Case series | How do I treat patients with RRMM after failure of BCMA-targeted therapies?

The Multiple Myeloma Hub spoke with Paul Richardson, Dana-Farber Cancer Institute, Boston, US. We asked, How should I approach treating patients with relapsed/refractory multiple myeloma (RRMM) after failure of B-cell maturation antigen (BCMA)-targeted therapies?

In this case, Paul Richardson discusses strategies for treating RRMM after relapse from BCMA-targeted therapies, including chimeric antigen receptor (CAR) T-cell therapies, bispecific antibodies, and antibody−drug conjugates (ADCs). He emphasizes the importance of alternative approaches, such as targeting non-BCMA antigens, using small molecule drugs, and combining antibodies with other agents. Dr Richardson highlights that while CAR T-cell therapies show remarkable results, they also present challenges like T-cell exhaustion, whereas salvage options remain more flexible with ADCs. He also notes ongoing research into next-generation therapies for more effective treatment.

Key points

• CAR T-cell therapies have demonstrated potential with high response rates; however, there remain significant challenges after relapse, such as T-cell exhaustion and difficult to manage toxicities.
  • For patients who relapse after CAR T-cell therapy, emerging strategies include GPRC5D- or FcRH5-targeted therapies, as well as treatments like CELMoDs.
• Novel therapies being investigated that target antigens other than BCMA include both CAR T-cell therapies and bispecific antibodies, which target GPRC5D or FcRH5.
• GPRC5D is a therapeutic target in MM due to its elevated expression on malignant plasma cells.
  • Talquetamab is a bispecific antibody targeting GPRC5D that has received breakthrough therapy designation from the U.S. Food and Drug Administration (FDA) for RRMM based on results from the MonumenTAL-1 (NCT03399799) trial.¹
  • Forimtamig is an investigational agent that uses a dual-binding mechanism, with high avidity binding to GPRC5D on plasma cells and with high affinity to CD3 on T cells, promoting T-cell activation and malignant plasma cell death.²
• FcRH5 is expressed on nearly 100% of myeloma cells and is highly prevalent at all stages of B-cell maturation, located near a chromosomal breakpoint.
  • Cevostamab is a bispecific antibody targeting FcRH5, currently being evaluated as part of the phase I/II CAMMA-2 (NCT05535244) trial. 
  • This trial is evaluating the efficacy and safety of cevostamab in patients with RRMM who are triple-class refractory and have previously received a BCMA-targeted therapy.
  • Early data from the CAMMA-2 study suggests that cevostamab is effective in heavily pretreated patients with RRMM with prior BCMA-targeted ADC or CAR T-cell therapy, demonstrating a safety profile that is clinically manageable.³
• Bispecific antibodies have shown efficacy, but transitioning to CAR T-cell therapy afterward may reduce effectiveness. However, CAR T-cell therapy can still be considered, particularly when targeting different antigens.
• In clinical trials, CELMoDs, including mezigdomide-based approaches, have shown significant promise in cases where CAR T-cell therapy has failed.
• ADCs, such as belantamab mafodotin, have yielded positive outcomes, and salvage strategies after ADC failure benefits from fewer concerns related to T-cell exhaustion.
• Novel agents, including selinexor, are being investigated for their potential to enhance T-cell responses. 
• To conclude, treatment strategies should be personalized, taking into account individual patient history and overall health.