Cilta-Cel Continues to Sustain PFS and OS in Relapsed/Refractory Multiple Myeloma

Surbhi Sidana, MD

The CAR T-cell therapy ciltacabtagene autoleucel (cilta-cel; Carvykti) demonstrated improvements in progression-free survival (PFS) and overall survival (OS) compared with standard of care (SOC) daratumumab (Darzalex) plus pomalidomide (Pomalyst) and dexamethasone (Dara-Pd), or pomalidomide plus bortezomib (Velcade) and dexamethasone (PVd) for the treatment of patients with relapsed/refractory multiple myeloma, according to Surbhi Sidana, MD.

Data from an intention-to-treat population from the phase 3 CARTITUDE-4 trial (NCT04181827), presented at the 2025 ASCO Annual Meeting, evaluated the efficacy of cilta-cel in patients with relapsed/refractory multiple myeloma, which also included those with extramedullary disease (EMD) and had received at least 1 prior line of therapy.1

Of note, the FDA approved cilta-cel in April 2024 for the treatment of patients with relapsed/refractory multiple myeloma who had previously received at least 1 line of therapy, consisting of a proteasome inhibitor and an immunomodulatory agent, and are refractory to lenalidomide (Revlimid).2 The regulatory decision was supported by data from the CARTITUDE-4 study.

“For patients who are functionally high-risk or high-risk, we want to use cilta-cel early, because they may never get to a point where they relapse later that they can use it,” Sidana said during an interview with OncLive® at the meeting. “We see this with all therapies—there is attrition at every step. Therefore, we want to use our best therapies up front for standard-risk patients, as well.”

During the interview, Sidana highlighted the background and rationale for evaluating cilta-cel in the CARTITUDE-4 study, delved into the efficacy data, clinical implications for the utilization of cilta-cel, and ongoing and future research directions for cilta-cel in multiple myeloma.

Sidana is an associate professor of medicine, associate director for Clinical Research in BMT/Cell Therapy, and leader of the Myeloma Disease in BMT/Cell Therapy at Stanford University in California.

OncLive: What was the background and rationale for the CARTITUDE-4 study?

Sidana: CARTITUDE-4 is a randomized clinical trial of cilta-cel CAR T-cell therapy compared with SOC Dara-Pd or PVd in 1 to 3 prior lines of treatment. To set the stage, what we have seen in the past couple of years is that there's a PFS benefit, [which has] led to FDA approval of cilta-cel in the second line. Then, there was an OS benefit that Dr María-Victoria Mateos presented at the [International Myeloma Society Annual Meeting] in 2024, so what our abstract and poster builds on is the analysis of the overall survival and progression free survival in subgroups, particularly patients who have high-risk cytogenetics, as defined by 4;14 translocation, 17p deletions, or gain of 1q.

What were the key efficacy data?

With cilta-cel, the PFS was better in patients with high-risk cytogenetics than not, and even OS was better. We then looked at patients with extra-medullary disease, and these are patients with true EMD that is not contiguous to bone. Although this was a small subset, patients with cilta-cel [had a median PFS of] 12.6 months vs only 4.0 months with SOC. The 12 months tell us that this is the area that we need to improve upon and add different strategies. We also looked at different lines of therapy because many people say, “Well, that's great that we have cilta-cel, but do you have to use it in the second line? It's approved, but do you have to use it?” Therefore, we looked at it by 1 prior line of therapy, 2 prior lines of therapy, and 3 prior lines of therapy. The benefit was sustained in all of these subgroups, suggesting that [cilta-cel] is a superior therapy in terms of efficacy [regarding] PFS and also a trend for OS in each of these subgroups.

What data opened up an avenue for future investigation?

We were able to identify subgroups in this analysis that open up lots of avenues for future investigation. It was interesting to see that in the high-risk patients, [the PFS was 37.1 months (95% CI, 26.7-not evaluable)], but in the EMD patients, the median PFS was just 1 year. [Historically,] many of these patients actually never even got to [receive] CAR T-cell therapy; they had progressed between apheresis and CAR T-cell therapy. This is the area we now need to focus on. Given that it's only about 15% to 20% of patients with all myelomas, this is still a significant subgroup that we need to improve upon.

What are the overall implications of cilta-cel in relapsed/refractory multiple myeloma, and what effect could it have on clinical practice?

Cilta-cel is now available as second-line therapy after the first relapse. These data are very reassuring, especially seeing that patients with 1 prior line of therapy also have a PFS benefit vs 2 vs 3 [prior lines of therapy]. Even in those subgroups, there is a benefit. These data are very reassuring [and support the] use [of cilta-cel] in earlier lines. The challenge is that there are so many different treatment options for multiple myeloma, especially for patients who are naive to many of the conventional treatment options, like anti-CD38 antibodies. How do we select them? Things that work in high-risk [disease] work better in standard-risk patients. As long as we can manage the toxicity, this is a good option for early relapse, and I would particularly select patients who are functionally high-risk, but many of the standard-risk patients also want this option because it gives them a time limited duration option that is not currently available with other therapies that are continuous.

In your practice, are there any patient populations you would not select cilta-cel for?

Nothing would deter me [from selecting cilta-cel]. The things that [could] deter [someone] include the pros and cons of safety, as long as patients understand [these aspects] and we can manage or mitigate toxicity, [there wouldn’t be a population of] patients that I wouldn't choose cilta-cel for. This is a limited-duration therapy, [where patients] get bridging [therapy], and cilta-cel, then there's observation after that; there is no continuous therapy. A lot of patients prefer that. Other patients might say, “OK, there's a small risk of increased toxicities in the short term, and I don't want to take that risk,” or “I may not want to relocate,” and there are other options there, but this is an option for patients who want a limited-duration therapy that has a PFS benefit. [Cilta-cel demonstrates] a PFS benefit, even with our best available therapies, like Dara-Pd. The PFS is better [with cilta-cel], and maybe better than what we have with [Dara-Pd].

When considering using cilta-cel, is there research indicating use in earlier lines of treatment or in combination with other treatments?

Cilta-cel is now being explored in the first-line setting, both for transplant-eligible patients and transplant-ineligible or -deferred patients. For the transplant upfront patients, it's being compared with autologous stem cell transplant with quadruple induction therapy in a clinical trial called CARTITUDE-6 [NCT05257083]. That's a large, randomized study with over 700 patients and is nearly fully accrued. Of course, these patients have [achieved] very good PFS, and it will take us some time to get to the PFS data, but hopefully, we'll see minimal residual disease data coming up in the next few years. In transplant-deferred or -ineligible patients, we have CARTITUDE-5 [NCT04923893] that [is evaluating VRd followed by] cilta-cel VRD vs [VRd followed by] lenalidomide and dexamethasone.

Reference

1. Sidana S, Martinez-López J, Khan AM, et al. Ciltacabtagene autoleucel (cilta-cel) vs standard of care (SOC) in patients (pts) with relapsed/refractory multiple myeloma (MM): CARTITUDE-4 survival subgroup analyses. J Clin Oncol. 2025;43(suppl 16):7539. doi: 10.1200/JCO.2025.43.16_suppl.753
2. 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. News release. Johnson & Johnson. April 5, 2024. Accessed June 19, 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