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581 Qip-Mass Spectrometry in High Risk Smoldering Multiple Myeloma Patients Included in the GEM-CESAR Trial: Comparison with Conventional and Minimal Residual Disease IMWG Response Assessment

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma: Therapy, excluding Transplantation: Novelty in CAR T in Relapsed/Refractory Multiple Myeloma
Hematology Disease Topics & Pathways:
Adult, Diseases, Non-Biological, Therapies, Combinations, Adverse Events, chemotherapy, Study Population, Clinically relevant, Quality Improvement , Myeloid Malignancies
Monday, December 9, 2019: 8:00 AM
Hall D, Level 2 (Orange County Convention Center)

Noemi Puig, MD, PhD1*, Maria-Victoria Mateos2, Teresa Contreras3*, Bruno Paiva, PhD4*, María Teresa Cedena5*, José J Pérez6*, Irene Aires7*, Cristina Agullo3*, Joaquin Martinez-Lopez, MD, PhD8*, Paula Rodriguez Otero9*, Veronica Gonzalez De La Calle, MD, PhD7*, Marta Sonia Gonzalez, MD10*, Albert Oriol11*, Norma C. Gutierrez, MD, PhD7*, Rafael Rios, MD, PhD12*, Laura Rosiñol13*, Miguel Angel Alvarez, MD14*, Maria Jose Calasanz, PhD, BSc15*, Joan Bargay, MD, PhD16*, Ana Pilar Gonzalez, PhD17*, Adrián Alegre, MD18, Fernando Escalante, MD19*, Rafael Martínez20*, Javier de la Rubia, MD, PhD21*, Ana Isabel Teruel, Medical Doctor22*, Felipe De Arriba, PhD23*, Luis Palomera, MD, PhD24*, Miguel-Teodoro Hernández25*, Javier López, MD26*, Jesús Martín27*, Aránzazu García Mateo, PhD28*, Ramón García-Sanz, MD, PhD1*, Enrique M. Ocio29*, Joan Bladé, MD, PhD30, Juan-José Lahuerta, MD, PhD31* and Jesus F. San-Miguel, MD32

1Hospital Universitario de Salamanca Hematología. Instituto de investigación biomédica de Salamanca (IBSAL), Salamanca, Spain
2Institute of Cancer Molecular and Cellular Biology, University Hospital of Salamanca, Salamanca, Spain
3Hospital De Salamanca, Salamanca, Spain
4Centro de Investigación Médica Aplicada, University of Navarra, Clínica Universidad de Navarra, Pamplona, Spain
5Hospital Universitario 12 de Octubre, Madrid, Spain
6Hospital Universitario de Salamanca (IBSAL). Centro de Investigación del Cáncer (IBMCC-CSIC). Universidad de Salamanca., Salamanca, Spain
7Departamento de Hematología, Hospital Universitario de Salamanca (HUSAL), IBSAL, IBMCC (USAL-CSIC), CIBERONC, Salamanca, Spain
8Hospital Universitario de Salamanca, Salmanca, Spain
9Clínica Universidad de Navarra, Pamplona, Spain
10Hospital Universitario de Santiago, Santiago de Compostela, Spain
11ICO - Hospital Germans Trias I Pujol, Barcelona, Spain
12Servicio de Hematología y Hemoterapia, Hospital Universitario Virgen de las Nieves, Granada, Spain
13Hospital Clinic, MADRID, ESP
14Hospital Universitario Reina Sofia, Cordoba, Spain
15Scientific co-Director of CIMA LAB Diagnostics, CIMA Lab Diagnostics, University of Navarra, Pamplona, Spain
16Hospital Sont LLatzer, Palma de Mallorca, Spain
17Hospital Central de Asturias, Oviedo, Spain
18Hospital Universitario de La Princesa, Madrid, Spain
19Hospital de León, León, Spain
20Hospital Clínico San Carlos, Madrid, Spain
21Hematology Department, Catholic University of Valencia and Hospital Doctor Peset, Valencia, Spain
22Hospital Clínico Universitario de Valencia, VALENCIA, ESP
23Hospital Morales Meseguer, Murcia, Spain
24Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
25Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
26Hematology, National Autonomous University, Mexico City, AG, MEX
27Hospital Universitario Virgen del Rocío, Sevilla, Spain
28Hospital General de Segovia, Segovia, Spain
29University Hospital of Salamanca (IBSAL) & Cancer Research Center (IBMCC-CSIC-USAL), Salamanca, Spain
30Servicio de Onco-Hematología, Hospital Clínica de Barcelona, Barcelona, Spain
31HARMONY, European Network, Spain
32Clinica Universidad de Navarra, Pamplona, Spain

Introduction: The GEM-CESAR trial is a potentially curative strategy for high-risk smoldering multiple myeloma (HRsMM) patients in which the primary endpoint is the assessment of bone marrow minimal residual disease negativity by next generation flow (NGF). However, alternative methods of tumor burden evaluation in serum, like Quantitative Immunoprecipitation Mass Spectrometry (QIP-MS), a polyclonal antibody-based technology to identify intact immunoglobulins, have been also evaluated.

Patients and Methods: Ninety HRsMM patients included in the GEM-CESAR trial received six 4-weeks cycles of carfilzomib, lenalidomide and dexamethasone followed by high dose melphalan and ASCT and 2 further cycles of consolidation with the same regimen. All patients received maintenance with lenalidomide up to 2 years. SPEP and IFE were performed using standard procedures and MRD was analyzed by flow cytometry following EuroFlow recommendations. QIP-MS assessment has been previously described (1) and allowed us the characterization of the isotype of each Ig trough immunoprecipitation with paramagnetic beads as well as the measurement of the molecular mass of each Ig for each specific patient, with enough precision and accuracy to establish clonality. Standard response assignment was carried out as per the IMWG guidelines.

Results: First, we confirmed the higher sensitivity of QIP-MS to identify the presence of a serum M-spike as compared to conventional protein immunofixation electrophoresis methods. Amongst patients in CR, QIP-MS identified the M-spike in 18/30 (60%) post-induction, 18/47(38%) post-ASCT and 25/58(43%) post-consolidation. Interestingly, similar results were obtained with MRD-NGF post-induction [17/30(57%)] and post-ASCT [15/47(32%)] although the positive rate post-consolidation [15/58(26%)] was higher with QIP-MS.

Then, we analyzed the overall concordance between the results obtained with QIP-MS and MRD-NGF at the three timepoints of disease evaluation, finding an overall concordance of 81% post-induction (n=76), 70% post-transplant (n=76) and 68% post-consolidation (n=77). Thus, when compared to the results of MRD-NGF, QIP-MS demonstrated sensitivities of 100%, 79% and 77% post-induction, post-ASCT and post-consolidation, and negative predictive values (NPV) of 100%, 79% and 82% at each respective time-point. (P < 0,0001; P = 0,0004; P = =,0012)

Evaluation of discrepant cases showed 14 out of 22 MRD-NGF-negative patients post-induction for whom QIP-MS identified a M-spike; in some cases (i.e. IgG MM isotype) this may be related to a longer immunoglobulin half-life. There were no cases with detectable disease by NGF but QIP-MS negative. By contrast, post-ASCT, QIP-MS was negative in seven MRD-positive patients, two of whom became MRD-NGF-negative after consolidation; at last follow-up, none of them have progressed. On the other hand, sixteen patients with negative MRD-NGF after ASCT had a detectable M-spike by mass spectrometry. Of note, the M-spike became undetectable after consolidation in six out of these 16 patients. Post-consolidation, there were 7 patients in which MRD-NGF was positive but QIP-MS negative: MRD evaluation during maintenance is pending but none of them have so far progressed. By contrast, there were 18 patients with the M-spike detectable by QIP-MS but MRD-NGF negative: follow-up of these patients will address their outcome but, the only patient that has progressed so far had MRD-NGF negative post-induction, becoming positive post-transplant and consolidation, but the M-spike was detectable by QIP-MS throughout.

Conclusions: M-spike monitoring by QIP-MS shows a moderate concordance with the MRD assessment by NGF in this group of HRsMM homogeneously treated. Longer follow-up will allow us to unravel the outcome of discordant cases and to define the specificity of QIP-MS and its complementary value to NGF.

  1. North S, Barnidge D, Brusseau S, Patel R, Haselton M, Du Chateau B, et al. QIP-MS: A specific, sensitive, accurate, and quantitative alternative to electrophoresis that can identify endogenous m-proteins and distinguish them from therapeutic monoclonal antibodies in patients being treated for multiple myeloma. Clinica Chimica Acta 2019;493:S433.

Disclosures: Puig: Takeda: Consultancy, Honoraria; The Binding Site: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria. Mateos: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; EDO: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Paiva: Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche, and Sanofi; unrestricted grants from Celgene, EngMab, Sanofi, and Takeda; and consultancy for Celgene, Janssen, and Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau. Rodriguez Otero: Takeda: Consultancy; Kite Pharma: Consultancy; BMS: Honoraria; Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria. Oriol: Celgene, Amgen, Takeda, Jansse: Consultancy, Speakers Bureau. Rios: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Alegre: Celgene, Amgen, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees. de la Rubia: AbbVie: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Takeda: Consultancy. De Arriba: Amgen: Consultancy, Honoraria; Takeda: Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Ocio: Mundipharma: Research Funding; Pharmamar: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; AbbVie: Consultancy; Takeda: Consultancy, Honoraria; Array Pharmaceuticals: Research Funding; Sanofi: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy; Novartis: Consultancy, Honoraria; BMS: Honoraria. Bladé: Janssen, Celgene, Amgen, Takeda: Membership on an entity's Board of Directors or advisory committees; Irctures: Honoraria. Lahuerta: Takeda, Amgen, Celgene and Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH