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544 Assessment of Treatment Response By Ife, Next Generation Flow Cytometry and Mass Spectrometry Coupled with Liquid Chromatography in the GEM2012MENOS65 Clinical Trial

Program: Oral and Poster Abstracts
Type: Oral
Session: 652. Multiple Myeloma and Plasma cell Dyscrasias: Clinical and Epidemiological: Reoptimizing Standards and Redefining Approaches
Hematology Disease Topics & Pathways:
Clinical Research, Plasma Cell Disorders, Clinically Relevant, Diseases, Lymphoid Malignancies, Technology and Procedures, Serologic Tests
Sunday, December 12, 2021: 5:15 PM

Noemi Puig, MD, PhD1,2, Teresa Contreras Sanfeliciano3*, Bruno Paiva, PhD4*, María Teresa Cedena, MD, PhD5*, Laura Rosinol6*, Ramón Garcia-Sanz, MD, PhD2, Joaquín Martínez-López7,8,9,10*, Albert Oriol11*, María Jesús Blanchard, MD12*, Rafael Rios, MD, PhD13*, Jesus Martin, MD14*, Anna Sureda15, Miguel Hernández16*, Javier De La Rubia, MD17*, Isabel Krsnik, MD, PhD18*, Jose Maria Moraleda, MD, PhD19*, Belén Iñigo, MD20*, Luis Palomera, MD, PhD21*, Cristina Agulló1*, Joan Bargay22*, Joan Bladé Creixenti23,24, Jesús San-Miguel, MD, PhD4,25, Juan-José Lahuerta, MD, PhD26* and Maria-Victoria Mateos27,28,29

1University Hospital of Salamanca, Salamanca, Spain
2Departamento de Hematología, Hospital Universitario de Salamanca (HUSAL), IBSAL, IBMCC (USAL-CSIC), CIBERONC, Salamanca, Spain
3Servicio Análisis Clínicos y Bioquímica Clínica del Complejo Asistencial Salamanca, Complejo Asistencial Salamanca, Salamanca, Spain
4Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC number CB16/12/00369, Pamplona, Spain
5Hematology Department, Hospital Universitario 12 de Octubre, CIBERONC, Instituto de Investigación IMAS12, Madrid, Spain
6Hematology, Hematology Department, Hospital Clinic i Provincial, IDIBAPS, Barcelona, Spain
7Hospital 12 De Octubre, Madrid, Spain
8H12O-CNIO Clinical research unit, CIBERONC, Complutense University, Madrid, Spain
9Department of Hematology, Hospital Universitario 12 de Octubre; H12O-CNIO Haematological Malignancies Clinical Research Unit, Spanish National Cancer Research Centre, Madrid, Spain
10Hematology Department, Hospital Universitario 12 de Octubre, CNIO, Complutense University, Madrid, Spain
11Institut Català d’Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Barcelona, Spain
12Hematology Service, Hospital Universitario Ramón y Cajal, Madrid, Spain
13Hospital Universitario Virgen de las Nieves de Granada, Instituto de Investigación Biosanitaria IBS GRANADA, Granada, Spain
14Hospital Universitario V. Rocio, Sevilla, ESP
15Clinical Hematology Department, Institut Català d'Oncologia, Hospital Duran i Reynals, IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain
16Hospital Universitario de Canarias, Santa Cruz de Tenerife, La Laguna, ESP
17Hospital Universitari i Politècnic La Fe, Catholic University of Valencia, Valencia, Spain
18Hospital Universitario Puerta de Hierro, Madrid, Spain
19Hospital Clínico Universitario Virgen de la Arrixaca. IMIB-Arrixaca. University of Murcia, Murcia, ESP
20Hospital Universitario Clínico San Carlos, Madrid, Spain
21Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
22Hospital Universitario Son Llatzer, Institut d’ investigacio Illes Balears (IdISBa), Palma de Mallorca, Spain
23Amyloidosis and Myeloma Unit, Hospital Clínic, Barcelona, Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
24Hospital Clinic de Barcelona, IDIBAPS, Barcelona, Spain
25Hematology Department, Clínica Universidad De Navarra, Pamplona, Spain
26Instituto de Investigación del Hospital Universitario 12 de Octubre, European Network, Spain
27Cancer Research Center (IBMCC-CSIC/USAL-IBSAL), Salamanca, Spain
28CIBERONC, Salamanca, Spain
29Hospital Universitario Salamanca, IBSAL, IBMCC (USAL-CSIC), Salamanca, Spain

Introduction: In patients (pts) with multiple myeloma (MM), next generation flow cytometry (NGF) and next generation sequencing have shown an increased capacity to identify the presence of disease and to anticipate patient’s prognosis as compared to serum protein immunofixation (IFE). However, both methods rely on bone marrow (BM) samples and it is important to explore alternative techniques applicable in more accessible samples such as peripheral blood.

Patients and Methods: Newly diagnosed MM pts enrolled in the PETHEMA/GEM2012MENOS65 trial received six cycles of induction with bortezomib, lenalidomide and dexamethasone (VRD), intensification with high-dose therapy (melphalan or busulfan and melphalan) followed by autologous stem cell transplantation and consolidation with two more cycles of VRD. At the end of the treatment (post-consolidation), the M-protein (MP) was analyzed in serum by conventional IFE and by EXENT Quantitative Immunoprecipitation Mass Spectrometry using IgG/A/M, κ, λ, free κ and free λ isotypic beads; negative samples by EXENT were re-analyzed by liquid chromatography mass spectrometry (LC-MS). The presence of clonal plasma cells in BM samples was investigated by NGF following the Euroflow guidelines (sensitivity≥10-5). Samples from the first 164 pts enrolled in the trial were analyzed in this study.

Results: After consolidation, persistent disease was detected in 42 (26%) pts by IFE, in 56 (34%) by EXENT and in 72 (44%) by NGF. Surprisingly, the presence or absence of disease by IFE did not discriminate pts with different progression-free survival (PFS), but both EXENT and NGF segregated two cohorts with a significantly different PFS (p=0.0016 and p<0.0001, respectively; fig1A and 1C). Importantly, we observed that among pts in complete response (IFE negative), EXENT and NGF also distinguished two groups with different PFS (p=0.002 and p=0.0001, respectively.)

Analyzing the results obtained with EXENT and NGF, we found that 76% were concordant (44 EXENT+/NGF+, 80 EXENT-/NGF-) and 24% discordant (28 EXENT-/NGF+ and 12 EXENT+/NGF-). When we compared pts´ PFS according the combined results of both methods (fig 1D), we learnt that the 3 comparisons reaching statistical significance were EXENT+/NGF+ vs EXENT-/NGF- (p<0.0001), EXENT+/NGF+ vs EXENT+/NGF- (p=0.0394) and EXENT-/NGF- vs EXENT-/NGF+ (p=0.0363). Considering NGF as a reference, the negative predictive value (NPV) of EXENT was 74% overall (96% in MRD levels ≥10-4, p<0.0001; 89% in <10-4 - ≥10-5 p<0.0001; and 84% in ≥10-6 cases, p=0.0524).

Samples deemed negative by EXENT were re-analyzed with LC-MS. In 63 of them (58%) the MP was identified using LC-MS and therefore a total of 119 samples (73%) were considered positive with EXENT&LC-MS. We first confirmed that EXENT&LC-MS segregated two cohorts with different PFS (fig 1B, p=0.0193) Then, as earlier, we analyzed the results obtained with EXENT&LC-MS and NGF, finding that 65% were concordant (67 EXENT&LC-MS+/NGF+, 40 EXENT&LC-MS -/NGF-) and 35% discordant (5 EXENT&LC-MS -/NGF+ and 52 EXENT&LC +/NGF-). Again, we compared pts´ PFS according the combined results of both methods (fig 1E) learning now that only the comparisons EXENT&LC-MS+/NGF+ vs EXENT&LC-MS-/NGF- (p=0.0006) and EXENT&LC-MS+/NGF+ vsEXENT&LC-MS+/NGF- (p=0.0006) reached statistical significance. With these results, the NPV of EXENT&LC-MS was 89% overall (100% in MRD levels ≥10-4 p<0.0001; 100% in <10-4 - ≥10-5 p<0.0001; and 89% in ≥10-6 cases p=0.0914).

Finally, we observed that whereas among pts deemed EXENT+, NGF identified 2 cohorts with different PFS (a NGF-group of 12 pts displaying a longer PFS as compared with those NGF+; median PFS: 4 years vs not reached, p=0.039) among EXENT&LC-MS- cases (n=45) NGF was not able to show any added clinical value.

Conclusions: The use of IFE post-consolidation in pts with MM, as opposed to EXENT and NGF, did not identify pts with different PFS. When referred to NGF, EXENT provided a similar clinical value and displayed a very high NPV, increased further with the addition of LC-MS; this could be utilised to avoid the performance of a BM aspiration after treatment in pts with undetectable disease. Regarding EXENT+ and/or LC-MS+ cases future quantitative and sequential studies could reveal whether are due to the long half-lives of the MP or represent quiescent low-level disease.

Disclosures: Puig: Amgen, Celgene, Janssen, Takeda and The Binding Site: Honoraria; Amgen, Celgene, Janssen, Takeda: Consultancy; Celgene: Speakers Bureau; Celgene, Janssen, Amgen, Takeda: Research Funding. Paiva: Bristol-Myers Squibb-Celgene, Janssen, and Sanofi: Consultancy; Adaptive, Amgen, Bristol-Myers Squibb-Celgene, Janssen, Kite Pharma, Sanofi and Takeda: Honoraria; Celgene, EngMab, Roche, Sanofi, Takeda: Research Funding. Cedena: Janssen, Celgene and Abbvie: Honoraria. Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. Martínez-López: Roche, Novartis, Incyte, Astellas, BMS: Research Funding; Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy. Oriol: Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Sureda: Bluebird: Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; Mundipharma: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau. Moraleda: Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Educational Grants, Research Funding; Gilead: Consultancy, Honoraria, Other: Educational Grants, Research Funding; Novartis: Consultancy, Honoraria, Other: Educational Grants, Research Funding; Sandoz: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Educational Grants, Research Funding; ROCHE: Consultancy, Honoraria, Other: Educational Grants, Research Funding; MSD: Other: Educational Grants, Research Funding; Sanofi: Other: Educational Grants, Research Funding; Pfizer: Other: Educational Grants, Research Funding; NovoNordisk: Other: Educational Grants, Research Funding; Janssen: Other: Educational Grants, Research Funding; Celgene: Other: Educational Grants, Research Funding; Amgen: Other: Educational Grants, Research Funding. Bladé Creixenti: Janssen, Celgene, Takeda, Amgen and Oncopeptides: Honoraria. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mateos: Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Bluebird bio: Honoraria; Sanofi: 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; GSK: Honoraria; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria.

*signifies non-member of ASH