Indirect Comparison Shows Superiority of Cilta-Cel vs SOC Regimens in Lenalidomide-Refractory Myeloma

Michel Delforge, MD, PhD

Findings from an indirect comparison showed that ciltacabtagene autoleucel (cilta-cel; Carvykti) produced superior outcomes compared with standard-of-care (SOC) regimens in patients with relapsed/refractory multiple myeloma that was refractory to lenalidomide (Revlimid).¹

The analysis, which was presented at the 21st Annual International Myeloma Society Annual Meeting, included 208 patients who received the CAR T-cell therapy during the phase 3 CARTITUDE-4 trial (NCT04181827), along with 800 patients who received daratumumab (Darzalex)-based regimens across 9 other clinical trials. Notably, findings from CARTITUDE-4 supported the April 2024 FDA approval of cilta-cel for adult patients with relapsed or refractory multiple myeloma who have received at least 1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, and who are refractory to lenalidomide.²

Data from the indirect comparison showed that in the cilta-cel arm, the overall response rate (ORR), very good partial response (VGPR) or better rate, and complete response (CR) or better rate were 83.70%, 79.80%, and 72.10%, respectively.1 In the comparator arm, the unadjusted ORR, VGPR or better rate, and CR or better rate were 51.90%, 29.10%, and 11.90%, respectively. The respective adjusted ORR, VGPR or better rate, and CR or better rate were 59.30%, 35.30%, and 13.60%.

Benefits in favor of cilta-cel were also observed regarding progression-free survival (PFS; HR, 0.37; 95% CI, 0.26-0.52; P < .0001), real-world PFS (HR, 0.27; 95% CI, 0.19-0.37; P < .0001), and time to next treatment (HR, 0.28; 95% CI, 0.20-0.39; P < .0001).

In an interview with OncLive®, lead study author Michel Delforge, MD, PhD, detailed the methodology and patient selection criteria used in the statistical analysis, underscored the findings, and detailed the implications of these data on top of the findings derived from CARTITUDE-4.

Delforge is a professor of medicine in the Department of Hematology at the University of Leuven in Belgium.

OncLive: How did prior data from CARTITUDE-4 establish the rationale for this current study comparing the efficacy of cilta-cel with alternative treatments?"

Deforge: CARTITUDE-4 was a pivotal study because it was 1 of the first studies to explore the role of a single infusion of a CAR T-cell product—in this case, cilta-cel— compared with SOC regimens in patients with relapsed/refractory multiple myeloma. [In this setting], the SOC is usually based on combination treatments, which are given until [disease] progression. Despite the efficacy of many of these regimens, the majority of patients will ultimately [experience disease] relapse, and there is also the burden of continuous treatment.

CARTITUDE-4 compared cilta-cel with 2 SOC regimens, [including] pomalidomide [Pomalyst], bortezomib [Velcade], and dexamethasone, or daratumumab [Darzalex], pomalidomide, and dexamethasone, in patients who had received at least 1 prior line of therapy and were lenalidomide refractory. The major result of that study [showed] that there was a clear superiority of cilta-cel over SOC regimens in terms of efficacy, ORR, CR rate, PFS, and, from the most recent update, a significant benefit in overall survival [OS].

Why was it important to compare cilta-cel with other treatments commonly used in clinical practice?

[CARTITIUDE-4] was limited to 2 regimens [in the control arm]. Although [they are] effective regimens, they're not the only regimens that are currently being used in relapsed/refractory multiple myeloma. Therefore, in order to gain more evidence of the superiority of cilta-cel in both a trial-based and a real-world setting, this large dataset was used to prove the superiority of cilta-cel over all these different SOC regimens.

What was the methodology and patient selection for this analysis?

The [comparator] dataset included [patients] from 9 large phase 3 [trials], where patients received several different types of treatment regimens [featuring daratumumab]. Because these data come from clinical trials, the quality of the data [can be controlled]. These were trials in relapsed/refractory myeloma and trials conducted in newly diagnosed myeloma, where we also have data on follow-up and patient relapse to observe. We had data for which regimen they received, how well they responded, and their duration [of response].

Overall, there were data on 204 patients in the cilta-cel arm of CARTITUDE-4 and data from 800 patients who received 1045 [eligible] lines of therapy. That's quite a large dataset, and there were 175 different treatment regimens.

What efficacy results were seen regarding response rates and time-to-event outcomes?

[The results must be adjusted to ensure] the dataset matched the population of CARTITUDE-4 in terms of inclusion criteria. Overall, this analysis showed that there was a highly [statistically] significant superiority of cilta-cel in terms of ORR and CR rate. For the CR rate, the odds ratio was 16.45 [95% CI, 9.99-28.00], so that's quite impressive. There PFS favored the cilta-cel arm [with a reduction in the risk of progression or death] of 63% [HR, 0.37; 95% CI, 0.26-0.52; P < .0001].

We didn’t see a mild or moderate superiority of the cilta-cel data; we saw a highly significant superiority. The data are not showing the benefit in OS, but the data are compelling and speak for themselves.

Considering all these data, what is the main clinical significance of these results?

The clinical significance is that [this study] confirms the results from CARTITUDE-4. On top of that, it shows that cilta-cel, based on this indirect comparison, has a clear superiority over all the other SOC regimens that are used in the relapsed/refractory setting. This large dataset covers more or less every [SOC regimen] that's used in the relapsed/refractory setting.

[We] also have to [consider] the limitations of this [study], because indirect comparisons come with some limitations. The scientific world is not eagerly waiting for too many indirect comparisons. Sometimes indirect comparisons are being drafted just to try to prove something that's maybe not so compelling. However, here it's confirmatory—nothing more, nothing less.

References

1. Delforge M, Avivi I, Mateos MV, et al. Comparative efficacy of Carvykti in CARTITUDE-4 versus alternative treatments from daratumumab clinical trials for the treatment of patients with lenalidomide-refractory multiple myeloma‌. Presented at: 21st Annual International Myeloma Society Annual Meeting; September 25-28, 2024; Rio de Janeiro, Brazil. Abstract P-016.
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 November 1, 2024. 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