Effective Bridging Therapy Correlates With Improved PFS After Cilta-Cel in Multiple Myeloma

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Ciltacabtagene autoleucel (cilta-cel; Carvykti) led to prolonged progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma who experienced a 25% or greater tumor burden reduction between baseline and the start of lymphodepletion pre-infusion vs those who did not, according to data from the phase 3 CARTITUDE-4 trial (NCT04181827) presented at the 51st Annual EBMT Meeting.1

The estimated 15-month PFS rate was 87.5% (95% CI, 80.6%-92.1%) in patients who had a 25% or greater reduction in tumor burden between baseline and start of lymphodepletion vs 74.0% (95% CI, 52.9%-86.7%) in those whose change was less than 25%. At a median follow-up of 15.9 months, the median PFS was not reached (95% CI, not estimable [NE]-NE) in those with a 25% or greater reduction in tumor burden vs 19.2 months (95% CI, 15.8-NE) in those who experienced a decrease below 25% (HR, 0.32; 95% CI, 0.16-0.66).

“In CARTITUDE-4, an improved response to bridging therapy correlates with longer PFS, highlighting the importance of optimizing bridging therapy for effective disease control prior to administering cilta-cel,” lead study author Martin Vogel, of Johnson & Johnson, Neuss, Germany, and coauthors, wrote in the poster. “The correlation between tumor burden reduction and PFS may be explained mechanistically by a higher in vivo E:T [effector-to-target cell] ratio (calculated by the ratio peak CAR-T expansion and pre-infusion soluble BCMA [sBCMA]), which was previously shown to be associated with longer PFS with cilta-cel.”

Prior findings from CARTITUDE-4 illustrated a high overall response rate (99.4%), complete response or better rate (86.4%), and 12-month PFS rate (89.7%) in patients who did not have disease progression prior to cilta-cel infusion. Initial findings from the study served as the basis for the FDA approval of cilta-cel for the treatment of patients with relapsed or refractory multiple myeloma who have received at least 1 prior line of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), and are refractory to lenalidomide (Revlimid).2

Bridging therapy is often used to control disease during CAR T-cell therapy manufacturing, with the intention of reducing the risk of toxicity through tumor debulking.1 However, the relationship between disease control before CAR T-cell therapy infusion and post-infusion outcomes is not well understood.

As such, investigators conducted a post-hoc analysis of cilta-cel’s efficacy according to bridging therapy use in the pivotal CARTITUDE-4 trial.

The trial enrolled patients at least 18 years of age with multiple myeloma who had received between 1 and 3 prior lines of therapy, including a PI and IMiD. Patients were required to be refractory to lenalidomide and have an ECOG performance status of 0 or 1. Patients who had received prior CAR T-cell therapy or BCMA-directed therapy were excluded. Patients underwent a 1:1 random assignment to standard-of-care treatment with pomalidomide (Pomalyst), bortezomib (Velcade), and dexamethasone (PVd) or daratumumab (Darzalex), pomalidomide, and dexamethasone (DPd); or apheresis and bridging therapy with at least 1 cycle of PVd or DPd, followed by a single infusion of cilta-cel at a target dose of 0.75 x 106 CAR+ T cells/kg 5 to 7 days after the start of lymphodepletion.

PFS was evaluated from randomization and analyzed in patients with at least a 25% tumor burden reduction from baseline to the start of lymphodepletion vs those with less than a 25% tumor burden reduction. Tumor burden change was calculated by determining the difference between paraprotein at baseline and at lymphodepletion for each patient. In vivo E:T ratio was calculated by peak CAR T-cell expansion, according to flow cytometry, normalized to pre-infusion serum sBCMA levels.

A total of 176 patients received cilta-cel as study treatment, 158 of whom received DPd and 18 of whom received PVd. During bridging therapy, 84% (n = 148) of patients experienced a 25% or greater tumor burden reduction, and 16% (n = 28) had less than a 25% decrease. Relative to those who had less than a 25% decrease, the population of patients who had at least a 25% decrease had more patients with International Staging System stage I disease (70.9% vs 57.1%) and fewer patients with at least 60% plasma cells (15.6% vs 35.7%).

In the group of patients who experienced at least a 25% decrease in tumor burden, the median years since diagnosis was 3.4 (range, 0.3-18.1); 16.9% (n = 25) of patients also had soft tissue plasmacytomas and 59.9% (n = 88) had high cytogenetic risk. In the group of patients who had less than a 25% reduction, the median years since diagnosis was 3.2 (range, 0.3-12.1); 17.9% (n = 5) had soft tissue plasmacytomas and 60.7% (n = 17) had high cytogenetic risk. 

Additional biomarker corelative analyses were performed to understand the relationship between response to bridging therapy and post cilta-cel outcomes. Results illustrated that patients who had a 25% or greater reduction in tumor burden had comparable CAR T peak expansion in the blood (Cmax; median, 479.5 vs 508 cells/mL), lower sBCMA levels pre-infusion (median, 6.2 vs 64.0 mg/mL), and a significantly higher in vivo E:T ratio (median, 62.6 vs 5.4) vs those whose reduction was less than 25%.

Also of note was the fact that lower pre-infusion sBCMA levels were seen in patients with greater tumor burden reduction, although no difference in Cmax was seen. Additionally, the in vivo E:T ratio, adjusted for baseline tumor burden variations, was higher in patients whose bridging therapy was effective.

Furthermore, patients with higher E:T ratios demonstrated improved PFS. “In vivo E:T ratio has previously been shown to have a strong correlation with PFS in cilta-cel–treated patients,” the authors explained. “In vivo E:T ratio is defined by the ratio of Cmax to tumor burden (pre-infusion sBCMA). Our data show that Cmax is similar in both higher and lower tumor burden subgroups, hence the key driver of association to higher PFS probability is reduced tumor burden at baseline, estimated by pre-infusion sBCMA.”

They concluded that the data support the benefits of effective bridging therapy, and that additional research is needed to further optimize bridging strategies to maximize patient outcomes.

Disclosures: Vogel is currently employed by and has stock ownership in Johnson & Johnson.

References

1. Effectiveness of bridging therapy corresponds to improved outcomes after receiving CAR-T therapy: phase 3 CARTITUDE-4 study of patients with relapsed, lenalidomide-refractory multiple myeloma. Presented at: 51st Annual EBMT Meeting; March 30-April 2, 2025. Florence, Italy. Abstract A347.
2. 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 least one prior line of therapy. News release. Johnson & Johnson. April 5, 2024. Accessed March 31, 2025. https://www.jnj.com/media-center/press-releases/carvykti-is-the-first-and-only-bcma-targeted-treatment-approved-by-the-u-s-fda-for-patients-with-relapsed-or-refractory-multiple-myeloma-who-have-received-at-least-one-prior-line-of-therapy