Cilta-cel Demonstrates Superior MRD-Negativity Outcomes in Len-Refractory Multiple Myeloma

The CARTITUDE-4 trial (NCT04181827) demonstrated the superior efficacy of ciltacabtagene autoleucel (cilta-cel; Carvykti) vs standard of care (SOC) in patients with lenalidomide (Revlimid)-refractory multiple myeloma after 1 to 3 prior lines of therapy, according to findings presented at the 2024 ASH Annual Meeting.¹

Cilta-cel markedly improved overall minimal residual disease (MRD) negativity rates vs SOC, achieving 89% vs 38% at the 10⁻⁵ threshold and 86% vs 19% at the 10⁻⁶ threshold in evaluable patients. With cilta-cel, MRD-negativity onset was rapid, typically taking place within 2 months from the time of infusion. Further, an MRD benefit with cilta-cel was observed across all prespecified subgroups.

“Cilta-cel significantly increased overall MRD negativity rates compared [with] standard of care at the 10^-5 threshold of 89% compared with 38% in the evaluable patients. Their MRD responses with cilta-cel were deeper at the 10^-6 threshold compared [with] standard of care at 86% compared to 19%,” explained Rakesh Popat, MBBS, MRCP, FRCPath, PhD, St. Bartholomew's and the Royal London Hospitals, London, UK.

At a median follow-up of 33.6 months (range, 0.1-45.0), the secondary end point of overall MRD negativity in the intention-to-treat (ITT) population with 10^-5 sensitivity was 62.0% in the cilta-cel arm vs 18.5% in the SOC arm (odd ratio [OR], 7.6; P <.0001). In the population evaluable for MRD, the rates were 89.0% vs 37.9% (OR, 13.3; P <.0001), respectively. Rapid MRD negativity was observed in 48% of patients treated with cilta-cel by day 56, increasing to 60% by 6 months post-infusion. At the 10⁻⁶ MRD threshold, cilta-cel maintained superior rates at 57% vs 9% (P <.0001).^1,2

Cilta-cel improved MRD-negative complete response (CR) rates, with 44% of patients achieving MRD-negative CR or better at 12 months vs 8% with SOC. For these patients, median progression-free survival (PFS) exceeded 3 years, and overall survival (OS) was not reached.¹

Multiple myeloma multiplex: © LASZLO - stock.adobe.com

Previously reported PFS data from an earlier CARTITUDE-4 analysis supported the FDA approval of cilta-cel in April 2024 for the treatment of adult patients with relapsed/refractory multiple myeloma who have received at least 1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, and who are refractory to lenalidomide.³

Background of the CARTITUDE-4 Trial

In the CARTITUDE-4 trial, 419 patients were randomly assigned to receive either cilta-cel (n = 208) or SOC (n = 211), which consisted of pomalidomide (Pomalyst), bortezomib (Velcade), and dexamethasone (PVd) or daratumumab (Darzalex), pomalidomide, and dexamethasone (DPd) after 1 to 3 prior lines of therapy. In the cilta-cel arm, patients underwent apheresis, bridging therapy, and a single cilta-cel infusion following lymphodepletion.¹

Baseline characteristics were well balanced between the 2 study arms.² Among those treated with cilta-cel, the median age was 61.5 years (range, 27-78) and 55.8% of patients were male. A total of 65.4% of patients were ISS stage I and the rest were stage II (28.8%) or stage III (5.8%). Soft tissue plasmacytomas were seen in 21.2% of patients, the median number of prior lines of therapy was 2 (range, 1-3), and 67.3% of patients had received 2 or 3 prior lines. Further, 25.5% of patients were triple-class exposed and 6.7% were penta-drug exposed, and refractory status showed that 14.4% of patients were triple-class refractory.

In the SOC arm, the median age was 61.0 years (range, 35-80) and 58.8% of patients were male. Staging data showed that 62.6% of patients were ISS stage I and the remainder were stage II (30.8%) or stage III (6.6%). Soft tissue plasmacytomas were reported in 16.6% of patients, and the median number of prior lines of therapy was 2 (range, 1-3). A total of 67.8% of patients had received 2 or 3 prior lines. A total of 26.1% of patients were triple-class exposed and 4.7% were penta-drug exposed, and refractory status showed that 15.6% of patients were triple-class refractory.

MRD negativity was evaluated at a sensitivity threshold of 10⁻⁵ using next-generation sequencing. This was assessed as a secondary end point alongside other outcomes, including CR rates or better, sustained MRD negativity, PFS, and OS.

Prior data from CARTITUDE-4 showed that patients randomized to receive cilta-cel had significantly improved PFS rates vs those treated with SOC. The 30-month PFS rate was 59.4% with cilta-cel vs 25.7% with SOC, translating to a 71% reduction in the risk of disease progression or death (HR, 0.29; 95% CI, 0.22-0.39; P <.0001). The PFS benefit seen among those treated with cilta-cel was observed across all prespecified patient subgroups. The median PFS with cilta-cel had not been reached.

At the same median follow-up of 33.6 months, the 30-month overall survival (OS) rate with cilta-cel was 76.4% vs 63.8% with SOC (HR, 0.55; 95% CI, 0.39-0.79; P = .0009). The OS benefit with cilta-cel vs SOC was observed across all prespecified patient subgroups and the median OS with cilta-cel had also not been reached.

“We [now] report MRD-negativity outcomes, including overall and sustained MRD-negative CR at a median follow-up of 33.6 months in CARTITUDE-4,” said Popat.

Additional Findings Presented at ASH 2024

Sustained MRD negativity (≥12 months apart) was achieved in 52% of the cilta-cel arm vs 10% of the SOC arm (P <.0001). This corresponds with high rates of PFS and OS at 30 months (93.2% and 97.3%), respectively. Among evaluable patients, 75% receiving cilta-cel sustained MRD negativity compared with 50% on SOC (P =.0159).

MRD-negative CR status was linked with better immune fitness at apheresis, lower inflammatory cytokines before infusion, and higher chimeric antigen receptor T-cell expansion compared with patients who were MRD-positive. Overall, higher rates of MRD negativity were seen in the CARTITUDE-4 trial where patients had 1, 2, or 3 prior lines of therapy vs those in the CARTITUDE-1 trial, with 3 or more prior lines of therapy.

“We can see clearly that MRD negativity onset was very rapid with cilta-cel and was occurring typically at about 2 months following the infusion. All prespecified subgroups demonstrated MRD benefits with cilta-cel. Also, when you compare it with the historical data with CARTITUDE-1, there were higher rates of MRD negativity observed,” said Popat.

These findings underscore cilta-cel’s ability to deliver deep, durable remissions, offering a transformative option for patients with lenalidomide-refractory multiple myeloma, even as early as first relapse.

“Patients treated with cilta-cel achieved rapid and deep MRD negativity, sustained results, and these corresponded to high rates of progression-free survival and overall survival, which therefore supports its prognostic value in patients being treated with CAR T-cell therapy,” added Popat.

REFERENCES:

1. Popat R, Oriol A, Cavo M, et al. 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.Blood. 2024;144(suppl 1):1032. doi:10.1182/blood-2024-198104

2. Mateos M-V, San-Miguel J, Dhakal, et al. Overall Survival (OS) With Ciltacabtagene Autoleucel (Cilta-cel) Versus Standard of Care (SoC) in Lenalidomide (Len)-Refractory Multiple Myeloma (MM): Phase 3 CARTITUDE-4 Study Update. Presented at: 2024 International Myeloma Society Annual Meeting; September 25-28, 2024; Rio de Janeiro, Brazil. Abstract OA – 65.

3. Carvykti is the first and only BCMA-targeted treatment approved by the US FDA for patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy. News release. Johnson & Johnson. April 5, 2024. Accessed December 10, 2024. https://tinyurl.com/5n72va24