Immune biomarkers of increased risk of infection in multiple myeloma (MM)
Abstract
Abstract Background: Infections are one of the leading causes of morbidity and early mortality in MM. Preventing infections is paramount and immune profiles could reflect the cumulative effect of host, tumor and treatment-related immunosuppression. However, current understanding of how immune dysfunction is associated with infection risk is limited. Aim: Characterize immune profiles throughout MM progression and identify immune biomarkers of increased infection risk. Methods: The study included2,150 patients (pts). The Spanish cohort included monoclonal gammopathies of undetermined significance (MGUS, n=47) smoldering (SMM, n=374), newly-diagnosed (NDMM, n=743) and relapsed/refractory MM (RRMM, n=373). Transplant-eligible and ineligible NDMM pts were treated according to the GEM2012MENOS65 (VRd) and CLARIDEX (Rd) trials. Among RRMM pts, 149 received CD38, BCMA or GPRC5D targeting agents. Immune profiling was performed at baseline in 1,958 bone marrow (BM) and peripheral blood (PB) samples using NGF. Ten cell types were systematically quantified in BM and PB after removing tumor plasma cells (PC) from the differential (naïve and mature B cells, CD27- and CD27+ T and NK cells, basophils, eosinophils, monocytes and neutrophils). Another 5 subsets were analyzed in BM (hematopoietic progenitors, erythroblasts, mast cells, B-cell precursors and normal PC). Healthy adults of similar age (n=24) provided a reference of normal BM immune profiles. Immune biomarkers of increased infection risk identified in the Spanish cohort were validated in three external datasets: 36 pts with high-risk MGUS or low-risk SMM treated with daratumumab in the Dana-Farber D-PRISM trial, 125 NDMM frail pts enrolled in the HOVON-143 trial treated with daratumumab/ixazomib/dexamethasone, and 424 NDMM Greek pts treated with standard regimens. Results: Infection risk (per CTCAE 5.0) progressively increased in the Spanish cohort of MGUS, SMM, NDMM and RRMM (13%, 19%, 47%, 54%, p<.001). Grade 3/4 infections also increased from SMM to NDMM and RRMM (10%, 22% and 24%, p<.001). When compared to normal BM immune profiles, pts showed a higher CD27-/CD27+ T-cell ratio, eosinophils and neutrophils were reduced, while monocytes and erythroblasts were increased. Of the 15 cell types in BM, 14 had significantly different distribution across disease stages. Progression from MGUS to SMM was characterized by a reduction in B-cell precursors and normal PC, and increase in CD27- T cells. Progression to NDMM was associated with further reduction of B-cell precursors, naïve B cells and normal PC. RRMM was characterized by further reduction of memory B cells and increased CD27-/CD27+ T-cell ratio. There was an expansion of monocytes in NDMM and RRMM, mast cells were significantly increased in RRMM, while basophils and erythroblasts were reduced in NDMM. Hematopoietic progenitors progressively decreased from SMM to RRMM. Of note, these differences were observed despite similar age across disease stages, suggesting that immune profiles may better reflect immunological aging than chronological age. In the Spanish cohort, pts with any grade infection had fewer memory B cells and CD27- NK cells, as well as a higher CD27-/CD27+ T-cell ratio. These biomarkers were modeled to stratify pts with ≤1 vs ≥2 risk factors, which was associated with increased risk of infection (37% vs 60%; p<.001). Hemoglobin levels also associated with infection and non-IgA isotype was borderline significant. A logistic regression including these factors together with disease stage and CD38, BCMA or GPRC5D targeting agents unveiled that having NDMM or RRMM and ≥2 immune risk factors had independent predictive value. In the D-PRISM cohort, fewer memory B cells associated with infection risk. In the HOVON-143 trial, a higher CD27-/CD27+ T-cell ratio associated with infection risk. In the Greek cohort, fewer memory B cells and CD27- NK cells associated with infection risk. Moreover, Greek pts having ≤1 vs ≥2 of the immune risk factors identified in the Spanish cohort respectively showed 38% vs 52% infection risk. Conclusion: This is one of the largest studies analyzing immune profiles in MM. We described the effects of malignant transformation and treatment, and developed an immune score that independently predicts infection risk. Of note, the percentages of all cell types in BM and PB were significantly correlated, suggesting that these immune biomarkers could be monitored using minimally-invasive methods.
Article Details
Authors (49)
Aintzane Zabaleta
Cancer Center Clinica Universidad de Navarra (CCUN), Centro de Investigacion Medica Aplicada (CIMA), Instituto de Investigacion Sanitaria de Navarra (IdiSNA), CIBER-ONC number CB16/12/00369, Pamplona, Spain, Pamplona, Spain
Luis-Esteban Tamariz-Amador
Ioannis V. Kostopoulos
2Department of Biology, National and Kapodistrian University of Athens, Athens, Greece
Romanos Sklavenitis-Pistofidis
Febe Smits
6Department of Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Carmen Roncal
1Cancer Center Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada, Instituto de Investigacion Sanitaria de Navarra, CIBER-ONC number CB16/12/00369, Pamplona, Spain
Michelle Aranha
3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Boston, United States
David Zihala
9Department of Hematooncology, University Hospital Ostrava and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
Michaela Machu
10Faculty of Medicine, Masaryk University, Brno, Czech Republic
Nikolaos Tsakirakis
2Department of Biology, National and Kapodistrian University of Athens, Athens, Greece
Panagiotis Bakouros
2Department of Biology, National and Kapodistrian University of Athens, Athens, Greece
Ourania Tsitsilonis
National and Kapodistrian University of Athens, Athens, Greece
Eirini Solia
1Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
Cristina Moreno
Catarina Maia
1Cancer Center Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada, Instituto de Investigacion Sanitaria de Navarra, CIBER-ONC number CB16/12/00369, Pamplona, Spain
Esperanza Martin-Sanchez
1Cancer Center Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada, Instituto de Investigacion Sanitaria de Navarra, CIBER-ONC number CB16/12/00369, Pamplona, Spain
José J. Perez
13Department of Hematology, Hospital Universitario de Salamanca Hematología, Instituto de Investigación Biomédica de Salamanca, CIBER-ONC number CB16/12/00233, Salamanca, Spain
Cristina Encinas
14Department of Hematology, Hospital General Universitario Gregorio Marañón, liSGM, Madrid, Spain
Rafael Rios Tamayo
14Hospital Universitario Virgen de las Nieves, ibs.Granada, Spain, Granada, Spain
Albert Oriol
Institut Català d’Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Badalona, Spain
María-Jesús Blanchard
Hospital Ramon y Cajal, madrid, Spain
Felipe de Arriba
18Department of Hematology, Hospital Morales Meseguer, IMIB Pascual Parrilla, Universidad de Murcia, Murcia, Spain
Esther González García
18Hospital Universitairo Cabueñes, Gijón, Spain, Gijón, Spain
Sunil Lakhwani
Hospital Universitario de Canarias. Universidad de La Laguna., San Cristobal de La Laguna, Tenerife, Spain
Anna Sureda Balarí
7Institut Català d'Oncologia - Hospital Duran i Reynals, Hospitalet de Llobregat, Spain
Valentin Cabanas Perianes
12Hematology Department, IMIB-Virgen de la Arrixaca University Hospital, University of Murcia, El Palmar, Murcia, Spain
Fernando Escalante Barrigón
21Complejo Hospitalario de León, León, Spain, León, Spain
Estrella Carrillo-Cruz
23Unidad de Gestión Clínica de Hematología, Hospital Virgen del Rocío, Instituto de Biomedicina (IBIS/CSIC/CIBERONC), Universidad de Sevilla
Albert Pérez-Montaña
24Department of Hematology, Hospital Universitario Son Espases, Palma, Spain
Enrique Ocio
1HOSPITAL UNIVERSITARIO MARQUÉS DE VALDECILLA, Hematology, Santander, Spain
Joan Bargay
Hospital Universitario Son LLatzer, Instituto de Investigación Sanitaria Illes Balears (IdISBa),, Palma de Mallorca, Spain
Alberto Orfao
Tomas Jelinek
Department of Hemato-oncology, University Hospital Ostrava, Ostrava, Czech Republic
Irene Ghobrial
1Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, United States
Tuna Mutis
6Department of Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Sonja Zweegman
Evangelos Terpos
Efstathios Kastritis
Joaquín Martínez-López
Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre, Complutense University of Madrid, Centro Nacional de Investigaciones Oncológicas, Madrid Institute of Cancer, Madrid
Juan-Jose Lahuerta Palacios
6Hematology Department, Hospital 12 de Octubre, Madrid, España., Madrid, Spain
Carlos Fernandez de Larrea
29Department of Hematology, Hospital Clínic, IDIBAPS, University of Barcelona, Barcelona, Spain
Laura Rosiñol
Hospital Clínic de Barcelona, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona
Joan Batista Blade Creixenti
4Hospital Clinic of Barcelona, Instituto de Investigaciones Biomédicas August Pi I Sunyer (IDIBAPS), Barcelona., Barcelona, Spain
Paula Rodriguez-Otero
María-Victoria Mateos
Jesus San-Miguel
Maria Teresa Cedena Romero
11Hospital Universitario 12 de Octubre, Hematology, Madrid, Spain
Noemi Puig
Bruno Paiva