Ciltacabtagene autoleucel (cilta-cel; Carvykti) continues to demonstrate a significant overall survival (OS) benefit in patients with lenalidomide-refractory multiple myeloma who have received one to three prior lines of therapy. Updated findings from the phase 3 CARTITUDE-4 trial, presented at the 2024 International Myeloma Society Annual Meeting, reveal a 45% reduction in the risk of death compared to standard of care (SOC). This data reinforces cilta-cel's potential as a transformative treatment option in earlier lines of multiple myeloma therapy.
Significant Survival Improvement with Cilta-cel
At a median follow-up of 33.6 months, the 30-month OS rate with cilta-cel reached 76.4%, compared to 63.8% with SOC (HR, 0.55; 95% CI, 0.39-0.79; P = .0009). The SOC regimen comprised physician’s choice of pomalidomide, bortezomib, and dexamethasone (PVd), or daratumumab plus pomalidomide and dexamethasone (DPd). According to Dr. María-Victoria Mateos, presenting author and hematologist/oncologist at the University of Salamanca Hospital in Spain, “Cilta-cel is the first CAR T-cell therapy to show a significant overall survival benefit in multiple myeloma.”
Progression-Free Survival and Response Rates
The CARTITUDE-4 trial (NCT04181827) also reported updated progression-free survival (PFS) data, indicating a 71% reduction in the risk of disease progression or death with cilta-cel (HR, 0.29; 95% CI, 0.22-0.39; P <.0001). The 30-month PFS rate was 59.4% with cilta-cel versus 25.7% with SOC. Furthermore, the overall response rate (ORR) with cilta-cel was 84.6%, including a stringent complete response (sCR) rate of 69.2%. This sCR rate increased from 58.2% at the 15.9-month follow-up, demonstrating sustained, deep responses over time.
In contrast, the SOC arm achieved an ORR of 67.3%, with an sCR rate of 18.5%. The median duration of response was not reached in the cilta-cel arm, while it was 18.7 months (95% CI, 12.9-23.7) in the SOC arm. The 30-month duration of response rates were 67.4% and 35.5% for cilta-cel and SOC, respectively.
Minimal Residual Disease Negativity
Deep responses were further evidenced by minimal residual disease (MRD) negativity rates. In the intention-to-treat (ITT) population, the MRD negativity rate with 10-5 sensitivity was 62.0% in the cilta-cel arm versus 18.5% in the SOC arm (OR, 7.6). In the population evaluable for MRD, the rates were 89.0% versus 37.9% (OR, 13.3), respectively. Dr. Mateos emphasized that the MRD negativity rates at sensitivities of 10-5 and 10-6 were similar, indicating very deep responses induced by cilta-cel.
Safety Profile
The safety data remained consistent with previous analyses. All-grade treatment-emergent infections occurred in 63.5% (grade 3/4, 28.4%) of the cilta-cel arm versus 76.4% (grade 3/4, 29.8%) of the SOC arm. Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in approximately 97% of both arms, with cytopenia being the most common. Second primary malignancies (SPMs) occurred in 13.0% of the cilta-cel arm versus 11.5% of the SOC arm. Notably, there were no new cases of cranial nerve palsy or movement and neurocognitive TEAEs since the prior analysis.
Impact on Quality of Life
Cilta-cel also demonstrated an improvement in quality of life by delaying the time to symptom worsening, as measured by the MySlm-Q total symptom scale (HR, 0.38; 95% CI, 0.24-0.61; P <.0001).
CARTITUDE-4 Trial Design
The CARTITUDE-4 trial is an open-label, phase 3 study involving 419 patients with lenalidomide-refractory multiple myeloma who had received one to three prior lines of treatment. Patients were randomized 1:1 to either SOC or a single infusion of cilta-cel. The primary endpoint was PFS, with secondary endpoints including response, MRD negativity, OS, and safety.
Regulatory Implications
Based on earlier PFS data from CARTITUDE-4, the FDA approved cilta-cel in April 2024 for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, and who are refractory to lenalidomide.
