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Review
. 2022 Dec 30;24(1):645.
doi: 10.3390/ijms24010645.

Innovative Anti-CD38 and Anti-BCMA Targeted Therapies in Multiple Myeloma: Mechanisms of Action and Resistance

Danilo De Novellis  1   2 , Raffaele Fontana  2 , Valentina Giudice  1   2 , Bianca Serio  1   2 , Carmine Selleri  1   2
Affiliations
Review

Innovative Anti-CD38 and Anti-BCMA Targeted Therapies in Multiple Myeloma: Mechanisms of Action and Resistance

Danilo De Novellis et al. Int J Mol Sci. .

Abstract

CD38 and B-cell maturation antigens (BCMAs) are prevalently expressed on neoplastic plasma cells in multiple myeloma (MM), making them ideal therapeutic targets. Anti-CD38 monoclonal antibodies, such as approved daratumumab and isatuximab, are currently the milestone in MM treatment because they induce plasma cell apoptosis and kill through several mechanisms, including antibody-dependent cellular cytotoxicity or phagocytosis. BCMA is considered an excellent target in MM, and three different therapeutic strategies are either already available in clinical practice or under investigation: antibody-drug conjugates, such as belantamab-mafodotin; bispecific T cell engagers; and chimeric antigen receptor-modified T cell therapies. Despite the impressive clinical efficacy of these new strategies in the treatment of newly diagnosed or multi-refractory MM patients, several mechanisms of resistance have already been described, including antigen downregulation, the impairment of antibody-dependent cell cytotoxicity and phagocytosis, T- and natural killer cell senescence, and exhaustion. In this review, we summarize the current knowledge on the mechanisms of action and resistance of anti-CD38 and anti-BCMA agents and their clinical efficacy and safety.

Keywords: BCMA; CD38; anti-BCMA CAR-T; anti-BCMA bispecific antibodies; anti-CD38 antibodies; mechanisms of resistance; multiple myeloma; targeted therapy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Mechanisms of action of anti-CD38 agents. Anti-CD38 monoclonal antibodies induce complement-dependent cytotoxicity (CDC) with the formation of a complement membrane attack complex leading to cell lysis; antibody-dependent cellular phagocytosis (ADCP) mediated by macrophages (Mφ); antibody-dependent cellular cytotoxicity (ADCC) mainly mediated by natural killer (NK) cells and cytotoxic T cells; direct cellular apoptosis; and modulation of extracellular ectoenzyme activity. Made using smart.servier.com.
Figure 2
Figure 2
Mechanisms of action of anti-BCMA agents. Anti-BCMA agents can induce antibody-dependent cellular phagocytosis (ADCP) mediated by macrophages (Mφ); antibody-dependent cellular cytotoxicity (ADCC), mainly mediated by natural killer (NK) cells; direct cellular apoptosis through the intracellular release of cytotoxic agents; and tumor cell killing by cytotoxic T cells (CTL) and engineered chimeric antigen receptor (CAR)-T cells. Made using smart.servier.com.
See this image and copyright information in PMC

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