Long-term efficacy and safety observed with ciltacabtagene autoleucel (cilta-cel) in patients with lenalidomide-refractory multiple myeloma reinforce the agent’s role as a personalized, novel therapeutic standard for this patient population as early as first relapse, according to Binod Dhakal, MD, MS.

Updated findings from the phase 3 CARTITUDE-4 study (NCT04181827), which were presented at the 21st International Myeloma Society (IMS) Annual Meeting, demonstrated that patients treated with cilta-cel (n = 208) experienced a 45% reduction in the risk of death compared with those who received the standard of care (SOC; n = 211). At a median follow-up of 33.6 months, the median overall survival (OS) had not yet been reached in the cilta-cel arm; the 30-month OS rates were 76.4% vs 63.8% with the SOC (HR, 0.55; 95% CI, 0.39-0.79; P = .0009).¹

“These data are very significant, because this is the first time we have shown that BCMA CAR T[-cell therapy] has improved OS compared with the SOC in patients with 1 to 3 prior lines of therapy who are lenalidomide refractory.” Dhakal said in an interview with OncLive^®.

In the interview, Dhakal expanded on the design of CARTITUDE-4, the significance of these long-term efficacy and safety data with cilta-cel, and continued investigations of this CAR T-cell therapy in newly diagnosed multiple myeloma.

Dhakal is an associate professor of medicine at the Medical College of Wisconsin and a hematologist/oncologist at Froedtert & the Medical College of Wisconsin Cancer Network in Milwaukee.

OncLive: What results from CARTITUDE-4 have been previously reported?

Dhakal: In the previous interim analysis of CARTITUDE-4, we showed that cilta-cel improved PFS vs the SOC in patients with 1 to 3 prior lines of therapy who are lenalidomide refractory. Based on these data, the FDA granted approval cilta-cel for use in patients with [at least]1 prior one prior line of therapy, including a [proteosome inhibitor or immunomodulatory drug], who were lenalidomide refractory.

What was the design and methodology of CARTITUDE-4?

[CARTITUDE-4] is a phase 3 randomized trial comparing cilta-cel with the SOC. Patients were randomly assigned 1:1 to either the cilta-cel arm or SOC arm. The SOC arm consisted of 1 of the 2 regimens: pomalidomide [Pomalyst], bortezomib [Velcade], and dexamethasone [PVd] or daratumumab [Darzalex], pomalidomide, and dexamethasone [DPd]). Both [were considered to be] effective SOC regimens at that point of time.

Those who received cilta-cel [went on to receive] bridging therapy with either DPD or PVD based on the physician's choice. After that, they received a single infusion of cilta-cel, and then went into follow-up. The primary end point was progression-free survival [PFS] and secondary end points [included] OS, response rates, minimal residual disease negativity rates, quality of life and so on.

What updated efficacy results were presented at the 21st IMS Annual Meeting?

At this meeting, we reported on our core protocol analysis of the updated efficacy and safety, including OS at approximately 33.6 months of follow-up.

At [a median follow-up of] 33.6 months, cilta-cel significantly improved OS compared with SOC regimens. The HR was 0.55, and the median OS [had not been] reached with cilta-cel or the SOC. The OS [rate] was significantly higher [with cilta-cel]. at 76.4% vs 63.8% with the SOC. Cilta-cel also provided survival benefit across all subgroups, including high-risk subgroups, compared with the SOC.

The [30-month median] PFS was not reached in the cilta-cel arm but was 11.8 months in the SOC arm, with a HR of 0.29. Cilta-cel also significantly prolonged the medium time to symptom worsening vs the SOC.

What should be known about the regimen’s safety profile based on these data?

There were no new safety signals [observed]; this was consistent with the interim analysis. There are 50 deaths in the cilta-cel arm and 82 in the SOC arm. The majority [of deaths] were [attributed to] disease progression in [both arms].

The added follow-up also [confirmed] the favorable risk-benefit profile of cilta-cel for use in this patient population.

What research is planned to further investigate cilta-cel in earlier treatment lines within multiple myeloma?

We will continue to follow patients in CARTITUDE-4 for both efficacy and safety, [as the median PFS has yet to be reached]. That's important for this trial.

[Overall], this trial showed that CAR T-[cell therapy] is a very effective treatment [option] for this patient population, [and] that has already inspired the use of this [therapy] in the newly diagnosed setting. [There are currently] 2 ongoing [phase 3] trials, CARTITUDE-5 [NCT04923893] and CARTITUDE-6 [NCT05257083], which are investigating the use of cilta-cel in patients with newly diagnosed multiple myeloma.

CARTITUDE-5 focuses on patients who are either transplant ineligible or have deferred transplant. CARTITUDE-6 is comparing cilta-cel with a stem cell transplant–based approach in transplant-eligible patients. These trials will provide critical data to determine the value of CAR T-cell therapy in multiple myeloma as early as the first-line setting.

Reference

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.