Mechanisms of Resistance to Anti-CD38 Daratumumab in Multiple Myeloma

Abstract

Daratumumab (Dara) is the first-in-class human-specific anti-CD38 mAb approved for the treatment of multiple myeloma (MM). Although recent data have demonstrated very promising results in clinical practice and trials, some patients do not achieve a partial response, and ultimately all patients undergo progression. Dara exerts anti-MM activity via antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), and immunomodulatory effects. Deregulation of these pleiotropic mechanisms may cause development of Dara resistance. Knowledge of this resistance may improve the therapeutic management of MM patients.

Keywords: CD38 antigen; daratumumab; drug resistance; multiple myeloma.

Figure 1

Dara mechanisms of action. Dara recognizes CD38 on MM cells and exerts anti-MM activity via Fc-dependent mechanisms and via immunomodulatory effects. The Fc-dependent mechanisms involve (i) ADCC and (ii) ADCP via the engagement of Dara Fc fragment to FcRs-expressing effector cells (i.e., NK cells, γδ T cells, neutrophils, and macrophages), causing the lysis and/or the phagocytosis of MM cells, respectively; (iii) CDC via the engagement of C1q that activates the complement cascade resulting in the assembly of MAC complex that enables the lysis of the target cells. Dara has also an immunomodulatory effect via inhibition of CD38 ectoenzymatic activity, resulting in a reduction of the immunosuppressive ADO and via the elimination of CD38⁺ immunosuppressive cells (i.e., MDSCs, Tregs, and Bregs): these mechanisms promote T-cell proliferation and effector functions.

Figure 2

Dara mechanisms of resistance include the following: (i) clone selection of CD38^dim MM cells; (ii) CD38 reduction via CD38 endocytosis, trogocytosis by granulocytes and monocytes, and via release of CD38-expressing microvescicles that contribute to ADO production and immunosuppression; (iii) immunomodulatory effects via downregulation of intracellular pathways in BMSCs, a decrease of effector memory T cells, M1 macrophages, and of the co-stimulatory CD28 expression on T cells; (iv) MM cells overexpression of CD46 and of the membrane-associated complement-inhibitory proteins (CD55 and CD59) that prevent CDC; (v) MM cells’ overexpression of CD47 that recognizes SIRPα on TAMs inhibiting ADCP; and (vi) depletion of CD38⁺ NK cells via fratricide ADCC.