PF609 HEAVY&LIGHT CHAIN MONITORING IN HIGH RISK SMOLDERING MULTIPLE MYELOMA PATIENTS INCLUDED IN THE GEM‐CESAR TRIAL: COMPARISON WITH CONVENTIONAL AND MINIMAL RESIDUAL DISEASE IMWG RESPONSE ASSESSMENT
Authors: Puig N. , Contreras T. , Paiva B. , Cedena M.‐T. , Pérez J.J. , Aires I. , Agullo C. , Martínez‐López J. , Rodríguez‐Otero P. , González de la Calle V. , González M.‐S. , Oriol A. , Gutiérrez N.‐C. , Rios R. , Rosiñol L. , Alvarez M.A. , Calasanz M.J. , Bargay J. , González A.P. , Alegre A. , Escalante F. , Martínez R. , de la Rubia J. , Teruel A.I. , de Arriba F. , Palomera L. , Hernández M.T. , López J. , Martín J. , Mateo A. García , Ocio E.M. , Bladé J. , Lahuerta J.J. , Miguel J. San , Mateos M.V. 
Published: June 2019

Background:

The GEM‐CESAR trial is a potentially curative strategy for high‐risk smoldering multiple myeloma (HRsMM) patients (pts) in which the primary endpoint is the assessment of bone marrow minimal residual disease (MRD) negativity. However, alternative methods of disease evaluation in serum such as heavy+light chain (HLC), with a potential added value to the IMWG response criteria, have also been tested.

Aims:

To analyze HLC disease in this group of pts at diagnosis and before maintenance, comparing the results with standard serological methods and with MRD assessed by Next Generation Flow (NGF).

Methods:

The 90 HRsMM pts included in the GEM‐CESAR trial received six 4‐weeks cycles of carfilzomib, lenalidomide and dexamethasone followed by high dose melphalan and 2 further cycles of consolidation with the same regimen. All pts received maintenance with lenalidomide up to 2 years. SPEP and IFE were performed using standard procedures. Serum IgGk, IgGl, IgAk and IgAl HLC concentrations were measured using Hevylite (The Binding Site Group Ltd, Birmingham, UK) on a SPA PLUS turbidimeter. HLC concentrations and ratios were considered abnormal if they were outside the 95% reference ranges provided by the manufacturer. MRD was analyzed by flow cytometry following EuroFlow recommendations. Standard response assignment was carried out as per the IMWG guidelines. HLC responses and HLC‐pair suppression were calculated as in Michalet et al (Leukemia 2018).

Results:

We analyzed 75 out of the 90 pts in the trial with intact immunoglobulin and available samples at diagnosis (50 IgG and 25 IgA). HLC ratio was abnormal in 98% (49/50) of the IgG pts and in 100% of IgA pts. A comparison of HLC‐ vs standard IMWG response rates post‐consolidation is detailed in Table 1. In the 60 cases with paired samples for both methods at this moment, there was a moderate agreement between them, with 78.3% of concordant results. The number of cases in the PR and VGPR groups is limited to extract any conclusion but among the 45 in CR as per the IMWG, there were 3 and 8 categorized as in PR and VGPR according to the HLC method, respectively. We then compared these results with those from the analysis of MRD by NGF in 59 out of the 60 cases with paired BM samples available. HLC and NGF reported concordant results in 71.1% of cases (42/59; HLC+/NGF+ in 15 cases and HLC‐/NGF‐ in 27 cases) and discordant in the remaining 28.9% (17/59; HLC‐/NGF+ in 7 cases and HLC+/NGF‐ in 10 cases). The percentage of positive cases post‐consolidation was 25% by SPEP, 37.2% by NGF and 43% by HLC. HLC‐pair suppression was identified in 13/60 pts (21.6%) and 10 of them (16.6%) had severe HLC‐pair suppression at the end of consolidation. After a median follow‐up of 32 months (8–128), 93% of pts remain alive and free of progression. We have analyzed responses post‐consolidation of the 2 cases included in this study that had already progressed. The first pt was in VGPR by the IMWG, in PR by HLC and MRD positive by NGF; the second one in RC by IMWG and by HLC but had severe HLC‐pair immunosuppression and was MRD positive by NGF.

Summary/Conclusion:

Response monitoring by HLC shows a moderate concordance with the IMWG response criteria as well as with MRD assessment by NGF. Most discordances are due to persistent disease by HLC while negative with the alternative methods, but longer follow‐up is needed to ascertain its clinical value. HLC assessment could have anticipated the progression noted in the 2 cases included in the study.

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