-Author name in bold denotes the presenting author
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1827 Immune Biomarkers of Survival and Severe Infection in Newly Diagnosed Multiple Myeloma (NDMM) Patients (pts) Treated with the Backbone Regimen Lenalidomide and Dexamethasone (Rd)

Program: Oral and Poster Abstracts
Session: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: Poster I
Hematology Disease Topics & Pathways:
Research, Translational Research, elderly, Plasma Cell Disorders, bioinformatics, Diseases, immunology, Lymphoid Malignancies, Adverse Events, computational biology, Biological Processes, Technology and Procedures, profiling, Study Population, Human, Animal model, machine learning, omics technologies
Saturday, December 10, 2022, 5:30 PM-7:30 PM

Catarina Maia1*, Noemi Puig, MD, PhD2,3, Cristina Pérez Ruiz4*, Maria Teresa Cedena Romero, MD, PhD5*, Camila Guerrero, MSc4*, Marta Larrayoz, PhD6,7*, Cirino Botta, MD, PhD8, Norma C. Gutierrez9,10*, María José Calasanz, PhD11*, Maria Luisa Martin-Ramos12*, Miguel Hernández13*, Laura Rosinol Dachs14*, Esther González Garcia, MD15*, Felipe De Arriba, PhD16*, Albert Oriol17*, Veronica Gonzalez-Calle, MD, PhD18*, Fernando Escalante, MD19*, Javier de la Rubia, MD20*, Mercedes Gironella Mesa, MD21*, Rafael Rios, MD, PhD22*, Ricarda Belen Garcia Sanchez23*, Jose Maria Arguiñano PEREZ24*, Adrian Alegre, MD25*, Jesus Martin, MD26*, María del Carmen Couto Caro27*, Maria Casanova, MD28*, Mario Arnao Herraiz, MD29*, Ernesto Pérez30*, Sebastián Garzón López31*, Marta Sonia Gonzalez Perez32*, Guillermo Martín-Nuñez33*, Adriana Rossi, MD, MSc34, Morton Coleman, MD35*, Cristina Encinas36*, Ana M. Vale37*, Ana Isabel Teruel, MD38*, María Cortés Rodríguez39*, Jose A. Martinez-Climent, MD6,40,41, Juan-José Lahuerta, MD, PhD42*, Joan Bladé Creixenti, MD, PhD43,44, Ruben Niesvizky, MD45, Jesús San-Miguel, MD, PhD4, Maria-Victoria Mateos, MD46,47 and Bruno Paiva4*

1Centro de Investigación Médica Aplicada, Clinica Universidad de Navarra, ) Centro de Investigacion Medica Aplicada, Instituto de Investigacion Sanitaria de Navarra (IdiSNA), CIBER-ONC number CB16/12/00369, Pamplona, Spain, Pamplona, Spain
2Departamento de Hematología, Hospital Universitario de Salamanca (HUSAL), IBSAL, IBMCC (USAL-CSIC), CIBERONC, Salamanca, Spain
3Instituto Biosanitario de Salamanca (IBSAL) and Cancer Research Centre (Instituto de Biología Molecular y Celular del Cáncer; CSIC-USAL), 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
5Department of Hematology, Hospital Universitario 12 de Octubre, CNIO, Madrid, Spain
6Department of Hemato-Oncology, University of Navarra, CIBERONC, IDISNA, Pamplona, Spain
7Centro de Investigación Médica Aplicada, University of Navarra, Clínica Universidad de Navarra, Pamplona, Spain
8Department of Health Promotion, Mother and Child Care,Internal Medicine and Medical Specialties, University of Palermo, Italy, Palermo, Italy
9Hematology, Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain
10Hospital Universitario de Salamanca,Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
11Centro de Investigación Médica Aplicada, University of Navarra, Pamplona, Spain
12Hospital Universitario 12 de Octubre, Madrid, Spain
13Hospital Universitario de Canarias, Santa Cruz de Tenerife, La Laguna, ESP
14Hospital Clinic i Provincial, Barcelona, Spain
15Hospital Universitario de Cabueñes, Gijón, Spain
16Hospital Morales Meseguer, IMIB-Arrixaca, Universidad de Murcia, Murcia, Spain
17Institut Català d’Oncologia and Institut Josep Carreras. Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain
18Servicio de Hematologia, Hospital Universitario de Salamanca (CAUSA), Salamanca, Spain
19Hematology Department, Hospital Universitario de León, León, Spain
20Hematology Service Hospital La Fe and School of Medicine and Dentistry, Catholic University of Valencia, Valencia, Spain
21Department of Hematology, University Hospital Vall d’Hebron, Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035, Spain, Barcelona, Spain
22Hospital Universitario Virgen de las Nieves, Instituto de Investigación Biosanitaria, Granada, Spain
23Complejo Hospitalario de Especialidades Virgen de La Victoria, Málaga, Spain
24Complejo Hospitalario de Navarra, Pamplona, Spain, Pamplona, ESP
25Hospital Universitario de La Princesa, Madrid, Spain, Madrid, Spain
26Hospital Universitario V. Rocio, Sevilla, Spain
27Hospital Universitario Virgen de Valme, Sevilla, Spain
28Hospital Costa del Sol Marbella, Marbella, Spain
29Haematology Department, Hospital Universitari i Politecni La Fe, Valencia, Spain
30Osakidetza Basque Health Service, Araba University Hospital,[Hematology department], Vitoria-Gasteiz, Spain
31Hospital del SAS de Jerez, Jerez De La Frontera, Spain
32Hospital Clinico Universitario Santiago, Santiago De Compostela, La Coruna, ESP
33Departamento de Hematología, Hospital Virgen del Puerto, Plasencia, Spain
34Icahn School of Medicine, Mount Sinai Hospital, New York, NY
35Division of Hematology & Medical Oncology, Weill Cornell Medical College, New York, NY
36Hospital Universitario Gregorio Marañó, Madrid, Spain
37CHUAC, A Coruña, Spain, Coruña, Spain
38Hospital Clínico Universitario de Valencia, VALENCIA, ESP
39Hematology Dept., Hospital Universitario de Salamanca, Spain, Salamanca, Spain
40Centre for Applied Medical Research (CIMA), Pamplona, Spain
41Department of Hemato-Oncology, Cima University of Navarra, Pamplona, Navarra, Spain
42Hospital Universitario 12 de Octubre; Instituto de Investigación Sanitaria Hospital Universitario 12 de Octubre i+12,H12O-CNIO Haematological Malignancies Clinical Research Unit, Spanish National Cancer Research Centre, Madrid, Spain
43Hospital Clinic de Barcelona, IDIBAPS, Barcelona, Spain
44Amyloidosis and Multiple Myeloma Unit, Department of Hematology, IDIBAPS, Hospital Clínic, Barcelona, Spain
45Division of Hematology & Medical Oncology, Weill Cornell Medicine/New York Presbyterian Hospital, New York, NY
46Hospital Universitario de Salamanca Hematología. Instituto de investigación biomédica de Salamanca (IBSAL), Salamanca, Spain
47Hematology Department, IBSAL-University Hospital of Salamanca. University of Salamanca, Salamanca, Spain

Introduction: Rd is a backbone of treatment in MM. The strong immunomodulatory effects of this regimen would suggest that immune profiling might complement conventional prognostic factors. However, immune signatures predictive of survival were not well defined in the past, and nowadays it is challenging to detach the effect of Rd from other backbone drugs in triplets or quadruplets, as well from high dose therapy in transplant eligible patients.

Aim: Identify immune biomarkers in elderly NDMM pts treated with Rd.

Methods: The GEM-CLARIDEX trial randomized transplant ineligible NDMM pts to Rd +/- clarithromycin until disease progression. Because clarithromycin had no effect in survival, the trial design yielded a unique opportunity to identify immune biomarkers in elderly MM pts treated with Rd. Immune profiling was performed in bone marrow (BM) at baseline in 186 pts, using multidimensional and computational flow cytometry together with lasso penalized Cox regression and 10-fold cross validation, for a holistic and unbiased definition of prognostic immune signatures. 38 cell populations were identified, including seven myeloid/erythroid and 29 lymphoid subsets plus normal and clonal plasma cells (PC). Single cell RNA sequencing (scRNAseq, 10x Genomics) was performed on BM immune cells sorted from healthy adults, MGUS, smoldering and active MM pts (n = 17).

Results: An immune signature associated with inferior survival was defined based on increased frequency of cytotoxic CD314+ NK and CD4+ central memory (CM) CD127+ PD1+ T cells, and decreased percentages of CD4+ CM CD127+ PD1- and CD8+ CD127low PD1+ terminally differentiated T cells, as well as of B cell precursors. Median progression-free survival (PFS) of NDMM pts with high risk immune score (106/186 [57%]) was 18 months vs not reached in those with low risk (80/186 [43%]) (p=.0008, Fig 1A). The respective median overall survival (OS) rates at three years were 50% and 80% (p = .0021, Fig 1B). In multivariate analyses including age, ISS, LDH and cytogenetic risk, immune profiling showed independent prognostic value for PFS (HR: 2.6, p = .001) and OS (HR: 2.9, p = .003).

Increased frequency of cytotoxic CD314+ NK cells was the immune biomarker with the highest negative impact in the survival predictive model. In an attempt to better understand this finding, we analyzed scRNAseq data of 61,637 NK cells from normal and tumor BM. Up to 47 NK-cell clusters were identified, and the one showing the highest expression of CD314 also displayed upregulation of granzymes K, H and B, perforin, CD16, CD38, CD69 and IFNγ, and therefore appeared to be associated with cytolytic activity and inflammation. Interestingly, there was a progressive expansion of this cluster within the NK cell compartment of normal vs pre-malignant vs neoplastic BM samples. Similarly, in genetically engineered BIcγ1 mice that develop active MM preceded by precursor states, there was a progressive expansion of CD314+ NK cells in normal vs benign vs malignant BM (p = .001).

Being infection an important cause of morbidity and mortality in elderly MM pts as those included in this study, we next investigated if immune profiling at diagnosis could help predicting severe infection (≥ grade 3 CTCAE v4.0, n=43/186). The combination of five clinical features – age ≥ 75y, low hemoglobin and albumin, high β2m and LDH – plus seven immune biomarkers – increased percentages of eosinophils, together with decreased frequencies of CD4+ CM CD127+ PD1- , CD8+ naïve and CD127low PD1+ and PD1- terminally differentiated T cells, B cell precursors and normal PC – resulted in the most effective model to predict severe infection. B cell precursors and eosinophils, which are easily identified using flow cytometry at diagnosis, showed the strongest association. The area under the curve (AUC) of the model was 0.90 with a 4-fold cross validation showing a mean AUC = 0.86 ± 0.06.

Conclusions: This study shows the clinical value of immune profiling at diagnosis and defined immune cell types, including a previously unidentified subset of CD314+ cytotoxic NK cells, which were predictive of survival in transplant ineligible NDMM pts treated with the backbone regimen Rd. Furthermore, this study uncovered immune biomarkers complementary to clinical features for predicting severe infection in elderly MM pts, which could be used to intensify prophylactic measures in specific subgroups that are more susceptible to severe infection.

Disclosures: Puig: Amgen, Celgene, Takeda and The Binding Site: Honoraria; Amgen, Celgene, Janssen and Takeda: Consultancy; Celgene: Honoraria, Speakers Bureau; Celgene, Janssen, Amgen andTakeda: Research Funding. Hernández: Celgene, Janssen, Amgen, Takeda, GSK: Consultancy; Janssen, Celgene, Amgen: Speakers Bureau. Rosinol Dachs: GlaxoSmithKline: Honoraria; BMS-Celgene: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Janssen: Honoraria. Garcia: Janssen ,Celegene (BM), Takeda, GSK , Sanofi, Amgen: Honoraria, Speakers Bureau; Janssen, Celgene (BM), Takeda: Consultancy. De Arriba: Amgen: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Glaxo Smith Kline: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau. Oriol: Sanofi: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy; GlaxoSmithKline: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Gonzalez-Calle: Janssen, Pfizer, Bristol-Myers Squibb/Celgene, GlaxoSmithKline: Honoraria, Speakers Bureau; Janssen: Consultancy. Escalante: GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. de la Rubia: Pfizer: Honoraria; Ablynx/Sanofi: Honoraria; Janssen: Honoraria; Bristol Myers Squibb: Honoraria; GSK: Honoraria. Rios: Becton-Dickinson, Celgene, GSK, Janssen, Sanofi, Binding Site: Consultancy. Arguiñano PEREZ: Abbvie: Honoraria; Amgen: Honoraria; AstraZeneca: Honoraria; BMS/Celgene: Honoraria; GSK: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Sandoz: Speakers Bureau; Sanofi: Honoraria. Rossi: gsk: Consultancy; janssen: Consultancy; adaptive: Consultancy; BMS: Consultancy; sanofi: Consultancy. Coleman: Arcus Biosciences, AstraZeneca, Acerta Pharma, BeiGene, BMS, Lily, EMD Serono, Genentech/Roche, Genfleet, GSK, Hutchison MediPharma, Incyte, Ipsen, MEI Pharma, Merck, Napo Pharmaceuticals, Novartis, Pfizer, Seattle Genetics: Research Funding; BMS: Consultancy. Encinas: Bristol Myers Squib: Honoraria; GlaxoSmithKline: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Pfizer: Honoraria; Sanofi: Honoraria, Speakers Bureau. Bladé Creixenti: Janssen, Calegen/BMS,Amgen, Takeda, Oncopeptides: Honoraria. Niesvizky: Takeda: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. San-Miguel: Abbvie, Amgen, BMS, Celgene, GSK, Haemalogix, Janssen-Cilag, Karyopharm, MSD, Novartis, Takeda, Regeneron, Roche, Sanofi, and SecuraBio: Consultancy, Other: Advisory Board. Mateos: Sanofi: 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Paiva: Takeda: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Adaptive: Honoraria; EngMab: Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Roche Glycart AG: Honoraria, Research Funding; Amgen: Honoraria; Gliead: Honoraria; Oncopeptides: Honoraria.

*signifies non-member of ASH