CAR T Deepens Myeloma Response Over Time, Could Overcome High Risk

Ciltacabtagene autoleucel (cilta-cel, Carvykti), a B-cell maturation antigen (BCMA)–directed chimeric antigen receptor (CAR) T-cell therapy, has emerged as a pivotal option for patients with lenalidomide (Revlimid)-refractory multiple myeloma. At a live event in White Plains, New York, Adriana Rossi, MD, assistant professor of medicine and director of CAR T and the Stem Cell Transplant Clinical Service at the Center of Excellence for Multiple Myeloma at Mount Sinai, moderated an event on the use of CAR T in multiple myeloma. Rossi highlighted updated data from the CARTITUDE-4 trial (NCT04181827) and efficacy seen in overcoming high-risk disease.

Register today to join a Case-Based Roundtable near you.

This article is part 2 of a 2-part series from a Case-Based Roundtable event.

What have you noticed about CARTITUDE-4 from updated response data?

Adriana Rossi, MD: The first time the data was presented was at about 16 months of follow up. Then at International Myeloma Society meeting in 2024, we got the long-term follow up, which was 33.6 months. Remember, this was a single infusion of CAR T cells that now is 3 years out, and we had a deepening of response.¹

We see this a lot, even if it's a transplant, maintenance, single-agent deepening of response with continuous therapy. I don't think there's continuous therapy. The CAR T cells aren't there 3 years later. I don't know [what the mechanism is]. The overall response rate didn't change, but the quality of those responses got deeper. In part, I think it's to do also with the half-life of the protein. We had a lot of patients who were minimal residual disease [MRD] negative at 30 days who still had the M spike. That's why we stopped doing the 30-day marrow [biopsy]; let's wait and give them a chance to actually meet complete response criteria.

Do you feel the MRD is a good predictor for patients with multiple myeloma?

I think we are moving beyond being able to achieve an MRD negative state to sustaining MRD negativity. In general, most of us have accepted 10^-5 as the standard in 2025. Some of us have access to 10^-6. I think when you get to 10^-6, it looks exactly the same as the sustained 10^-5. So if you can get deeper, it will last you longer. Sustained is defined as MRD negative at 100 days and then at 1 year. Getting to an MRD-negative state is the goal. It's good no matter how you get there, but it seems that your odds are much improved of getting there if you go the CAR T route.

How does high risk change survival compared with standard-risk disease?

With cilta-cel, you're going to do better.² When the patient is sitting in front of you, you can't change if they are standard risk or high risk, but you can change the therapy. You can [improve their survival] by picking CAR T over at least 1 of these triplets. I think that was really astonishing. There are things we can't change, but the things that we can are real opportunities to have amazing outcomes. The overall survival Kaplan-Meier curves are already starting to separate, already looking much flatter, but this will take a while.

For patients who have more than 2 cytogenetic abnormalities, which in my mind are the bad players, benefit is way in the favor of cilta-cel. The cytogenetic risk is a very tangible risk—[although] I have patients with deletion 17p who are 15 years out, and I have standard-risk patients who first relapse with extramedullary disease, so the [disease] doesn't follow the rules. But as a population and as a guidance, I think this is really helpful.

Looking at the functionally high-risk patients, [there were] fairly evenly distributed baseline characteristics, similar across the board.³ Looking at patients who only had 1 prior line of therapy, and separating out the functional high risk, I think the Kaplan-Meier curves look very close to being identical. The overall response rate in patients in that first relapse is 90%, and the functionally high risk, 88%. With numbers this small, we are getting close to being able to overcome that high risk [issue]. Time will tell for how long. The MRD negativity rate at 10^-5 is the same. We'll need to have the sustainability, but I think it's encouraging.

How do you treat cytokine release syndrome (CRS) for this multiple myeloma population receiving cilta-cel?

CRS is seen about [76%] of the time.⁴ You need to have CRS to get tocilizumab [Actemra] by the book. So we can't give it to you until you have your fever. But at the first fever…it tends to be enough.

We give a single dose of tocilizumab. We don't give a second, because it has a 3-week half-life, and by then it's over, there's no benefit to that. If a patient continues to be febrile after tocilizumab, we do steroids and we do it reassessing every 24 hours, because between the neutropenia, hypogammaglobulinemia, and the BCMA-target [adverse events], we try to limit steroids as much as possible. That's different from bispecific therapy.

We've learned that C-reactive protein [CRP] is a surrogate for interleukin [IL]-6. So when you see the CRP rise without a tocilizumab intervention, a few patients will have a second fever with a ferritin rise. That's an IL-1 surrogate. And we do have anakinra [Kineret].

Register today to join a Case-Based Roundtable near you.

DISCLOSURES: Rossi previously reported consulting for Adaptive, Bristol Myers Squibb, Janssen, Karyopharm, Johnson & Johnson, and Sanofi.

REFERENCES:

1. 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.

2. Sidana S, Martínez-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.7539

3. Weisel K, Costa LJ, van de Donk NWCJ, et al. Ciltacabtagene autoleucel vs standard of care in patients with functional high-risk multiple myeloma: CARTITUDE-4 subgroup analysis. Presented at: European Hematology Association annual congress; Madrid, Spain; June 13-16, 2024. Abstract P959

4. Sidiqi MH, Corradini P, Purtill D, et al. Efficacy and safety in patients with lenalidomide-refractory multiple myeloma after 1-3 prior lines who received a single infusion of ciltacabtagene autoleucel as study treatment in the phase 3 CARTITUDE-4 trial. Blood. 2023;142(suppl 1):4866. doi.10.1182/blood-2023-178778