Bird Regimen Followed By Anti-BCMA CAR T-Cell Immunotherapy As First-Line Therapy for Newly Diagnosed Multiple Myeloma: A Prospective, Single-Arm, Phase 3 Trial

Introduction Multiple myeloma (MM) remains incurable despite numerous advances in novel target drugs. Early remission, such as MRD negativity is considered to be strongly associated with better prognosis. According to previous literature, the incidence of peripheral neuropathy (PN) related to bortezomib was approximately 40%, and even up to 70% in patients treated with thalidomide, which adversely impacted quality of life (QoL) for the patients. The BiRD regimen (clarithromycin, lenalidomide and dexamethasone) was evaluated for NDMM (newly diagnosed MM) patients in 2008, which demonstrated good efficacy and tolerance without neurotoxicity. BCMA (B-cell maturation antigen) CAR T-cell therapy exerted profound efficacy in heavily pretreated RRMM (refractory or relapsed MM) patients. However, few studies have used BCMA CAR T-cell as first-line therapy for NDMM. In this study, to minimize side effects of chemotherapy, achieve sCR early and improve the OS,PFS and also QoL of NDMM patients, BiRD regimen was used as induction therapy to reduce the tumor burden, followed by BCMA CAR T-cell therapy as first-line therapy, and whether to perform ASCT is according to the patients' wills. Methods Twenty NDMM patients were enrolled from October 2017 to November 2023 at the First Affiliated Hospital of Soochow University. The final date of follow-up was June 1st, 2024 for patients without events. All patients received BiRD regimen for a median of 2 cycles. After objective response (PR or better) was achieved, patients received BCMA CAR-T cell infusion at a median dose of 2.0×107/kg. All patients underwent lymphodepleting chemotherapy prior to infusion. BCMA CAR T-cells were infused as three divided infusions at escalating doses: 4.0×106/kg on day 0, 6.0×106/kg on day 1 and 1.0×107/kg on day2. The primary endpoints were ORR after induction treatment and MRD-negativity after BCMA CAR T-cell. Secondary endpoints were adverse events (AEs) ，QoL and survival. Results The median age of the patients was 60 years old (range: 43-69). Five patients were in R-ISS stage I, ten patients in stage II and five patients in stage III. Nine patients were classified as high-risk according to mSMART 3.0, among which five patients(5/9, 55.6%) were double-hit. After 2 cycles of BiRD regimen, the ORR was 100%: 5 (25%) patients achieved partial response (PR), 13 (65%) patients achieved very good PR (VGPR), and 2 (10%) patients achieved complete response (CR). After BCMA CAR-T cell infusion, 85% (17/20) of the patients achieved stringent CR (sCR), the other 15% (3/20) patients achieved VGPR, and 16 (80%) patients achieved MRD-negativity. To date, fourteen patients underwent ASCT and three patients did not receive ASCT according to their wills, the other three patients have just finished BCMA CART. With a median follow up of 25 months (range: 5.8-80.1), one patient relapsed (18 months after ASCT) and two patients died of infection, one was severe pulmonary infection (51 months after ASCT) and the other one was dead of COVID-19 (33 months after ASCT) . The estimated 3-year OS and PFS were both 100%, and the estimated 5-year OS and PFS were 57.14% ± 24.94% and 55.56% ± 24.85%, respectively. The estimated 3-year and 5-year CIR were both 9.09% ± 8.67%. The median OS, PFS and DOR were not yet reached. There was no significant difference between the high-risk and standard-risk subgroups regarding OS and PFS. After the BiRD regimen, 3 patient suffered thromboembolic events, 1 patient had pulmonary infection, and 1 patient had significant fatigue,which were all successfully resolved. No neurotoxic adverse events were reported in all patients. After CAR T-cell infusion, 95% (19/20) of the patients suffered grade 1-2 cytokine release syndrome (CRS) and no patient had grade 3 or more severe CRS. No ICANS was observed. The incidence of III-IV grade of neutropenia, anemia and thrombocytopenia was 85%, 35% and 50%, respectively. All adverse events recovered. Moreover, an improvement of most QoL domains of the QLQ-C30 and QLQ-MY20 was observed from baseline to the period after BCMA CAR T cell, especially pain and disease symptom. Conclusion This study firstly demonstrates that BiRD regimen followed by anti-BCMA CAR T-cell therapy can induce deep and early remission for NDMM patients with good tolerance even for high risk patients, providing a novel front-line treatment option for NDMM.