Real-World Evidence Reveals CAR T Sequencing Approach in Myeloma

Patients with relapsed/refractory multiple myeloma are moving to receive chimeric antigen receptor (CAR) T-cell therapy earlier, which has raised new questions about sequencing. Real-world evidence is accumulating to help answer these questions, as Jorge Monge, MD, assistant professor of medicine in the division of hematology at the University of Colorado, discussed in a recent virtual Case-Based Roundtable meeting with oncologists in Colorado and neighboring states. Monge evaluated how exposure to B-cell maturation antigen (BCMA)-targeted therapies may impact response to CAR T-cell therapy, which has become an important consideration in coming years as more patients are likely to receive multiple BCMA therapies.

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

Targeted Oncology: What does real-world evidence show about how CAR T-cell therapy can be used earlier in multiple myeloma?

Jorge Monge, MD: There are some real-world data for sequencing the CAR Ts. We've been trying to figure out what should we be giving. Should we give a CAR T first or a bispecific first, and ciltacabtagene autoleucel [cilta-cel; Carvykti] first or idecabtagene vicleucel [ide-cel; Abecma] first? Here we have 16 academic centers. There were 255 patients being apheresed, only 236 being infused. We lose some patients; we either don't get the actual product, or the patient experiences progression in the middle and then doesn't get back to us. There's some conforming product and some non-conforming product. [Looking at] how many patients getting apheresis and infusion would have met the eligibility criteria for CARTITUDE-1 [NCT03548207] at time of apheresis, that is barely above half of the patients. I think that that's the strength of these real-world data. It's not just a chart review. It's not just a retrospective study. These are very important data to try to compare what happened in the ivory tower somewhere with perfect-looking patients with all the support available vs what we actually see in patients getting apheresis for these therapies.¹

What factors affected real-world outcomes with CAR T-cell therapy?

In patients who did or did not receive a prior BCMA therapy, we see a little bit of a drop in the overall response rate [ORR]. If they are BCMA naive, the response rate was 92% but if they are BCMA exposed, 70% responded. It doesn't just matter that they got BCMA therapy, it matters how recently they got it, and we're thinking that the most likely explanation is that if you give BCMA therapy to a patient, their myeloma cells are going to have antigen escape, meaning the myeloma will stop projecting these BCMA antigens. Therefore, the BCMA therapy won't be as effective. It stands to reason that if they got the BCMA therapy within the last 6 months, they'll have a worse overall response rate than if they got it over 6 months ago.

Comparing the progression-free survival [PFS], patients who are BCMA naive do better than patients who were BCMA exposed.¹ We tried to tease out whether the type of BCMA therapy mattered, and apparently here it didn't. We have other data that suggest that giving the BCMA antibody-drug conjugate [ADC] or the bispecific gives a worse outcome, that having given a prior CAR T, it also matters which flavor of CAR T they got. I think that this is a bit more confusing than elucidating, but clearly the time to [next therapy] matters the most.

On the other side of the coin, we have real-world data for patients who received ide-cel and with prior BCMA therapies.² These are 49 patients who received a prior BCMA targeted therapy, vs 144 who didn't, and we again see that drop from 88% ORR to 74% ORR, and what I was alluding to before was that the type of BCMA therapy mattered. If they had gotten an ADC, they responded less than if they have gotten a bispecific, who then in turn, responded less than if they had gotten a CAR T. This also goes hand in hand with the time to last prior therapy.

Patients with no prior BCMA therapy had a median PFS of 9 months whereas those with prior BCMA therapy had a median PFS of only 3.2 months.² This gives you a very different overall survival with a median OS of about 1 year if they are BCMA naive vs a much lower overall survival if they are BCMA exposed.

Would you use another BCMA-targeted therapy instead of a CAR T in early relapse?

I've used some bispecific therapies before CAR T. There are some patients who can't wait and don't have other options for debulking or for bridging. Then sometimes we use BCMA-targeted therapy, not before apheresis, but during bridging therapy. Before apheresis, I've used more GPRC5D bispecific antibodies. The only problem is that you do have to leave a much longer washout. Otherwise, all of the T cells that you're engaging are sinking in the tumor. But the International Myeloma Working Group guidelines recommend that anybody who is a candidate for BCMA-directed CAR T receives a BCMA-directed CAR T before any other BCMA-directed therapy.³

How have cilta-cel and ide-cel been compared retrospectively when given as standard of care?

This is the one and only study that we have comparing cilta-cel and ide-cel [as] standard of care. This is from a big consortium of cellular therapy at many academic centers. Three hundred and fifty patients received ide-cel and 236 patients received cilta-cel, all as commercial CAR T.⁴

Most of the baseline characteristics here are well balanced. A little more patients received other lymphodepletion on the ide-cel arm; by other lymphodepletion, they mean bendamustine most of the time. This is something that can happen when fludarabine is on shortage. Also, more patients on the ide-cel arm went in with a higher ferritin, and more patients on the cilta-cel arm received a lower cell dose.

All in all, most outcomes were quite comparable on the safety side, except for the grade 3 CRS. There's a higher proportion of patients on the cilta-cel arm getting grade 3 CRS [12% vs 6% with ide-cel], and there was quite a bit more patients on cilta-cel getting delayed neurotoxicities and infections. However, this also comes with a better response. More patients, 70% got a complete response or better, vs only 47% on the ide-cel arm. These are retrospective chart reviews; they're not apples to apples, but when you compare the two, cilta-cel has a much greater PFS and overall survival, both in the intention-to-treat cohort and in the infused cohort.

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DISCLOSURES: Monge previously reported consulting fees with Janssen.

REFERENCES:

1. Sidana S, Patel KK, Peres LC, et al. Safety and efficacy of standard-of-care ciltacabtagene autoleucel for relapsed/refractory multiple myeloma. Blood. 2025;145(1):85-97. doi:10.1182/blood.2024025945

2. Ferreri CJ, Hildebrandt MAT, Hashmi H, et al. Real-world experience of patients with multiple myeloma receiving ide-cel after a prior BCMA-targeted therapy. Blood Cancer J. 2023;13(1):117. doi:10.1038/s41408-023-00886-8

3. Costa LJ, Banerjee R, Mian H, et al. International myeloma working group immunotherapy committee recommendation on sequencing immunotherapy for treatment of multiple myeloma. Leukemia. 2025;39(3):543-554. doi:10.1038/s41375-024-02482-6

4. Hansen DK, Peres LC, Dima D, et al. Comparative safety and efficacy of ciltacabtagene autoleucel and idecabtagene vicleucel CAR T-cell therapies in relapsed or refractory multiple myeloma. Blood. 2024;144(suppl 1):936. doi:10.1182/blood-2024-194390