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

Int J Mol Sci. 2022 Dec 30;24(1):645. doi: 10.3390/ijms24010645.


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.

Publication types

  • Review

MeSH terms

  • Humans
  • Immunoconjugates* / therapeutic use
  • Immunotherapy
  • Immunotherapy, Adoptive
  • Multiple Myeloma* / drug therapy
  • T-Lymphocytes


  • Immunoconjugates

Grants and funding

This research received no external funding.