Long-Term CARTITUDE-4 Data Point to Potential Cure Fraction With Cilta-Cel in Standard-Risk R/R Myeloma

Long-term data from the phase 3 CARTITUDE-4 trial (NCT04181827) demonstrated that patients with standard-risk relapsed/refractory multiple myeloma experienced low rates of disease progression when treated with ciltacabtagene autoleucel (cilta-cel; Carvykti), suggesting a potential cure fraction in this patient population.¹

Findings presented at the 2025 ASH Annual Meeting and Exposition showed that in the standard-risk, as-treated patient population from CARTITUDE-4 (n = 59), cilta-cel elicited a 30-month progression-free survival (PFS) rate of 80.5% and a 30-month overall survival (OS) rate of 87.3%. When expanding this population to include patients harboring 1q gains or amplifications (n = 105), the 30-month PFS and OS rates were 71.7% and 86.1%, respectively.

Notably, 86% of patients with standard-risk cytogenetics (n = 51/59) were alive and progression-free 1 year after treatment; the respective 30-month PFS and OS rates for this subgroup were 93.1% and 93.7%. Furthermore, 81% of evaluable patients at 1 year (n = 26/32) achieved a minimal residual disease (MRD)–negative complete response (CR). All of these patients remained progression-free at 30 months.

“We believe that low rates of progression seen in these [standard-risk] patients are indicative of a potential cure fraction, which will be further defined with additional follow-up,” lead study author Luciano Costa, MD, said in a presentation of the data.

Costa is the Mary and Bill Battle Professor of Multiple Myeloma and director of the Multiple Myeloma Research and Treatment Program at The University of Alabama at Birmingham.

What data were previously reported from CARTITUDE-4?

In April 2024, the FDA approved cilta-cel 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 (PI) and an immunomodulatory agent (IMiD), and who are refractory to lenalidomide (Revlimid), based on prior data from CARTITUDE-4.² The CAR T-cell therapy was initially approved by the FDA in February 2022 for the treatment of adult patients with relapsed/refractory multiple myeloma following 4 or more prior lines of therapy, including a PI, an IMiD, and an anti-CD38 monoclonal antibody, based on findings from the phase 1/2 CARTITUDE-1 trial (NCT03548207).³

In CARTITUDE-4, at a median follow-up of 33.6 months (range, 0.1-45.0), patients with standard-risk cytogenetics treated with cilta-cel (n = 69) achieved a 30-month PFS rate of 71.0% compared with 43.2% for those treated with standard-of-care (SOC) therapy (n = 70; HR, 0.43).^1,4 The 30-month OS rates were 79.7% and 69.6%, respectively (HR, 0.62).¹ In patients with high-risk cytogenetics, the 30-month PFS rates were 52.3% for cilta-cel (n = 123) vs 17.5% for SOC (n = 123; HR, 0.38). The 30-month OS rates in the high-risk subgroup were 75.5% and 62.1%, respectively (HR, 0.54).

How was the CARTITUDE-4 trial designed?

Investigators enrolled patients at least 18 years of age with relapsed/refractory multiple myeloma who had received 1 to 3 prior lines of therapy, including a PI and IMiD, and were refractory to lenalidomide. Patients needed to have an ECOG performance status of 0 or 1, and prior treatment with CAR T-cell therapy or a BMCA-targeted therapy was not allowed.

Patients were randomly assigned 1:1 to receive cilta-cel or SOC therapy comprising pomalidomide (Pomalyst) plus bortezomib (Velcade) and dexamethasone or daratumumab (Darzalex) plus pomalidomide and dexamethasone.

PFS served as the trial’s primary end point, and secondary end points comprised CR or better rate, overall response rate (ORR), MRD-negativity rate, OS, and safety.

For the current long-term analysis of CARTITUDE-4, the as-treated population included patients with standard-risk cytogenetics per study protocol, along with those harboring only 1q gains or amplifications. Investigators also examined long-term outcomes for patients with standard-risk cytogenetics, including those with 1q gains or amplifications, treated in CARTITUDE-1.

In the CARTITUDE-4 as-treated population, including those with 1q gain/amplification, the median age was 62.0 years (range, 27-78), and 52.4% of patients were male. International Staging System (ISS) stages included I (71.4%), II (23.8%), and III (4.8%). Patients received 1 prior line of therapy (31.4%), 2 prior lines of therapy (40.0%), or 3 prior lines of therapy (28.6%), with a median of 2 prior lines of therapy (range, 1-3). All patients were refractory to lenalidomide, 20.0% were refractory to daratumumab, and 10.5% were triple-class refractory. Notably, 5.7% of patients had soft tissue plasmacytomas.

In the CARTITUDE-1 standard-risk population, which included those with 1q gain/amplification (n = 68), the median age was 60.5 years (range, 43-78), and 57.4% were male. Patients had ISS stage I disease (58.8%), stage II disease (22.1%), or stage III disease (19.1%). Notably, 16.2% of patients in this study received 3 prior lines of therapy, and the remainder were administered at least 4 prior lines of therapy; the median was 6 prior lines of therapy (range, 3-18). In the CARTITUDE-1 population, 77.9% were refractory to lenalidomide, 97.1% were refractory to daratumumab, and 89.7% were triple-class refractory. Soft tissue plasmacytomas were reported in 16.2% of patients at baseline.

What other outcomes were reported at this year’s ASH Annual Meeting?

Findings from the analysis also showed that the ORR was 100% for patients with standard-risk cytogenetics without 1q gain/amplification treated with cilta-cel in CARTITUDE-4, including a CR or better rate of 90%. When including patients with 1q gain/amplification, the ORR remained at 100%, with a CR or better rate of 92%. In the CARTITUDE-1 population, the ORR was 94.1%, with a CR or better rate of 82%.

In the CARTITUDE-1 group, the 30-month PFS and OS rates were 59.9% and 70.6%, respectively.

In the CARTITUDE-4 standard-risk subgroup without 1q gain/amplification, the safety profiled of cilta-cel was consistent with the overall study population. Non-hematologic serious adverse effects occurred in 52.5% of patients, and 28.8% had grade 3/4 infections. Any-grade cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome were reported in 74.6% and 1.7% of patients, respectively. Additionally, 6.8% of patients had cranial nerve palsy, and no patients had immune effector cell–parkinsonism.

Secondary primary malignancies were reported in 13.6% of patients in the CARTITUDE-4 standard-risk subgroup, including cutaneous/non-invasive malignancies (n = 4) and non-cutaneous/invasive malignancies (n = 4). No secondary hematologic malignancies were reported.

The non-relapsed mortality rate was 10.2%; this included 4 deaths reported in the first year due to COVID-19 (n = 2), subdural hematoma (n = 1), and multiple organ dysfunction (n = 1). The 2 deaths that occurred beyond 1 year were attributed to gastric adenocarcinoma (n = 1) and angiosarcoma (n = 1).

Disclosures: Costa reported receiving honoraria from AbbVie, Pfizer, AstraZeneca, Johnson & Johnson, Regeneron, Amgen, Sanofi, Bristol Myers Squibb, Adaptive Biotechnologies, and Genentech; consultancy (including expert testimony) for Caribou, Regeneron, Sanofi, Pfizer, Genentech, Johnson & Johnson, Bristol Myers Squibb, AbbVie, and Amgen; and receiving research funding from Genentech, AstraZeneca, AbbVie, Pfizer, Bristol Myers Squibb, Johnson & Johnson, Caribou, and Amgen.

References

1. Costa L, Oriol A, Dytfield D, et al. Long-term progression-free survival benefit with ciltacabtagene autoleucel in standard-risk relapsed/refractory multiple myeloma. Blood. 2025;146(suppl 1):94. doi:10.1182/blood-2025-94
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 lease one prior line of therapy. News release. Johnson & Johnson. April 5, 2024. Accessed December 6, 2024. 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
3. FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. February 28, 2022. Accessed December 6, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ciltacabtagene-autoleucel-relapsed-or-refractory-multiple-myeloma
4. Sidana S, Martinez-Lopez J, Khan AM, et al. Ciltacabtagene autoleucel (cilta-cel) vs standard of care (SOC) in patients (pts) with relapsed/refractory multiple myeloma (MM): CARTITUDE-4 survival subgroup analyses. J Clin Oncol. 2025;43(suppl 16):7539. doi:10.1200/JCO.2025.43.16_suppl.7539