Cilta-Cel Significantly Prolongs OS Vs SOC in Lenalidomide-Refractory Multiple Myeloma

Image Credit: © ChaoticMind – stock.adobe.com

A one-time infusion of ciltacabtagene autoleucel (cilta-cel; Carvykti) significantly improved overall survival (OS) compared with standard-of-care (SOC) treatment in patients with lenalidomide (Revlimid)-refractory multiple myeloma, according to updated data from the pivotal phase 3 CARTITUDE-4 trial (NCT04181827) presented during the 51st Annual EBMT Meeting.1

At a median follow-up of 33.6 months (range, 0.1-45.0), the CAR T-cell therapy (n = 208) led to a 45% reduction in the risk of death vs physician’s choice of SOC treatment (n = 211), which could have comprised pomalidomide (Pomalyst) plus bortezomib (Velcade) and dexamethasone (PVd) or daratumumab (Darzalex) plus pomalidomide and dexamethasone (DPd; HR, 0.55; 95% CI, 0.39-0.79; P = .0009). The 30-month OS rate in the cilta-cel arm was 76.4% vs 63.8% in the SOC arm. A consistent reduction in risk of death was observed across prespecified subsets, with the exception of those with International Staging System (ISS) stage III disease (HR, 1.14; 95% CI, 0.40-3.26).

“Cilta-cel is the first CAR T-cell therapy to show significant OS benefit in multiple myeloma, [with a] 45% percent reduction in the risk of death with cilta-cel vs SOC in patients with lenalidomide-refractory multiple myeloma after 1 to 3 prior lines of therapy,” Maria-Victoria Mateos, MD, PhD, head of myeloma and clinical trials unit at the Haematology Department and professor of medicine at the University of Salamanca, Spain, said in a presentation of the data. “[There was a] consistent OS benefit across the subgroups. The median OS and progression-free survival [PFS] were not reached with cilta-cel and quality of life [QOL] was significantly improved with cilta-cel vs SOC.”

A Closer Look at CARTITUDE-4: Design, Treatment, End Points, and What Came Before

The phase 3 trial enrolled patients with lenalidomide-refractory multiple myeloma who received 1 to 3 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD). Patients were at least 18 years of age and had an ECOG performance status no higher than 1. If they had prior exposure to CAR T-cell therapy or BCMA-targeted treatment, they were excluded.

Study participants were randomly assigned 1:1 to receive SOC, which was physician’s choice of PVd or DPd, or cilta-cel. Those in the cilta-cel arm received at least 1 cycle of bridging therapy with PVd or DPd, followed by lymphodepletion, and then were infused with cilta-cel at a target dose of 0.75 x 106 CAR+ T cells/kg on day 1. Stratification factors included SOC (PVd vs DPd), ISS disease stage, and number of prior lines of therapy. Investigators collected safety, efficacy and pharmacokinetic or pharmacodynamic data every 28 days from day 1 to day 112.

The primary end point of the study was PFS, and secondary end points included complete response (CR) or better rate, overall response rate (ORR), minimal residual disease (MRD) negativity, OS, patient-reported outcomes, and incidence and severity of adverse effects (AEs).

Previous data from the study showed that cilta-cel (n = 208) significantly improved PFS vs SOC (n = 211).2 The median PFS was not evaluable (NE; 95% CI, 22.8-NE) with the CAR T-cell therapy vs 12 months (95% CI, 9.8-14.0) with SOC (HR, 0.41; 95% CI, 0.30-0.56; P < .0001). The CR or better rates in the respective arms were 74.0% (95% CI, 67.5%-79.9%) and 22.3% (95% CI, 16.8%-28.5%), respectively. These data supported the FDA’s decision to approve cilta-cel in April 2024 for use in adult patients with relapsed/refractory multiple myeloma who had received at least 1 prior therapy, including a PI and IMid and who are refractory to lenalidomide.3

The data cutoff date for the current analysis was May 1, 2024.1 The intention-to-treat population included 208 patients randomly assigned to cilta-cel and 211 randomly assigned to SOC; 208 patients in both arms comprised the safety population. The as-treated population consisted of 176 patients who received the CAR T-cell therapy; 117 of these patients were ongoing in the post-treatment phase of the trial. Of the 208 patients who received SOC therapy, 43 were ongoing on SOC treatment.

Baseline characteristics were generally well balanced across the treatment arms, according to Mateos. The median patient age in the cilta-cel and SOC arms was 61.5 years (range, 27-78) and 61.0 years (range, 35-80), more than half of patients were male (55.8%; 58.8%), had stage ISS stage I disease (65.4%; 62.6%), had high cytogenetic risk (59.4%; 62.9%), and had received 2 or 3 prior lines of therapy (67.3%; 67.8%).

The median number of prior lines of therapy received in both arms was 2, with a range of 1 to 3 lines. About one-quarter of patients in both arms were triple-class exposed (25.5%; 26.1%), and under 10% were penta-drug exposed (6.7%; 4.7%). Moreover, 14.4% of patients in the CAR T-cell therapy arm were triple-class refractory vs 15.6% of those in the SOC arm. Patients were refractory to bortezomib (Velcade; 26.4%; 22.7%), pomalidomide (Pomalyst; 3.8%; 4.3%), daratumumab (Darzalex; 23.1%; 21.3%), or any PI (49.5%; 45.5%).

Examining More Updated Efficacy Data

Cilta-cel continued to showcase a significant improvement in PFS over SOC, with a 71% reduction in the risk of disease progression or death (HR, 0.29; 95% CI, 0.22-0.39; P < .0001). The 30-month PFS rates in the respective arms were 59.4% and 25.7%. Notably, a consistent PFS benefit was observed with cilta-cel across all prespecified subgroups.

Mateos also noted numerically higher OS and PFS rates compared with what was seen in the as-treated population of the phase 1/2 CARTITUDE-1 study (NCT03548207). Again, the 30-month OS rate in CARTITUDE-4 was 84.3% vs 68.0% in CARTITUDE-1; the 30-month PFS rates in the respective trials were 68.4% and 54.2%.

“Cilta-cel use in earlier lines demonstrated numerically higher rates of overall and progression-free survival,” Mateos noted.

Moreover, increased rates of deep responses were observed with additional follow-up with the CAR T-cell therapy, she added. Updated data indicated that cilta-cel elicited an ORR of 84.6%, with a CR or better rate of 76.9%. In this arm, the stringent CR (sCR) rate was 69.2%, the CR rate was 7.7%, the very good partial response (VGPR) rate was 4.3%, and the partial response (PR) rate was 3.4%. In comparison, SOC induced an ORR of 67.3%, with a CR or better rate of 24.2%. In this arm, the sCR, CR, VGPR, and PR rates were 18.5%, 5.7%, 22.3%, and 20.9%, respectively.

Additionally, the median duration of response in the cilta-cel arm was not reached (95% CI, NE-NE) vs 18.7 months (95% CI, 12.9-23.7) with SOC; the 30-month DOR rates in the respective arms were 67.4% (95% CI, 59.7%-74.0%) and 35.5% (95% CI, 27.6%-43.6%).

The CAR T-cell therapy also provided a significantly higher rate of MRD negativity than SOC. In those evaluable for MRD in the cilta-cel arm (n = 145) and the SOC arm (n = 103), the MRD negativity rates with a sensitivity of 10-5 were 89.0% vs 37.9% (odds ratio [OR], 13.3%). In those evaluable for MRD in the cilta-cel (n = 139) and SOC (n = 102) arms, the MRD negativity rates with a sensitivity of 10-6 were 85.6% and 18.6%, respectively (OR, 28.5). “Cilta-cel increased MRD negativity more than 2-fold at 10-5, and more than 4-fold at 10-6 vs SOC,” Mateos said.

Patient-Reported Outcome and Safety Revelations

Cilta-cel was also found to significantly improve quality of life vs SOC by extending time to symptom worsening (HR, 0.38; 95% CI, 0.24-0.61; P < .0001).

The toxicity profile of the CAR T-cell therapy was consistent with prior analyses. Both treatment arms experienced grade 3 and 4 treatment-emergent adverse effects, with cytopenia most frequently reported. Notably, no new cases of cranial nerve palsy or movement and neurocognitive effects were observed in the cilta-cel vs the prior report.

Disclosures: Dr Mateos disclosed receipt of honoraria from AbbVie, Amgen, BMS, GSK, Johnson & Johnson, Pfizer, Regeneron, Sanofi, and Stemline. She has participated in an advisory role for AbbVie, Amgen, BMS, GSK, Johnson & Johnson, Kit, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, Stemline, and Takeda.

References

1. Mateos M-V, San-Miguel J, Dhakal B, et al. Overall survival with ciltacabtagene autoleucel versus standard of care in lenalidomide-refractory multiple myeloma: phase 3 CARTITUDE-4 study update. Presented at: 51st Annual EBMT Meeting; March 30-April 2, 2025; Florence, Italy. Abstract OS14-02.
2. Carvykti. Prescribing information. Janssen Biotech, Inc.; April 2024. Accessed April 1, 2025. https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/CARVYKTI-pi.pdf
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 April 1, 2025. https://www.jnj.com/media-center/press-releases/carvykti-is-the-first-and-only-bcma-targeted-treatment-approved-by-the-u-s-fda-for-patients-with-relapsed-or-refractory-multiple-myeloma-who-have-received-at-least-one-prior-line-of-therapy