To date, over 100 clinical trials investigating the use of CAR-T cells in MM have been registered at clinicaltrials.gov. Although several CD19-directed CAR-T cell products have been approved (Ghobadi 2018; Yassine et al. 2020), CD19 surface expression on plasma cells is limited or absent, leading to uncertain efficacy in clinical trials that used anti-CD19 alone in patients with MM (Garfall et al. 2015, 2019). Using superresolution microscopy, CD19 can be detected on a large proportion of myeloma cells, which could explain the successful targeting and lysis of myeloma cells by CD19-detecting CAR-T cells (Nerreter et al. 2019). Of note, some ongoing studies in which CD19 is targeted in combination with other antigens, especially BCMA, are being conducted (Beauvais et al. 2020).

BCMA-directed CAR-T cells have shown promising efficacy and safety profiles in various phase I/II clinical trials (Munshi et al. 2021; Brudno et al. 2018; Cohen et al. 2019; Mailankody et al. 2020; Zhao et al. 2018). Indeed, the overall response rate ranged from 75 to 100%, with median event-free survival ranging from 11 to 24 months, in heavily pretreated MM patients, which is far better than all other currently available drugs and agents in this patient cohort.

At least two BCMA-directed CAR-T cell products will likely move into routine clinical use in the near future. Outside clinical trials, the main indication for CAR-T cell therapy in MM would be limited to patients with R/R MM after at least two lines of prior therapy that included PIs (proteasome inhibitors), iMIDs (immunomodulatory agents, e.g., lenalidomide, pomalidomide), and anti-C38 monoclonal antibodies.

Although CAR-T cell therapy appears promising, the duration of disease control is limited, and almost all patients ultimately relapse. This might partially reflect the fact that CAR-T cells have thus far only been given to heavily pretreated patients with advanced, resistant disease (Beauvais et al. 2020; Gauthier and Yakoub-Agha 2017). Thus, CAR-T cell exhaustion and the reduction and even irreversible loss of expression of the target antigen BCMA on tumour cells (Da Vià et al. 2021; Samur et al. 2021), which are often genetically highly unstable, are other factors limiting CAR-T cell efficacy. Thus, novel targets or even dual targeting (including targeting of GPRC5D (de Larrea et al. 2020), SLAMF7 (Gogishvili et al. 2017), CD229 (Radhakrishnan et al. 2020), and CD38 (Gauthier and Yakoub-Agha 2017; Verkleij et al. 2020)) is currently being explored.

Additionally, to increase efficacy, CAR-T cell therapy is moved to earlier lines of therapy to increase the fitness and persistence of the generated MM-specific CAR-T cells. However, CAR-T cell therapy in MM—less when compared to patients with aggressive lymphomas—can be associated with substantial, potentially life-threatening toxicity. Thus, administering CAR-T cells with a better effector function and proliferation potential may be a challenge as CAR-T therapy is used at earlier stages of disease (Prommersberger et al. 2018).

FormalPara Key Points

  • BCMA is the major target for CAR-T cell therapy in MM.

  • Two BCMA-directed CAR-T cell products are moving into the clinical routine in the near future (one has already been approved by the FDA and EMA).

  • Irreversible BCMA loss on MM cells has been described in a few patients as a cause of failure of BCMA-directed CAR-T cells.

  • CAR-T cell therapy is moving to earlier lines of therapy in MM patients.