High-Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action

• Type of Material: Article
• Authors: Homer C. Adams, Janssen Research & Development; Frederik Stevenaert, Janssen Research & Development; Jakub Krejcik, University of Southern Denmark; Koen Van der Borght, Janssen Research & Development; Tina Smets, Janssen Research & Development; Jaime Bald, Janssen Research & Development; Yann Abraham, Janssen Research & Development; Hugo Ceulemans, Janssen Research & Development; Chirstopher Chiu, Janssen Research & Development; Greet Vanhoof, Janssen Research & Development; Saad Z. Usmani, Levine Cancer Institute/Atrium Health; Torben Plesner, University of Southern Denmark; Sagar Lonial, Emory University; Inger Nijhof, VU University Medical Center; Henk M. Lokhorst, VU University Medical Center; Tuna Mutis, VU University Medical Center; Niles W.C.J. van de Donk, VU University Medical Center; Amy Kate Sasser, Genmab US, Inc.; Tineke Casneuf, Janssen Research & Development
• Language: English
• Date: 2019-03-01
• Publisher: Wiley: 12 months
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/cyto.a.23693
• Title of Journal or Parent Work: Cytometry Part A
• ISSN: 1552-4922
• Volume: 95A
• Issue: 3
• Start Page: 279
• End Page: 289
• Grant/Funding Information: S.L. served as a consultant for Millennium, Merck, BMS, Celgene, Novartis, Janssen, and Onyx. H.M.L. received research funding from Janssen and Genmab and served on advisory committees for Janssen.; Editorial support was provided by Jason Jung, PhD, and Sima Patel, PhD, of MedErgy, and was funded by Janssen Global Services, LLC.; T.P. served on advisory committees for Janssen and Genmab and received research funding from Janssen.; T.M. received research funding from Celgene, Janssen, and Genmab, and served on advisory committees for Janssen.; N.W.C.J.vdD. received research funding from and served on advisory committees for Janssen, Celgene, BMS, and Amgen.; S.Z.U. received research funding from Onyx, Sanofi, Array BioPharma, Pharmacyclics, Takeda, Celgene, and BMS; served as a consultant for Sanofi, Takeda, Celgene, and Amgen; served on advisory committees for Onyx, Sanofi, Celgene, Skyline, Millennium, and Janssen; and served on speakers bureaus for Takeda, Celgene, and Amgen.
• Keywords: SUBSETS; MONOTHERAPY; IDENTIFICATION; CyTOF; ANTIBODY DARATUMUMAB; DEXAMETHASONE; cytometry by time of flight; immune profiling; Biochemistry & Molecular Biology; Life Sciences & Biomedicine; NK-CELLS; LYMPHOCYTE; Science & Technology; CD38; Biochemical Research Methods; Cell Biology; LENALIDOMIDE; NATURAL-KILLER-CELLS
• Research Categories: Health Sciences, Oncology; Health Sciences, Medicine and Surgery

Abstract

Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry. Daratumumab is a CD38-targeted human monoclonal antibody with direct anti-myeloma cell mechanisms of action. Flow cytometry in relapsed and/or refractory multiple myeloma (RRMM) patients treated with daratumumab revealed cytotoxic T-cell expansion and reduction of immune-suppressive populations, suggesting immune modulation as an additional mechanism of action. Here, we performed an in-depth analysis of the effects of daratumumab on immune-cell subpopulations using high-dimensional mass cytometry. Whole-blood and bone-marrow baseline and on-treatment samples from RRMM patients who participated in daratumumab monotherapy studies (SIRIUS and GEN501) were evaluated with high-throughput immunophenotyping. In daratumumab-treated patients, the intensity of CD38 marker expression decreased on many immune cells in SIRIUS whole-blood samples. Natural killer (NK) cells were depleted with daratumumab, with remaining NK cells showing increased CD69 and CD127, decreased CD45RA, and trends for increased CD25, CD27, and CD137 and decreased granzyme B. Immune-suppressive population depletion paralleled previous findings, and a newly observed reduction in CD38 + basophils was seen in patients who received monotherapy. After 2 months of daratumumab, the T-cell population in whole-blood samples from responders shifted to a CD8 prevalence with higher granzyme B positivity (P = 0.017), suggesting increased killing capacity and supporting monotherapy-induced CD8 + T-cell activation. High-throughput cytometry immune profiling confirms and builds upon previous flow cytometry data, including comparable CD38 marker intensity on plasma cells, NK cells, monocytes, and B/T cells. Interestingly, a shift toward cytolytic granzyme B + T cells was also observed and supports adaptive responses in patients that may contribute to depth of response.