Editor's Note: The “Gaobo Medical Forum—6th Clinical Application Seminar and Training Course on Autologous Hematopoietic Stem Cell Transplantation,” hosted by the National Clinical Research Center for Hematologic Diseases of the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences, and organized by Shanghai Zhaxin Hospital/Gaobo Medical Group and Shanghai Liquan Hospital, was held in Shanghai on August 29–30, 2026. During the meeting, Oncology Frontier – Hematology Frontier invited Dr. Su Li, Director of the Department of Hematology and Director of the Myeloma Center at Gaobo Shanghai Liquan Hospital, to discuss new advances from his team's work in immunotherapy for relapsed/refractory multiple myeloma (RRMM). Dr. Li provided an in-depth analysis of the mechanisms and clinical benefits of BCMA/GPRC5D dual-target CAR-T therapy and shared valuable clinical insights into optimizing combination treatment pathways and refining precision risk stratification.01
Oncology Frontier – Hematology Frontier: In recent years, BCMA-targeted CAR-T therapy has demonstrated high efficacy in RRMM, but antigen escape remains an important mechanism contributing to disease relapse. From the perspectives of mechanism and clinical need, what potential advantages does BCMA/GPRC5D dual-target CAR-T therapy offer over single-target CAR-T therapy? What key unmet challenges in RRMM treatment is this design intended to address?
Dr. Su Li: At present, BCMA-targeted CAR-T-cell therapy has entered commercial use and has enabled many patients with relapsed/refractory multiple myeloma (RRMM) to achieve deep responses. Relevant clinical studies have also reported impressive positive results. However, this approach still has certain limitations in specific patient subgroups, particularly those with extramedullary disease and high-risk cytogenetic abnormalities.
At a fundamental level, one reason is closely related to BCMA antigen escape. BCMA is a specific marker of plasma cells, and under the selective pressure of targeted therapy, tumor cells can readily develop downregulation or loss of BCMA expression, which is an important mechanism underlying disease relapse. Another factor is that the extracellular domain of BCMA may be cleaved during treatment, releasing soluble or free BCMA into the plasma. These soluble antigens can bind to receptors on the surface of CAR-T cells, thereby consuming effector cells and reducing the actual efficacy of CAR-T therapy.
To overcome these limitations, BCMA/GPRC5D dual-target CAR-T therapy was developed. This design introduces GPRC5D as an additional myeloma target. GPRC5D is highly expressed on the surface of myeloma cells, and its expression is independent of BCMA. This means that even when some patients have low or absent BCMA expression, their tumor cells may continue to express high levels of GPRC5D. Therefore, the dual-target design can more comprehensively cover tumor-clone heterogeneity.
In addition, GPRC5D expression in normal tissues is extremely limited and is mainly found in keratinocytes of the skin, nails, and taste buds, which are not critical organs. Therefore, the risk of severe adverse events associated with targeting GPRC5D is relatively low. Although early animal studies suggested a potential risk of cerebellar toxicity, current clinical studies have adopted novel antibody designs based on nanotechnology. These designs feature a small molecular size and high affinity for tumor cells, effectively reducing off-target effects. Available clinical trial data indicate that cerebellar toxicity is extremely rare, supporting the favorable safety profile of this therapeutic approach.
In summary, BCMA/GPRC5D dual-target CAR-T therapy can simultaneously eliminate tumor subclones expressing either or both of these antigens, thereby more effectively reducing minimal residual disease that could give rise to treatment resistance. At the same time, the therapy can substantially enhance antitumor efficacy without adding significant toxicity, achieving a favorable balance between efficacy and safety.
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Oncology Frontier – Hematology Frontier: Existing studies have shown that BCMA/GPRC5D dual-target CAR-T therapy achieves high response rates and deep responses in RRMM, particularly in patients with extramedullary disease. Based on the available clinical data, how would you evaluate its efficacy and safety? Which patient populations may be the highest-priority candidates for further exploration of this therapeutic strategy?
Dr. Su Li: Our center, in collaboration with Gaobo Hospital in Beijing, conducted a clinical study of BCMA/GPRC5D dual-target CAR-T-cell therapy. Preliminary findings showed that the therapy achieved significant efficacy, with an overall response rate (ORR) of 100% and a complete response (CR) rate of 83.3%, demonstrating the ability to achieve deep clearance of malignant plasma cells. In particular, among patients with extramedullary disease and high-risk cytogenetic abnormalities, the therapy demonstrated significant advantages, with a stringent complete response (sCR) rate of 66.7%. In terms of safety, patients generally tolerated the treatment well, with no patients discontinuing the study because of adverse events, and the vast majority were able to complete treatment successfully.
The main adverse events were hematologic toxicity and infection. Grade 3–4 hematologic toxicities, primarily thrombocytopenia and neutropenia, occurred in approximately 20% of patients and were generally manageable. The infection rate was 44%, with pulmonary infections being the most common. Therefore, particular attention should be paid to infection prevention and treatment during CAR-T therapy.
Regarding the specific adverse events of greatest concern, we observed no cases of hemophagocytic syndrome or cerebellar toxicity, suggesting that this CAR-T design effectively avoided severe off-target effects. Cytokine release syndrome (CRS) occurred at a relatively high rate of 88%, but the vast majority of cases were grade 1, with a small number being grade 2. No grade ≥3 cases occurred. The median duration was 6 days, and most patients recovered and were discharged within two weeks after symptomatic treatment. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 5% of patients (3 cases), all of which were grade 1. This incidence was similar to that observed with single-target BCMA CAR-T therapy, and all cases resolved following treatment. In addition, a small proportion of patients developed skin toxicities, such as shedding of the nail keratin layer, 2–4 months after treatment. However, long-term follow-up showed that new nails gradually returned to normal.
Based on these clinical data, we believe BCMA/GPRC5D dual-target CAR-T therapy is particularly applicable to two major patient populations. First, patients who have previously failed BCMA-targeted immunotherapy. The dual-target design can effectively address antigen escape and limitations associated with single-target therapy. Second, patients with extensive extramedullary disease or high-risk cytogenetic abnormalities. For these patients, early intervention with dual-target CAR-T therapy may be recommended to achieve better outcomes.
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Oncology Frontier – Hematology Frontier: As BCMA- and GPRC5D-targeted therapies continue to expand, treatment options and sequencing strategies following previous CAR-T or bispecific antibody therapy have become important areas of clinical interest. Looking ahead, how can BCMA/GPRC5D dual-target CAR-T therapy be further optimized in terms of treatment timing, patient selection, response prediction, and resistance management? How do you expect its role in the overall treatment landscape of RRMM to evolve?
Dr. Su Li: In clinical practice, when multiple myeloma relapses, patients and their families often have questions regarding treatment options. As mentioned above, for BCMA/GPRC5D dual-target CAR-T therapy, the population with the strongest rationale for treatment remains patients who have previously failed BCMA-targeted immunotherapy, as these patients often develop low BCMA expression or immune escape. The second group comprises patients with extramedullary disease. Biopsy studies have confirmed that extramedullary lesions generally express high levels of GPRC5D and frequently co-express GPRC5D and BCMA, making the dual-target strategy particularly effective in minimizing antigen escape. Finally, patients with high-risk cytogenetic abnormalities may also benefit significantly, as demonstrated by our research.
At the same time, there remains substantial room for optimization of dual-target CAR-T therapy in clinical practice. Our clinical trials have shown that insufficient depth of response or subsequent relapse in some patients is closely associated with inadequate in vivo expansion and persistence of CAR-T cells. Therefore, future efforts should focus on optimizing CAR-T vectors and structural designs to enhance their in vivo expansion capacity and persistence.
Combination treatment strategies represent another important direction for improving efficacy. To enhance CAR-T-cell activity and prolong their expansion in vivo, clinical studies are actively exploring the use of hypomethylating agents, such as decitabine, or immunomodulatory agents as maintenance therapy following CAR-T treatment. In addition, for patients with extramedullary disease or high-risk genetic abnormalities such as TP53 abnormalities, combining CAR-T therapy with agents such as ixazomib may potentially produce synergistic effects. The core objective of these combination strategies is to further eliminate minimal residual disease that CAR-T therapy has failed to completely eradicate, thereby achieving a “1 + 1 > 2” antitumor effect.
Finally, developing biological markers capable of predicting treatment efficacy is critical for achieving precision patient stratification. For example, patients with impaired T-cell function at baseline may experience poor CAR-T-cell expansion and suboptimal efficacy regardless of whether single-target or dual-target CAR-T therapy is used. To address this challenge, some studies have explored pretreatment with EZH2 inhibitors, such as tazemetostat, before CAR-T-cell manufacturing to improve T-cell function and subsequently enhance CAR-T efficacy. In the future, if reliable predictive biomarkers can be developed, they will help clinicians make more precise treatment decisions among CAR-T therapy, antibody-drug conjugates (ADCs), and bispecific antibodies.
Expert Profile
Dr. Su Li
Gaobo Shanghai Liquan Hospital
- Deputy Chief Physician, MD; Director of the Department of Hematology and Director of the Myeloma Center at Gaobo Shanghai Liquan Hospital
- Former Attending Physician, Department of Hematology, Shanghai General Hospital, with 10 years of professional experience in the diagnosis and treatment of hematologic diseases
- Member, Hematologic Disease Prevention Professional Committee, Chinese Preventive Medicine Association
- Member, Youth Group, Shanghai Society of Infectious Diseases and Chemotherapy, 2023
- Has published multiple related papers in the Chinese Journal of Hematology and Chinese Journal of Internal Medicine
- Principal investigator of one municipal-level research project
- Areas of expertise: Diagnosis and treatment of common hematologic malignancies, including acute leukemia, multiple myeloma, and lymphoma; extensive clinical experience in comprehensive management throughout the hematopoietic stem cell transplantation process and in the management of pulmonary complications
