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Controversy in the Use of CD38 Antibody for Treatment of Myeloma: Is High CD38 Expression Good or Bad?

During a time span of just a few years, the CD38 antibody, daratumumab, has been established as one of the most important new drugs for the treatment of multiple myeloma, both in the relapsed/refractory setting and, more recently, as a first-line treatment. Although much is known about the pleiotrop...

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Autores principales: Plesner, Torben, van de Donk, Niels W. C. J., Richardson, Paul G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072398/
https://www.ncbi.nlm.nih.gov/pubmed/32041300
http://dx.doi.org/10.3390/cells9020378
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author Plesner, Torben
van de Donk, Niels W. C. J.
Richardson, Paul G.
author_facet Plesner, Torben
van de Donk, Niels W. C. J.
Richardson, Paul G.
author_sort Plesner, Torben
collection PubMed
description During a time span of just a few years, the CD38 antibody, daratumumab, has been established as one of the most important new drugs for the treatment of multiple myeloma, both in the relapsed/refractory setting and, more recently, as a first-line treatment. Although much is known about the pleiotropic modes of action of daratumumab, we are still not sure how to use it in an optimal manner. Daratumumab targets CD38 on myeloma cells and a high level of CD38 expression facilitates complement-mediated cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Since the expression of CD38 by myeloma cells is downregulated during treatment with daratumumab, it may seem reasonable to introduce a wash-out period and retreat with daratumumab at a later time point when CD38 expression has recovered in order to gain the maximum benefit of daratumumab’s capacity to kill myeloma cells by CDC, ADCC and ADCP. In other aspects, CD38 seems to serve as a survival factor for myeloma cells by facilitating protective myeloma cell–stromal-cell interactions, contributing to the formation of nanotubes that transfer mitochondria from the stromal cells to myeloma cells, boosting myeloma cell proliferation and survival and by generation of immunosuppressive adenosine in the bone marrow microenvironment. In addition, continuous exposure to daratumumab may keep immune suppressor cells at a low level, which boosts the anti-tumor activity of T-cells. In fact, one may speculate if in the early phase of treatment of a myeloma patient, the debulking effects of daratumumab achieved by CDC, ADCC and ADCP are more important while at a later stage, reprogramming of the patient’s own immune system and certain metabolic effects may take over and become more essential. This duality may be reflected by what we often observe when we watch the slope of the M-protein from myeloma patients responding to daratumumab: A rapid initial drop followed by a slow decline of the M-protein during several months or even years. Ongoing and future clinical trials will teach us how to use daratumumab in an optimal way.
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spelling pubmed-70723982020-03-19 Controversy in the Use of CD38 Antibody for Treatment of Myeloma: Is High CD38 Expression Good or Bad? Plesner, Torben van de Donk, Niels W. C. J. Richardson, Paul G. Cells Viewpoint During a time span of just a few years, the CD38 antibody, daratumumab, has been established as one of the most important new drugs for the treatment of multiple myeloma, both in the relapsed/refractory setting and, more recently, as a first-line treatment. Although much is known about the pleiotropic modes of action of daratumumab, we are still not sure how to use it in an optimal manner. Daratumumab targets CD38 on myeloma cells and a high level of CD38 expression facilitates complement-mediated cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Since the expression of CD38 by myeloma cells is downregulated during treatment with daratumumab, it may seem reasonable to introduce a wash-out period and retreat with daratumumab at a later time point when CD38 expression has recovered in order to gain the maximum benefit of daratumumab’s capacity to kill myeloma cells by CDC, ADCC and ADCP. In other aspects, CD38 seems to serve as a survival factor for myeloma cells by facilitating protective myeloma cell–stromal-cell interactions, contributing to the formation of nanotubes that transfer mitochondria from the stromal cells to myeloma cells, boosting myeloma cell proliferation and survival and by generation of immunosuppressive adenosine in the bone marrow microenvironment. In addition, continuous exposure to daratumumab may keep immune suppressor cells at a low level, which boosts the anti-tumor activity of T-cells. In fact, one may speculate if in the early phase of treatment of a myeloma patient, the debulking effects of daratumumab achieved by CDC, ADCC and ADCP are more important while at a later stage, reprogramming of the patient’s own immune system and certain metabolic effects may take over and become more essential. This duality may be reflected by what we often observe when we watch the slope of the M-protein from myeloma patients responding to daratumumab: A rapid initial drop followed by a slow decline of the M-protein during several months or even years. Ongoing and future clinical trials will teach us how to use daratumumab in an optimal way. MDPI 2020-02-06 /pmc/articles/PMC7072398/ /pubmed/32041300 http://dx.doi.org/10.3390/cells9020378 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Viewpoint
Plesner, Torben
van de Donk, Niels W. C. J.
Richardson, Paul G.
Controversy in the Use of CD38 Antibody for Treatment of Myeloma: Is High CD38 Expression Good or Bad?
title Controversy in the Use of CD38 Antibody for Treatment of Myeloma: Is High CD38 Expression Good or Bad?
title_full Controversy in the Use of CD38 Antibody for Treatment of Myeloma: Is High CD38 Expression Good or Bad?
title_fullStr Controversy in the Use of CD38 Antibody for Treatment of Myeloma: Is High CD38 Expression Good or Bad?
title_full_unstemmed Controversy in the Use of CD38 Antibody for Treatment of Myeloma: Is High CD38 Expression Good or Bad?
title_short Controversy in the Use of CD38 Antibody for Treatment of Myeloma: Is High CD38 Expression Good or Bad?
title_sort controversy in the use of cd38 antibody for treatment of myeloma: is high cd38 expression good or bad?
topic Viewpoint
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072398/
https://www.ncbi.nlm.nih.gov/pubmed/32041300
http://dx.doi.org/10.3390/cells9020378
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