Cilta-Cel Significantly Boosts MRD Negativity Rates in Lenalidomide-Refractory Myeloma

Cilta-Cel in Lenalidomide-Refractory

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Treatment with ciltacabtagene autoleucel (cilta-cel; Carvykti) significantly increased overall rates of minimal residual disease (MRD)–negativity at a 10–5 threshold compared with standard of care (SOC) in patients with lenalidomide (Revlimid)–refractory multiple myeloma following 1 to 3 lines of therapy, according to an analysis of MRD negativity outcomes from the phase 3 CARTITUDE-4 trial (NCT04181827).1

Findings, which were presented at the 51st Annual EBMT Meeting and at the 2025 Transplantation and Cellular Therapy Meetings, revealed that 69% of evaluable patients who received cilta-cel (n = 145) achieved MRD negativity at a threshold of 10–5 by day 56 following cilta-cel infusion; this rate rose to 86% 6 months after infusion. Among patients in the intention-to-treat (ITT) population who received cilta-cel (n = 208), these respective rates were 48% and 60%. In the MRD-evaluable population, the odds ratio (OR) for MRD negativity at a threshold of 10–5 between the cilta-cel and SOC (n = 103) arms was 13.3 (P < .0001). In the ITT population, the OR for MRD negativity at a threshold of 10–5 between the cilta-cel and SOC (n = 211) arms was 7.6 (P < .0001).

Most patients in the cilta-cel arm who were MRD negative at a sensitivity of 10–5 remained MRD negative at a sensitivity of 10–6. In the MRD-evaluable population, the OR for MRD negativity at a threshold of 10–6 between the cilta-cel (n = 139) and SOC (n = 102) arms was 28.5 (P < .0001). In the ITT population, the OR for MRD negativity at a threshold of 10–6 between the cilta-cel and SOC arms was 7.6 (P < .0001).

Of note, among patients evaluable for MRD who received cilta-cel vs SOC, the rates of MRD negativity at a threshold of 10–5 with complete response (CR) or better were 82.1% vs 25.2%, respectively. Specifically, among those treated with cilta-cel, 51.7% sustained MRD negativity and CR for at least 12 months; 11.0% required additional sample confirmation; and 19.3% had disease progression, received subsequent systemic therapy, or died after MRD negativity with a CR or better. Among patients who received SOC, 9.7% sustained MRD negativity with at least a CR; 9.7% required additional sample confirmation; and 5.8% had disease progression, received subsequent systemic therapy, or died after MRD negativity with a CR or better.

“The probability of MRD negativity at any time in the ITT population with a sensitivity level of 10–5 was more than 3-fold higher for patients in the cilta-cel group as compared with [those in] the control group, and the achievement of MRD negativity was very quick,” Michele Cavo, MD, of IRCCS Azienda Ospedaliero-Universitaria di Bologna, Seràgnoli Institute of Hematology, and Bologna University School of Medicine in Italy, said during a presentation of the data.

Background and CARTITUDE-4 Design

The randomized study included patients at least 18 years of age with multiple myeloma who had previously received 1 to 3 lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD); were refractory to lenalidomide; and had an ECOG performance status of 0 or 1. Patients in the ITT population (n = 419) were randomly assigned 1:1 to receive cilta-cel or SOC. SOC treatment consisted of pomalidomide (Pomalyst) plus bortezomib (Velcade) and dexamethasone, or daratumumab (Darzalex) plus pomalidomide and dexamethasone. Patients in the cilta-cel arm underwent apheresis and lymphodepletion before day 1 of cilta-cel infusion.

Overall survival (OS) data from the ITT population of CARTITUDE-4 were previously presented at the 2024 International Myeloma Society Annual Meeting.2 Notably, the 30-month OS rates were 76.4% vs 63.8% with cilta-cel vs SOC (HR, 0.55; 95% CI, 0.39-0.79; P = .0009), and the median OS was not reached (NR) with cilta-cel. Patients in the ITT population treated with cilta-cel also achieved significantly improved progression-free survival (PFS) compared with those who received SOC (HR, 0.29; 95% CI, 0.22-0.39; P < .0001); the median PFS was NR with cilta-cel.

Additional Efficacy Data

In the present analysis, among patients with sustained MRD negativity with a CR or better after cilta-cel infusion (n = 75), the 30-month PFS rate was 93.2% compared with 46.8% among those with MRD-positive disease missing MRD data, or non-evaluable disease (n = 79); The 30-month OS rates were 97.3% vs 64.6%, respectively.1

“The PFS benefit afforded by cilta-cel compared with [SOC] was retained across almost all pre-specified subgroups of patients, including several difficult-to-treat populations, such as [patients] with extramedullary disease, patients with high-risk cytogenetic profiles, and patients with triple-class refractoriness,” Cavo noted during the presentation.

Biological Correlate Findings

A comparison between patients with MRD-positive disease with a CR or better and those with MRD-negative disease with a CR or better showed that MRD negativity with CR or better was associated with enhanced immune fitness at apheresis, including higher levels of CD4-positive T cells naive to BCMA-targeted agents (evaluable MRD-negative patients, n = 109; evaluable MRD-positive patients, n = 16; P = .013) and lower levels of CD4-positive effector memory cells (n = 109; n = 16; P = .000606); lower levels of the inflammatory cytokine IFN-γ prior to infusion (n = 109; n = 16; P = .02); and higher levels of CAR-positive T-cell expansion, including serum BCMA levels prior to infusion (n = 116; n = 17; P = .516) and maximum serum concentration levels (n = 117; n = 17; P = .019). Notably, these covariates were also associated with longer PFS outcomes in the phase 1/2 CARTITUDE-1 trial (NCT03548207), which evaluated cilta-cel in patients with relapsed/refractory multiple myeloma who had previously received at least 3 prior lines of therapy or were double-refractory to an IMiD and a PI.3

Comparison With CARTITUDE-1

Furthermore, investigators of the present analysis compared 30-month PFS and OS rates between the cilta-cel arm of CARTITUDE-4 and CARTITUDE-1.1 The 30-month PFS rate was 54.2% among patients from CARTITUDE-1 (n = 97) vs 68.4% among those who received cilta-cel in CARTITUDE-4 (n = 176); these respective rates for 30-month OS were 68.0% vs 84.3%. Notably, the higher 30-month PFS and OS rates seen in CARTITUDE-4 vs CARTITUDE-1 corresponded with the higher rates of MRD negativity that were observed in CARTITUDE-4, which enrolled patients who had received fewer prior lines of therapy compared with those in CARTITUDE-1.

“Overall, these results do highlight the benefit of [using] a CAR T-cell [therapy] targeting BCMA in earlier lines of therapy,” Cavo concluded.

Disclosures: Cavo reported performing consultant roles with Amgen, Bristol-Myers Squibb, Celgene, GSK, Janssen, Menarini Stemline, Pfizer, and Sanofi; performing speakers bureau roles with Amgen, Celgene, Janssen, and Sanofi; receiving honoraria from Amgen, Bristol-Myers Squibb, Celgene, GSK, Janssen, Pfizer, and Sanofi; and performing scientific advisory board roles with Amgen, Bristol-Myers Squibb, Celgene, GSK, Janssen, Pfizer, and Sanofi.

References

1. Cavo M, Popat R, Oriol A, et al. Ciltacabtagene autoleucel vs standard of care in lenalidomide-refractory multiple myeloma after 1-3 lines of therapy: minimal residual disease negativity in phase 3 CARTITUDE-4 trial. Presented at: EBMT 51st Annual Meeting; March 30-April 2, 2025. Florence, Italy. Abstract OS14-05.
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. A study of JNJ-68284528, a chimeric antigen receptor T cell (CAR-T) therapy directed against B-cell maturation antigen (BCMA) in participants with relapsed or refractory multiple myeloma (CARTITUDE-1). ClinicalTrials.gov. Updated April 2, 2024. Accessed April 1, 2025. https://clinicaltrials.gov/study/NCT03548207