(PA-105) CART–ASCT–CART2 Sandwich Regimen as Frontline Therapy: A Phase II Trial in Patients with Primary Plasma Cell Leukemia

Primary plasma cell leukemia (pPCL) is the most aggressive form of plasma cell neoplasm, associated with poor prognosis and lacking effective treatment options. Previous studies have  demonstrated that pPCL patients may benefit from BCMA CAR T-cell therapy, and promising results have also been reported with the combination of ASCT with CAR T-cell therapy in HRNDMM. Based on these findings, we initiated an ongoing phase II trial (NCT05870917) to evaluate the sequential CART–ASCT–CART2 (CAC) sandwich regimen as frontline therapy for newly diagnosed, transplant-eligible (TE) pPCL patients. This approach aims to deepen remission with pre-transplant CAR T therapy and eradicate MRD through post-ASCT consolidation. Notably, this is the first study to combine ASCT with CAR T therapy in pPCL.

Methods:

This is a single-arm, open-label, phase II investigator-initiated trial enrolling transplant-eligible NDpPCL patients. All patients first receive PI+IMID-based induction therapy, followed by a single infusion of anti-BCMA CAR T-cells after 3-day lymphodepletion with fludarabine and cyclophosphamide. One month post-CAR T infusion, patients undergo three cycles of consolidation therapy followed by ASCT. On day +3 (±1) post-ASCT, a second CAR T infusion (CART2) is administered. Maintenance therapy continues until progression. Autologous stem cells are infused on day 0, and the target CAR T-cell dose for each infusion ranged from 2 × 10^6/kg to 4 × 10^6/kg.

Results:

As of April 20, 2025, with the median follow-up time was 12.5 months (range 6.2-25.7), a total of 20 patients have been enrolled. The median age of these patients is 53 years (range 31-66). 11 patients completed CAC therapy and are currently in the maintenance phase and 7 patients are in the consolidation phase after the first CART.

The current median follow-up from the first CAR T-cell infusion is 6.7 months (range 0.2–13.0). Following the first CAR T-cell infusion, 80% of patients achieved CR or better, and 90% achieved MRD negativity. Among 11 patients who completed CAC regimen, all achieved sCR, with only one case of MRD re-positivity occurring 3 months after the initial CAR T-cell infusion. No cases of relapse, disease progression, or death have been observed among these patients to date. The median time of neutrophil and platelet recovery were 15 days (range 11–23) and 12 days (range 9–17) after ASCT, respectively.

Excluding two patients who died of adenovirus infection following the first CAR T-cell infusion, no severe CRS ( >grade 2) were reported among the remaining patients. And no cases of ICANS were observed in any of the enrolled patients. The CART2 was also well tolerated, with no ICANS reported.

Conclusions:

The CART–ASCT–CART2 sandwich regimen demonstrated a favorable safety profile and encouraging efficacy in newly diagnosed, transplant-eligible patients with primary plasma cell leukemia (pPCL).These encouraging results warrant confirmation in a larger cohort to assess durability and long-term outcomes.