BCMA CAR T-cell therapy in newly diagnosed transplant-ineligible multiple myeloma: An open label, single-arm, phase 2 study (CAREMM-001)

Abstract

Abstract Background: BCMA-directed CAR-T cell therapies have demonstrated deep and durable responses in relapsed/refractory multiple myeloma, including in elder and frail patients. However, prospective data in transplant-ineligible (TIE) newly diagnosed multiple myeloma (NDMM) patients are lacking. Here, we report the efficacy and safety data of BCMA CAR-T therapy in frontline setting for transplant-ineligible NDMM patients in CAREMM-001 study (NCT05860036). Methods: This single-arm, phase 2 trial enrolled NDMM patients deemed ineligible for ASCT due to age, frailty, comorbidities, or repeated failure of stem cell mobilization. After 3–4 cycles of VRd-based induction treatment, patients received lymphodepletion and a single infusion of academic BCMA CAR-T cells (3×10⁶ cells/kg), followed by consolidation and lenalidomide maintenance. Primary endpoints were safety and MRD negativity following infusion. Secondary endpoints included complete response rate, PFS, OS, and duration of remission (DOR). Results: Between April 2023 and December 2024, forty patients were enrolled, with a median age of 68 years (range, 46-75). High-risk characteristics were prevalent: 45% were ISS III, and 38.5% met criteria for ultra-high-risk, defined by extramedullary disease, circulating plasma cells ≥2%, or double-hit cytogenetics. All patients underwent apheresis within induction period, but four patients withdrew due to severe infection (n=2) and renal dysfunction (n=2). Finally, 36 patients received standard lymphodepleting and infusion. At a median follow-up of 12.8 months, all infused patients achieved MRD negativity at day 28 post-infusion and sustained through last follow-up. The overall response rate (ORR) was 100%, with 88.9% achieving sCR. Among 23 patients with enough follow-up, all demonstrated sustained MRD negativity for ≥12 months. No relapses have occurred to date; median PFS, OS, and DOR were not reached. The most common AEs were hematological that were thought to be associated with the lymphodepletion, with grade ≥3 neutropenia (88.9%) and lymphopenia (100%). Early ICAHT occurred in 52.8%, with only 2 grade 3; late ICAHT occurred in 37.5% of patients, and only one grade 3. Hypogammaglobulinemia occurred in 44.4% of patients, most recovered with reduced supportive IVIG frequency. Infections occurred in 31.2% (≥3 grade in 18.8%), most commonly respiratory. CRS occurred in 52.8% (all grade 1–2), with a median onset of 2 days and duration of 3 days. Two patients had grade 1 ICANs. All patients exhibited robust peripheral expansion. Median Cmax was 56,742 copies/μg gDNA (range, 6,627–235,215), median time to reach peak expansion was 11 days, and AUC0–28 was 605,180 (range, 57,001–2,828,539). Conclusion: Frontline BCMA CAR-T therapy induced deep and durable responses with a favorable safety profile in TIE NDMM patients, including those with ultra-high-risk features. These results support its potential as a transformative first-line option for transplant-ineligible myeloma.