Earlier Cilta-Cel Improves Myeloma Outcomes Via Enhanced Immune Fitness

Administration of the chimeric antigen receptor (CAR) T-cell therapy ciltacabtagene autoleucel (cilta-cel; Carvykti) in earlier lines of therapy for patients with relapsed/refractory multiple myeloma (RRMM) is associated with significantly improved clinical outcomes, driven by superior baseline immune health and a more favorable tumor microenvironment (TME).¹

New correlative analyses from the CARTITUDE-1 (NCT03548207) and CARTITUDE-4 (NCT04181827)clinical trials presented at the 67th American Society of Hematology Annual Meeting and Exposition provide a biological rationale for initiating CAR T-cell therapy before immune fitness deteriorates.

The analysis evaluated data from 273 patients across the 2 studies. CARTITUDE-1 enrolled heavily pretreated patients with ≥3 prior lines of therapy, whereas CARTITUDE-4 compared cilta-cel against standard of care in patients with 1 to 3 previous lines of therapy.

Clinical efficacy data demonstrated a clear benefit to earlier intervention. While patients in CARTITUDE-1 achieved a median progression-free survival (PFS) of 34.9 months, the median PFS was not reached for patients in the CARTITUDE-4 cohort at a median follow-up of 34.0 months. Furthermore, overall survival analyses stratified by line of therapy indicated that patients treated at 1 previous line of therapy experienced the highest survival rates, followed sequentially by those at 2, 3, and 4 or more previous lines.

“Our data support treating patients with relapsed/refractory myeloma with cilta-cel in earlier lines of therapy,” said Samir Parekh, MBBS, professor of Medicine (Hematology and Medical Oncology) and Oncological Sciences at the Icahn School of Medicine at Mount Sinai in New York, New York.

Baseline Immune Fitness Correlations

Investigating the mechanisms driving these outcomes, researchers utilized flow cytometry on peripheral blood and bulk RNA sequencing on bone marrow aspirates. A key finding was the condition of the patient’s immune system at apheresis. Patients who had undergone 1 or 2 previous lines of therapy exhibited significantly higher percentages of CD4-positive naive T cells in peripheral blood compared with those with 3 or more previous lines of therapy (P <.001). High baseline levels of these cells were strongly correlated with longer PFS, suggesting they serve as a marker for immune fitness necessary for optimal CAR T expansion and persistence.

Notably, the deterioration of immune fitness appears to plateau; no significant differences in CD4-positive naive T-cell levels were observed between patients with 3 to 4, 5 to 6, or 7 or more prior lines of therapy.

The Tumor Microenvironment

Beyond peripheral blood, the baseline TME in patients treated earlier (1 to 2 previous lines of therapy) was distinct from those treated later. The earlier-line TME was characterized by elevated gene expression scores for costimulatory molecules, the MHCII pathway (critical for antigen presentation), and the TCRA pathway (associated with T-cell activation).

Postinfusion analyses revealed that successful treatment with cilta-cel induces a profound immune response within the TME. In patients achieving durable responses, therapy triggered the activation of beneficial myeloid cells—specifically M1 tumor-associated macrophages (TAMs)—and broad T-cell activation. Patients with a PFS exceeding 18 months demonstrated higher levels of M1 TAMs at day 28 postinfusion. Conversely, patients with a PFS of 18 months or less exhibited an increasingly immune-suppressive TME over time, marked by higher levels of regulatory T cells and upregulation of epithelial-mesenchymal transition and PI3K/AKT pathways.

In the CARTITUDE-1 cohort, long-term responders (PFS ≥5 years) displayed significantly higher T-cell receptor repertoire diversity (P =.03) and a higher proportion of expanded endogenous CD4 memory T-cell clonotypes (P =.02) at day 28.

These findings suggest that the superior efficacy of cilta-cel in earlier lines of therapy is not solely a function of lower tumor burden but is mechanistically linked to a more immunocompetent host environment.

Earlier Findings From CARTITUDE-4

Data presented at the 66th ASH Annual Meeting and 2025 Transplant and Cellular Therapy Meetings showed that cilta-cel significantly increased measurable residual disease negativity rates compared with standard of care, with sustained responses in patients with lenalidomide-refractory myeloma after 1 to 3 previous lines of therapy.^2,3

Cilta-cel also showed a 45% reduction in the risk of death vs standard of care in lenalidomide-refractory myeloma and at least 1 prior line of therapy in data presented at the 2024 International Myeloma Society Annual Meeting.⁴

In April 2024, the FDA approved cilta-cel for patients with RRMM after at least 1 prior line of therapy who are refractory to lenalidomide, updating the previous indication for patients who had received at least 4 prior lines of therapy.⁵

DISCLOSURES: Parekh reported research funding from the Multiple Myeloma Research Foundation, Caribou, GRAIL, Bristol Myers Squibb, and Amgen, as well as consultancy with GRAIL and Genentech.

REFERENCES

1. 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: 67th American Society of Hematology Annual Meeting and Exposition; December 6–9, 2025; Orlando, Florida. Abstract 92.

2. Popat R, Oriol A, Cavo M, et al. Ciltacabtagene autoleucel (cilta-cel) vs standard of care (SoC) in patients with lenalidomide (Len)-refractory multiple myeloma (MM) after 1-3 lines of therapy: minimal residual disease (MRD) negativity in the phase 3 CARTITUDE-4 trial. Blood. 2024;144(suppl 1):1032. doi:10.1182/blood-2024-198104

3. Popat R, Oriol A, Cavo M, et al. Ciltacabtagene autoleucel vs standard of care in patients with lenalidomide-refractory multiple myeloma after 1-3 lines of therapy: Minimal residual disease negativity in the phase 3 CARTITUDE-4 trial. Presented at: 2025 Transplant and Cellular Therapy Meetings; February 12-15, 2025; Honolulu, HI. Abstract 44.

4. Mateos M-V, San-Miguel J, Dhakal, et al. Overall Survival (OS) With Ciltacabtagene Autoleucel (Cilta-cel) Versus Standard of Care (SoC) in Lenalidomide (Len)-Refractory Multiple Myeloma (MM): Phase 3 CARTITUDE-4 Study Update. Presented at: 2024 International Myeloma Society Annual Meeting; September 25-28, 2024; Rio de Janeiro, Brazil. Abstract OA – 65.

5. Carvykti is the first and only BCMA-targeted treatment approved by the US FDA for patients with relapsed or refractory multiple myeloma who have received at lease one prior line of therapy. News release. Johnson & Johnson. April 5, 2024. Accessed December 6, 2025. https://tinyurl.com/43znj9t2