on the velocity and the depth of response.
Design and methods: Data from two recent clinical trials conducted by IFM were analysed. The first analysis was based on patients enrolled in the IFM DFCI 2009 clinical trial who benefited of each of the three MRD points planned in this trial (after induction and autograft for one arm, pre-maintenance and post-maintenance). Patients were categorized on the isotype of the monoclonal component involved : IgG, IgA or IgD intact immunoglobulin multiple myelomas (IIMM) with serum measurable disease according to IMWG criteria (i.e. serum monoclonal peak ≥ 10 g/L), LCMM, and IIMM without any serum measurable disease (i.e. serum monoclonal peak < 10 g/L).The percentage of patients who achieved at least a very good partial response (VGPR) was evaluated globally as well as for each category defined. The same analysis was carried out for the IFM 2013-04 clinical trial with one response assessment, after four induction cycles.
Results: Concerning IFM DFCI 2009 trial, 398 patients evaluated on the three MRD points could be included in this analysis, divided into 185 and 213 in each arm of treatment. Within the total enrolment, two types of response kinetics could be distinguished : for IgA, IgD IIMM, IIMM without serum measurable disease and LCMM, the gain of response between post-induction +/- autograft and post-maintenance is on average 11,1 points (6,7 - 15) when IgG myelomas presented a difference of VGPR percentage of 27,9 points. The same observation could be made for each arm of treatment : 16,6 and 5,8 points of VGPR percentage gained in each arm for the "faster response" group as defined previously, whereas 33,3 and 23,3 points were gained for IgG myelomas. Apart from this difference of kinetics, we notably observed that IgG myelomas never reached VGPR rates obtained with other isotype myelomas. About IFM 2013-04 trial, 264 patients could be evaluated in our analysis after four cycles of VTD (131) or VCD (133) for induction. 98,0% of IgA myelomas achieved at least VGPR after induction (96,3% for VTD arm and 100% for VCD arm) whereas only 50,6% for IgG myelomas (57,3% and 43,2%) and 68,3% for LCMM (46,7% for VTD arm and 80,8 for VCD arm).
Conclusion: This study shows that time of evaluation is a key factor regarding the different speed of response for each isotype of Ig. IgA myelomas and LCMM have a faster response than IgG myelomas. IgG myelomas have a lower biochemical response than other isotype myelomas. Consequently, for an accurate interpretation of data in clinical trials, patients should be equally distributed in each arm of treatment according to their isotype. Ideally, to be compared, clinical trials should always have the same isotype distribution, especially when an early evaluation is performed such as after induction.

Disclosures
Attal: jansen: Honoraria; celgene: Membership on an entity's Board of Directors or advisory committees. Moreau:Celgene, Janssen, Takeda, Novartis, Amgen: Membership on an entity's Board of Directors or advisory committees.