Deep immune profiling of patients treated with lenalidomide and dexamethasone with or without daratumumab

Tineke Casneuf*, Homer C. Adams, Niels W.C.J. van de Donk, Yann Abraham, Jaime Bald, Greet Vanhoof, Koen Van der Borght, Tina Smets, Brad Foulk, Karl C. Nielsen, Joshua Rusbuldt, Amy Axel, Andrew Lysaght, Hugo Ceulemans, Frederik Stevenaert, Saad Z. Usmani, Torben Plesner, Herve Avet-Loiseau, Inger Nijhof, Tuna MutisJordan M. Schecter, Christopher Chiu, Nizar J. Bahlis

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

CD38-targeted antibody, daratumumab, is approved for the treatment of multiple myeloma (MM). Phase 1/2 studies GEN501/SIRIUS revealed a novel immunomodulatory mechanism of action (MOA) of daratumumab that enhanced the immune response, reducing natural killer (NK) cells without affecting efficacy or safety. We further evaluated daratumumab’s effects on immune cells in whole blood samples of relapsed/refractory MM patients from both treatment arms of the phase 3 POLLUX study (lenalidomide/dexamethasone [Rd] or daratumumab plus Rd [D-Rd]) at baseline (D-Rd, 40; Rd, 45) and after 2 months on treatment (D-Rd, 31; Rd, 33) using cytometry by time-of-flight. We confirmed previous reports of NK cell reduction with D-Rd. Persisting NK cells were phenotypically distinct, with increased expression of HLA-DR, CD69, CD127, and CD27. The proportion of T cells increased preferentially in deep responders to D-Rd, with a higher proportion of CD8+ versus CD4+ T cells. The expansion of CD8+ T cells correlated with clonality, indicating generation of adaptive immune response with D-Rd. D-Rd resulted in a higher proportion of effector memory T cells versus Rd. D-Rd reduced immunosuppressive CD38+ regulatory T cells. This study confirms daratumumab’s immunomodulatory MOA in combination with immunomodulatory drugs and provides further insight into immune cell changes and activation status following daratumumab-based therapy.

Original languageEnglish
Pages (from-to)573-584
Number of pages12
JournalLeukemia
Volume35
Issue number2
DOIs
Publication statusPublished - Feb 2021

Cite this