In long-term results from the CARTITUDE-1 trial, investigators had found that the autologous cellular immunotherapy ciltacabtagene autoleucel was potentially curative for one-third of patients with heavily pretreated relapsed or refractory multiple myeloma.1 These patients remained progression-free for at least 5 years after a single infusion of ciltacabtagene autoleucel without any subsequent or maintenance treatment.
Among a small group of these patients who were tested for measurable residual disease (MRD) and positron-emission tomography/computed tomography (PET/CT) imaging annually, all 12 patients maintained a complete metabolic response at 5 years or more after ciltacabtagene autoleucel treatment, “suggesting potential cure, or at the bare minimum, unprecedented durability of complete response,” said study author Peter M. Voorhees, MD, Professor of Cancer Medicine, Atrium Health/Levine Cancer Institute, Wake Forest University School of Medicine, Charlotte, North Carolina, when presenting the findings at the 2025 ASCO Annual Meeting.1 These study results were also simultaneously published in the Journal of Clinical Oncology.2
About the Study
Patients enrolled in the phase Ib/II CARTITUDE-1 trial had to have progressive multiple myeloma; an Eastern Cooperative Oncology Group performance status of 0 or 1; measurable disease; at least three prior lines of therapy or be double-refractory to a proteasome inhibitor and an immunomodulatory drug; and prior exposure to a proteasome inhibitor, immunomodulatory drug, and an anti-CD38 monoclonal antibody.
Following screening, 97 patients underwent apheresis then bridging therapy as needed and lymphodepletion with fludarabine and cyclophosphamide prior to infusion of ciltacabtagene autoleucel. The target dose was 0.75 × 106 chimeric antigen receptor (CAR)-positive viable T cells/kg. After the CARTITUDE-1 study analysis, patients who were still alive were allowed to go on to the CARTinue postinfusion follow-up study, which evaluated patients for 15 years to assess the durability of responses and any possible late-term toxicities.
Long-Term Findings
From the intent-to-treat population, 2 patients were lost to follow-up and 17 died. Of the remaining patients, 46 had progressive disease and 32 were progression-free for at least 5 years. Of the patients who experienced disease progression, 2 withdrew consent, 1 was lost to follow-up, and 30 died; the other 13 patients remained in postprogression follow-up.
Previously published findings showed a median progression-free survival of 34.9 months (95% confidence interval [CI] = 25.2 months to not evaluable).3 At a median follow-up of 61.3 months, the 5-year progression-free survival rate was 33%, and the median overall survival was 60.7 months (95% CI = 41.9 months to not evaluable). Almost half of all patients (45%) were still alive at 5 years. “This median overall survival of 5 years truly sets a new benchmark in this patient population,” Dr. Voorhees said.
“This median overall survival of 5 years truly sets a new benchmark in this patient population.”— PETER M. VOORHEES, MD
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A total of 12 patients who were progression-free and had achieved stringent complete response underwent serial MRD testing at a single center; all were found to have achieved MRD negativity (≤ 10-5) and PET/CT imaging negativity at 5 years or more. All but one patient achieved MRD negativity to a 10-6 threshold testing.
Comparing the baseline demographics and disease characteristics of the two groups that remained in long-term follow-up, the investigators found similar rates of high-risk cytogenetics and extramedullary plasmacytomas between those who were progression-free at 5-plus years and those who had disease progression within 5 years. Additionally, there was a similar proportion of patients in each group with triple-class–refractory disease.
However, there was an observed difference in the burden of disease between the two groups. The median rate of bone marrow plasmacytosis in the progression-free group was 5% (range, 0.8%–80%) compared with 24% in the progressive disease group (range, 0%–95%). The median soluble B-cell maturation antigen level was 36 µg/L (range, 3.7–864.6 µg/L) in the progression-free group vs 58.5 µg/L (range, 3.8–1,342.9 µg/L) in the progressive disease group. There was also a lower tumor burden in the progression-free group. “This would suggest that a lower burden of disease going into ciltacabtagene autoleucel infusion may predict better long-term outcomes,” Dr. Voorhees commented.
Correlative analysis showed there was a higher ratio of T cells to neutrophils and a higher proportion of naive T cells in the CAR T-cell drug product prior to infusion in patients who were progression-free at 5-plus years compared with those who had disease progression within 5 years. Following infusion, there was a higher effector-to-target ratio at peak expansion for patients achieving progression-free survival of 5 years or more than for those who had disease progression, in terms of both total CAR-positive T cells and CAR-positive, CD4-positive T cells with a central memory phenotype.
The safety profile for ciltacabtagene autoleucel remained consistent, with approximately an additional 28 months of follow-up. There were no new cases of parkinsonism or cranial nerve palsy observed. Two new cases of secondary primary malignancies were reported including one lung adenocarcinoma and one squamous cell carcinoma of the anus, as well as two new neurologic events of encephalopathy and a grade 1 taste disorder; however, both were not ascribed to ciltacabtagene autoleucel treatment. Four new-onset grade 3 infections were observed (appendicitis and upper respiratory tract infections), but none were considered related to treatment with ciltacabtagene autoleucel; in addition, there was one reported case of urosepsis.
Going forward, investigators are looking at earlier uses of ciltacabtagene autoleucel in the CARTITUDE-4, -5, and -6 trials as well as analyzing other methods for extending patients’ long-term remissions with CAR T-cell therapy.
Putting the Findings Into Perspective
In the prospective registry LocoMMotion study looking at real-world data for heavily pretreated patients with relapsed or refractory multiple myeloma, a patient population similar to that of the CARTITUDE-1 study had a median progression-free survival of 4.6 months and a median overall survival of 12.4 months.4 Comparatively, the median progression-free survival in the CARTITUDE-1 study was 34.9 months with ciltacabtagene autoleucel treatment, and the median overall survival was 60.7 months.
DISCLOSURE: The study was funded by Johnson & Johnson and Legend Biotech USA. Dr. Voorhees has served as a consultant or advisor to AbbVie/Genentech, Ascentage Pharma, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Kite (a Gilead company), Pfizer, Regeneron, and Sanofi; and has received institutional research funding from AbbVie, GlaxoSmithKline, Janssen, Regeneron, and TeneoBio. For full disclosures of the other study authors, visit coi.asco.org.
REFERENCES
1. Voorhees PM, Martin TG, Lin Y, et al: Long-term (≥ 5 year) remission and survival after treatment with ciltacabtagene autoleucel in CARTITUDE-1 patients with relapsed/refractory multiple myeloma. 2025 ASCO Annual Meeting. Abstract 7507. Presented June 3, 2025.
2. Jagannath S, Martin TG, Lin Y, et al: Long-term (≥ 5-year) remission and survival after treatment with ciltacabtagene autoleucel in CARTITUDE-1 patients with relapsed/refractory multiple myeloma. J Clin Oncol. June 3, 2025 (early release online).
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. 2023 ASCO Annual Meeting. Abstract 8009. Presented June 5, 2023.
4. Mateos MV, Weisel K, De Stefano V, et al: LocoMMotion: A study of real-life current standards of care in triple-class exposed patients with relapsed/refractory multiple myeloma: 2-year follow-up (final analysis). Leukemia 38:2554-2560, 2024.
