General Updates | CAR T-cell therapy in multiple myeloma: highlights from ASH 2025

Hello everybody. Today we talk about post-ASH 2025. Today we focus on CAR-T therapy in multiple myeloma and several presentations by several doctors. The first one is by Dr. Richard. She presents a dual CAR-T targeting CD19 and BCMA for relapsed and refractory multiple myeloma. The total efficacy, the ORR, is 96%, and the CR rate is 78%. Interestingly, for some patients who is BCMA CAR-T exposed, the ORR is 100% and the CR rate is 80%. The median follow-up is 3.9 months, and the median time to first response is 28 days. So, our department is also developing a clinical trial to evaluate dual CAR-T also targeting CD19 and BCMA, so we hope we can show our data recently.

The second presentation is by Dr. Sidana. In this presentation, they evaluated the safety and efficacy of cilta-cel in real-world data, focusing on delayed neurotoxicity and other side effects of CAR T-cell. The Parkinsonism rate is 2.9%. There were 22 patients who developed Parkinson disease. This is a severe delayed neurotoxicity post CAR-T therapy. They also evaluated what kind of predictors for the risk of Parkinsonism. They found that the ALC threshold is a risk factor for Parkinsonism. If the ALC is increased to more than 3,000 or 2,500 cells per microliter, the Parkinsonism risk will be increases dramatically compared with others whose ALC is less than 2,500-3,000 cells per microliter. Also, for CAR-T therapy, including CD19-targeted CAR-T therapy in large B-cell lymphoma and BCMA-targeted CAR T-cell in multiple myeloma, the bridging therapy is not necessary or not is debated. We also do not recommend that patients necessarily receive bridging therapy before CAR-T therapy. However, in this presentation, they found that response to bridging therapy is associated with the risk of Parkinsonism. In the multivariable analysis, if patients achieved a partial response (PR) to bridging therapy, there is a lower risk of developing Parkinsonism after CAR-T therapy. This is a very interesting result that helps us evaluate whether these kinds of patients are at risk of developing Parkinsonism and non-relapse mortality. Also, the bridging therapy and peak ALC were the two independently identified risk factors for evaluating whether patients are at risk of developing Parkinsonism and non-relapse mortality after cilta-cel. This is an interesting presentation.

Another presentation was by Professor Hansen, Dr. Hansen, evaluating whether high-risk myeloma could influence the outcome of CAR-T therapy. They evaluated many definitions of high-risk using the IMWG high-risk definition. They also focused more than one high-risk factor, including 1q gain or amplification, 1p deletion, and translocation of IGH. They found that also for these patients receiving CAR-T therapy, for the 12-month PFS, for the high-risk patients will have a shorter PFS compared with those patients without high-risk disease. This indicates that although patients can respond to CAR-T therapy, the high-risk disease may still have shorter PFS compared with patients without high-risk factors. They also detected the MRD status and the relationship between high-risk factors and MRD status. They found that patients with more than one high-risk factor had lower MRD-negative response rates, and this could also affect the 12-month PFS rate. Also, if these patients have more than one high-risk factor, these patients will have a shorter PFS and shorter overall survival. The p-values were all below 0.05. They performed multivariable analyses for PFS and for relapse within 18 months. They found that high-risk factors were independently associated with PFS after adjusting for ferritin, previous BCMA therapy, and ECOG performance status greater than 2. Also, for patients who relapse within 18 months, IMWG high-risk status was also an independent relapse risk factor. However, extramedullary disease (EMD) was not a risk factor for patients who relapse within 15 months. Also, in the Cox model analysis, for the high-risk factors associated with inferior PFS within 15 months, this shows that functional high-risk and IMWG high-risk associated with relapse within 15 months, but not with PFS beyond 15 months. This indicates that high-risk patients have a greater risk of relapse within 15 months compared with patients without high-risk factors. Also the EMD PFS is similar in both time periods, the EMD was also isolated as a factor affecting response to CAR-T therapy. This conclusion that high-risk patients could have a lower PFS, lower response rates, and shorter survival after cilta-cel. We think that after CAR-T therapy, we may need more consolidation therapy or combination with other strategies, such as bispecific antibodies or immunomodulatory drugs, to improve MRD-negative rates in the high-risk patients. Maybe this could help improve survival in high-risk patients after CAR-T therapy.

Dr. Mian also provided some efficacy analysis of CAR-T therapy comparing frail and non-frail cohorts. This showed that the PFS and OS in the frail cohort was inferior compared with the non-frail cohort. This means that prolonged cytopenia was more prevalent in the frail cohort compared with the non-frail cohort, but infection rates were balanced, so prolonged cytopenia could be preferred in the frail cohort. Also, in the multivariable analysis, the overall response rate and CR rate were comparable between the frail and non-frail cohort. This means that the efficacy of CAR-T was not affected by frailty. However, the PFS and OS, especially all-grade ICANS, were affected by frailty. This suggests that frailty status could affect PFS, OS, and the all-grade ICANS. For frail patients, we should pay attention to prolonged cytopenia and all-grade ICANS. If we can better manage these side effects, we may be able to improve PFS and OS in this group of frail patients. This presentation highlights the supportive therapy for frail patients who accepted CAR-T therapy. This is a very interesting and valuable result for helping us manage patients undergoing CAR-T therapy. That’s all.