Real-World Analysis Shows Superior Efficacy With Cilta-Cel vs Ide-Cel in R/R Multiple Myeloma

Findings from a retrospective analysis showed that real-world responses and survival outcomes with ciltacabtagene autoleucel (cilta-cel; Carvykti) were superior to those with idecabtagene vicleucel (ide-cel; Abecma) in patients with relapsed/refractory multiple myeloma; however, ide-cel was frequently chosen for older, frailer patients with unfavorable prognostic factors, indicating that treatment selection accounting for individual patient profiles can greatly influence outcomes, according to Pooja Phull, MD.

In a presentation at the 2024 ASH Annual Meeting, results from this analysis showed that the overall response rate (ORR) was significantly higher with cilta-cel (86%; n = 49/57) compared with ide-cel (60%; n = 30/51; P = .002). The median progression-free survival (PFS) was not reached (NR) with cilta-cel vs 7.5 months with ide-cel (P < .0001), and overall survival was NR in either group (P = .12). Furthermore, according to a univariate analysis, extramedullary disease was identified as a significant unfavorable prognostic factor (HR, 4.3; 95% CI, 2.3-7.9; P < .001); conversely, treatment with cilta-cel was a favorable prognostic factor (HR, 0.28; 95% CI, 0.14-0.54; P < .001).

“Clearly, we see superior outcomes with cilta-cel, but we’re also mindful of adverse effects [AEs] when selecting agents,” said Phull, who is a hematologist/oncologist at John Theurer Cancer Center, Hackensack University Medical Cancer, in New Jersey. “As many people in the field are discussing, there’s no right answer at this time.”

In an interview with OncLive®, Phull reviewed real-world findings from the single-center retrospective analysis showing response rates with cilta-cel and ide-cel; noted differences in the efficacy and toxicity profiles of the agents between real-world and clinical trial data; and addressed the challenges of sequencing BCMA-targeted therapies in multiple myeloma.

OncLive: Why is it important to compare long-term clinical trial data with real-world outcomes for CAR T-cell therapies in multiple myeloma?

Phull: As we've seen at the 2024 ASH Annual Meeting and in the past couple years, we're increasingly seeing what a major game changer CAR T-cell therapy has been for patients with myeloma, especially. The longest-term follow-up data we have are from the phase 1b/2 CARTITUDE-1 [NCT03548207] and phase 2 KarMMA [NCT03361748] trials investigating the efficacy and safety of cilta-cel and ide-cel, respectively. Now that those trials have matured, and we have a lot of long-term data [with these agents], it’s important to see how they compare with real-world outcomes for patients in the clinic who we’re seeing every day. Many of these patients do not meet the eligibility criteria for these clinical trials, and it’s important to see how these patients do when they receive these therapies.

What should be known about the design of this analysis, including the patient population?

This was a single-center, retrospective analysis [conducted at John Theurer Cancer Center], which [includes our] large-volume myeloma center. We evaluated outcomes in 101 patients who had received CAR T-cell therapy since it became commercially available. These patients were not included in the KarMMA or CARTITUDE-1 clinical trials but were real-world patients with relapsed myeloma who had received approximately 6 prior lines of therapy in both arms. We assessed their outcomes in terms of safety and efficacy.

What did the study show regarding the efficacy of cilta-cel vs ide-cel in real-world and clinical trial settings? Did outcomes differ for those with extramedullary disease and other high-risk features?

In patients who previously had dismal outcomes, we still saw an ORR of [at least 60%] in both [the cilta-cel and ide-cel] arms. [These response rates] were slightly lower than [the response rates seen in the] clinical trial data, but we still saw comparably high efficacy and tolerability in patients who may not have necessarily met the eligibility criteria for the clinical trials.

We also reported on patients with extramedullary disease. These are patients who have disease outside the bone and bone marrow, and they tend to have higher-risk disease. In the KarMMA and CARTITUDE-1 trials, these patients experienced significantly poorer PFS and ORR with [CAR T-cell] therapy. It’s important to understand that each patient with myeloma is a unique individual, and outcomes differ, especially when you evaluate high-risk patients, functionally high-risk patients, and patients with extramedullary disease.

What were the key similarities and differences between the real-world and clinical trial outcomes with cilta-cel and ide-cel, particularly regarding the efficacy and safety profiles? How do these differences influence treatment selection between these agents?

These data reflect and mirror the data that we [have seen] on clinical trials. Across trials, we see that cilta-cel seems to [elicit] superior response rates [to those of ide-cel], as well as more durable responses, and that was also seen in our real-world analysis. However, some of [those outcomes] may be a bit subselecting because we saw in the CARTITUDE-1 vs KarMMA trials that there are higher rates of cytokine release syndrome [CRS] and delayed neurotoxicity with cilta-cel [vs ide-cel]. In our real-world analysis, patients treated with ide-cel tended to be much older and have more extramedullary disease. We tend to select ide-cel for the frailer, older patients who may have increased risks of neurotoxicity and such AEs.

Some of the key differences that we saw were slightly lower response rates and outcomes in the real-world vs clinical trial data. This reflects [the fact] that the patient population we’re treating in the real world does somewhat differ from [patient populations] in the clinical trial arena, where [factors] are much more controlled. It’s also striking that there were significantly lower rates of CRS in the real-world analysis vs the clinical trial data, especially for the cilta-cel group. It’s hard to say exactly what's driving that—[maybe] using more effective bridging therapies at this time is a potential explanation. Most patients are still experiencing CRS, and a minority of patients are experiencing neurotoxicity, but we’re seeing less CRS in in the real world, which is a reassuring finding.

Does the 8-day difference in vein-to-vein time with cilta-cel vs ide-cel influence treatment decision-making for patients requiring more expedited treatments?

We talk a lot about vein-to-vein time and CAR T-cell therapy not being an off-the-shelf therapy. The difference in vein-to-vein time in this real-world analysis was approximately 8 days for cilta-cel vs ide-cel. This was much more of an issue when CAR T-cell therapy first became commercially available, and there was a significant issue with slot allocation. Now that those issues have essentially resolved, we no longer have such a struggle, and that difference isn’t necessarily clinically meaningful.

[For] a patient who’s progressing rapidly, an 8-day difference isn’t going to be a major change. It’s moreso going to affect how we select bridging therapy. Depending on the patient’s prior treatment history and whether they’re progressing too rapidly, we might have to consider an alternative cellular therapy, like a bispecific T-cell engager.

What questions remain regarding the sequencing and timing of BCMA-targeted therapies in multiple myeloma?

With all the data coming out at [the 2024 ASH Annual Meeting], we’re realizing that the more we know [about] BCMA-targeted cellular therapies and non-cellular therapies, the more we don’t know. There’s a lot of talk about the resurgence of belantamab mafodotin-blmf [Blenrep] in the relapsed setting, but there have also been some data presented regarding the use of belantamab mafodotin up front in the newly diagnosed setting. That poses the question of sequencing and how we can effectively sequence therapies that are all targeting BCMA.

We’ll need to include more patients on clinical trials for CAR T-cell therapies that target BCMA, including patients who have received prior BCMA-targeted therapies, who have been historically excluded in the earlier CARTITUDE and KarMMA trials. In that same vein, we also have to look at biomarkers for T-cell fitness to understand when we can best administer [treatment to] patients who have received prior cellular therapies when their T cells are not exhausted, and when they are fit enough to maximize clinical benefit with CAR T-cell therapy. We’ll need to investigate the sequencing and timing of these therapies to understand how to best use them now that we’re starting to use them in earlier lines, especially for the patients who have the highest unmet need.

How do you see the incorporation of quadruplet regimens and BCMA-directed therapies shaping the treatment paradigm for multiple myeloma?

We’re now seeing a completely new era where quadruplet therapy with anti-CD38 therapies and BCMA-directed therapies is being used earlier in [myeloma]. We’re always balancing the immune milieu of these patients and effective disease control, as well as managing toxicities, especially regarding infections. It’s going to be interesting to see how we navigate this tightrope walk of balancing effective therapies with AEs and understanding the sequencing of these agents to best serve our patients.

Reference

Amoozgar B, Bangolo AI, Vesole DH, et al. Comparative efficacy and safety of ciltacabtagene autoleucel and idecabtagene vicleucel in real-world relapsed/refractory multiple myeloma: a retrospective intention-to-treat analysis. Blood. 2024;144(suppl 1):2408. doi:10.1182/blood-2024-211671