Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma

Casneuf, Tineke; Xu, Xu Steven; Adams, Homer; Axel, Amy; Chiu, Christopher; Khan, Imran; Ahmadi, Tahamtan; Yan, Xiaoyu; Lonial, Sagar; Plesner, Torben; Lokhorst, Henk M.; Donk, Niels W.C.J. van de; Clemens, Pamela L.; Sasser, A. Kate

doi:10.1182/bloodadvances.2017006866

Cited by 177 publications

(186 citation statements)

References 18 publications

(31 reference statements)

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“…We undertook the present study to complement the findings of Krejcik et al , Nijhof et al , and Casneuf et al assessing the effects of daratumumab on a more comprehensive profile of immune‐cell populations and immune functional characteristics. Our objective was to identify changes in immune‐cell profiles that correlated with efficacy and depth of response observed during treatment with daratumumab.…”

Section: Discussionmentioning

confidence: 94%

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

et al. 2018

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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. © 2018 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.

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Section: Discussionmentioning

confidence: 94%

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

et al. 2018

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“…Daratumumab is associated with a marked reduction in NK cell counts (Casneuf et al, 2017). No significant difference in maximal reduction of total or activated NK cells in peripheral blood or bone marrow due to FCGR polymorphisms was observed in this patient population.…”

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confidence: 56%

Impact of Fc gamma receptor polymorphisms on efficacy and safety of daratumumab in relapsed/refractory multiple myeloma

Donk

Casneuf

Cara³

et al. 2018

Br J Haematol

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“…Elotuzumab enhanced NK cytotoxicity to myeloma cells in an independent CD16 expression manner when the expression level of NKG2D was high on NK cells . On the contrary, daratumumab decreases the number of NK cells in patients with RRMM . Daratumumab decreased CD38 + NK cells significantly, which are present in the majority of the population, accounting for approximately 85%, although daratumumab did not decrease CD38 ‐/low NK cells .…”

Section: Discussionmentioning

confidence: 92%

Elevated eosinophil level predicted long time to next treatment in relapsed or refractory myeloma patients treated with lenalidomide

et al. 2020

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Lenalidomide is an immunomodulatory drug that is administered commonly in patients with relapsed or refractory multiple myeloma (RRMM). Eosinophils have immunological functions, for instance, in allergic diseases and asthma. The purpose of this study was to investigate the clinical significance of elevated eosinophil levels in patients with RRMM treated with lenalidomide. A total of 59 patients were included. Elevated eosinophil level was defined as an increase in the eosinophil count of ≥250/µL from the eosinophil count on day 1 during the first cycle. The percentage of patients with elevated eosinophil levels was 22.0%. The overall response ratio in the elevated eosinophil group and nonelevated eosinophil group was 84.6% and 63.0% (P = .189), respectively. The median time to next treatment (TTNT) in the elevated eosinophil group was significantly longer than that in the nonelevated group (40.3 months vs 8.4 months; P = .017). Additionally, TTNT in the elevated eosinophil group with partial response (PR) or better was significantly longer than that in the nonelevated eosinophil group with PR or better (40.3 months vs 11.9 months; P = .021). We concluded that elevated eosinophil levels were frequently observed and might predict a longer TTNT in patients with RRMM treated with lenalidomide.

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Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma

Abstract: Key Points• NK cells decline as daratumumab exposure increases in a maximum effect type doseresponse relationship, with no efficacy and safety impact.• Remaining PBMC cell fractions maintained the ability to carry out daratumumab-mediated ex vivo ADCC.

Cited by 177 publications

References 18 publications

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

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

Impact of Fc gamma receptor polymorphisms on efficacy and safety of daratumumab in relapsed/refractory multiple myeloma

Elevated eosinophil level predicted long time to next treatment in relapsed or refractory myeloma patients treated with lenalidomide

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