Long-Term Benefits in Patient-Reported Outcomes and Time to Next Anti-Myeloma Therapy of Ciltacabtagene Autoleucel (Cilta-cel) Versus Standard of Care for Patients with Lenalidomide-Refractory Multiple Myeloma: Results from the Phase 3 Cartitude-4 Clinical Trial

Background:

Ciltacabtagene autoleucel (cilta-cel) demonstrated superior progression-free survival (PFS) and overall survival compared to standard of care (SOC; pomalidomide, bortezomib, and dexamethasone or daratumumab, pomalidomide, and dexamethasone) in patients with lenalidomide-refractory multiple myeloma (MM) after 1-3 prior lines of therapy (LOTs) in the phase 3 CARTITUDE-4 trial. A single cilta-cel infusion showed significant and clinically meaningful PFS vs. SOC (hazard ratio [HR]: 0.26 [protocol-specified weighted analysis]; P<0.0001) at a median follow-up of 15.9 months. A second interim analysis demonstrated a significant reduction in the risk of death by 45% (HR: 0.55; P=0.0009), compared to continuous SOC, with an estimated 30-month survival rate of 76.4%. To support these significant clinical benefits, here we report the patient reported outcomes (PROs) and time to next anti-myeloma therapy (TTNT) at ~3-year median follow-up.

Methods:

Eligible patients enrolled in CARTITUDE-4 included those with lenalidomide-refractory MM who received 1-3 prior LOTs including an immunomodulatory agent and a proteasome inhibitor. A total of 419 patients were randomized to receive either cilta-cel (N=208) or SOC (N=211). The Multiple Myeloma Symptom and Impact Questionnaire (MySIm-Q), including symptom (pain, fatigue, digestion, cognition) and impact (activity limitations, social functioning, emotional impact) domains, and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), were administered to all patients until disease progression. Time to worsening (TTW) of symptoms and impact were defined as the time from randomization to a decrease in score of at least 0.5 standard deviation from baseline without an observed superior subsequent improvement, and TTW of global health status/quality of life (GHS/QoL) was defined using an anchor-based approach with CARTITUDE-4 data. TTNT was defined as time from randomization to the start of subsequent anti-myeloma therapy or death due to progressive disease. These outcomes were assessed using the Kaplan-Meier method. Cox proportional hazards models were used to estimate HRs and 95% confidence intervals (CIs). The clinical data cut-off of this analysis was May 1, 2024, with median follow-up of 34 months.

Results:

Based on the MySIm-Q symptom and impact domain scores, cilta-cel was associated with significantly longer TTW of symptoms (HR: 0.38; 95% CI: 0.24-0.61; P<0.0001) and impact (HR: 0.42; 95% CI: 0.26-0.70; P=0.0007), compared to SOC. By 30 months after randomization, 77% of patients treated with cilta-cel had not experienced worsening of symptoms, compared to 63% of patients on SOC. Similarly, 83% of patients on cilta-cel had not experienced worsening of functional impacts, compared to 69% of the SOC arm at 30 months. The median time until symptom worsening was not reached (NR) for cilta-cel, and was 34.33 (95% CI: 32.20-NR) months for SOC. A median time to impact worsening of 39.16 (95% CI: 38.70-NR) months was estimated for the cilta-cel arm, compared to 35.88 (95% CI: 32.20-NR) months for SOC. MySIm-Q results are further supported by those observed on the EORTC QLQ-C30 GHS/QoL scale, with time to worsening significantly delayed (HR: 0.40; 95% CI: 0.25-0.64; P<0.0001) for cilta-cel compared to SOC. For patients treated with cilta-cel, 79% had not experienced a worsening of GHS/QoL by 30 months, compared to 66% of patients on SOC. The median time to GHS/QoL worsening for cilta-cel was 39.92 (95% CI: 39.92-NR) months, compared to 34.33 (95% CI: 32.03-NR) months for SOC. Treatment with cilta-cel significantly delayed, by 66%, the time to subsequent anti-myeloma treatment or death due to progressive disease (HR: 0.34; 95% CI: 0.26-0.46; P<0.0001) compared to SOC. The median TTNT was not reached for the cilta-cel arm and was 13.37 (95% CI: 11.99-17.08) months for the SOC arm.

Conclusion:

The increase in the TTNT and sustained benefits in PROs, along with prolonged survival, support cilta-cel as a new SOC treatment for MM patients who are refractory to lenalidomide and have received 1-3 prior LOTs. Importantly, with ~3 years of follow-up, a single infusion of cilta-cel provided patients with a longer delay in worsening of MM related symptoms, functional impacts, and GHS/QoL. The totality of clinical and patient-reported evidence demonstrates the significant benefit of cilta-cel.