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
Authors: Popat Rakesh , Oriol Albert , Cavo Michele , Karlin Lionel , Avivi Mazza Irit , Roeloffzen Wilfried , Kim Seok Jin , Lipe Brea , Bar Noffar , Horvath Noemi , Spencer Andrew , Min Chang-Ki , Chen Diana , Li Quanlin , Li Katherine , Slaughter Ana , Lonardi Carolina , Benachour Nina , Ghosh Arnab , Vogel Martin , Lendvai Nikoletta , Lengil Tamar , Patel Nitin , Costa Filho Octavio , Florendo Erika , Lin Yi 
Published: December 2024

Introduction: Cilta-cel is approved in the US and EU for the treatment (tx) of patients (pts) with len-refractory MM after ≥1 line based on the randomized, phase 3 CARTITUDE-4 trial (NCT04181827). At the first interim analysis (15.9-month [mo] median follow-up), cilta-cel significantly improved progression-free survival (PFS) vs SoC (hazard ratio [HR], 0.26 [protocol-specified weighted analysis]; P&lt;0.0001). At the second interim analysis, overall survival (OS) was significantly improved with cilta-cel vs SoC (HR, 0.55; P=0.0009). MRD negativity is a prognostic marker of prolonged survival outcomes for pts with MM. We report MRD negativity, including overall and sustained MRD negativity, overall MRD-negative complete response or better (≥CR), and MRD-negative ≥CR at mo 12, from the prespecified second interim analysis of CARTITUDE-4.

Methods: Eligibility criteria were previously described. Pts were assigned 1:1 to cilta-cel or SoC (pomalidomide, bortezomib, and dexamethasone [PVd]/daratumumab, pomalidomide, and dexamethasone [DPd]). Pts in the cilta-cel arm underwent apheresis, received bridging therapy (PVd/DPd), and then a single cilta-cel infusion (target dose, 0.75×106 CAR+ viable T cells/kg) 5-7 days (d) after the start of lymphodepletion. PFS was the primary endpoint; ≥CR rate, overall response rate, overall MRD-negativity rate, and OS were key secondary endpoints. MRD was assessed centrally via next-generation sequencing (clonoSEQ v2.0; Adaptive Biotechnologies). MRD was evaluated at d 56 post infusion in the cilta-cel arm; and in both arms at suspected ≥CR and at 6, 12, 18, and 24 mo post infusion (cilta-cel arm) or cycle 1 d 1 (SoC arm), as well as yearly until progression/start of subsequent therapy in pts in ≥CR. Sustained MRD negativity (10−5) was defined as confirmed MRD negativity ≥12 mo apart and without MRD positivity in between. Pts were evaluable for sustained MRD negativity if they achieved MRD negativity and had ≥1 evaluable MRD sample ≥12 mo after the first negative result or progressed/died/started subsequent tx &lt;12 mo after the first negative result.

Results: 419 pts were randomized (intent-to-treat [ITT] set; cilta-cel, n=208; SoC, n=211); 176 pts in the cilta-cel arm received cilta-cel as study tx. As of May 1, 2024, median follow-up for the study was 33.6 mo. At the 10−5 threshold, 145 pts in the cilta-cel arm and 103 in the SoC arm were evaluable for MRD. MRD-negativity rates (10−5) in the ITT set and the MRD-evaluable subset were higher with cilta-cel vs SoC (ITT, 62% vs 18%; MRD evaluable, 89% vs 38%; both P&lt;0.0001). Across subgroups, cilta-cel vs SoC consistently increased overall MRD-negativity rates (10−5). In the ITT set, 48% of the cilta-cel arm achieved MRD negativity (10−5) by d 56, with the MRD-negative rate rising to 60% by 6 mo post cilta-cel infusion. Overall MRD-negativity rates at the 10−6 threshold in the ITT set were higher with cilta-cel vs SoC (57% vs 9%; P&lt;0.0001). In the cilta-cel arm, 119 (57%) pts vs 26 (12%) in the SoC arm achieved overall MRD-negative (10−5) ≥CR (P&lt;0.0001). At the 12-mo MRD assessment, 92 (44%) pts in the cilta-cel arm vs 17 (8%) in the SoC arm (P&lt;0.0001) had MRD-negative (10−5) ≥CR. In pts with MRD-negative (10−5) ≥CR at mo 12, median PFS was not reached (NR; 95% CI, not estimable [NE]-NE) with cilta-cel and 37.8 mo (95% CI, 25.0-NE) with SoC; median OS was NR (95% CI, NE-NE) and NR (95% CI, 37.8 mo-NE), respectively. Sustained MRD-negativity rates (10−5) in the ITT set were 40% in the cilta-cel arm vs 6% in the SoC arm (P&lt;0.0001); among 110 and 26 evaluable pts for sustained MRD, sustained MRD-negativity rates were 75% vs 50% (P=0.0159). Among the 176 pts who received cilta-cel as study tx, overall MRD negativity at 10−5 was achieved by 129 (73%) pts (89% of 145 evaluable pts).

Conclusions: At 33.6-mo median follow-up in CARTITUDE-4, cilta-cel vs SoC significantly increased overall MRD-negativity rates &gt;3-fold in the ITT set, with pts achieving MRD negativity rapidly post cilta-cel. The prognostic value of MRD-negative ≥CR at mo 12 was shown, as median PFS was &gt;3 years in pts with MRD-negative ≥CR at mo 12, regardless of tx. These data further underscore the benefit of cilta-cel, which led to significant &gt;3-fold increases vs SoC in rates of MRD-negative ≥CR at any time and at mo 12, and sustained MRD negativity. Our MRD data 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.