P58 | Trial in Progress: Quintessential-2 – A Phase 3 Study of Arlocabtagene Autoleucel vs. Standard of Care in Adult Patients With Relapsed and Refractory Multiple Myeloma Exposed to Lenalidomide

Introduction. Despite advances in multiple myeloma (MM) treatment, most patients (pts) will relapse, highlighting the need for new drug classes in relapsed/refractory (RRMM). Further, with the extensive use of lenalidomide (LEN), an immunomodulatory drug (IMiD), in frontline and maintenance therapies, lenalidomide-refractoriness has become increasingly common and poses an additional challenge as the disease is less likely to respond to subsequent treatment. G protein-coupled receptor class C group 5 member D (GPRC5D) is a promising therapeutic target for MM as the receptor is highly expressed on malignant plasma cells; it has little to no expression on non-plasma cell immune populations and limited expression on other tissues. Arlocabtagene autoleucel (arlo-cel) is a GPRC5D-directed autologous chimeric antigen receptor (CAR) T-cell therapy that has demonstrated safety and efficacy in pts with RRMM in a first-in-human phase 1 study. Overall response rate (ORR) was 94% and 91% in pts with 1-3 and ≥3 prior lines of therapy (pLOT), respectively, following a single arlo-cel infusion of 150×106 CAR T-cells; ORR was 92% in pts with ≥3 pLOT following an infusion of 75×106 CAR T-cells. These phase 1 study outcomes support further development of arlo-cel in clinical trials.Methods. QUINTESSENTIAL-2 (NCT06615479) is a randomized, open-label, multicenter, phase 3 confirmatory study comparing the efficacy and safety of arlo-cel versus standard of care (SOC) in adults with RRMM and prior LEN exposure. Key inclusion criteria were age ≥18 years, confirmed diagnosis of MM as per International Myeloma Working Group (IMWG) criteria, 1-3 pLOT (may include a proteasome inhibitor, IMiD, anti-CD38 antibody, and BCMA-targeted therapy), be exposed to lenalidomide (with ≥2 consecutive cycles, unless progressive disease [PD] was the best response to LEN-containing treatment or if there was LEN intolerance or unacceptable toxicity), have measurable disease, and ECOG performance status 0 or 1. Pts who received prior GPRC5D-targeted therapy are excluded. Eligible pts will be randomized 1:1 to two arms. Arm A includes leukapheresis within 3-4 days of randomization, mandatory bridging therapy within 6 days of randomization with DPd (daratumumab, pomalidomide, dexamethasone) or Kd (carfilzomib, dexamethasone) per investigator choice and lymphodepleting chemotherapy prior to a single arlo-cel infusion. Arm B includes SOC of DPd or Kd per investigator choice, dosed per labeling, until PD. Primary endpoints are progression-free survival and minimal residual disease (MRD) negativity in complete response (CR). Key secondary endpoints include overall survival and ORR. Other endpoints include safety, MRD-negative status, CR rate, time to response, duration of response, pharmacokinetics, and pt-reported outcomes. Pts will be followed for ≤5 years after the last pt is randomized, and with a long-term follow-up study (≤15 years post-infusion) for pts receiving arlo-cel. Results. This trial in progress is expected to enroll 440 pts at ~125 sites globally. The first pt was enrolled in March 2025.Conclusion. This phase 3 study will compare the efficacy and safety of arlo-cel vs SOC in adult pts with RRMM after 1-3 pLOT.