Cilta-Cel Demonstrates "Curative Potential" in R/R Multiple Myeloma

“This median overall survival of 5 years sets a new benchmark in this population,” Voorhees said. “Long-term follow-up from CARTITUDE-1, with one-third of patients remaining treatment- and progression-free for at least 5 years after a single infusion, shows the curative potential of cilta-cel in relapsed/refractory multiple myeloma," according to presenting investigator Peter M. Voorhees, MD.

A single dose of ciltacabtagene autoleucel (cilta-cel; Carvykti) elicited progression-free status across a third of patients with relapsed/refractory multiple myeloma, according to a presentation on long-term follow-up data from the phase 1b/2 CARTITUDE-1 trial (NCT03548207) at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

Additionally, the median overall survival (OS) was 60.7 months (95% CI, 41.9-not estimable). Of the patients who were progression free (n = 32), 12 of them underwent serial minimal residual disease (MRD) assessments at a single center. Data showed that all of these patients were MRD negative and experienced complete metabolic response via PET/CT imaging at the time of follow-up after cilta-cel without additional treatment, “suggesting potential cure or at a bare minimum, unprecedented durability of complete response.”

Lead study author Peter M. Voorhees, MD, a multiple myeloma specialist at Atrium Health/Levine Cancer Institute, in Charlotte, North Carolina, compared the findings historically to the LocoMMOTION trial (NCT04035226), of which the median OS was 12.4 months.²

“This median overall survival of 5 years sets a new benchmark in this population,” Voorhees said. “Long-term follow-up from CARTITUDE-1, with one-third of patients remaining treatment- and progression-free for at least 5 years after a single infusion, shows the curative potential of cilta-cel in relapsed/refractory multiple myeloma.”

Patients with heavily pretreated relapsed/refractory multiple myeloma have a general prognosis for approximately 1 year.

In the CARTITUDE-1 trial, investigators explored cilta-cel in patients with heavily pretreated relapsed/refractory multiple myeloma. Cilta-cel was given as a single infusion at a target dose of 0.75 x 10⁶ at CAR+ viable T cells/kg following apheresis, bridging therapy as needed, and lymphodepletion with fludarabine and cyclophosphamide.

To be eligible for enrollment, patients needed to have progressive relapsed/refractory multiple myeloma per International Myeloma Working Group criteria, an ECOG performance status of 1 or lower, measurable disease, 3 or more prior lines of therapy or double refractory to a proteasome inhibitor (PI) and an immunomodulatory (IMiD) agent, and prior exposure to a PI, IMiD, and anti-CD38 monoclonal antibody.

Prior data from CARTITUDE-1 showed that at a median follow-up of 33.4 months, the median PFS was 34.9 months (95% CI, 25.2-NE) and the median OS was not reached.³

In February 2022, the FDA approved cilta-cel for the treatment of adult patients with relapsed/refractory multiple myeloma after at least 4 lines of therapy, including a PI, IMiD agent, and an anti-CD38 monoclonal antibody, based on CARTITUDE-1 data.⁴

At the 2025 ASCO Annual Meeting, PFS and safety data were reported with more than 5 years of follow-up.

Analyses were conducted in 97 patients, across the phase 1b (n = 29) and phase 2 (n = 68) portions and tested for efficacy and safety. Investigators also performed post-infusion assessments from day 1 to 100, posttreatment assessments from day 101 to end of cohort, and biomarker correlative analyses.

Of the 97 patients treated, 46 patients had disease progression and discontinued study due to withdrawal of consent (n = 2), loss to follow-up (n = 1), and death (n = 30); 13 patients continued follow-up post progressive disease onto the CARTinue study (NCT05201781) for 15 years, which will have, at minimum, annual readouts. Thirty-two patients (33.0%) were alive and progression free at the extended follow-up and without further treatment, totaling 45 patients alive and in long-term follow-up.

Of the 32 patients, the median time to start of their last line of therapy to disease progression was 4.0 months (range, 0.7-48.6) prior to their enrollment on CARTITUDE-1.

In post hoc analyses, the baseline characteristics were generally comparable for patients who were progression free for 5 years or longer (n = 32) and within 5 years (n = 46), Voorhees noted, including median age (60.0 years; range, 43-78 vs 61.5 years; range, 47-77), extramedullary disease (12.5% vs 13.0%), median number of prior lines of therapy (6.5; range, 3-14 vs 5.0; range, 3-18), and high-risk cytogenetics (23.3% vs 26.7%), respectively. A total 90.6% vs 84.8%, respectively, were triple-class refractory and 46.9% vs 32.6% were penta-drug refractory.

“Importantly, there was a signal for a difference in the burden of disease between these groups of patients,” said Voorhees, noting that the in the beyond-5-years and within-5-years groups, the median bone marrow plasma cells was 5.0% (range, 0.8-80.0) vs 24.0% (range, 0.0-95.0), and soluble BCMA levels were 36.0 ug/L (range, 3.7-864.6) vs 58.5 ug/L (range, 3.8-1342.9), respectively. “This would suggest that a lower burden of disease going into cilta-cel infusion does predict for better long-term outcomes.”

Voorhees added that long-term disease control was linked with a higher fraction of naive T cells in the drug product, lower neutrophil to T-cell ratio, higher hemoglobin and platelets at baseline, and higher effector-to-target ratio.

Regarding safety in the patients progression free beyond 5 years (n = 32), the additional estimated 28 months of follow-up showed no new cases of parkinsonism or cranial nerve palsy, 2 additional cases of second primary malignancy, both of which were solid tumors (1 lung adenocarcinoma and 1 squamous cell carcinoma of the anus), and 2 neurologic events unrelated to cilta-cel were reported; there was 1 case each of encephalopathy and taste disorder. Voorhees reported 4 new-onset grade 3 infections that were also unrelated to cilta-cel.

Voorhees concluded that earlier cilta-cel use may further extend long-term remissions due to fitter CAR T-cell profiles and more effective bridging therapies to improve effector-to-target ratios.

Subgroup analysis data from the CARTITUDE-4 trial (NCT04181827), which were also presented at the meeting, suggests a plateau in the PFS curve in patients with standard-risk disease following 1 to 3 prior lines of therapy.

Looking ahead, Voorhees pointed to the CARTITUDE-5 trial (NCT04923893), which is exploring cilta-cel in patients with relapsed/refractory multiple myeloma compared with pomalidomide (Pomalyst), bortezomib (Velcade), and dexamethasone.⁵ The CARTITUDE-6 trial (NCT05257083) is testing daratumumab (Darzalex), bortezomib, lenalidomide (Revlimid) and dexamethasone (DVRd) followed by cilta-cel versus DVRd followed by autologous stem cell transplant in the newly diagnosed setting.⁶

Disclosures: Voorhees cited consulting or advisory roles with AbbVie/Genentech, Ascentage Pharma, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Kite Pharma, Pfizer, Regeneron, and Sanofi; and research funding from Abbvie (Inst), GlaxoSmithKline (Inst), Janssen (Inst), Regeneron (Inst), and TeneBio (Inst).

References

1. Voorhees PM, Martin TG, Lin Y, et al. Long-term (≥5 year) remission and survival after treatment with ciltacabtagene autoleucel (cilta-cel) in CARTITUDE-1 patients (pts) with relapsed/refractory multiple myeloma (RRMM).J Clin Oncol. 2025;43(suppl 16):7507.
2. Mateos MV, Weisel K, De Stefani V, et al. Leukemia. 2024;38(12):2554-2560. doi:10.1038/s41375-024-02404-6
3. Lin Y, Martin TG, Usmani SZ, et al. CARTITUDE-1 final results: Phase 1b/2 study of ciltacabtagene autoleucel in heavily pretreated patients with relapsed/refractory multiple myeloma. J Clin Oncol. 2023;41(suppl 16):8009. doi:JCO.2023.41.16_suppl.8009
4. US FDA approves Carvykti (ciltacabtagene autoleucel), Janssen’s first cell therapy, a BCMA-directed CAR-T immunotherapy for the treatment of patients with relapsed or refractory multiple myeloma. News release. Janssen. February 28, 2022. Accessed June 3, 2025. https://www.jnj.com/media-center/press-releases/u-s-fda-approves-carvykti-ciltacabtagene-autoleucel-janssens-first-cell-therapy-a-bcma-directed-car-t-immunotherapy-for-the-treatment-of-patients-with-relapsed-or-refractory-multiple-myeloma
5. A study comparing JNJ-68284528, a CAR-T therapy directed against B-cell Maturation Antigen (BCMA), versus pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) in participants with relapsed and lenalidomide-refractory multiple myeloma (CARTITUDE-4). ClinicalTrials.gov. Updated May 20, 2025. Accessed June 3, 2025. https://www.clinicaltrials.gov/study/NCT04181827
6. A study of daratumumab, bortezomib, lenalidomide and dexamethasone (DVRd) followed by ciltacabtagene autoleucel versus daratumumab, bortezomib, lenalidomide and dexamethasone (DVRd) followed by autologous stem cell transplant (ASCT) in participants with newly diagnosed multiple myeloma (CARTITUDE-6). ClinicalTrials.gov. Updated May 28, 2025. Accessed June 3, 2025. https://clinicaltrials.gov/study/NCT05257083