HemaSphere | Sequencing of BCMA and GPRC5D-targeting Immunotherapies in Multiple Myeloma: Evidence-Based Recommendations from the European Myeloma Network

This study systematically summarizes the sequencing application of BCMA- and GPRC5D-targeting immunotherapies in multiple myeloma, providing evidence-based practical recommendations to help optimize patient treatment strategies.

Literature Overview
The article titled 'Sequencing BCMA- and GPRC5D-Targeting Immunotherapies in Multiple Myeloma: Practical Guidance from the European Myeloma Network,' published in the journal HemaSphere, reviews and summarizes current strategies for sequencing BCMA- and GPRC5D-targeted immunotherapies in multiple myeloma (MM), including clinical evidence and mechanisms of drug resistance for newer therapies such as CAR T-cell therapy, bispecific antibodies (BsAbs), and antibody-drug conjugates (ADCs). The article highlights the importance of patient and tumor characteristics, drug availability, and impact on treatment efficacy. It also discusses drug resistance mechanisms, such as antigen escape, decline in T-cell function, and expansion of drug-resistant T-cell clones, providing valuable practical guidance for clinicians.

Background Knowledge
Multiple myeloma is a malignant plasma cell disorder characterized by high heterogeneity and refractoriness, especially in the relapsed or refractory setting. In recent years, immunotherapies targeting B-cell maturation antigen (BCMA) and GPRC5D, such as CAR T-cell therapy, bispecific antibodies, and antibody-drug conjugates, have significantly improved clinical outcomes for patients. However, challenges remain in the sequencing and combination strategies of these therapies, as antigen loss, reduced T-cell fitness, and expansion of drug-resistant clones may all affect treatment effectiveness. Optimizing treatment sequences to enhance efficacy, reduce toxicity, and improve cost-effectiveness remains a key focus of research. This article systematically reviews sequencing strategies based on multiple clinical trials and real-world data, providing evidence-based, practical recommendations with significant implications for clinical practice.

Research Methods and Experiments
The article evaluates the efficacy and safety of various BCMA- and GPRC5D-targeted immunotherapies in patients with relapsed/refractory multiple myeloma based on data from multiple clinical trials and retrospective real-world analyses. It covers the application of CAR T-cell therapy, bispecific antibodies, and antibody-drug conjugates across different lines of treatment, analyzing the impact of antigen expression changes, T-cell fitness, treatment intervals, and resistance mechanisms on therapeutic outcomes. The study compares the performance of different drugs in treatment sequences, explores the impact of treatment intervals on efficacy, and proposes that switching between targets may be a more effective strategy.

Key Conclusions and Perspectives

• BCMA-targeted CAR T-cell therapy is most effective when used first, while bispecific antibodies and ADCs should ideally be avoided before CAR T therapy to prevent potential impairment of T-cell function.
• Administration of GPRC5D-targeted BsAbs as bridging therapy post T-cell collection can significantly reduce tumor burden and thereby enhance the efficacy of subsequent BCMA-targeted CAR T-cell therapy.
• Antigen loss and reduced T-cell fitness are major mechanisms of drug resistance that impact the effectiveness of subsequent targeted therapies, particularly those targeting the same antigen.
• Sequential treatment with bispecific antibodies targeting different antigens is more effective than repeating the same target, and treatment intervals may further enhance efficacy.
• Under certain circumstances, switching targets (e.g., from BCMA to GPRC5D) may be more beneficial than continuing therapy against the same target.
• The study recommends avoiding non-cell-based BCMA-targeted therapies prior to CAR T-cell therapy to preserve T-cell quality.

Conclusion
This article systematically reviews the sequencing strategies for BCMA- and GPRC5D-targeted immunotherapies in multiple myeloma. It identifies antigen loss, reduced T-cell fitness, and expansion of drug-resistant clones as key mechanisms that affect subsequent treatment efficacy. CAR T-cell therapy should be prioritized, while bispecific antibodies or ADCs are better reserved for later lines of treatment to avoid compromising T-cell quality. Furthermore, switching antigen targets and incorporating appropriate treatment intervals can significantly enhance therapeutic outcomes. The article also emphasizes that while multiple targeted therapies have been approved, optimizing treatment sequencing to maximize efficacy and minimize toxicity remains a critical challenge in clinical practice. Future studies should focus on validating current evidence-based recommendations through randomized controlled trials and exploring novel gene-editing or cell-engineering approaches to improve treatment durability and anti-tumor activity.

PTM Hotspot

View Tool Details

PTM Hotspot is a tool designed to identify potential post-translational modification (PTM) risk sites within antibody sequences. By scanning sequences, it accurately locates PTM sites that may affect antibody stability, activity, or immunogenicity, providing critical data support for antibody drug development. Additionally, PTM Hotspot features powerful visualization capabilities, presenting PTM risk site information in an intuitive sequence map. It also enables users to visually assess, via scatter plots, whether sequences fall within therapeutic antibody risk regions. This helps researchers quickly interpret analysis results, optimize antibody sequence design, reduce risks in biopharmaceutical development, and accelerate the R&D process.