A Phase 2 Study of CART-ASCT-CART2 Sandwich Regimen Treatment in Patients with Primary Plasma Cell Leukemia

Background: Primary plasma cell leukemia (pPCL) is the most aggressive plasma cell neoplastic disorder with unfavorable prognosis and no effective treatment. A phase 1 study demonstrated pPCL patients could benefit from BCMA CART [Clin Transl Med. 2021 Mar;11(3): e346]. Additionally, the study of ASCT combined with CART in high-risk newly diagnosed multiple myeloma patients also showed exciting results [Am J Hematol. 2022 May;97(5):537-547.]. Based on these promising results, we initiated a study aimed at deepening patients' remission through CART therapy before transplantation and eliminating MRD via ASCT combined with CART therapy. Here, we assessed the safety and feasibility of CART-ASCT-CART2 sandwich regimen as frontline treatment for newly diagnosed transplant-eligible (TE) pPCL patients in this ongoing phase 2 study (NCT05870917). Notably, it was the first time of ASCT combined with CART in pPCL patients. Methods: This is a single arm, open-label phase II investigator-initiated study. The study enrolled newly diagnosed pPCL patients, aged 18-65 years. Patients were firstly treated with PIs+IMIDs-based induction therapy. The academic anti-BCMA CART was administered as a single infusion after a 3-day lymphodepletion with fludarabine and cyclophosphamide. One month after CART infusion, patients underwent three-course consolidation therapy. Then patients received the second anti-BCMA CART cell infusion after ASCT followed by maintenance until disease progression. Autologous stem cells were infused on day 0, and CART cells were infused on day +3 (±1 day). The target dose for each infusion ranged from 2×106/kg to 4×106/kg. Results: As of July 25, 2024, with the median follow-up time was 405 days (range 154-681), a total of 11 patients have been enrolled. Of those, 4 patients have undergone CART-ASCT-CART2 therapy and are currently in the maintenance phase, 6 patients are in the consolidation phase, and 1 patient has withdrawn from the study due to failure of stem cell collection. The median age of these 10 patients was 49 years (31-65), with an equal distribution of 50% for each sex. The median course of induction therapy was 4 cycles (range 3-7). Six patients achieved a very good partial response (VGPR), and four patients achieved a complete response (CR). At one month post the first CART infusion, 100% of patients achieved VGPR or better, with 80% reaching stringent complete response (sCR). All four patients who underwent the entire sandwich regimen achieved MRD-negative sCR one month after ASCT+CART2 combination therapy. Up to date, the longest duration of remission was 22.4 months. The median time of neutrophil and platelet recovery were 16.5 days (range 12-19 days) and 11 days (range 9-15 days) after ASCT, respectively. 80% (8/10) of the patients experienced CRS after the first CART infusion, among which 4 were grade 1 and 4 were grade 2. No ICANS was found in enrolled patients. CART2 was also well tolerated with all four patients experiencing grade 2 or lower CRS and no ICANS observed. Conclusion: The CART-ASCT-CART2 sandwich regimen showed a very favorable safety profile and high efficacy. These promising preliminary results warrant further assessment of the sandwich regimen for TE pPCL with more patients and longer follow-up.