CAR T Cells Inching Toward FDA Approval in Heavily Pretreated Multiple Myeloma

Jesus G. Berdeja, MD

Chimeric antigen receptor (CAR) T-cell therapy has been investigated in clinical trials of patients with multiple myeloma over the past few years and demonstrated both efficacy and tolerability. The CAR T-cell agents leading in the multiple myeloma paradigm include idecabtagene vicleucel (ide-cel; BB2121) and ciltacabtagene autoleucel (cilta-cel; JNJ-68284528).

Results from the primary analysis pivotal phase 2 KarMMa study (NCT03361748) were used to support a Biologics License Application for ide-cel, which was granted Priority Review by the FDA in September 2020. The agent achieved an objective response rate (ORR) of 73% (95% CI, 65.8%-81.1%; P <.0001), with a complete response (CR) rate of 33% (95% CI, 24.7%-40.9%; P <.0001). On March 27, 2021, the FDA plans to make a decision on the approval of ide-cel as treatment of adult patients with multiple myeloma who have received at least 3 prior therapies, including an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and an anti-CD38 antibody.

Cilta-cel received a Breakthrough Therapy designation from the FDA in 2019 for the treatment of previously treated patients with multiple myeloma. The agent has since demonstrated impressive efficacy in the phase 2 CARTITUDE-1 clinical trial (NCT03548207), according to results presented at the 2020 American Society of Hematology (ASH) Annual Meeting.

Now that the efficacy and safety of these 2 BCMA-targeting CAR T cells have been shown, ongoing questions include how these agents will perform as treatment of patients who are very heavily pretreated, above the age of 70 years, and who are clinically recognized as frail.

In an interview with Targeted Oncology, Jesus G. Berdeja, MD, director of Myeloma Research at Sarah Cannon Research Institute, discussed a subanalysis of the KarMMA study and updated results from CARTITUDE-1, which provide insights on the use CAR T-cell therapy in heavily pretreated patients with multiple myeloma, including the elderly and frail.

TARGETED ONCOLOGY: What does the treatment landscape currently look like for the

older population of patients with multiple myeloma?

Berdeja: The median age for patients with myeloma is 69, so the majority of these patients fall into the elderly category, but what we’ve come to find out is that not all older people are the same. It’s really about the frailty of the patient. We know that as patients get older, they can become frailer, especially after the age of 80. That alone creates a likelihood that a patient will be frail.

There are other comorbidities that go into frailty score that determine a patient's ability to tolerate aggressive therapies. If you look patients who are elderly or frail. The tolerance of treatments is difficult. We often have to dose adjust because they are not able to withstand the intensity and the length of treatment that the less frail patients can and because of that, oftentimes we see worse outcomes. The survival in elderly patients is much shorter than for young patients.

TARGETED ONCOLOGY: How have CAR T cell therapies excited the field in recent years?

Berdeja: CAR T cells are very potent therapies. The idea with CAR Ts is that you need a target that you can go after, and luckily in myeloma, we have several targets that are very specific to the disease. It engages the part of the immune system that should be fighting the myeloma to begin with, but it’s not. CAR T cells modify a patient’s own T cells, and by incorporating the use of this CAR on the surface, you allow those T cells to go directly after the cells of interest, which in this case is myeloma cells.

We’re seeing some very impressive results with all of the product, but especially the lead CAR T contenders, ide-cel and cilta-cel. We are seeing response rates in patients who are heavily pretreated of about 70% to 100%. This is very different from what we’ve seen in this relapsed or refractory setting with other types of therapy.

TARGETED ONCOLOGY: What was the rationale for the use of a BCMA-directed CAR T cell therapy in this patient population?

Berdeja: Unlike the CD19[-directed] CAR T trials that had an age cap for the patient population, we decided not to have an age cap. This is because, again, elderly patients make up the majority of patients with myeloma. We looked at whether outcomes in these patients were any different to younger patients.

TARGETED ONCOLOGY: What did you find in the subanalysis of the KarMMA trial?

Berdeja: We found that there was no difference in the tolerability and effectiveness of CAR t cell therapies. One of the worries, as I’ve mentioned, is that older patients cannot tolerate the intensity of those therapies, but this was not the case in this subanalysis. It is important to remember that even though these were older patients, these were also fit patients who had to meet the other criteria of the study which included good organ function and good performance status. I think what we’re finding is that age alone is not a reason not to consider this type of therapy.

We saw that the rates of cytokine release syndrome (CRS) and neurotoxicity were no different in the elderly population. The other toxicities that we see often in elderly patients are low blood counts, and hepatotoxicity, which also did not seem to differ in the older cohort.

TARGETED ONCOLOGY: What is the key takeaway from this research? How can this be applied to practice?

Berdeja: The most important take-home message is that oftentimes if a 70-year-old patient is too old for CAR T-cell therapy, what we can safely tell the referring physician is that age alone should not make the decision as to whether patients are eligible for CAR T-cell therapy or not.

TARGETED ONCOLOGY: Ages for patients in the CARTITUDE-1 study ranged from 43 to 78. Can you discuss the background and rationale for CARTITUDE-1?

Berdeja: The CARTITUDE-1 study is a study of the CAR T-cell therapy cilta-cel, which is also a BCMA-directed therapy. This is the same CAR construct used for the LEGEND trials in China, which are now being tested in a more rigorous fashion and in a more refractory population.

The difference between this CAR T-cell product and others is that it has 2 binding sites to BCMA that we feel can form a stronger binding to BCMA. We think this may explain some of the impressive response rates.

This was another study with very heavily pretreated patients. The median prior lines of therapy was 5. These patients had pretty much failed most standard therapies, and the goals here were to confirm the dose from the Chinese study and to do a phase 2 expansion study to determine efficacy.

TARGETED ONCOLOGY: What results were presented during the 2020 ASH Annual Meeting?

Berdeja: At ASH 2019, were presented the phase 1B results, which again was the confirmation of the dose found in the LEGEND trials. This year, we were able to present the phase 2 results. We went from 29 patients with 97 patients for the phase 2 analysis.

We were gratified in that those response rates that we reported before were sustained in the larger cohort. We saw an ORR of 97% with 57% of patients achieving astringent CR and 92% achieving a PR. We have not yet reached the median progression-free survival, but at 12 months, about 76.6% of patients remained in remission.

TARGETED ONCOLOGY: What are the implications of these data in the treatment landscape?

Berdeja: I think these data are very exciting because we’re seeing results that we’ve never seen before in the relapsed/refractory setting. Like the results we saw with ide-cel, the results with cilta-cel are equally impressive. One of the things that distinguish this particular drug from other CAR T-cell products is the onset to CRS. Again, we see CRS in almost every patient with CAR T-cell therapy, but the median time to onset of CRS was 7 days compared to 1 or 2 days with other products. One of the questions becomes, could you potentially do outpatient dosing of this product that you wouldn’t be able to do with another product that has a quick onset of CRS? That is something that I think is going to be tested in future studies.

TARGETED ONCOLOGY: How do you see the use of CAR T cells evolving in multiple myeloma over the next 5 years?

Berdeja: I think we will have FDA-approved products for myeloma within the next year. That will make a big impact. There are competitors that may dictate where CAR T cells will fall in 5 years. One of the problems with the current CAR T-cell therapies in development is that they’re all autologous CAR T products, which means they’re a bit cumbersome. There is about a month from collection to infusion in these patients and their health often deteriorates and they may become ineligible for the therapy.

Some of the so-called “off-the-shelf” CAR T cells that are allogeneic are being looked at to allow the patients to be treated immediately, and the same goes for the bispecific antibodies. We had 6 abstracts for bispecific antibodies presented at this year’s ASH meeting, and these are also off-the-shelf and can provide treatment for patients immediately. The question becomes, if these therapies turn out to be equivalent, which 1 is more likely to be used? That may impact where CAR T cells are positioned in the treatment landscape.