Trial in progress: QUINTESSENTIAL—a phase 2 study of arlocabtagene autoleucel (arlo-cel) in patients with relapsed/refractory multiple myeloma (RRMM)

Abstract Background and Significance: Limited treatment options exist for patients (pts) with RRMM who have been exposed to 3 or more drug classes, including immunomodulatory drugs (IMiD), anti-CD38 antibodies, proteasome inhibitors (PI), and B-cell maturation antigen (BCMA)-targeted therapy. To address this unmet need, new treatment options are needed for late-line populations, which will continue to grow with more quadruple-class exposed (QCEx) pts due to the approval of BCMA-targeted therapies in earlier lines. G protein-coupled receptor class C group 5 member D (GPRC5D) is an orphan receptor expressed on plasma cells, with limited expression elsewhere, making it a promising therapeutic target for MM. Data from a phase 1 first-in-human study (NCT04674813) suggested that arlo-cel, a GPRC5D-directed autologous chimeric antigen receptor (CAR) T-cell therapy, is safe and efficacious in pts with heavily pretreated RRMM, including pts who received prior BCMA-targeted therapy. Following a single infusion of arlo-cel (150×106 CAR T cells), overall response rate (ORR) was 91% (21/23), median progression-free survival (PFS) was 18.3 months, and median overall survival (OS) was not reached in those with ≥3 prior lines of therapy (pLOT) (Bal S et al. ASH 2024. Abstract 922). These outcomes from the phase 1 study support further development of arlo-cel in clinical trials. Study Design and Methods QUINTESSENTIAL (NCT06297226) is an open-label, multicenter, phase 2 study evaluating arlo-cel in pts with RRMM. For analyses, enrollment is planned at 175 pts. Key inclusion criteria were age ≥18 years, confirmed diagnosis of MM as per International Myeloma Working Group (IMWG) criteria, ≥3 classes of MM treatment (including IMiD, PI, and anti-CD38), and ≥3 pLOT. Pts must also have documented disease progression (PD) during or after the most recent regimen as per IMWG, measurable disease, and an ECOG performance status of 0 or 1. Pts who previously received a GPRC5D-targeted therapy are excluded. After screening, pts will undergo leukapheresis followed by bridging therapy. Pts will then receive lymphodepleting chemotherapy followed by a single infusion of arlo-cel. The primary endpoint is ORR by IMWG response criteria per an independent review committee in pts who are QCEx and received ≥4 pLOT. Key secondary endpoints are ORR and complete response rate in all pts. Other secondary and exploratory endpoints include time to response, duration of response, PFS, OS, minimal residual disease-negative status, and safety. Pts will be followed for ≤5 years after the last patient receives arlo-cel, with a subsequent long-term follow-up study continuing for ≤15 years. This is a trial in progress and will recruit at ~47 centers across the USA, Canada, and Japan. The first patient first visit was achieved on March 21, 2024.