Ciltacabtagene Autoleucel (Cilta-cel) Vs Standard of Care (SoC) in Patients with Lenalidomide (Len)-Refractory Multiple Myeloma (MM) after 1–3 Lines of Therapy: Minimal Residual Disease (MRD) Negativity in the Phase 3 Cartitude-4 Trial

Abstract

Introduction

Cilta-cel is approved for the treatment (tx) of patients (pts) with len-refractory MM after ≥1 line based on results of the phase 3 CARTITUDE-4 trial (NCT04181827) showing significantly improved progression-free survival (PFS) vs SoC (hazard ratio [HR], 0.26; P<0.0001 [protocol-specified weighted analysis]) at the first interim analysis (15.9-month [mo] median follow-up [MFU]) and significant improvements in overall survival (OS) vs SoC (HR, 0.55; P=0.0009) at the second interim analysis. We report MRD negativity results from a second interim analysis.

Methods

Pts were assigned to cilta-cel or SoC (pomalidomide, bortezomib, dexamethasone [PVd]/daratumumab, pomalidomide, dexamethasone [DPd]). Pts in the cilta-cel arm underwent apheresis and received bridging therapy (PVd/DPd) followed by cilta-cel infusion (target dose, 0.75 × 10⁶ CAR+ viable T cells/kg) 5–7 days (d) after the start of lymphodepletion. MRD was assessed via next-generation sequencing (clonoSEQ v2.0; Adaptive Biotechnologies) at d 56 and 6, 12, 18, and 24 mo post infusion in the cilta-cel arm; cycle 1 d 1 in the SoC arm; and in both arms at suspected complete response or better (≥CR) and yearly until progression/start of subsequent therapy in pts in ≥CR. MRD negativity ≥12 mo apart without MRD positivity in between was considered sustained MRD negativity (10^-5).

Results

419 pts were randomized (intent-to-treat [ITT] set; cilta-cel, n=208; SoC, n=211); MFU was 33.6 mo as of May 1, 2024. 145 pts in the cilta-cel arm and 103 in the SoC arm were MRD-evaluable (10^-5). MRD-negativity rates (10⁻⁵) in the ITT set and the MRD-evaluable subset were higher with cilta-cel vs SoC (Table 1). Across subgroups, cilta-cel vs SoC consistently increased overall MRD-negativity rates. In the ITT set, 48% of the cilta-cel arm achieved MRD negativity by d 56, with the MRD-negative rate rising to 60% by 6 mo post cilta-cel infusion. Overall MRD-negativity rates (10⁻⁶) and rates of overall and 12-mo MRD-negative (10^-5) ≥CR were higher with cilta-cel vs SoC. Median PFS for pts with 12-mo MRD-negative ≥CR was not reached (NR; 95% CI, not estimable [NE]–NE) for cilta-cel and 37.8 mo (95% CI, 25.0–NE) for SoC; median OS was NR (95% CI, NE–NE) and NR (95% CI, 37.8 mo–NE), respectively. Sustained MRD-negativity rates were higher with cilta-cel vs SoC (Table 2). Overall MRD negativity at 10⁻⁵ was achieved by 129/176 (73%) pts who received cilta-cel as study tx (89% of 145 evaluable pts).

Conclusions

At 33.6-mo MFU in CARTITUDE-4, cilta-cel vs SoC significantly increased overall MRD-negativity rates, with pts achieving MRD negativity rapidly post cilta-cel. These data underscore the benefit of cilta-cel, which led to significant increases vs SoC in rates of MRD-negative ≥CR and sustained MRD negativity and demonstrate higher rates of deep and sustained MRD negativity achieved with cilta-cel vs SoC in tx of len-refractory MM as early as first relapse.