CART–ASCT–CART2 sandwich regimen as frontline therapy: A phase II trial in patients with primary plasma cell leukemia

Abstract Background: Primary plasma cell leukemia (pPCL) is the most aggressive form of plasma cell malignancy with poor prognosis and lacking effective treatment options. Previous studies have shown 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 high-risk NDMM. 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 through pre-transplant CAR T therapy and eradicate MRD through post-ASCT CAR T 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 received PI+IMID-based induction therapy, followed by a single infusion of academic anti-BCMA CAR T-cells after 3-day lymphodepletion with fludarabine and cyclophosphamide. One month after the CAR T infusion, patients underwent three cycles of consolidation therapy and subsequently ASCT. On day +3 (±1) post-ASCT, a second CAR T infusion (CART2) was administered. Maintenance therapy continued until progression. ASCT was administered on day 0, and the target CAR T-cell dose for each infusion ranged from 2 × 10⁶/kg to 4 × 10⁶/kg. Results: As of June 30, 2025, a total of 21 patients had been enrolled. The median age at enrollment was 54 years, and the cohort include 12 males and 9 females. Among them, 20 patients received the first CAR T-cell infusion, but two patients withdrew from the study after the first CAR T-cell infusion due to poor physical condition. Of the remaining 18 patients, 14 completed the CAC regimen and 11 have entered the maintenance phase. The median follow-up from the first CAR T-cell infusion was 8.0 months (range, 1.0–26.7). Following the first CAR T-cell infusion, 95% (19/20) of patients achieved NGF-MRD negativity. Among the 14 patients who completed the second CAR T-cell infusion, 13 were evaluable for efficacy; all achieved sCR, with one case of MRD re-positivity observed 3 months after the initial infusion. No cases of relapse and disease progression have been observed to date. The treatment was well tolerated. Among patients who received CAR-T infusion, the most common adverse events were hematologic toxicities (100%), mainly related to the lymphodepletion. Excluding two patients who died of adenovirus infection after the first CAR T-cell infusion, no severe CRS was observed among the remaining patients, and no cases of ICANS were reported in the entire cohort. The second CAR T-cell infusion was also well tolerated, with no ICANS observed. Conclusion: 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. These encouraging results merit validation in larger studies to determine durability and long-term outcomes.