5-Year Follow-up of Combined Infusion of Anti-CD19 and Anti-BCMA CAR-T after ASCT for High-Risk Newly Diagnosed Multiple Myeloma

Background: The high-risk multiple myeloma (MM) exhibits a highly aggressive course characterized by rapid relapse and early progression to refractory disease state. Either anti-CD19 or anti-B-cell maturation antigen (BCMA) chimeric antigen receptors (CAR) T cells could improve clinical response for relapsed/refractory MM. Our preliminary study showed that anti-CD19 and anti-BCMA CAR-T cell therapy followed by lenalidomide maintenance after ASCT yielded encouraging activity for high-risk NDMM. Nevertheless, the long-term safety and efficacy requires further evaluation. Therefore, we reported the long-term follow-up results of this study (NCT 03455972).

Methods: In this study, high-risk MM was defined as having extramedullary disease, and/or at least one of the following high-risk chromosomal abnormalities [1q21+, del(17p), t(4;14), t(14;16), and t(14;20)], and/or R-ISS stage III at diagnosis. Patients received anti-CD19 (1×10⁷/kg) and anti-BCMA (5×10⁷/kg) CAR-T cells infusion after ASCT. Lenalidomide (10 mg/d) was given as the maintenance therapy. The anti-CD19 lentiviral vector encoded an anti-CD19 single-chain variable fragment (ScFv) linked to 4-1BB and CD3ζ signaling domains, and IL6 shRNA. The anti-BCMA lentiviral vector encoded an anti-BCMA ScFv linked to CD28, OX40, and CD3ζ signaling domains.

Results: 43 patients were enrolled in this study. One patient died of rapid progression before ASCT, and the preparation of CAR-T cells failed in 3 patients. 39 patients underwent ASCT. One patient did not receive CAR-T infusion due to prolonged hematopoietic reconstitution (one month) after ASCT, and another one withdrew the informed consent form during treatment. The remaining 37 patients received this therapy. With the median follow-up of 63.4 (range: 19.2-83.3) months, the overall response rate was 100%, 100% VGPR or better，92.1% CR or better (89.2% sCR, 2.7% CR). MRD negativity was 94.6% at 10^-5 level. Moreover, 59.5% patients achieved sustained MRD negativity for over than 3 years. The median PFS and OS of all patients were not reached. The 60-month PFS rate and OS rate were 59.2% and 85.3% respectively. The median PFS and OS of patients with ≥ 2 HRCAs were not reached while the 60-month PFS rate was 59.7%. All the CRS were low-grade and no ICANS occurred. There were no treatment-related mortalities. Other adverse events were manageable and reversible. All adverse events recovered to ≤ grade 1 within three months. We evaluated the EORTC QLQ-C30 from 34 patients to evaluate the quality of life (QoL) and found the QoL of these patients was significantly improved one year after ASCT+CAR-T.

Among these 37 patients, the CAR-T cells could persist in the blood for median 25 (range 12 to 69) months. The median peak expansion level of CAR-T cells was 120132.54 (2236.28~2281538.55) copies/μg DNA, and the median time to reach the corresponding peak level was day 8 (6~16) after infusion. We found significant decrease in circulating B lymphocytes from 4.05 cells/μL (95% CI: 4.48-12.98) (after ASCT) to 0.41 cells/μL (95% CI: 0.40-4.27) by day 9 post-CAR-T infusion (P<0.05). At 100 days post ASCT+CART, B lymphocytes gradualy recovered to initial diagnosis levels, without B lymphocyte dysplasia (P>0.05). CAR-T Cell reactivation was observed in a subset of patients following MRD negativity changing to positivity. These results demonstrate the efficacy, safety, and long-term benefits of the combined ASCT and dual-target CAR-T cell therapy approach in high-risk NDMM patients, with promising survival outcomes and manageable toxicity profiles.

Conclusions: To the best of our knowledge, this is the first clinical trial to incorporate anti-BCMA and anti-CD19 CAR-T cells as consolidation therapy for high-risk NDMM patients. Our long-term follow-up, extending beyond five years, demonstrates that this approach yields a favorable prognosis and improved QoL for these patients. Importantly, the treatment exhibited a satisfactory safety profile with manageable adverse events throughout the extended follow-up period.

This novel therapeutic strategy shows promise in addressing the unmet needs of high-risk NDMM patients, potentially offering a new direction in the management of this challenging subgroup of multiple myeloma. Further studies are warranted to confirm these encouraging results and to fully elucidate the role of dual-target CAR-T cell therapy in the treatment paradigm for high-risk NDMM.