Comparative Efficacy of Ciltacabtagene Autoleucel Versus Isatuximab, Carfilzomib and Dexamethasone in the Treatment of Patients with Lenalidomide-Refractory Multiple Myeloma with 1-3 Prior Lines of Therapy Using a Matching-Adjusted Indirect Comparison
Authors: Mina Roberto , Corradini Paolo , Cavo Michele , San-Miguel Jesús F. , Shune Leyla O. , Khan Abdullah Mohammad , Sidana Surbhi , Leleu Xavier , Manier Salomon , Lipe Brea , Weisel Katja C. , van Sanden Suzy , Diels Joris , Mendes João , Lee Seina , Van Hoorenbeeck Sandra , Pons Adrián , Slaughter Ana , Benachour Nina , Lonardi Carolina , Ghosh Arnab , Patel Nitin , Florendo Erika , Martínez-Lopez Joaquín 
Published: December 2024

Introduction:
The immunomodulatory agent lenalidomide is the backbone of several regimens approved for the treatment of both newly diagnosed and relapsed/refractory multiple myeloma patients and is currently administered until progression. Consequently, the early development of lenalidomide-resistance, that has been shown to be associated with poor outcomes, is rapidly increasing. Ciltacabtagene autoleucel (cilta-cel; Carvykti) was evaluated for the treatment of relapse and lenalidomide-refractory and PI-exposed multiple myeloma (MM) after 1-3 prior lines of therapy (LOT) in a phase 3 randomized controlled trial (CARTITUDE-4). Treatment approaches for patients with MM who have received at least 1 prior LOT and are LEN-refractory vary across countries, lacking a clear standard of care, and can include isatuximab, carfilzomib, and dexamethasone (IsaKd). The IKEMA study included RRMM patients with 1-3 prior LOT, of whom only 31% were refractory to lenalidomide, limiting indirect comparisons between studies. Published results for the len-refractory subgroup on IKEMA were reported, specifically for progression-free survival (PFS) (probabilities at 6, 12 and 18 months and number of events), overall response rate (ORR), very good partial response or better (≥VGPR) rate and complete response or better (≥CR) rate, which were then used to perform unanchored matching adjusted indirect comparison (MAIC) of cilta-cel from CARTITUDE-4 versus IsaKd from the IKEMA subpopulation.
Methods:
The unanchored MAIC was carried out by initially applying the primary exclusion criteria from the IKEMA study to the patient-level data (IPD) of cilta-cel. Subsequently, the IPD for cilta-cel cohort were reweighted to align the average baseline characteristics with those reported for IsaKd. To generate the necessary patient-level data for IsaKd for the MAIC analysis of PFS, we employed a two-step process. First, an exponential model was fitted between each of the provided data points to approximate the complete KM curve. Next, the Guyot algorithm was utilized, leveraging the KM curve and reported event data, to simulate the patient-level data for PFS. A weighted Cox proportional hazards model was then applied to all the IPD from both treatments to obtain hazard ratios (HRs) with 95% confidence intervals (CIs). For binary endpoints, relative effects were quantified using relative response ratios (RRs) with 95% CIs derived from a weighted logistic regression analysis.
Results:
After applying the exclusion criteria from IKEMA to the IPD from CARTITUDE-4 (excluding patients refractory to an anti-CD38 monoclonal antibody), 158 cilta-cel patients were retained. When further adjusting for differences in cytogenetic risk and ISS stage, patients in the cilta-cel group (effective sample size [ESS]=79) had a 49% reduction in risk of disease progression or death (PFS) versus IsaKd (adjusted median not reached vs 19.4 months; HR: 0.51 [0.29,0.90], p=0.0213). Cilta-cel also demonstrated superior efficacy in response rates vs IsaKd (ORR RR: 1.07 [0.93,1.23], p=0.3497; ≥VGPR RR: 1.26 [1.02,1.55], p=0.0191; ≥CR RR: 2.09 [1.48,2.95], p&lt;0.0001).
A sensitivity analysis additionally excluding patients with prior carfilzomib exposure confirmed previous reported results with a PFS HR of 0.45 [0.22,0.94], p=0.0338, in favor of cilta-cel vs IsaKd. Additional sensitivity analyses, matching patients based on prior lines and age, yielded consistent findings, showing the robustness of the results.
Conclusions:
This analysis demonstrated favorable efficacy outcomes of cilta-cel compared to IsaKd, despite the limited data available on lenalidomide-refractory patients in the IKEMA trial. Notably, cilta-cel demonstrated significant clinical improvement in terms of progression-free survival and depth of response, underscoring its potential as an effective therapeutic option for patients with PI exposed and len-refractory MM as early as first relapse. The findings of this analysis will be particularly relevant for countries where len-refractory patients may be treated with IsaKd.
References:
Dimopoulos et al, AJH Wiley, DOI: 10.1002/ajh.26602