QUINTESSENTIAL-2: A phase 3 study of arlocabtagene autoleucel versus standard of care in adult patients with relapsed and refractory multiple myeloma (RRMM) exposed to lenalidomide.

TPS7577 Background: Despite advances in multiple myeloma (MM) treatment, most patients (pts) will relapse, highlighting the need for new drug classes in RRMM. Further, with the extensive use of lenalidomide (LEN), an immunomodulatory drug (IMiD), in frontline and maintenance therapies, LEN-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 CAR T cell therapy that has demonstrated safety and efficacy in pts with RRMM in a first-in-human phase 1 study. ORR was 94% and 91% in pts with 1-3 and ≥3 prior LOT (pLOT), respectively, after a single arlo-cel infusion (150×10 6 CAR T-cells); ORR was 92% in pts with ≥3 pLOT following a 75×10 6 CAR T cell infusion. These phase 1 study outcomes support further clinical development of arlo-cel. Methods: QUINTESSENTIAL-2 (NCT06615479) is a randomized, open-label, multicenter, phase 3 confirmatory study comparing the efficacy and safety of arlo-cel vs SOC in adults with RRMM and prior LEN. Key inclusion criteria were age ≥18 years, confirmed diagnosis of MM per IMWG criteria, 1-3 pLOT (may include a proteasome inhibitor, IMiD, anti-CD38 antibody, and BCMA-targeted therapy), be exposed to LEN (≥2 consecutive cycles, unless PD was the best response to LEN-containing treatment or if there was LEN intolerance or unacceptable toxicity), have measurable disease, and ECOG PS of 0 or 1. Pts who received prior GPRC5D-targeted therapy are excluded. Eligible pts will be randomized 1:1 across 2 arms. Arm A includes leukapheresis within 3-4 days of randomization, mandatory bridging therapy ≤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 PFS and minimal residual disease (MRD) negativity in CR. Key secondary endpoints include OS 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. Anticipated enrollment is 440 pts at ~125 sites globally. The first pt was enrolled in March 2025. © American Society of Hematology (2025). Reused with permission. Clinical trial information: NCT06615479 .