BCMA CAR-T Therapy As First-Line Consolidation Treatment in Transplant-Ineligible Patients with Newly-Diagnosed Multiple Myeloma: An Open Label, Single-Arm, Phase 2 Study (CAREMM-001)

Background: BCMA CAR-T therapy had revolutionized the treatment paradigm of relapsed or refractory multiple myeloma (MM), demonstrating profound and sustained responses with an acceptable safety profile. The potential for earlier application of CAR-T in MM is currently under investigation. Here, we report the efficacy and safety data of BCMA CAR-T therapy in a frontline setting for transplant-ineligible patients with newly-diagnosed multiple myeloma in CAREMM-001 study (NCT05860036). Methods: CAREMM-001, an open-label, phase 2, single-arm study, included NDMM patients who were evaluated not eligible for autologous stem cell transplant or experienced multiple failures of stem cell mobilization. Patients would receive three cycles of induction therapy prior to infusion. Subsequent to the first to third cycle of induction therapy, these patients underwent T cell collection via leukapheresis for CAR-T cell manufacture. Following lymphodepletion with fludarabine-cyclophosphamide, patients received a single infusion at the dose of 3×106 BCMA CAR-T cells/Kg. Subsequently, patients underwent another three cycles of bortezomib-lenalidomide treatment and lenalidomide maintenance therapy. The primary efficacy endpoint was defined as the proportion of patients achieving minimal residual disease (MRD) negativity (MRD-, sensitivity <10-5) rate before maintenance therapy and progression-free survival (PFS). Results: As of July 20, 2024, 20 patients (65.0% male; median age 69 years [range, 51,73]) received BCMA CAR-T infusion, with a median follow-up period of 12.7 months (range, 5.7-24.5). Five patients were enrolled due to multiple failures of stem cell mobilization, while the remaining patients were deemed ineligible for transplantation on the evaluation of age, comorbidity, and organ function by investigators. 41.2% of patients exhibited high-risk cytogenetics, while 30% were classified as R-ISS stage III. Two patients had extramedullary disease. With median follow-up period of 7.1 months after BCMA CAR-T infusion, all patients achieved MRD negativity. The overall response rate (ORR) was observed as 100%, and 95% of patient attained very good partial response (VGPR) or better, with 75% of patients achieving stringent complete response (sCR). Of note, 61.5% (8/13) patients exhibited an improvement in their response depth and 100% (10/10) converted to MRD-negative status following the administration of BCMA CAR-T infusion. Among 14 patients with sufficient follow-up, all achieved sustained MRD negativity over 6 months, while 3 patients demonstrated sustained MRD negativity over 12 months. The median duration of remission (DOR) and median progression-free survival (PFS) were not reached. Thus far, no patient has experienced MRD recurrence or disease progression. Cytokine release syndrome (CRS) was observed in 15 patients (75%), with 50% grade 1 (n=10) and 25% grade 2 (n=5), respectively. Only two patients experienced grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) events. No treatment-related grade ≥3 CRS/ICANS event was observed. Early immune effector cell-associated hematotoxicity (ICAHT) events were observed in 11 patients (55%), with 45% exhibiting grade 1(n=9), 5% grade 2 (n=1), and 5% grade 3 (n=1), respectively. Late ICAHT events were observed in 7 patients (35%), with 5% grade 1 (n=1), 25% grade 2 (n=5), and 5% grade 3 (n=1), respectively. Robust CAR T-cell expansion occurred in all patients with a median time of 10 days (range 7-14) days, and peak copy number of 67032 copies /μg DNA. Conclusion: BCMA CAR-T notably improved the response depth and effectively cleared detectable MRD in transplant-ineligible patient with NDMM. Lower incidence and severity of CRS and hematological toxicities demonstrated a more favorable safety profile of BCMA CAR-T in first-line than that in later-line treatment. These results support a favorable clinical benefit-risk profile of BCMA CAR-T as frontline treatment for transplant-ineligible NDMM patients.