Navigating Cilta-Cel Sequencing in Multiple Myeloma: Surbhi Sidana, MD, MBBS

September 10, 2025

Commentary

Video

Cilta-cel demonstrates superior efficacy and durability in treating high-risk myeloma, balancing effectiveness with safety concerns for patients.

In this interview, Surbhi Sidana, MD, MBBS, vice chair of the American Society of Hematology’s Committee on Communications and director of the Myeloma Disease Focused Group at Stanford University, discusses the evolving role of ciltacabtagene autoleucel (cilta-cel; Johnson & Johnson/Legend Biotech) in multiple myeloma treatment. With evidence of efficacy and progression-free survival (PFS) benefit even after just 1 prior line of therapy, questions now focus less on whether it works and more on when to use it. Sidana highlights key considerations around safety risks, functional high-risk disease, and patient preference when weighing earlier vs later sequencing. She also reflects on trial results that exceeded expectations, including overall survival (OS) gains and encouraging outcomes in high-risk subgroups.

This transcript has been lightly edited for clarity; captions were auto-generated.

Transcript

With cilta-cel showing efficacy even after 1 prior line, what factors should clinicians weigh for earlier vs later sequencing decisions?

Cilta-cel has shown effectiveness and PFS benefit even after 1 prior line of therapy and also favorable OS after 1 prior line of therapy. Efficacy is not in question. I think then it becomes a trade-off with safety. We talked about safety; small increased risk of second primary malignancies in terms of hematologic malignancies, increased risk of infections in the first year following CAR T [chimeric antigen receptor T-cell therapy], and also some delayed neurotoxicity. Mostly it was just cranial nerve palsies, which are reversible in the majority of patients; it just takes a while. There was 1 case of Parkinsonism in this earlier line setting. Of course, in later-line setting in CARTITUDE-1 [NCT03548207], we had no more cases, but those were in patients who went in with a lot of disease burden. These are the safety tradeoffs that we need to have.

I think who I will definitely use it for is for patients who have functional high-risk or high-risk disease, because again with myeloma therapy, we see an attrition at every stage. Many second-line patients never make it to third line because disease becomes so aggressive, it's impossible to rescue and their functional status deteriorates, so people who are progressing very quickly after frontline therapy, and this is a moving target. We used to say 18 months or 24 months, but that was with VRd-type therapies [bortezomib (Velcade)/lenalidomide (Revlimid)/dexamethasone]. Now we have quadruplet therapies, which by the way were not very common. Most of these patients were on Dara, and they couldn't be Dara-refractory, and only a quarter of these patients were Dara-exposed in CARTITUDE-4 [NCT04181827].

In reality, many of our patients today are Dara-exposed, even Dara-refractory. For them, even maybe 3 years is functional high risk. I think we have defined that functional high risk in Dara-treated patients, but patients who are relapsing at least within 2 years and perhaps even longer with Dara-refractory

disease, for sure I will treat with early-line CAR T. Patients who are high risk, patients have extramedullary disease, and other patients, I think it's a lifestyle choice also.

Some patients prefer this limited-duration therapy, and especially certain younger patients who want that freedom to have a treatment-free interval over coming back to the infusion center for ongoing treatment long term. I think it's patient preference, but definitely between functional high-risk and high-risk, and then it is a discussion of patient preference.

Revisit Parts 1 and 2 of This Interview:

Part 1: CARTITUDE-4 Data Solidify Cilta-cel’s Role in RRMM: Surbhi Sidana, MD, MBBS

Part 2: Safety Should Always Be a Priority With CAR T for Multiple Myeloma: Surbhi Sidana, MD, MBBS

Were these results expected or were there any surprises?

I would say, personally, the results have outperformed my expectations, because we rarely see an overall survival benefit in myeloma these days, especially in early-relapse trials. That, to me, was very encouraging to see the overall survival benefit and also the benefit in the high-risk subgroup. I think it was very encouraging and has done better than I anticipated it to.

Does cilta-cel’s benefit lie more in disease control than survival extension, considering your findings on a lack of overall survival difference vs ide-cel?

I think many of us have this gut reaction that cilta-cel probably has more effectiveness or efficacy in terms of response rate and durability of response, but there are some safety tradeoffs. We found that the overall response rate and complete response rate in this matched cohort of patients was significantly superior in favor of cilta-cel. Progression-free survival was also in favor of cilta-cel, including in high-risk subgroups, but there was a safety tradeoff. We saw that the risk of delayed neurotoxicity and the risk of infections was higher with cilta-cel. The risk of second primary malignancies was not significantly different, but the odds ratio was more towards cilta-cel than ide-cel [idecabtagene vicleucel; Bristol Myers Squibb]. I think these are tradeoffs to consider.

I think when you look at effectiveness and response rate and PFS, clearly cilta-cel has the advantage there. But in certain patients where safety may be of a greater concern, in frail and older patients I think, this data does give us the comparison. We don't have a head-on-head from clinical trials to be able to make those decisions for patients in clinic.