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therapy and are currently in the maintenance phase, 6 patients are in the consolidation phase, and 1 patient has withdrawn from the study due to failure of stem cell collection.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.