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Sequencing BCMA- and GPRC5D-targeting immunotherapies in multiple myeloma: Practical guidance from the European
Niels W C J van de Donk1,2, Philippe Moreau3, Jesus F San-Miguel4
1Department of Hematology, Amsterdam UMC Vrije Universiteit Amsterdam Amsterdam The Netherlands.
Abstract:
The treatment landscape of heavily pretreated relapsed/refractory MM has changed considerably in recent years with the introduction of novel BCMA- and GPRC5D-directed immunotherapies, including CAR T-cell therapy, bispecific antibodies (BsAbs), and antibody-drug conjugates (ADCs). Treatment selection and sequencing become increasingly complex with the broad range of therapeutic options. In this review, the European Myeloma Network provides recommendations on how to best incorporate these novel therapies into the present treatment landscape using current evidence. The optimal treatment sequence depends on various patient- and tumor-related features, but also reimbursement and availability issues. In addition, mechanisms underlying relapse (e.g., antigen loss, reduced T-cell fitness, or outgrowth of T-cell resistant clones) dictate the efficacy of sequential BCMA- or GPRC5D-directed immunotherapy. BCMA-targeting BsAbs and ADCs should preferably be avoided prior to CAR T-cell therapy, as some studies have shown that these agents negatively influence clinical outcomes after CAR T-cell therapy. Therefore, we recommend the selection of CAR T-cell therapy first, and BsAbs and/or belamaf later in the disease course, if patients are eligible for CAR T-cell therapy and in case CAR T-cell therapy is available within a short time frame. However, bridging therapy with GPRC5D-directed BsAbs (initiation after apheresis) can be considered to significantly reduce tumor burden, because this was shown to improve the efficacy of consecutive BCMA-directed CAR T-cell therapy. Sequential treatment with agents targeting the same antigen, but with different modes of action, is feasible, but several studies have demonstrated that target switch is a more effective strategy. In addition, there is increasing evidence indicating that the efficacy of sequential use of BsAbs can be improved by creating a BsAb-free interval.
Insights
Novel immunotherapies like CAR T-cell therapy, bispecific antibodies, and antibody-drug conjugates offer new options for relapsed/refractory multiple myeloma. Sequencing these treatments, particularly avoiding BCMA-targeting agents before CAR T-cell therapy, is crucial for optimal patient outcomes.
Area of Science:
- Hematology
- Immunotherapy
- Oncology
Background:
- The treatment of relapsed/refractory multiple myeloma (MM) has evolved with new BCMA- and GPRC5D-directed immunotherapies.
- These novel agents include chimeric antigen receptor (CAR) T-cell therapy, bispecific antibodies (BsAbs), and antibody-drug conjugates (ADCs).
- Treatment selection and sequencing are complex due to the expanding therapeutic options.
Purpose of the Study:
- To provide European Myeloma Network recommendations for integrating novel immunotherapies into the MM treatment landscape.
- To guide optimal sequencing strategies based on current evidence, patient, and tumor characteristics.
- To address challenges related to reimbursement and availability of therapies.
Main Methods:
- Review of current evidence on BCMA- and GPRC5D-directed immunotherapies in relapsed/refractory MM.
- Analysis of factors influencing treatment efficacy, including mechanisms of relapse and antigen expression.
- Formulation of expert recommendations for treatment sequencing.
Main Results:
- BCMA-targeting BsAbs and ADCs may negatively impact outcomes if used before CAR T-cell therapy.
- CAR T-cell therapy is recommended first, followed by BsAbs or belamaf if eligible and available promptly.
- Bridging therapy with GPRC5D-directed BsAbs can reduce tumor burden and enhance subsequent BCMA-directed CAR T-cell therapy efficacy.
- Switching targets is generally more effective than sequential treatment with agents targeting the same antigen.
- A treatment-free interval may improve the efficacy of sequential bispecific antibody use.
Conclusions:
- Optimal sequencing of novel immunotherapies in relapsed/refractory MM is critical and depends on patient/tumor factors and logistical considerations.
- Prioritizing CAR T-cell therapy, followed by other agents, and considering target switching strategies can improve outcomes.
- Further research into optimal sequencing and management of resistance mechanisms is warranted.
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