Trial in progress: A phase 1 study to evaluate the safety and preliminary efficacy of arlocabtagene autoleucel (arlo-cel), a GPRC5D-targeted chimeric antigen receptor (CAR) T cell therapy, in combination with mezigdomide (MEZI) in patients (pts) with relapsed/refractory multiple myeloma (RRMM)

Abstract Background and Significance: MM is a highly heterogenous disease and novel therapies are required to better address pt needs and improve outcomes over the current standard of care. Arlo-cel (BMS-986393) is a CAR T cell therapy that targets the orphan transmembrane G protein-coupled receptor class C, group 5, member D (GPRC5D), which is expressed by malignant plasma cells in pts with MM. MEZI is an oral CELMoD™ agent optimized for maximal Ikaros/Aiolos degradation, leading to increased MM cell apoptosis and immunostimulatory effects, and may enhance arlo-cel efficacy via added cytotoxicity and T cell stimulation. The CA088-1005 study aims to determine the safety, tolerability, and recommended phase 2 dose (RP2D) of arlo-cel plus other therapies, including MEZI, in pts with RRMM. Study Design and Methods: In this multicenter (United States and Canada), open-label, phase 1 study (NCT06121843), eligible pts will be assigned to 1 of multiple treatment arms to evaluate arlo-cel plus various compounds; here we focus on Arm B (arlo-cel plus MEZI). The study consists of 2 parts: dose finding (part 1) and dose expansion (part 2). Eligible pts are ≥ 18 years of age and have a diagnosis of RRMM. Pts in part 1 and the first 10 pts in part 2 must have received ≥ 3 prior anti-myeloma treatment regimens (including an immunomodulatory drug [IMiD®] agent, proteasome inhibitor, anti-CD38 agent, and if eligible, autologous hematopoietic stem cell transplant), whereas all additional pts in part 2 must have received between 1 and 3 prior anti-myeloma treatment regimens (including an IMiD agent and proteasome inhibitor). Prior to starting combination treatment, all pts will receive lymphodepleting chemotherapy. In part 1, pts assigned to Arm B will receive arlo-cel by intravenous infusion on day 1 at a dose of either 75 × 106 cells (dose level 1) or 150 × 106 cells (dose level 2); pts will then receive 0.6 mg oral MEZI administered once daily on days 1–21 of 28-day cycles, starting as early as day 60 after arlo-cel infusion. Pts will be observed for dose-limiting toxicities (DLTs) during the DLT evaluation period, which begins on the first day the pt is exposed to the assigned combination therapy and ends 28 days later. Pts will receive study treatment until progressive disease, unacceptable toxicity (defined as adverse events [AEs] that require discontinuation of combination therapy), or withdrawal of consent. Dose escalation and de-escalation decisions will be guided by the Bayesian optimal interval (BOIN) design. Upon completion of part 1, preliminary estimation of the RP2D of arlo-cel plus MEZI will be based on the incidence rate of DLTs across all doses using a BOIN algorithm and the cumulative safety, efficacy, and pharmacokinetic and pharmacodynamic data. In part 2, the safety and efficacy of arlo-cel plus MEZI at the selected RP2D will be further evaluated. After the completion of part 1, 10 pts who have received ≥ 3 prior anti-myeloma regimens will be accrued to 1 or more dose-expansion cohorts. After data from pts in each expansion cohort are collected and reviewed, approximately 20 pts with 1–3 prior anti-myeloma regimens will be evaluated. All pts will complete a follow-up period after the end of the treatment period, and all pts who discontinue treatment for reasons other than disease progression, initiation of new anti-myeloma therapy, or withdrawal of consent will be assessed for myeloma response approximately every 3 months until progression, death, initiation of new anti-cancer therapies, or 24 months after arlo-cel therapy, whichever occurs sooner. All pts will undergo long-term follow-up for lentiviral vector safety, long-term toxicity, disease status, anti-cancer treatment, and survival until the end of combination therapy dosing or 24 months after arlo-cel infusion, whichever is longer, with pts then rolling over to a separate long-term follow-up study for up to 15 years after arlo-cel infusion. The primary endpoints are the incidence and severity of AEs, serious AEs, AEs of special interest, AEs leading to discontinuation and deaths, as well as the establishment of the RP2D. Secondary endpoints include preliminary efficacy as determined by the response rate (including overall, complete, and very good partial response rates) and pharmacokinetics. Statistical analysis details will be finalized in the statistical analysis plan. Enrollment began in February 2024 and is ongoing.

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