The 67th Annual Meeting of the American Society of Hematology (ASH) was held in Orlando, Florida, bringing together the most cutting-edge research findings and clinical advances in the global field of hematology. At this year’s meeting, the team led by Professor Yajing Zhang from GoBroad Healthcare Group had four studies accepted, including one selected for oral presentation. These studies addressed key areas such as multi-target CAR-T therapeutic strategies, mechanistic management of complex toxicities, and immunodynamic regulation, collectively demonstrating the team’s original contributions and global vision in the field of CAR-T therapy.

In this article, Professor Zhang discusses specific studies and further shares her strategic perspective on the evolution of CAR-T therapy “from technological breakthroughs to systemic maturity,” offering an insightful and practice-oriented roadmap for the field.

Overcoming Therapeutic Bottlenecks in High-Risk Extramedullary Disease: An Integrated Strategy of Sequential BCMA and GPRC5D CAR-T Therapy

Q1. What are the major therapeutic challenges in relapsed/refractory multiple myeloma (RRMM) with bulky or extensive extramedullary disease (EMD)?

RRMM accompanied by bulky or extensive EMD represents one of the most challenging subgroups in current multiple myeloma treatment. The therapeutic difficulty arises not from a single factor, but from the convergence of multiple barriers.

First, the “sanctuary effect” and physical barriers play a critical role. Extramedullary tumor masses often have poor vascularization and are surrounded by fibrotic tissue, forming a closed microenvironment that limits the penetration of drugs and immune effector cells. As a result, conventional chemotherapy, targeted agents, and even standard CAR-T cells may fail to adequately access the tumor core.

Second, these lesions are characterized by a distinct and profoundly immunosuppressive microenvironment. Extramedullary sites are enriched with regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and multiple inhibitory cytokines. CAR-T cells that infiltrate these lesions are prone to rapid functional exhaustion, making it difficult to sustain effective antitumor activity.

In addition, high tumor burden and antigen escape are particularly prominent. Under selective pressure from a single target, such as BCMA, tumor cells can downregulate or lose antigen expression, leading to immune escape and rapid disease relapse.

In essence, the treatment of extensive EMD is not merely an “intensification challenge,” but a systemic problem that requires simultaneous solutions to physical barriers, immunosuppression, and tumor evolutionary dynamics.

Q2. What is the rationale behind the integrated strategy of DCEP chemotherapy, low-dose radiotherapy bridging, and sequential BCMA and GPRC5D CAR-T therapy?

The core concept of this strategy is systematic design and stepwise implementation, rather than reliance on a single high-intensity intervention.

Phase 1: Bridging therapy — creating a “combat-ready” environment for CAR-T cells.

Bridging therapy should be viewed as an active preparatory phase rather than a passive waiting period during CAR-T manufacturing. DCEP chemotherapy helps to reduce systemic tumor burden, thereby lowering the cytotoxic pressure faced by CAR-T cells after infusion. Low-dose radiotherapy serves a dual purpose: it enables precise debulking of extramedullary lesions while also enhancing immune sensitivity. By disrupting physical tumor barriers and inducing immunogenic cell death, radiotherapy can remodel the local microenvironment, promote immune cell infiltration, and potentially induce abscopal effects.

Phase 2: Sequential CAR-T infusion — a time-oriented strategy to address antigen escape.

To overcome antigen heterogeneity and the risk of immune escape, a dual-target sequential CAR-T approach was adopted. BCMA-directed CAR-T cells are administered first to rapidly eliminate tumor cells with high BCMA expression. This is followed by GPRC5D-directed CAR-T cells to eradicate residual tumor populations with low or absent BCMA expression, thereby achieving sustained target coverage over time.

Fundamentally, this strategy optimizes the “battlefield” through effective bridging therapy and achieves continuous tumor eradication through rational temporal and spatial target deployment.

Q3. What key clinical outcomes were achieved with this integrated strategy?

This integrated approach yielded clinically meaningful and encouraging results in RRMM patients with bulky or extensive EMD. At a median follow-up of 8.5 months (range, 3–15 months), the overall response rate was 87.5%, with a stringent complete response rate of 62.5%. Importantly, 87.5% of responding patients achieved complete metabolic remission of extramedullary lesions, a result that has rarely been reported in previous studies.

Moreover, follow-up data demonstrated more durable responses, with notable improvements in both progression-free survival (PFS) and overall survival (OS). With careful and mechanism-informed management, the overall safety profile was favorable, and no unexpected severe toxicities were observed.

The key significance of this study lies in establishing a feasible, reproducible, and manageable CAR-T treatment paradigm for patients with bulky or extensive EMD — a population historically regarded as a “therapeutic no-man’s-land.”

A Holistic Strategic View of CAR-T Therapy: From Single Infusion to Full-Cycle Systems Engineering

Professor Zhang emphasized that the future of CAR-T therapy does not depend on the emergence of a single “super CAR,” but rather on the development of a scientific, dynamic, and interpretable full-cycle management framework. This framework can be summarized in three core principles:

• Upfront strategic optimization: achieving deeper and more durable responses through effective bridging therapy and rational multi-target design
• Mechanism-driven management: enabling precise toxicity control guided by mechanistic understanding
• Dynamic, longitudinal monitoring: ensuring long-term disease control through immunodynamic surveillance

Building around this framework, the team continues to develop evidence-based solutions for each critical stage of CAR-T therapy, driving the continued evolution of CAR-T therapy toward greater safety, higher efficacy, and long-term sustainability.