CAR T-Cell Therapy Explodes on the Scene in Heavily Pretreated Multiple Myeloma

Binod Dhakal, MD

The response rates observed with the novel chimeric antigen receptor (CAR) T-cell products idecabtagene vicleucel (ide-cel), orvacabtagene autoleucel (orva-cel), and ciltacabtagene autoleucel (ciltacel) in heavily pretreated patients with multiple myeloma are striking, explained Binod Dhakal, MD, but larger studies will inform whether the efficacy really holds up against standard regimens.

For example, in the pivotal phase 2 KarMMa trial (NCT03361748), which examined the use of ide-cel in patients with relapsed/refractory myeloma, the objective response rate (ORR) was 73%; the complete response (CR) rate was 33%.1 Based on these data, the FDA granted a priority review designation to a biologics license application for ide-cel in September 2020 as a treatment for adult patients with myeloma who have received at least 3 previous therapies, including a proteasome inhibitor, an immunomodulatory (IMiD) agent, and an anti-CD38 antibody.²

“That is very impressive,” said Dhakal. “We still have to wait a little bit longer to get the mature data, but the median duration of response was about 10.7 months and the median progression-free survival [PFS] was about 8.3 months. These kinds of responses for those heavily treated patients, I would say, are unprecedented.”

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on multiple myeloma, Dhakal, an associate professor of medicine in the Division of Hematology at the Medical College of Wisconsin, discussed the potential impact of ide-cel, orva-cel, and cilta-cel in multiple myeloma therapy.

OncLive^®: In your opinion, what was the most significant takeaway from the KarMMa trial that you can apply to practice?

Dhakal: Before the KarMMa trial, a phase 1 study looked at the safety and efficacy of ide-cel. This is a B-cell maturation antigen [BCMA]–directed CAR T-cell therapy. Results of the phase 1 study showed safety and very impressive efficacy [of the agent] in heavily treated patients with myeloma. That led to the design of the pivotal phase 2 KarMMA trial, which was a multicenter study that looked at the efficacy of ide-cel in heavily pretreated patients with myeloma. These data were presented by Nikhil C. Munshi, MD, of Dana- Farber Cancer Institute, at the 2020 American Society of Clinical Oncology [ASCO] Virtual Scientific Program.

The final number of patients who were treated [on that study with ide-cel] was 128. If you look at the baseline characteristics of those patients, it is a very heavily pretreated population; the median prior lines of treatment was about 6, but it ranged from 3 to 16. About 84% of patients were triple refractory to IMiDs, proteasome inhibitors, and CD38-directed antibodies.

In all [128] patients, the ORR was 73%, with a CR rate of 33%.

The ongoing KarMMa-3 trial [NCT03651128] is a randomized study. We have to see whether that response holds true compared [with standard therapies], as well. At this stage, I would say this looks very promising.

What is the mechanism of action of orva-cel? How is this agent different from other CAR T-cell products?

Orva-cel is another construct that is being tested in multiple myeloma. It is a BCMA CAR T-cell product; BCMA is the lead antigen target for the majority of CAR-T trials in myeloma right now. Compared with ide-cel, the main difference here is that it’s a fully human CAR T-cell construct and there is a very low affinity for soluble BCMA. We have seen that soluble BCMA is not affecting responses in myeloma so far. However, the affinity of this construct against soluble BCMA is very low. Even if there is a very low energy density in the target cells, the product can be very active.

What efficacy have we seen with orva-cel thus far in patients with multiple myeloma?

The data that were presented at the 2020 ASCO Virtual Scientific Program were the latest. About 62 patients were enrolled in the study [at] 3 different doses: 300 × 106, 450 × 106, and 600 × 106. The patient population was heavily pretreated; the prior lines of treatment [ranged from] 6 to 18. More than 94% of patients were triple refractory.

The ORR for all patients was very impressive at 92%. If we look at the minimal residual disease [MRD] negativity rates [for] the patients treated at 600 x 106 cells, they were about 84% for evaluable patients. That looks very promising, although you could say that the number of patients is fewer compared with the prior construct. We have to see how this pans out once the full data are [published].

How does the efficacy with cilta-cel compare with that of other CAR T-cell products in myeloma?

Cilta-cel is a very unique construct; it was originally used as the product of the LCAR-B38M trial that was initially presented from China. The data we have so far are from a phase 1b trial and also from the updated data presented at the 2020 American Society of Hematology Annual Meeting and Exposition by Deepu Madduri, MD, of Mount Sinai Hospital.

[The study] looked at a total of 97 patients who were treated with cilta-cel. [These were] also heavily pretreated patients, [similar to] the prior 2 constructs. The ORR was very impressive at 97%, which included very deep responses. If we look at the evaluable patients who had an MRD assessment done, about 93% of them achieved MRD negativity at 10-5 by next-generation sequencing. The median PFS in this study has not been reached and the 12-month PFS rate was close to 80%. That is very powerful; the data are very promising.

We have to look into all these [ongoing studies] to see whether the promise cilta-cel has shown [in earlier trials] is really going to hold up. However, at this stage, it is a very promising construct and a very promising study for the patients.

References

1. Munshi NC, Anderson LD, Shah N, et al. Idecabtagene vicleucel (ide-cel; bb2121), a BCMA-targeted CAR T-cell therapy, in patients with relapsed and refractory multiple myeloma (RRMM): initial KarMMa. J Clin Oncol. 2020;38(suppl 15):8503. doi:10.1200/JCO.2020.38.15_suppl.8503
2. US Food and Drug Administration (FDA) accepts for priority review Bristol Myers Squibb and bluebird bio application for anti-BCMA CAR T Cell therapy idecabtagene vicleucel (ide-cel; bb2121). News release. Bristol Myers Squibb and bluebird bio, Inc. September 22, 2020. Accessed September 22, 2020. https://bit.ly/2G0K3Iq.