CAC-MM-001: A B-Cell Maturation Antigen (BCMA)-Directed Chimeric Antigen Receptor T-Cell (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 Ab

Introduction: Multiple myeloma with P53 gene abnormalities is considered a distinct clinicogenomic entities with a poor prognosis. They are often resistant to standard-of-care anti-myeloma drugs and have a early relapse after autologous hematopoietic stem cell transplantation (ASCT). B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR-T) therapy have demonstrated high efficacy and a manageable safety profile, which is expected to address this significant unmet need. This is a single-arm, open-label investigator-initiated trial (NCT05850286) to explore the safety and efficacy of VRD (Bortezomib, Lenalidomide and Dexamethasone)-based regimen combined with CART-ASCT-CART2 in patients with newly diagnosed multiple myeloma with P53 gene abnormalities. Methods: Transplant-eligible patients with P53 gene abnormalities, defined as del(17p) by FISH or P53 mutation by sequencing, were enrolled. After induction with a VRd-based regimen, patients will receive a first infusion of BCMA-directed CAR-T cells following a standard 3-day lymphodepletion (fludarabine and cyclophosphamide). This is followed by 3 cycles of VR-based consolidation therapy. Patients then undergo high-dose melphalan conditioning followed by ASCT on day 1 and a second CAR-T infusion on day 3. R-based maintenance is started after 3 months post-transplant. Results: As of 24 July 2024, 10 patients had completed the first CAR-T infusion, including 4 NDMM patients who completed CART-ASCT-CART2. All patients had del(17p), of which 3 patients carried P53 mutations; median age was 55 years (range 40-60), 6 male, 4 patients with t(4;14), 2 with gain(1q), 8 ISS stage II or III, 3 EMB. The median time from diagnosis to first infusion was 145 days (range 111-280). Of the 8 evaluable patients, 6 (75%) experienced CRS (25% grade 2 and 50% grade 1) and fully recovered. The median time to onset of CRS was 3 days (range 1-7), with a median duration of 5 days (range 3-7). No ICANS event was reported. After the first CAR-T, neutropenia, anaemia and thrombocytopenia were reported in 100% (grade 3/4: 87.5%), 100% (75% grade 2, 25% grade 1) and 62.5% (grade 3/4: 25%) of pts, respectively, and all achieved successful haematological reconstitution with a median time of 18 days for ANC (≥1.5×109/L) and 4 days for PLT (≥100×109/L). Haematological reconstruction was also performed after ASCT in 3 evaluable patients, with a median time of 21 days for ANC (≥1.5×109/L). Median follow-up after first CAR-T infusion was 192 days (range: 56-495 days) for 7 evaluated patients. Responses deepened after first CAR-T was observed 7/7 (100%), including 5 CR + MRD negativity, 1 VGPR, and 1 PR. 3 patients receiving second CAR-T achieved CR + MRD negativity with a median duration of MRD negativity of 328 days (range: 243-344 days). Inclusion: Preliminary results from this trial suggest that CART-ASCT-CART2 has a favourable safety profile in NDMM patients with P53 gene abnormalities. Although the follow-up time is relatively limited, good response has been observed. We expect to see further deepening depth of response and durable MRD negativity with longer follow-up and additional patients.