At GoBroad Shanghai Liquan Hospital, Prof. Su Li shared his valuable clinical experience, research achievements, and forward-looking perspectives in the treatment of multiple myeloma .

Q1. While BCMA-targeted CAR-T therapy has achieved breakthroughs in multiple myeloma, plasmablastic myeloma (PBM), as an aggressive subtype, has long lacked effective treatment options. What is the current status of diagnosis and treatment for PBM patients?

Prof. Su Li: Plasmablastic myeloma is a special subtype of myeloma with unique clinical characteristics. In clinical practice, a small proportion of patients can be diagnosed at disease onset, but the majority are only identified at the relapsed/refractory stage. The overall incidence remains relatively low, though it varies among centers. Our research has shown an incidence of approximately 3%–18%.

In terms of treatment, current outcomes for PBM remain unsatisfactory. Neither traditional chemotherapy nor novel therapeutic strategies have significantly improved remission or long-term survival. Existing clinical data suggest a median overall survival of about 10 months (range 6–12 months) for most patients, underscoring the urgent need for more effective approaches to improve prognosis and break through current clinical limitations.

Q2. How do the outcomes of BCMA CAR-T monotherapy compare with BCMA CAR-T combined with transplantation in PBM patients? What factors are usually considered when formulating a treatment strategy?

Prof. Su Li: The application and progress of CAR-T therapy in PBM must be understood within its biological context and clinical practice. Our earlier studies found that BCMA expression rises significantly in refractory/relapsed myeloma, especially with extramedullary involvement, providing a clear biological basis for BCMA-targeted CAR-T therapy.

Studies comparing single-target versus multi-target CAR-T strategies have shown that single-target approaches often result in early extramedullary relapse. In contrast, dual-target regimens, such as BCMA/CD19 or BCMA/GPRC5d, achieve higher MRD-negativity rates, deeper responses, and more durable remissions compared to BCMA monotherapy.

In clinical practice, CAR-T selection requires a comprehensive assessment of several factors. Pathological testing (immunohistochemistry, bone marrow flow cytometry, etc.) must first confirm antigen expression. For patients with BCMA-only expression, a BCMA/CD19 dual-target CAR-T is preferable. For those co-expressing BCMA and GPRC5d, a BCMA/GPRC5d dual-target approach is recommended. Dual-target regimens are especially advantageous in extramedullary disease, whereas single-target therapy may still be effective in purely intramedullary disease.

Another critical factor is prior CAR-T exposure. With growing adoption, some patients relapse after initial CAR-T therapy, often due to antigen loss or residual CAR-T immunogenicity, leading to diminished efficacy. For relapsed patients, switching to a CAR-T with a different construct is essential to avoid immune interference. Clinical practice has confirmed that such heterologous construct selection yields significant efficacy in short-term relapsed or expansion-failure patients, demonstrating its value in real-world treatment.

Q3. What challenges remain in applying CAR-T therapy more broadly in multiple myeloma, and how might they be overcome to benefit more patients?

Prof. Su Li: As a rare disease, PBM has a low incidence, and large-scale international studies are scarce. CAR-T therapy still faces several challenges:

• Accessibility: High costs and frequent out-of-pocket payment limit widespread adoption. Future innovations in technology or payment models could lower costs, enabling CAR-T to be used earlier rather than only at terminal stages. Our research shows that most patients receive CAR-T late in the disease course, where efficacy is more limited.
• Timing: Treatment line strongly affects outcomes. Later-line patients have weaker immune function, and their harvested T cells are often senescent or functionally impaired, reducing CAR-T manufacturing quality and in vivo expansion. Early T-cell collection, when cells are healthier, could improve outcomes.
• Construct design: Efficacy varies among patients even with the same CAR-T product. Beyond T-cell quality, antigen-binding affinity between CAR-T and tumor cells plays a role. Continued optimization of CAR design to enhance antigen recognition and binding is a key research focus.
• Combination strategies: Sequential or combinatorial approaches are under active investigation, such as CAR-T followed by autologous stem cell transplantation, or maintenance with immunomodulators or PD-1 inhibitors. These strategies may prolong remission and improve survival, and related studies are ongoing.