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2024-10-17T08:31:54.000Z

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

Oct 17, 2024
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Learning objective: After reading this article, learners will be able to cite a new clinical development in relapsed/refractory MM.

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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?

How do I treat patients with RRMM after failure of 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.

Expert Opinion

Suggested reading from Dr Paul Richardson: 

Richardson P, et al. NEJM. 2023;389(11):1009-1022. DOI: 10.1056/NEJMoa2303194

Sonneveld P, et al. NEJM. 2024;390(4):301-313. DOI: 10.1056/NEJMoa2312054

Hungria V, et al. NEJM. 2024;391(5):393-407. DOI: 10.1056/NEJMoa2405090

Dimopoulos M, et al. NEJM. 2024;391(5):408-421. DOI: 10.1056/NEJMoa2403407

Grosicki S, et al. Lancet. 2020; 396(10262):1563-1573. DOI: 10.1016/S0140-6736(20)32292-3

Richardson P, et al. Lancet Oncol. 2019;20(6):781-794. DOI: 10.1016/S1470-2045(19)30152-4

  1. Chari A, Minnema M, Berdeja J, et al. Talquetamab, a T-cell-redirecting GPRC5D bispecific antibody for multiple myeloma. N Engl J Med. 2022;387(24):2232-2244. DOI: 1056/NEJMoa2204591
  2. Hasselbalch Riley AC. A novel GPRC5D T-cell engaging bispecific antibody, induces rapid responses in patients with relapsed/refractory multiple myeloma: Preliminary results from a first-in-human trial. Oral abstract #S180. Presented at: European Hematology Association 2022 Congress; Jun 11, 2022; Vienna, AT
  3. Kumar S. Cevostamab in patients with RRMM who are triple-class refractory and have received prior BCMA-targeted or ADC or CAR T-cell: Initial results from the phase I/II CAMMA-2 study. Presentation #S210. Presented at: European Hematology Association 2024 Hybrid Congress; Jun 13-16, 2024; Madrid, ES.

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