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Efficacy and Safety of Durvalumab Combined with Daratumumab in Daratumumab-Refractory Multiple Myeloma Patients

SIMPLE SUMMARY: The CD38-targeting antibody daratumumab has marked activity in multiple myeloma through direct anti-tumor effects and immunomodulatory activity. However, eventually most patients will develop daratumumab-refractory disease. We hypothesized that daratumumab-resistance could be reverse...

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Autores principales: Frerichs, Kristine A., Verkleij, Christie P. M., Dimopoulos, Meletios A., Marin Soto, Jhon A., Zweegman, Sonja, Young, Mary H., Newhall, Kathryn J., Mutis, Tuna, van de Donk, Niels W. C. J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158123/
https://www.ncbi.nlm.nih.gov/pubmed/34070044
http://dx.doi.org/10.3390/cancers13102452
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author Frerichs, Kristine A.
Verkleij, Christie P. M.
Dimopoulos, Meletios A.
Marin Soto, Jhon A.
Zweegman, Sonja
Young, Mary H.
Newhall, Kathryn J.
Mutis, Tuna
van de Donk, Niels W. C. J.
author_facet Frerichs, Kristine A.
Verkleij, Christie P. M.
Dimopoulos, Meletios A.
Marin Soto, Jhon A.
Zweegman, Sonja
Young, Mary H.
Newhall, Kathryn J.
Mutis, Tuna
van de Donk, Niels W. C. J.
author_sort Frerichs, Kristine A.
collection PubMed
description SIMPLE SUMMARY: The CD38-targeting antibody daratumumab has marked activity in multiple myeloma through direct anti-tumor effects and immunomodulatory activity. However, eventually most patients will develop daratumumab-refractory disease. We hypothesized that daratumumab-resistance could be reversed by the addition of an inhibitor of the PD-1/PD-L1 signaling pathway, resulting in improved T- and NK-cell mediated anti-tumor immune responses. We therefore performed a phase 2 study to investigate the efficacy and safety of adding the PD-L1 checkpoint inhibitor durvalumab to daratumumab at the time of daratumumab failure. The toxicity profile of the daratumumab/durvalumab combination was acceptable, but none of the 18 enrolled patients achieved a clinical response. Immunomonitoring of bone marrow samples at baseline and during treatment showed a reduction of regulatory T-cell numbers and a decrease in the proportion of T-cells expressing LAG3 and CD8(+) T-cells expressing TIM-3, whereas tumor cell characteristics were not affected. These results indicate that co-targeting PD-L1 at the time of daratumumab failure is insufficient to reverse daratumumab-resistance. ABSTRACT: Daratumumab is active both as a single agent and in combination with other agents in multiple myeloma (MM) patients. However, the majority of patients will develop daratumumab-refractory disease, which carries a poor prognosis. Since daratumumab also has immunomodulatory effects, addition of the PD-L1 blocking antibody durvalumab at the time of progression may reverse daratumumab-resistance. The efficacy and safety of daratumumab and durvalumab in daratumumab-refractory relapsed/refractory MM patients was evaluated in this prospective, single-arm phase 2 study (NCT03000452). None of the 18 enrolled patients achieved PR or better. The frequency of serious adverse events was 38.9%, with one patient experiencing an immune related adverse event (grade 2 hyperthyroidism). No infusion-related reactions were observed. Analysis of tumor- and immune cell characteristics was performed on bone marrow samples obtained at baseline and during treatment. Daratumumab combined with durvalumab reduced the frequency of regulatory T-cells and decreased the proportion of T-cells expressing LAG3 and CD8(+) T-cells expressing TIM-3, without altering T- and NK-cell frequencies. Durvalumab did not affect tumor cell characteristics associated with daratumumab resistance. In conclusion, the addition of durvalumab to daratumumab following development of daratumumab-resistance was associated with an acceptable toxicity profile, but was not effective. This indicates that inhibition of the PD-1/PD-L1 signaling pathway at the time of daratumumab-resistance is insufficient to reverse daratumumab-resistance.
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spelling pubmed-81581232021-05-28 Efficacy and Safety of Durvalumab Combined with Daratumumab in Daratumumab-Refractory Multiple Myeloma Patients Frerichs, Kristine A. Verkleij, Christie P. M. Dimopoulos, Meletios A. Marin Soto, Jhon A. Zweegman, Sonja Young, Mary H. Newhall, Kathryn J. Mutis, Tuna van de Donk, Niels W. C. J. Cancers (Basel) Article SIMPLE SUMMARY: The CD38-targeting antibody daratumumab has marked activity in multiple myeloma through direct anti-tumor effects and immunomodulatory activity. However, eventually most patients will develop daratumumab-refractory disease. We hypothesized that daratumumab-resistance could be reversed by the addition of an inhibitor of the PD-1/PD-L1 signaling pathway, resulting in improved T- and NK-cell mediated anti-tumor immune responses. We therefore performed a phase 2 study to investigate the efficacy and safety of adding the PD-L1 checkpoint inhibitor durvalumab to daratumumab at the time of daratumumab failure. The toxicity profile of the daratumumab/durvalumab combination was acceptable, but none of the 18 enrolled patients achieved a clinical response. Immunomonitoring of bone marrow samples at baseline and during treatment showed a reduction of regulatory T-cell numbers and a decrease in the proportion of T-cells expressing LAG3 and CD8(+) T-cells expressing TIM-3, whereas tumor cell characteristics were not affected. These results indicate that co-targeting PD-L1 at the time of daratumumab failure is insufficient to reverse daratumumab-resistance. ABSTRACT: Daratumumab is active both as a single agent and in combination with other agents in multiple myeloma (MM) patients. However, the majority of patients will develop daratumumab-refractory disease, which carries a poor prognosis. Since daratumumab also has immunomodulatory effects, addition of the PD-L1 blocking antibody durvalumab at the time of progression may reverse daratumumab-resistance. The efficacy and safety of daratumumab and durvalumab in daratumumab-refractory relapsed/refractory MM patients was evaluated in this prospective, single-arm phase 2 study (NCT03000452). None of the 18 enrolled patients achieved PR or better. The frequency of serious adverse events was 38.9%, with one patient experiencing an immune related adverse event (grade 2 hyperthyroidism). No infusion-related reactions were observed. Analysis of tumor- and immune cell characteristics was performed on bone marrow samples obtained at baseline and during treatment. Daratumumab combined with durvalumab reduced the frequency of regulatory T-cells and decreased the proportion of T-cells expressing LAG3 and CD8(+) T-cells expressing TIM-3, without altering T- and NK-cell frequencies. Durvalumab did not affect tumor cell characteristics associated with daratumumab resistance. In conclusion, the addition of durvalumab to daratumumab following development of daratumumab-resistance was associated with an acceptable toxicity profile, but was not effective. This indicates that inhibition of the PD-1/PD-L1 signaling pathway at the time of daratumumab-resistance is insufficient to reverse daratumumab-resistance. MDPI 2021-05-18 /pmc/articles/PMC8158123/ /pubmed/34070044 http://dx.doi.org/10.3390/cancers13102452 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Frerichs, Kristine A.
Verkleij, Christie P. M.
Dimopoulos, Meletios A.
Marin Soto, Jhon A.
Zweegman, Sonja
Young, Mary H.
Newhall, Kathryn J.
Mutis, Tuna
van de Donk, Niels W. C. J.
Efficacy and Safety of Durvalumab Combined with Daratumumab in Daratumumab-Refractory Multiple Myeloma Patients
title Efficacy and Safety of Durvalumab Combined with Daratumumab in Daratumumab-Refractory Multiple Myeloma Patients
title_full Efficacy and Safety of Durvalumab Combined with Daratumumab in Daratumumab-Refractory Multiple Myeloma Patients
title_fullStr Efficacy and Safety of Durvalumab Combined with Daratumumab in Daratumumab-Refractory Multiple Myeloma Patients
title_full_unstemmed Efficacy and Safety of Durvalumab Combined with Daratumumab in Daratumumab-Refractory Multiple Myeloma Patients
title_short Efficacy and Safety of Durvalumab Combined with Daratumumab in Daratumumab-Refractory Multiple Myeloma Patients
title_sort efficacy and safety of durvalumab combined with daratumumab in daratumumab-refractory multiple myeloma patients
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158123/
https://www.ncbi.nlm.nih.gov/pubmed/34070044
http://dx.doi.org/10.3390/cancers13102452
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