Cilta-Cel Prolongs OS in Lenalidomide-Refractory Multiple Myeloma

Ciltacabtagene autoleucel (cilta-cel; Carvykti) significantly reduced the risk of death by 45% compared with standard of care (SOC) in patients with lenalidomide (Revlimid)-refractory multiple myeloma following at least one prior line of therapy, according to updated results from the phase 3 CARTITUDE-4 trial (NCT04181827) that were presented at the 2024 International Myeloma Society Annual Meeting.¹

At a median follow-up of 33.6 months (range, 0.1-45.0), the 30-month overall survival (OS) rate with cilta-cel was 76.4% compared with 63.8% with SOC (HR, 0.55; 95% CI, 0.39-0.79; P = .0009). SOC consisted of physician’s choice of pomalidomide (Pomalyst), bortezomib (Velcade), and dexamethasone (PVd), or daratumumab (Darzalex) plus pomalidomide and dexamethasone (DPd). The OS benefit with cilta-cel vs SOC was observed across all prespecified patient subgroups. The median OS with cilta-cel has not been reached.

“Cilta-cel is the first CAR T-cell therapy to show a significant overall survival benefit in multiple myeloma,” said presenting author María-Victoria Mateos, MD, PhD, a hematologist/oncologist, associate professor of medicine, and director of the Myeloma Program and Clinical Trials Unit in the University of Salamanca Hospital in Spain.

Mateos also shared updated progression-free survival (PFS) data from CARTITUDE-4 (NCT04181827), which showed that at 33.6 months’ follow-up 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 with cilta-cel was observed across all prespecified patient subgroups. The median PFS with cilta-cel has not been reached, according to Mateos.

At the long-term follow-up, the overall response rate (ORR) with cilta-cel was 84.6%, comprising a stringent complete response (sCR) rate of 69.2%, a CR rate of 7.7%, a very good partial response (VGPR) rate of 4.3%, and a partial response (PR) rate of 3.4%. Mateos noted that the sCR rate increased from 58.2% at the 15.9-month follow-up to 69.2% at the 33.6-month follow-up, showing increased rates of sustained, deep responses.

In the SOC arm, the ORR was 67.3%, composed of an sCR rate of 18.5%, a CR rate of 5.7%, a VGPR rate of 22.3%, and a PR rate of 20.9%. The median duration of response was not reached in the cilta-cel arm (not estimable [NE]-NE) vs 18.7 months (95% CI, 12.9-23.7) in the SOC arm. The 30-month DOR rates were 67.4% vs 35.5%, respectively.

In the intention-to-treat (ITT) population, the minimal residual disease (MRD) negativity rate with 10-5 sensitivity was 62.0% in the cilta-cel arm vs 18.5% in the SOC arm (odd ratio [OR], 7.6). In the population evaluable for MRD, the rates were 89.0% vs 37.9% (OR, 13.3), respectively. With a sensitivity of 10-6 the MRD negativity rates in the ITT and MRD-evaluable populations were 57.2% vs 9.0% (OR, 14.9) and 85.6% vs 18.6% (OR, 28.5) in the cilta-cel and SOC arms, respectively.

“The MRD negativity rate in the cilta-cel arm with a sensitivity level of 10^-5 or 10^-6 is not very different, indicating that cilta-cel induced very deep responses,” said Mateos.

Mateos reported that safety data were consistent with those reported at the previous analysis. All-grade treatment-emergent (TE) infections occurred in 63.5% (grade 3/4, 28.4%) of the cilta-cel arm vs 76.4% (grade 3/4, 29.8%) of the SOC arm. There were 16 patient deaths due to TE- and non-TE infections in the cilta-cel arm vs 19 in the SOC arm.

Grade 3/4 TE adverse events (TEAEs) occurred in about 97% of both arms, with the most common grade 3/4 TEAE being cytopenia. Overall, 50 patients died in the cilta-cel arm vs 82 in the SOC arm. Progressive disease and TEAE were the cause of death in 21 vs 51 patients and 12 vs 8 patients in the 2 arms, respectively.

Second primary malignancies (SPMs) occurred in 13.0% of the cilta-cel arm vs 11.5% of the SOC arm. Hematologic SPMs occurred in 7 patients in the cilta-cel cohort and 1 patient in the SOC cohort. There were no new cases of cranial nerve palsy or movement and neurocognitive TEAEs since the prior analysis.

Mateos said cilta-cel improved quality of life by delaying the time to symptom worsening based on the MySlm-Q total symptom scale (HR, 0.38; 95% CI, 0.24-0.61; P <.0001).

CARTITUDE-4 Trial Background

The ITT population of the open-label phase 3 CARTITUDE-4 trial included 419 patients with lenalidomide-refractory multiple myeloma who had received 1 to 3 prior lines of treatment.

Patients were randomized in a 1:1 ratio to the SOC arm of physician’s choice of PVd or DPd (n = 211) or a single infusion of cilta-cel administered following physician’s choice of bridging therapy, consisting of PVd or DPd (n = 208). In the SOC cohort, patients received PVd in 21-day cycles or DPd in 28-day cycles, both administered until progressive disease.

Patients in the cilta-cel arm first underwent apheresis, had at least 1 cycle of bridging therapy, and received lymphodepletion in the form of cyclophosphamide at 300 mg/m² plus fludarabine at 30 mg/m². Cilta-cel was infused 5 to 7 days following the chemotherapy regimen. The target dose of cilta-cel was 0.75 × 10⁶ CAR-positive viable T cells per kg of body weight.

In general, baseline characteristics were well balanced between the 2 study arms. In the cilta-cel arm, the median age was 61.5 years (range, 27-78) and 55.8% of patients were male. Nearly two-thirds (65.4%) of patients were ISS stage I and the remainder were stage II (28.8%) or stage III (5.8%). About 1 in 5 patients (21.2%) had soft tissue plasmacytomas. 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. About one-fourth (25.5%) of patients were triple-class exposed and 6.7% were penta-drug exposed. Refractory status showed that 14.4% of patients were triple-class refractory.

The median age in the SOC arm 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. The median number of prior lines of therapy was 2 (range, 1-3) and 67.8% of patients had received 2 or 3 prior lines. A little over one-fourth (26.1%) of patients were triple-class exposed and 4.7% were penta-drug exposed. Refractory status showed that 15.6% of patients were triple-class refractory.

The primary study end point was PFS. Secondary end points included response, MRD negativity, OS, and safety.

Based on previously reported PFS data from an earlier CARTITUDE-4 analysis, 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 1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, and who are refractory to lenalidomide.²

References

1. 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.
2. 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 September 30, 2024. https://tinyurl.com/5n72va24