Five-Year CAR T Data Reflect Long-Term PFS in Multiple Myeloma

Chimeric antigen receptor (CAR) T-cell therapy has been in use for several years in multiple myeloma. The phase 1/2 trial of ciltacabtagene autoleucel (cilta-cel; Carvykti), CARTITUDE-1 (NCT03548207), reported 5-year results at the American Society of Clinical Oncology Annual Meeting (ASCO) this year. During a Case-Based Roundtable meeting in Houston, Texas, Thomas G. Martin, MD, clinical research director of hematologic malignancies at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, discussed the mechanism of action and logistics of CAR T-cells and reviewed the recent update from CARTITUDE-1. Martin observed that as updated response criteria for multiple myeloma are being developed, these results support the achievement of a landmark where B-cell maturation antigen (BCMA)-targeted CAR T-cell therapy would be defined as potentially curative therapy.

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Targeted Oncology: What is the current state of BCMA-targeted therapy for multiple myeloma?

Thomas G. Martin, MD: We have 3 different types of therapeutics. We have antibody-drug conjugates [ADCs]…and at the current time, our access to an ADC is very limited, and we don't know when the access is going to be approved [for] belantamab [Blenrep]. We have bispecifics, [which have] 2 arms, one that binds BCMA, another arm that binds to CD3 and activates the local T cells in the environment.¹ Then we have CAR T cells, where we do apheresis, pull out the lymphocytes, and then use gene therapy to insert the gene into the genome of the T cell to make a specialized lymphocyte that expresses a single-chain variable fragment on the cell surface that binds directly to BCMA.² All of these therapeutics have worked extremely well for our patients, but in my mind, nothing is better than CAR T-cell therapy.

Could you describe the challenges of the CAR T-cell process?

The CAR T cell process is one of the things that makes it the most difficult sometimes for patients, and it drives our problems with patients getting access. The general belief is that somewhere between 10% and 20% of patients who are CAR T eligible make it to CAR T. That's pretty low, unfortunately.

We've had this problem a long time with autologous [stem cell] transplant. We have 8000 autologous transplants in the United States each year and 32,000 newly diagnosed patients, so 1 in 4 make it to autologous transplant. Probably more than 2 out of 4 are eligible for autologous transplant, and a lot of it is [because] there are not enough centers doing it, it's hard to get there, and you have to have a caregiver. There are a number of other constraints…for patients who need CAR T-cell therapy.

CAR T cells have a binding domain to BCMA. A lot of the different CARs now have different binders. They have a transmembrane domain that, once it binds to BCMA, transmits a signal to the inside of the cell, where you have 2 costimulatory domains. In general, it's 4-1BB for myeloma, together with a CD3ζ domain. Once the T cell binds to BCMA, those 2 costimulatory domains and 1 activation domain make the T cell grow and secrete cytokines and recruit a lot more than just more T cells, [but also] other immune cells. It's probably all that [immune] response that provides the deep response that we're seeing with CAR T-cell therapy.

One of the big problems is getting in the clinic to get the leukapheresis done. When you refer somebody for CAR T, sometimes it isn't until 4, 6, or 8 weeks later that they're seen to get the CAR T, then we schedule the leukapheresis, which is another 2 to 4 weeks down the road. Then they get the leukapheresis, and we send it out at the company, and it comes back to us another 4 to 6 weeks down the road. So now 3 months has transpired since you...thought about doing CAR T to when the CAR T is actually infused in the patient...which is too long for us to wait and sit on patients and not do anything in the interim.

What was the design and enrollment of the CARTITUDE-1 trial?

This was initially a phase 1 trial, but the phase 1b component of the trial was using the dose they found was effective in China. It wasn't a dose escalation; they just used the dose. That was done in 29 patients, and those 29 patients did well. So then it was changed to phase 2, and 68 patients were added at the same dose, which brought the grand total to 97 patients.

[As many as] 116 patients received apheresis, [but] 97 got the CAR [T cells] and were infused. The difference is patients who decided not to go forward or their disease became too progressive and they couldn't go forward. But 97 patients went on to CAR T-cell therapy, and then they were assessed for efficacy and safety.

What are the latest updates from this trial?

Jump forward 5 years to the 2025 ASCO Annual Meeting, and we look at what happened to those 97 patients.³ We know initially, in the first 3 to 6 months, the response rate was 98% because 95 out of 97 of patients responded. One of the non-responders was deemed to have unmeasurable disease, but remained in remission for more than 2 years, so they were considered a non-responder. In fact, 96 out of 97 patients responded. These are patients with 6 prior lines of therapy.

Then they were followed over time, and the median progression-free survival [PFS] was found to be 36 months. At ASCO this year, there was a presentation of the 5-year follow up of these patients. At 36 months, there was a 50% [PFS rate], but from 36 months on, there haven't been many relapses since. One-third of patients are still in remission, 32 out of the 97 patients. This is one-and-done with no therapy. Five years later, the majority of these patients are minimal residual disease [MRD] negative, and what's going to come out in the new response criteria for multiple myeloma is the definition of cure in myeloma is going to be 5 years of MRD negativity off therapy. All these patients fit the new definition of cured myeloma.

Are they cured? I don't know. We know nobody relapses with lymphoma after lymphoma CAR T-cell therapy after 3 months.⁴ We're hoping to we see now that after 5 years, if somebody's in remission for that time, we're not going to see relapses with myeloma. That would be great.

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DISCLOSURES: Martin previously reported receiving honoraria from GSK, Sanofi, Amgen, and Janssen.

REFERENCES

1. Lancman G, Sastow DL, Cho HJ, et al. Bispecific antibodies in multiple myeloma: present and future. Blood Cancer Discov. 2021;2(5):423-433. Published 2021 Aug 17. doi:10.1158/2643-3230.BCD-21-0028

2. Yu B, Jiang T, Liu D. BCMA-targeted immunotherapy for multiple myeloma. J Hematol Oncol. 2020;13(1):125. doi:10.1186/s13045-020-00962-7

3. Jagannath S, Martin TG, Lin Y, et al. Long-term (≥5-year) remission and survival after treatment with ciltacabtagene autoleucel in CARTITUDE-1 patients with relapsed/refractory multiple myeloma. J Clin Oncol. 2025;43(25):2766-2771. doi:10.1200/JCO-25-00760

4. Cappell KM, Kochenderfer JN. Long-term outcomes following CAR T cell therapy: what we know so far. Nat Rev Clin Oncol. 2023;20(6):359-371. doi:10.1038/s41571-023-00754-1