Impressive CAR T-Cell Data Point to New Future in Relapsed/Refractory Myeloma

The CAR T-cell product ciltacabtagene autoleucel (cilta-cel) offers patients promising responses that may compare favorably with established agents such as idecabtagene vicleucel (Abecma; ide-cel), according to C. Ola Landgren, MD, PhD.

Data in support of the agent have emerged from the phase 1/2 CARTITUDE-1 trial (NCT03548207), which examined the BCMA-directed therapy in heavily pretreated patients with multiple myeloma. Updated results of the study recently read out at the 2021 ASCO Annual Meeting.¹

The latest findings indicated that after a median follow-up of 18 months, patients who received treatment with cilta-cel experienced an overall response rate of 97.9% with a stringent complete response (sCR) rate of 80.4%. The therapy yielded an 18-month progression-free survival rate of 66.0% in the overall patient population and was 75.9% in those who achieved a sCR.

On May 27, 2021, the FDA granted priority review status to a biologics license application for cilta-cel for the treatment of patients with relapsed/refractory disease.² The agency is expected to make a decision on the approval by November 29, 2021.

“Cilta-cel seems to have a longer progression-free survival [PFS] than [idecabtagene vicleucel; (Abecma)], which was approved earlier this year,” said Landgren, the inaugural leader of the Experimental Therapeutics Program at Sylvester Comprehensive Cancer Center, University of Miami. “We do not have very robust data, but the indications are that it may be a better CAR T-cell therapy. There is no randomized study to compare the two, though.”

The Institutional Perspectives in Cancer webinar on multiple myeloma covered advances across treatment settings and with immune-based therapies, utilizing genomic signatures, and getting patients to long-term sustained minimal residual disease negativity.

In an interview with OncLive^®, Landgren, a cochair of the webinar, focused on the cellular- and immunotherapy-based elements from the event and where these modern therapies optimally fit in multiple myeloma.

OncLive^®: What were some of the most exciting trials in multiple myeloma that read out at the 2021 ASCO Annual Meeting?

Landgren: The cilta-cel results are very interesting. We now have, for the first time, a CAR T-cell therapy in myeloma that seems to deliver PFS [that is] getting close to 2 years. That is strong. I recognize that the median follow-up time is limited, and the sample size is also not very large, but it is exciting to see that it seems to last for quite a long time.

Of course, there are all these new bispecific antibodies coming. You do not have to have the procedure of being in the hospital [with bispecifics], as you have to do with the CAR T-cell therapy. You could argue that they are going to maybe challenge CAR T cells.

However, I think CAR T cells and maybe natural killer [NK] cells could be attractive for patients, because [these comprise] a single infusion. There will be openings [in the paradigm] for both cell therapy and antibody therapy. It is great for patients to have a lot of options; I am very excited about it.

Pending regulatory approvals, where could these newer modalities fit into clinical practice?

That is a question that we ask every time a new therapy is being introduced. Usually, therapies [in the first round] are being tested in later lines. That is because those patients need new therapies; [therefore,] their needs are more unmet in that space. It also takes a shorter time to develop the drugs because you get the end points faster, [therefore] it comes faster to patients.

For therapies that have been approved, the next rule is that if a therapy works reasonably well in the later-line setting, it usually works even better in an early-line setting. These are general principles, [which are] not always true, but are for the most part.

We see now that all of these therapies are moving up in earlier lines. The questions on the table when it comes to cell therapy are: “Could that challenge autologous transplants, for example, for some patients? Could it be the first relapse therapy for patients? Could it be for patients who have a [suboptimal] response in the beginning? Where is it going?” A lot of people, including us, are working on all these questions.

What data showcase the advantages of autologous and allogeneic CAR T-cell therapies?

Cilta-cel is an autologous CAR T-cell therapy that targets BCMA. [There is] ide-cel [that is approved], and orvacabtagene autoleucel [JCARH125] is in development. There are 3 of them [that] all go after BCMA [and] are autologous.

[With regard to allogeneic stem cells], from a practical point of view, an allogenic CAR T-cell therapy implies that you could give it across the board; you do not have to collect individual patients or cells. If you use an autologous CAR T-cell therapy, you have to have the patient coming in, harvest their cells, and then you have to transduce them in the lab; you have to proliferate and activate the cells and [fuse them back into the patient]. It is about 1-month turnaround time from vein to vein. [With] allogeneic [CAR T-cell therapy], you can see the patient in the clinic [and] make the decision [to give] allogeneic T cells, and the patient could be treated within 2 days or so because it is an on-the-shelf product.

The downside could be that you have to pre-medicate with certain agents to avoid graft-vs-host disease [GVHD]. Genetically, these CAR T cells have been modified, for example, to turn off CD52. Then, you can give CD52 blockers to avoid GVHD, and then you give this cell. It is a natural cell engineering and treatment premedication to avoid GVHD. It is very attractive from a feasibility standpoint; the preliminary efficacy data look very promising. However, what we do not know are the long-term effects with these types of medications to avoid GVHD. We also do not know the long-term efficacy.

Lastly, there are other new technologies in development where you could have cells that are given without a receptor to go after the tumor cells. The same cells could be used for lymphomas or solid tumors. We will see a lot of new technologies coming; it is very exciting to see how the field is accelerating forward.

Let’s focus on quality of life (QoL). How are mobile wearables being used to establish sleep bioprofiles in patients with newly diagnosed myeloma?

There are some trends that I see across the board for myeloma, from my perspective. The next focus for research in myeloma has to be on the long-term QoL, and also to make sure that we do not cause new trouble in terms of secondary malignancies with older regimens.

One interest area of mine has been to work with a team to see how we could capture QoL, [such as] activity and sleeping patterns. Neha S. Korde, MD, of Memorial Sloan Kettering Cancer Center, who I have worked with for many years, designed the study together with myself and others, and we put wearables on patients. We can see how [the effect] of therapy goes beyond the traditional responses. We see how it [affects] sleeping, how it [affects] mobility, [and if] patients are active or not.

The short summary is: We see that both younger and older patients have better mobility and better sleep quality if we use more modern therapies. We can see these in both the short and the long term. This is important to think of how we can use new technology to capture these important aspects of patients’ lives.

References

1. Usmani SZ, Berdeja JG, Madduri D, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR-T) therapy, in relapsed/refractory multiple myeloma (R/R MM): updated results from CARTITUDE-1. J Clin Oncol. 2021,39(suppl 15):8005. doi:10.1200/JCO.2021.39.15_suppl.8005
2. US Food and Drug Administration grants BCMA CAR-T cilta-cel priority review for the treatment for relapsed/refractory multiple myeloma. News release. Legend Biotech Corporation. May 26, 2021. Accessed May 27, 2021. https://bwnews.pr/3fNCQK8