Research Summary
For patients with heavily pretreated relapsed/refractory multiple myeloma (RRMM), prior reports have shown median progression-free survival (PFS) of less than six months and median overall survival (OS) of approximately one year. Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)–directed chimeric antigen receptor T-cell (CAR-T) therapy, produced deep and durable responses in the Phase Ib/II CARTITUDE-1 trial and further improved PFS and OS in the earlier-line Phase III CARTITUDE-4 study. CARTITUDE-1 was a Phase Ib/II, open-label, multicenter study of cilta-cel in patients with RRMM who had at least three prior lines of therapy. This post hoc analysis of CARTITUDE-1 by Jagannath et al1 described OS, five-year and longer progression-free outcomes, associated biomarkers, and safety at a median follow-up of 61.3 months.
From July 2018 to October 2019, 97 patients were treated with cilta-cel. At the February 2025 cutoff (median follow-up: 61.3 months), 47 deaths had occurred. Three patients were lost to follow-up, including two without progressive disease (PD) and one after progression at last follow-up. Two patients withdrew after PD, leaving 45 alive in the long-term follow-up. Ninety-four of 97 patients (97%) were daratumumab-refractory, and 85 (87.6%) were triple-class refractory. Twenty-three patients (25.3%) had high-risk cytogenetics, and 13 (13.4%) had extramedullary plasmacytomas. The median time from the start of the last line of therapy to progression on that line was 4.2 months. At the time of data cutoff, median OS was 60.7 months (95% confidence interval [CI]: 41.9–not estimable).
There were 32 patients (33%) who remained alive and progression-free for at least five years after a single cilta-cel infusion without maintenance therapy. Of these 32 patients, 31 (96.9%) achieved stringent complete response (sCR) as best response by independent review committee assessment; independent review was not available for one patient, who had sCR as determined by investigator assessment. There were 46 patients (47%) who experienced PD within five years. Of the remaining 19 patients, 17 died without PD and two were lost to follow-up. Baseline characteristics were comparable between patients who were progression-free for at least five years and those with PD within five years; the median number of prior lines of therapy was 6.5 versus 5.0, 23.3 versus 26.7 percent of patients had high-risk cytogenetics, and 12.5 versus 13.0 percent of patients had extramedullary plasmacytomas, respectively. A lower proportion of progression-free patients versus patients with PD had high tumor burden (6.3% vs. 17.4%). Additionally, the progression-free group had numerically lower median soluble BCMA (36.0mg/L vs. 58.5mg/L, p=0.117) and bone marrow plasma cell percentage (median 5.0% vs. 24.0%, p=0.053).
Biomarker and pharmacokinetic analyses showed that patients who were progression-free for at least five years, compared to those with PD within five years, had higher effector-to-target (E:T) ratio (p=0.008) and higher CAR T-cell peak expansion (Cmax, median [interquartile range]: 961 cells/mL [482–1,380] vs. 450 cells/mL [246–1,040], p=0.028). Progression-free patients also had higher E:T ratios across most analyzed CAR-positive T-cell subsets, higher proportions of CAR-positive naïve T cells in the drug product (p=0.003), a lower neutrophil-over-leukocyte ratio at apheresis (p=0.03), and a higher T cell-to-neutrophil ratio at apheresis (p=0.05). Before infusion, progression-free patients had significantly higher hemoglobin (p=0.001) and platelet (p=0.049) levels and numerically lower ferritin (p=0.158) levels, compared to patients with PD. C-reactive protein levels were comparable between groups.
In the progression-free group, longer-term safety findings included two second primary malignancies (both solid tumors), two neurologic adverse events, and four grade 3 or greater infections, while there were no new cases of parkinsonism or cranial nerve palsies.
One limitation was that, after rollover into CARTinue, a 15-year postinfusion follow-up study, assessments followed local standard of care rather than centralized testing, potentially reducing uniform long-term data to identify predictors of response or progression. However, disease progression and survival status are reported at least annually.
This study showed that approximately one-third of patients remained in remission after five or more years after a single cilta-cel infusion without maintenance therapy in patients with heavily pretreated RRMM. Long-term remission occurred across clinical risk strata, as patients with high-risk cytogenetics and those with extramedullary plasmacytomas were similarly likely to be progression-free as those without these features. PFS was associated with a fitter immune phenotype and a higher E:T ratio at peak expansion. The proportion of patients achieving minimal residual disease negativity at the protocol-specified threshold was higher with cilta-cel in CARTITUDE-4 versus CARTITUDE-1 (73% vs. 59%), suggesting that earlier use could increase the proportion of patients who experience extended treatment-free remissions. To the authors’ knowledge, this study was the longest study follow-up after CAR-T therapy in MM, and the results potentially provide the first evidence that cilta-cel could be curative in RRMM.
Reference
- 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. 2025;43(25):2766–2771.