Trial in progress: 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

Abstract Background and Significance: Despite advances in multiple myeloma (MM) treatment, nearly all patients (pts) will relapse, highlighting the need for new drug classes to improve outcomes in RRMM. Further, with the extensive use of lenalidomide, 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 CAR T-cell therapy that has demonstrated safety and efficacy in pts with RRMM in a first-in-human phase 1 study. Following a single infusion of arlo-cel (150×106 CAR T-cells), overall response rate (ORR) was 96% (23/24) and 91% (21/23) in those with 1-3 and ≥3 prior lines of therapy (pLOT), respectively (Bal S, et al. ASH 2024. Abstracts 2069 and 922). These phase 1 study outcomes support further development of arlo-cel in clinical trials. Study Design and 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. 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, and anti-CD38 antibody), be exposed to lenalidomide (with ≥2 consecutive cycles, unless progressive disease was the best response to lenalidomide-containing treatment or if there was lenalidomide 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 Arm A or Arm B. Pts randomized to Arm A will have leukapheresis within 3-4 days of randomization, bridging therapy of DPd (daratumumab, pomalidomide, dexamethasone) or Kd (carfilzomib, dexamethasone) per Investigator choice within 6 days of randomization, and lymphodepleting chemotherapy prior to a single infusion of arlo-cel. Pts randomized to Arm B will receive SOC of DPd or Kd per Investigator choice, dosed per labeling, until disease progression. Primary endpoints are progression-free survival and minimal residual disease (MRD) negativity in complete response. Secondary endpoints include overall survival, ORR, MRD-negative status, complete response rate, time to response, duration of response, pharmacokinetics, and patient-reported quality of life outcomes. Pts will be followed for ≤5 years after the last patient is randomized, with a subsequent long-term follow-up study (≤15 years post-infusion) for pts receiving arlo-cel. This is a trial in progress and is expected to enroll 440 pts at ~126 sites globally across North America, South America, Europe, Asia, and Australia. The first patient was enrolled in March 2025.