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Review
. 2022 Oct;101(10):2123-2137.
doi: 10.1007/s00277-022-04917-5. Epub 2022 Aug 9.

Anti-CD38 antibody therapy for patients with relapsed/refractory multiple myeloma: differential mechanisms of action and recent clinical trial outcomes

Xavier Leleu  1 , Thomas Martin  2 , Katja Weisel  3 , Fredrik Schjesvold  4 , Shinsuke Iida  5 , Fabio Malavasi  6 , Salomon Manier  7 , Chang-Ki Min  8 , Enrique M Ocio  9 , Charlotte Pawlyn  10 , Aurore Perrot  11 , Hang Quach  12 , Joshua Richter  13 , Ivan Spicka  14 , Kwee Yong  15 , Paul G Richardson  16
Affiliations
Review

Anti-CD38 antibody therapy for patients with relapsed/refractory multiple myeloma: differential mechanisms of action and recent clinical trial outcomes

Xavier Leleu et al. Ann Hematol. 2022 Oct.

Abstract

CD38 is a transmembrane glycoprotein that functions both as a receptor and an ectoenzyme, playing key roles in the regulation of calcium signaling and migration of immune cells to tumor microenvironments. High expression on multiple myeloma (MM) cells and limited expression on normal cells makes CD38 an ideal target for the treatment of MM patients. Two monoclonal antibodies directed at CD38, isatuximab and daratumumab, are available for use in patients with relapsed and/or refractory MM (RRMM); daratumumab is also approved in newly diagnosed MM and light-chain amyloidosis. Clinical experience has shown that anti-CD38 antibody therapy is transforming treatment of MM owing to its anti-myeloma efficacy and manageable safety profile. Isatuximab and daratumumab possess similarities and differences in their mechanisms of action, likely imparted by their binding to distinct, non-overlapping epitopes on the CD38 molecule. In this review, we present the mechanistic properties of these two antibodies and outline available evidence on their abilities to induce adaptive immune responses and modulate the bone marrow niche in MM. Further, we discuss differences in regulatory labeling between these two agents and analyze recent key clinical trial results, including evidence in patients with underlying renal impairment and other poor prognostic factors. Finally, we describe the limited existing evidence for the use of isatuximab or daratumumab after disease progression on prior anti-CD38 mono- or combination therapy, highlighting the need for additional clinical evaluations to define optimal anti-CD38 antibody therapy selection and sequencing in RRMM.

Keywords: CD38; Monoclonal antibody; Myeloma; Therapy.

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Conflict of interest statement

Leleu X. declares that he has no conflict of interest. Martin T. has received research funding (to institution) from Amgen, Janssen, and Sanofi, and consulting honoraria from GSK. Weisel K. has received research funding from Amgen, Bristol Myers Squibb/Celgene, GSK, and Sanofi, and honoraria from AbbVie, Amgen, Adaptive Biotech, Bristol Myers Squibb/Celgene, Janssen, GSK, Karyopharm, Novartis, Oncopeptides, Pfizer, Roche Pharma, Sanofi, and Takeda. Schjesvold F. has received research funding from Bristol Myers Squibb/Celgene, Janssen, Oncopeptides, and Sanofi, and honoraria from AbbVie, Amgen, Bristol Myers Squibb/Celgene, GSK, Janssen, Novartis, Oncopeptides, Sanofi, Schain, SkyliteDX, and Takeda. Iida S. has received research funding and honoraria from AbbVie, Amgen, Bristol Myers Squibb/Celgene, Chugai, Daiichi Sankyo, Janssen, Kyowa Kirin, Ono, Sanofi, and Takeda. Malavasi F. declares that he has no conflict of interest. Manier S. has received research funding and consulting honoraria from AbbVie, Adaptive Biotechnology, Amgen, Celgene/Bristol Myers Squibb, GSK, Janssen, Novartis, Oncopeptide, Regeneron, Roche, and Takeda. Min C.-K. declares that she has no conflict of interest. Ocio E. M. has received honoraria from Amgen, Bristol Myers Squibb, GSK, Janssen, Oncopeptides, Pfizer, Sanofi, and Takeda. Pawlyn C. has received honoraria and non-financial support from Amgen, Bristol Myers Squibb/Celgene, Janssen, and Sanofi, and non-financial support from Oncopeptides. Perrot A. has received research funding from Takeda and honoraria from AbbVie, Amgen, Bristol Myers Squibb/Celgene, Janssen, Sanofi, and Takeda. Quach H. has received research funding from Bristol Myers Squibb/Celgene, GSK, Karyopharm, and Sanofi, and advisory board/consulting honoraria from Bristol Myers Squibb/Celgene, GSK, Janssen, Karyopharm, Sanofi, and Takeda. Richter J. has received advisory board/consulting honoraria from Adaptive Biotechnologies, Astra Zeneca, Bristol Myers Squibb/Celgene, Janssen, Karyopharm, Oncopeptides, Sanofi, Secura bio, and X4 Pharmaceuticals. Spicka I. has received advisory board/consulting honoraria from Amgen, Bristol Myers Squibb/Celgene, Janssen, Novartis, PharmaMar, Sanofi, and Takeda. Yong K. declares that she has no conflict of interest. Richardson P. G. has received research funding from Bristol Myers Squibb/Celgene, Oncopeptides, and Takeda, and honoraria from Celgene, Janssen, Karyopharm, Oncopeptides, Sanofi, and Takeda.

Figures

Fig. 1
Fig. 1
Mechanisms of action of the anti-CD38 monoclonal antibodies isatuximab and daratumumab. Dara, daratumumab; FcR, Fc receptor; Isa, isatuximab; MAC, membrane attack complex; MM, multiple myeloma; NK, natural killer; T-reg, regulatory T cell
See this image and copyright information in PMC

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