NK Cell Phenotype Is Associated With Response and Resistance to Daratumumab in Relapsed/Refractory Multiple Myeloma

Christie P.M. Verkleij, Kristine A. Frerichs, Marloes E.C. Broekmans, Carolien Duetz, Chloe A. O'Neill, Wassilis S.C. Bruins, Paola M. Homan-Weert, Monique C. Minnema, Mark David Levin, Annemiek Broijl, Gerard M.J. Bos, Marie José Kersten, Saskia K. Klein, Medya M. Shikhagaie, Tineke Casneuf, Yann Abraham, Tina Smets, Greet Vanhoof, Diana Cortes-Selva, Laure Van SteenbergenElena Ramos, Raluca I. Verona, Maria Krevvata, Pieter Sonneveld, Sonja Zweegman, Tuna Mutis, Niels W.C.J. Van De Donk*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Scopus)
27 Downloads (Pure)


The CD38-targeting antibody daratumumab has marked activity in multiple myeloma (MM). Natural killer (NK) cells play an important role during daratumumab therapy by mediating antibody-dependent cellular cytotoxicity via their FcγRIII receptor (CD16), but they are also rapidly decreased following initiation of daratumumab treatment. We characterized the NK cell phenotype at baseline and during daratumumab monotherapy by flow cytometry and cytometry by time of flight to assess its impact on response and development of resistance (DARA-ATRA study; NCT02751255). At baseline, nonresponding patients had a significantly lower proportion of CD16+and granzyme B+NK cells, and higher frequency of TIM-3+and HLA-DR+NK cells, consistent with a more activated/exhausted phenotype. These NK cell characteristics were also predictive of inferior progression-free survival and overall survival. Upon initiation of daratumumab treatment, NK cells were rapidly depleted. Persisting NK cells exhibited an activated and exhausted phenotype with reduced expression of CD16 and granzyme B, and increased expression of TIM-3 and HLA-DR. We observed that addition of healthy donor-derived purified NK cells to BM samples from patients with either primary or acquired daratumumab-resistance improved daratumumab-mediated MM cell killing. In conclusion, NK cell dysfunction plays a role in primary and acquired daratumumab resistance. This study supports the clinical evaluation of daratumumab combined with adoptive transfer of NK cells.

Original languageEnglish
Article numberE881
Issue number5
Publication statusPublished - 2 May 2023

Bibliographical note

Funding Information:
This research was funded by Janssen Research and Development.

Publisher Copyright:
© 2023 Wolters Kluwer Health. All rights reserved.


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