CAC-MM-001: Anti-BCMA CAR-T therapy followed by autologous stem cell transplantation and second CAR-T (CART-ASCT-CART2) in newly diagnosed multiple myeloma patients with P53 gene abnormalities.

Abstract Introduction: Despite notable advancements in treatments that have improved overall survival, patients with multiple myeloma (MM) harboring TP53 gene abnormalities continue to face poor prognoses. To address this urgent clinical need, we developed a globally pioneering strategy—CART–ASCT–CART2. This strategy is designed to induce a deep remission with the first BCMA-targeted CAR-T infusion, thereby improving response depth prior to transplantation. Following autologous stem cell transplantation (ASCT), a second infusion of BCMA-targeted CAR-T cells is infused, aiming to modulate the tumor microenvironment and eradicate residual malignant plasma cells. CAC-MM-001 (NCT05850286) is the first clinical trial to evaluate this CART–ASCT–CART2 strategy in newly diagnosed MM patients with TP53 abnormalities. The study was approved by the institutional ethics committee, and written informed consent was obtained from all patients in accordance with the Declaration of Helsinki. Methods: Transplant-eligible NDMM patients with TP53 abnormalities, defined as del(17p) by FISH or TP53 mutation by sequencing, were enrolled. After induction therapy, patients underwent standard lymphodepletion with fludarabine (30 mg/m²/day) and cyclophosphamide (300 mg/m²/day) on days -5 to -3, followed by the first infusion of BCMA-targeted CAR-T cells. Patients then received three cycles of consolidation therapy. Conditioning with high-dose melphalan (200 mg/m²/day on days -3 and -2) was administered prior to ASCT on day 0. A second CAR-T infusion (CAR-T2) was given on day 3 (±1). Maintenance therapy was initiated three months post-transplant. Results: As of July 31, 2025, 14 patients had completed the full CAR-T–ASCT–CAR-T2 regimen. Thirteen patients had del(17p), including 3 with concurrent TP53 mutations; the remaining patient had TP53 mutations only. The median age was 57.5 years (range, 40–65), with 8 males. Six patients had t(4;14), 5 had gain(1q), 4 were ISS stage III, and 4 had bone-related extramedullary disease. The median time from diagnosis to first CAR-T infusion was 171.5 days (range, 111–280). After the first CAR-T infusion, cytokine release syndrome (CRS) occurred in 57.1% (8/14) of patients (14.3% grade 2; 42.9% grade 1), all of whom recovered fully. Corticosteroids were administered to 6 patients and tocilizumab to 2. The median time to CRS onset was 3 days (range, 1–7), with a median duration of 3 days (range, 2–7). Hematologic toxicities included neutropenia in 100% (71.4% grade 3/4), anemia in 64.3% (7.1% grade 3), and thrombocytopenia in 35.7% (7.1% grade 4). All patients achieved hematologic recovery, with a median time to ANC ≥1.5×10⁹/L of 10.5 days (range, 4–57) and to PLT ≥100×10⁹/L of 4 days (range, 2–44). Following ASCT and CAR-T2, CRS occurred in 35.7% (5/14) of patients (14.3% grade 2; 21.4% grade 1). Two patients received corticosteroids and one received tocilizumab. No cases of immune effector cell-associated neurotoxicity syndrome (ICANS) were observed after either CAR-T infusion. After ASCT, median times to hematologic recovery were 17 days (range, 12–28) for ANC ≥0.5×10⁹/L and 13 days (range, 8–50) for PLT ≥20×10⁹/L. Two patients received stem cell boosts due to delayed engraftment. No treatment-related deaths occurred. At a median follow-up of 272 days (range, 160–724) from the first CAR-T infusion, all 14 patients achieved complete response (CR) with undetectable minimal residual disease at a sensitivity threshold of 1×10-6. The median duration of MRD negativity was 227 days (range, 64–523). Two patients relapsed after maintaining undetectable MRD for 12.0 and 15.7 months, respectively. Both two patients harbored biallelic TP53 inactivation. Inclusion: The available data indicate that CART–ASCT–CART2 demonstrates a favorable safety profile in newly diagnosed MM patients with TP53 gene abnormalities. Although follow-up is still ongoing, high rates of complete response (CR) and MRD negativity have been observed. However, patients with biallelic inactivation of the TP53 gene appear to remain vulnerable to early relapse, highlighting the urgent need for novel therapeutic strategies.