Paper Details

ABSTRACT

Introduction: The treatment landscape of newly diagnosed multiple myeloma (NDMM) has evolved substantially with the incorporation of quadruplet-based therapies which have become the standard of care regardless of transplant eligibility. However, unmet needs remain. In transplant-eligible (TE) NDMM, highly effective T-cell redirecting therapies may challenge the role of autologous stem cell transplantation (ASCT), while in transplant-ineligible (TIE) NDMM, the need for continuous therapy remains a major limitation. Anitocabtagene autoleucel (anito-cel) is a BCMA-directed CAR-T cell therapy incorporating a novel D-domain binder that has demonstrated deep and durable responses with a favorable safety profile in relapsed/refractory MM. GEM-AnitoFIRST is an investigator-initiated phase 2 study evaluating the feasibility, safety, and efficacy of anito-cel after induction therapy in TE and TIE NDMM.

Patients and Methods: Thirty patients were planned to receive anito-cel across three cohorts. Cohort A (TE) received six 28-day cycles of daratumumab-bortezomib-lenalidomide-dexamethasone (D-VRd), with leukapheresis after cycle 3, followed by fludarabine/cyclophosphamide lymphodepletion and infusion of anito-cel (target dose 115×10^6 CAR+ viable T cells). Cohorts B and C (TIE or transplant non-intended) received four 42-day cycles of isatuximab-VRd (Isa-VRd), with leukapheresis after cycle 2, followed by lymphodepletion and anito-cel infusion. Lenalidomide maintenance for up to 2 years is planned in cohorts A and B. The primary endpoints are safety and MRD-negative complete response (CR) rate (10^-5) at 12 months (±3 months) after anito-cel infusion.  Here we report efficacy outcomes following induction and after anito-cel infusion. Safety, response, and MRD negativity were assessed at Day +30 and Day +60 after anito-cel in evaluable patients.

Results: Between July 2025 and January 2026, 36 patients were enrolled (12 per cohort to ensure 30 infused patients). Baseline characteristics were balanced across cohorts except for age, with a median age of 59 years (range, 38–69) in cohort A and 69 years (range, 50–79) in cohorts B/C. Overall, 69% of patients had ECOG 0, 17% had R-ISS stage III disease, and 22% were classified as high-risk according to the 2025 CGS system (partial application). Paraskeletal plasmacytomas were present in 4% of patients and no patient had extramedullary disease.

All patients completed the induction. The ORR in cohort A following induction was 92%, including 17% ≥CR, with an MRD-negative 10^-6 rate of 33%. In cohorts B/C, ORR was 100%, including 29% ≥CR, with an MRD-negative rate 10^-6 of 25%. 

Leukapheresis was performed in all but one patient who relapsed during induction; manufacturing was successful in all products. One patient has not yet been infused.

Overall, responses after anito-cel infusion were consistent across the three cohorts. Despite a median follow-up of 2.5 months after anito-cel infusion (range, 0.3–5.0), responses deepened over time. At Day +30, 18 patients were evaluable for response; 50% achieved an sCR and 45% achieved a VGPR. At Day +60, 14 patients were evaluable, with 71% achieving an sCR and the remaining 29% a VGPR. Across evaluable patients, 100% achieved MRD negativity at a sensitivity of 10?6.

The safety profile during induction was consistent with the known safety profile of frontline quadruplets, with no treatment-related discontinuations or deaths. CRS occurred in 16 patients (50%), predominantly grade 1 (15/16, 94%), with only one grade 2 event. Median time to CRS onset was 3 days (range, 0–7) and median duration was 0.5 days (range, 0–4). All CRS events resolved with tocilizumab plus dexamethasone according to the protocol. No ICANS events were reported. Grade 3–4 neutropenia occurred in 42% of patients, grade 3 anemia in 3%, and grade 3 infections in 6%; no grade 3–4 thrombocytopenia was observed. No early discontinuations due to toxicity have been reported.

Conclusion: In this first frontline experience with anito-cel in NDMM, treatment was feasible, with successful leukapheresis and manufacturing in all enrolled patients, and was associated with a favorable safety profile characterized by predominantly low-grade CRS and no ICANS. Despite the short follow-up, anito-cel induced rapid deepening of responses, with all evaluable patients achieving MRD negativity by Day +60. Updated efficacy and safety data will be presented at the meeting.