BCMA CAR T-cell therapy in newly diagnosed primary plasma cell leukemia ineligible for transplantation: An open label, single-arm, phase 2 study (CAREMM-002)

Abstract Background: Primary plasma cell leukemia (PPCL) is the most aggressive subtype of plasma cell neoplasms. Following the recent revision of diagnostic criteria by IMWG, the incidence of PPCL had approximately doubled. Despite this, prognosis remains extremely poor-particularly in patients ineligible for transplantation-with median overall survival often less than 2 years. BCMA-directed CAR-T cell therapies have demonstrated deep and durable responses in relapsed/refractory multiple myeloma. However, due to its aggressive biology and rarity, PPCL has been consistently excluded from clinical trials, leaving a significant therapeutic gap. Thus, we initiated CAREMM-002 (NCT05979363), a prospective, single-arm phase 2 trial to evaluate the efficacy and safety of BCMA CAR-T therapy in frontline setting for transplant-ineligible PPCL patients. Methods: This single-arm, phase 2 investigator-initiated study enrolled PPCL patients deemed ineligible for ASCT due to age, frailty, comorbidities, or repeated failure of stem cell mobilization. After 3–4 cycles of VRd-based induction treatment, patients received lymphodepletion and a single infusion of BCMA CAR-T cells (3×10⁶ cells/kg), followed by consolidation and lenalidomide maintenance. Primary endpoints were safety and MRD negativity following infusion. Secondary endpoints included complete response rate (CRR), PFS, OS, and duration of remission (DOR). Results: As of May 10, 2025, nine patients were enrolled, with a median age of 68 years (range, 54-72) and 66.7% female. Eight patients completed BCMA CAR-T infusion, seven are currently in the maintenance phase, one remains in consolidation, and one is still undergoing induction. Among the infused patients, the overall response rate (ORR) was 100%, with 87.5% achieving stringent complete response (sCR). All patients achieved MRD negativity by next-generation flow cytometry (NGF), which was sustained through the most recent follow-up. At a median follow-up of 15.4 months, no relapses or deaths have been observed. The longest documented duration of remission is 26.7 months. Median PFS, OS, and DOR were not reached. Treatment was well tolerated and showed a favorable safety profile. The most common AEs were hematologic and attributed to lymphodepletion, including grade ≥3 leukopenia (87.5%), neutropenia (62.5%), anemia (37.5%), thrombocytopenia (25.0%), and lymphopenia (100%). CRS occurred in 62.5% (all grade 1–2), with a median onset of 1 days and duration of 4 days. No cases of immune effector cell-associated neurotoxicity syndrome (ICANS) were observed. All patients exhibited robust peripheral expansion. Median Cmax was 65,770 copies/μg gDNA (range, 29,579–147,410), median time to reach peak expansion was 13 days, and AUC0–28 was 430,767 (range, 356,153–2,110,005). Conclusion: Frontline BCMA CAR-T therapy demonstrated unprecedented depth and durability of response with manageable safety in transplant-ineligible PPCL patients-a population with historically dismal outcomes and limited therapeutic options.