Bold claim: standard-risk myeloma treated with cilta-cel may hint at a cure fraction, not just prolonged survival. And this is where the nuance gets real, because the long-term data from CARTITUDE-4 suggest something deeper than temporary control.
New long-term results from the phase 3 CARTITUDE-4 trial (NCT04181827) indicate that patients with standard-risk relapsed/refractory multiple myeloma experience remarkably low progression with ciltacabtagene autoleucel (cilta-cel; Carvykti), pointing toward a potential cure fraction in this group. These findings were presented at the 2025 ASH Annual Meeting and Exposition. In the standard-risk, as-treated cohort (n = 59), cilta-cel yielded a 30-month progression-free survival (PFS) of 80.5% and an overall survival (OS) of 87.3%. Extending the analysis to include patients with 1q gains or amplifications (n = 105) lowered the 30-month PFS to 71.7% and the 30-month OS to 86.1%.
A striking detail: among standard-risk cytogenetics, 86% were alive and progression-free at 1 year post-treatment (n = 51 of 59). The 30-month PFS and OS in this subgroup reached 93.1% and 93.7%, respectively. In addition, 81% of evaluable patients at 1 year achieved an MRD-negative complete response (CR) (n = 26 of 32), and all of these MRD-negative CR patients remained progression-free at 30 months.
Lead author Luciano Costa, MD, described the trajectory as indicative of a potential cure fraction in standard-risk patients, noting that further follow-up is needed to define this more precisely. Costa, 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, emphasized the importance of continued observation to confirm durability.
What the CARTITUDE-4 data show about cilta-cel in standard-risk relapsed/refractory myeloma:
- In the standard-risk, as-treated population, 30-month PFS and OS were 80.5% and 87.3%, respectively. When 1q gain/amplification were included, these figures were 71.7% PFS and 86.1% OS.
- Among patients with standard-risk cytogenetics, there is a strong signal of durability: 86% were progression-free and alive at 12 months, with 93.1% PFS and 93.7% OS at 30 months for the subset with standard-risk cytogenetics.
- MRD negativity at 1 year correlated with continued progression-free status at 30 months, suggesting deeper remission may translate into long-term disease control.
Context from CARTITUDE-4 prior data: In April 2024, the FDA approved cilta-cel for adults with relapsed/refractory multiple myeloma after at least one prior therapy, including a PI and an IMiD, and who are refractory to lenalidomide, building on CARTITUDE-4 findings. Earlier FDA approval (February 2022) targeted patients who had progressed after 4 or more prior lines, based on CARTITUDE-1 results.
Long-term outcomes from CARTITUDE-4 with a median follow-up of about 33.6 months showed favorable 30-month PFS (71.0%) and OS (79.7%) in standard-risk patients treated with cilta-cel vs SOC (43.2% PFS; 69.6% OS). In the high-risk cytogenetics group, cilta-cel also outperformed SOC, with substantially better 30-month PFS and OS, reinforcing the therapy’s impact across risk strata.
Trial design overview: Eligible adults (18+) with relapsed/refractory myeloma that had 1–3 prior lines of therapy, including a PI and IMiD and who were lenalidomide-refractory, were randomized 1:1 to cilta-cel or SOC, which consisted of pomalidomide–bortezomib–dexamethasone or daratumumab–pomalidomide–dexamethasone. Primary endpoint was PFS; secondary endpoints included CR or better, overall response rate (ORR), MRD negativity, OS, and safety. The long-term analysis focused on the as-treated population (standard-risk cytogenetics, with or without 1q gain/amplification).
Baseline characteristics for the CARTITUDE-4 as-treated group (including 1q gain/amplification): median age 62, about half male; most had ISS stage I or II. Prior therapies varied, with a median of 2 lines. Nearly all were lenalidomide-refractory; a minority were refractory to daratumumab or triple-class refractory. A subset presented with soft tissue plasmacytomas.
Safety snapshot in the standard-risk subgroup without 1q gain/amplification: non-hematologic serious adverse events occurred in roughly half the patients, with 28.8% experiencing grade 3/4 infections. Cytokine release syndrome occurred in 74.6%, and immune effector cell–associated neurotoxicity syndrome in 1.7%. Some cranial nerve palsies were reported, but there were no cases of immune effector cell–parkinsonism. Second primary malignancies appeared in 13.6% of standard-risk patients, with both cutaneous and non-cutaneous cancers represented. Non-relapsed mortality stood at 10.2%, with a few deaths due to COVID-19 in year one and other causes thereafter.
Disclosures: Costa reported various consulting, honoraria, and funding relationships with multiple pharmaceutical and biotech companies.
Bottom line: the CARTITUDE-4 long-term data in standard-risk relapsed/refractory myeloma treated with cilta-cel show very high 30-month PFS and OS, particularly among those with truly standard-risk cytogenetics, and a notable proportion achieving MRD-negative CR with durability through 30 months. If follow-up confirms, these results could redefine expectations for cure-like outcomes in this setting.
Questions to ponder: Is a cure fraction truly achievable with CAR T-cell therapy in a broader myeloma population, or will relapse re-emerge in later years? How should these data influence decisions about sequencing therapies and patient selection? And for those advocating alternative interpretations, what additional evidence would be needed to settle the debate? Share your perspective in the comments.
