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Novel immunotherapies in multiple myeloma – chances and challenges
Leo Rasche,1,2 Ralph Wäsch,3 Markus Munder,4,5 Hartmut Goldschmidt6,7 and Marc S. Raab6,8
1Department of Internal Medicine II, University Hospital of Würzburg, Würzburg; 2Mildred Scheel Early Career Center, University Hospital of Würzburg, Würzburg; 3Department of Internal Medicine I, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg; 4Third Department of Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; 5Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg University Mainz, Mainz; 6Department of Internal Medicine V, University Hospital of Heidelberg, Heidelberg; 7National Center of Tumor Diseases (NCT), Heidelberg and 8CCU Molecular Hematology/Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
ABSTRACT
In this review article, we summarize the latest data on antibody-drug conjugates, bispecific T-cell-engaging antibodies, and chimeric antigen receptor T cells in the treatment of multiple myeloma. We discuss the pivotal questions to be addressed as these new immunotherapies become standard agents in the management of multiple myeloma. We also focus on the selection of patients for these therapies and speculate as to how best to individualize treatment approaches. We see these novel immunotherapies as representing a paradigm shift. However, despite the promising preliminary data, many open issues remain to be evaluated in future trials.
Introduction
Novel immunotherapeutic approaches are seen as the next generation of game- changing treatments in multiple myeloma (MM). It is a challenge to provide a full overview of novel immunotherapies in this fast-moving field. In the first part of this article, we provide a summary of current clinical data, which have either been published in peer-reviewed journals or been presented at international confer- ences, including the 2020 American Society of Clinical Oncology, European Hematology Association, and American Society of Hematology (ASH) meetings. In the second part, we discuss these new reports in the context of current treat- ment paradigms in MM. Given the plethora of immunological approaches in MM, we focus here on the three most advanced classes of novel immunotherapies, anti- body-drug conjugates (ADC), bispecific antibodies or T-cell-engaging antibodies (TCE), and chimeric antigen receptor (CAR) T cells, targeting the antigens described below.
Antigens
Signaling lymphocytic activation molecule family member 7 (SLAMF7)
SLAMF7 (or CS1) is expressed on a variety of lymphocytes, including subsets of B and T cells, natural killer cells and plasma cells. SLAMF7 is the target of the monoclonal antibody elotuzumab. The development of CAR T cells directed against SLAMF7 may be more challenging because of this antigen’s expression on T-cell subsets which may lead to fratricide.1
Cluster of differentiation 38 (CD38)
CD38 is expressed on plasma cells and is the target of monoclonal antibodies such as daratumumab and isatuximab. It is also expressed on several other lym- phoid and myeloid cells, including hematopoietic precursors, raising concerns about on-target, off-tumor toxicity. The levels of expression of CD38 may also decline during the course of the disease or under the selective pressure of CD38- targeted treatment. This problem may be overcome by agents inducing selective
Ferrata Storti Foundation
Haematologica 2021 Volume 106(10):2555-2565
Correspondence:
MARC S. RAAB
Marc.Raab@med.uni-heidelberg.de
Received: February 12, 2021. Accepted: April 29, 2021. Pre-published: July 1, 2021.
https://doi.org/10.3324/haematol.2020.266858 ©2021 Ferrata Storti Foundation
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