Key Clinical Summary

• Correlative analyses from CARTITUDE-1 and CARTITUDE-4 show that earlier use of ciltacabtagene autoleucel (cilta-cel) is associated with better baseline immune fitness and longer progression-free survival (PFS).
• Patients with fewer prior lines of therapy (pLOT) had higher CD4⁺ naïve T-cell levels, stronger immune activation post-infusion, and deeper B-cell depletion and recovery patterns.
• Findings support improved clinical benefit when cilta-cel is used earlier in relapsed/refractory multiple myeloma management.

New biomarker data from the CARTITUDE-1 and CARTITUDE-4 trials demonstrate that earlier administration of ciltacabtagene autoleucel (cilta-cel) may enhance immune fitness and treatment durability in relapsed/refractory multiple myeloma (RRMM). The analysis, presented by investigators from Mount Sinai, Mayo Clinic, Amsterdam University Medical Center, and global collaborators, correlated peripheral blood and bone marrow tumor microenvironment (TME) biomarkers with survival outcomes.

Study Findings

Across CARTITUDE-1 and CARTITUDE-4, 273 patients received cilta-cel, with immunophenotyping available for 248 peripheral blood samples. CD4⁺ naïve T-cell percentages at apheresis were significantly higher among patients treated after one or two prior therapy lines compared with those receiving 3 or more. Importantly, higher baseline CD4⁺ naïve T-cell levels predicted longer PFS, and immune deterioration appeared to plateau beyond 3 pLOT.

Bone marrow gene expression analyses from 148 samples in CARTITUDE-4 showed marked B-cell and antibody depletion at day 28 post-infusion, followed by partial recovery at 6 months. This pattern was validated using flow cytometry and immunoglobulin measurements. Concurrently, gene signatures indicated increased activity of myeloid cells—particularly M1 tumor-associated macrophages—and cytotoxic T cells at day 28.

Patients with PFS beyond 18 months demonstrated higher M1 macrophage expression at day 28, whereas those with early relapse showed increased regulatory T-cell signatures and suppressed interferon pathways at six months. Earlier-line patients also exhibited more profound early B-cell depletion, stronger recovery, and higher B-cell receptor signaling.

Overall, data suggest that both peripheral immune fitness and TME dynamics influence treatment durability. Investigators conclude that earlier cilta-cel use yields stronger immune responses, enhances TME remodeling, and improves PFS relative to later-line administration.

Clinical Implications

These findings reinforce the clinical value of administering cilta-cel earlier in the treatment pathway for RRMM, particularly before significant decline in T-cell immune fitness. Higher CD4⁺ naïve T-cell levels at apheresis appear to contribute directly to improved response durability, aligning with broader evidence that CAR-T outcomes depend on baseline immune profiles.

Enhanced immune activation in the bone marrow—characterized by cytotoxic T-cell expansion, M1 macrophage activation, and B-cell signaling restoration—may underpin prolonged disease control. For clinicians, these biomarker insights support early referral for CAR-T therapy, careful assessment of prior treatment burden, and consideration of immunologic readiness during patient selection.

Moreover, recognizing immune suppression patterns associated with relapse may guide monitoring strategies and development of combination or consolidation approaches aimed at sustaining CAR-T activity.

Conclusion

Correlative biomarker evidence from CARTITUDE-1 and CARTITUDE-4 demonstrates that earlier-line cilta-cel therapy is linked with stronger immune responses and improved PFS in RRMM. These data support shifting CAR-T intervention earlier in the treatment continuum to optimize clinical benefit.

Reference

Parekh S, Li K, Van De Donk NWCJ et al. Earlier use of ciltacabtagene autoleucel (cilta-cel) is associated with better immune fitness and stronger immune effects as shown by correlative analysis of peripheral blood and the bone marrow tumor microenvironment (TME) from the CARTITUDE-4 study. Presented at: ASH 2025; December 6-9, 2025; Orlando, Florida.