Behind the FDA Approval: Cilta-cel for Treatment of Heavily Pretreated R/R Multiple Myeloma

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In an interview, Jesus Berdeja, MD, discussed the introduction of ciltacabtagene autoleucel into the treatment landscape for relapsed/refractory multiple myeloma, how it may differ from idecabtagene vicleucel, and the future of CAR T-cell use in the space.

Jesus Berdeja, MD

Jesus Berdeja, MD

The FDA’s approval of the second chimeric antigen receptor (CAR) T-cell therapy, ciltacabtagene autoleucel (cilta-cel; Carvykti), for the treatment of patients with relapsed or refractory multiple myeloma may fill a big gap, according to Jesus Berdeja, MD.

In particular, the approval–which was supported by results from the CARTITUDE-1 study (NCT03548207)–is indicated for those who have received 4 or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

“I think there is an underestimate of the need for these therapies. Patients with myeloma and other cancers do not get cured from their therapies. So eventually, most patients relapse. And I think that's why you see so many patients that could potentially benefit from therapies like this, because these are therapies that are unlike anything we've seen before and this sort of late myeloma process,” Berdeja told Targeted Oncology™.

In an interview, Berdeja, director of myeloma research at Sarah Cannon Research Institute and hematology specialist at Tennessee Oncology, discussed the introduction of cilta-cel into the treatment landscape for relapsed/refractory multiple myeloma, how it may differ from idecabtagene vicleucel (ide-cel; Abecma), and the future of CAR T-cell use in the space.

TARGETED ONCOLOGY: Can you talk about the CAR T-cell toolbox for multiple myeloma?

Berdeja: In myeloma we now have 2 approved CAR T therapies: ide-cel and cilta-cel. It’s been difficult to get patients on treatments with the first product that was approved. And so, the need is great. So, there's room for at least 2, if not more. … So, I would argue that it is not a crowded space yet, but I think it can become very crowded as there's quite a few other CAR T-cell products that are being evaluated in clinical trials. And the question will become how many can possibly come into the market. But at the same time, there's also these other drugs called bispecific antibodies, or T-cell redirecting therapies that are also coming into the market in the near future. And I think those will be a significant competition for CAR T cells because they will actually go after a similar patient population.

Can you discuss the CARTITUDE-1 study and what was most exciting about the results?

CARTITUDE-1 is the study for cilta-cel in relapsed/refractory patients with myeloma. These were heavily pretreated patients with a median of 6 lines of therapy. These patients underwent treatment with a relatively low dose of CAR T cells compared to other products. I think was point 0.5 to 1.0 x 106, which is roughly about 50 to 7 million CAR T cells compared to either ide-cel, for example, which went up to 450 million CAR T cells. So, the results are spectacular and unprecedented. Again, in this refractory population, the expectation for new drugs is that if we see a response rate of 20% to 30%, that that's an active drug. And that's often drugs in the past have been approved in myeloma.

So, the overall response rate of 98% seen with cilta-cel is quite impressive. Those are the kind of responses that we see in the frontline population. And furthermore, it was the depth of response that was even more impressive, with almost 80% of patients having complete remission or better. Again, those are very impressive results.

I think what's even more impressive thus far is that when we looked at the 2-year mark, the median progression-free survival had not been reached, which tells us that the median progression-free survival will be over 2 years. Again, something that we never see this late. In patients with myeloma, patients generally have a median progression-free survival of just a few months. So, there’s lot more to come from this trial as it becomes more mature, but that's what's making this very impressive, not only the response rates, but the durability of those responses.

What was observed in terms of safety and tolerability?

In terms of safety, this was not too dissimilar from other CAR T cells in myeloma, so the majority of patients had cytokine release syndrome [CRS]. but most of those patients had grade 1 or 2 CRS. It's very manageable. Very few patients had grade 3 or 4 CRS. And all those patients ultimately recovered.

ICANS for the neurotoxicity associated with CAR T cells was also very similar. With other CAR T products, the minority of patients had that toxicity. And again, most were grade 1 or 2, usually associated or in the setting of CRS. What was different with the study was that in a small subset of patients, there was a delayed neurotoxicity that was seen. The median was about 27 days, so a little bit removed from the traditional CRS and ICANS, which occurs about a week into CAR T cells. And this other neurotoxicity was manifested more with sort of motion, cognitive Parkinsonian-type symptoms that are not usual for traditional ICANS that we see with CAR T cells. There were also some peripheral nerves and gamma ray type syndrome and some cranial nerve abnormalities.

Again, this was a very small subset of patients, I believe, in total, the Parkinsonian syndromes were [in] 5% of the patients, but they were very high grade. And there were some patients that never recovered, did not respond to therapy, and ultimately died with this neurotoxicity still occurring. So, I think the bottom line is, again, this is rare, it appeared to be more common in patients who had high burden of disease who had prior ICANS or CRS. So, in patients who fit those criteria, I think that needs to be monitored, especially closely for the possibility of developing this later toxicity. With further studies in the CARTITUDE program as this was recognized , patients were treated to have their disease better controlled [and] patients who did develop CRS and ICANs had more aggressive control of their initial disease. And the secondary or late neurotoxicities have mitigated significantly. But [these] are worth knowing as this product goes to market and it's being utilized more broadly.

What tips can you provide to community oncologists referring patients with multiple myeloma to cilta-cel treatment?

The advice is that this is a very active drug and should be considered for your patients. It's a drug that is not going to be given by the community oncologists necessarily unless they have the ability to give CAR T cells, meaning it’s a very specialized sort of centralized center. But most likely, they're going to be working with a CAR T specialist to provide these drugs. But it's important to identify your patients early on. And I would recommend that as soon as you have a patient that has been exposed to a proteasome inhibitor and IMID, and an anti-CD38 antibody and is progressing, do not wait until you've exhausted all lines of therapy. I would refer that patient for CAR T evaluation because there will be a period of time the patient will be co-managed until the right time for the CAR T and as a patient in the system already. Ideally, that patient will be known to the CAR T-cell center and will be placed on a waitlist until they're eligible for treatment but that allows for good communication and hopefully maximize the chances that the patient will receive their CAR T cells.

Right now, there’s a lot of competition for some of these spots. We don’t know what it will be like for cilta-cel because it was just approved. But we know that with ide-cel, the completion was fierce. There were wait times of up to 6 to 9 months for some of these patients. So, having another product hopefully will mitigate some of that, but we don’t know for sure yet. So, I would recommend that early referral so that at the right time, the patient will be eligible for the product.

What role do you think CAR T cells will play in the near future?

Right now, the commercial CAR Ts (ide-cel and cilta-cel) are approved for patients who've had at least 4 prior lines of therapy, which is relatively late in the course of treatment. So, I think they'll have an immediate impact in the relapsed/refractory setting as they are now. But there definitely are studies ongoing and trying to move these therapies earlier in the course of treatment.

There are several studies, [including both KarMMA and CARTITUDE,] ongoing in patients with 1, 2, and 3 prior lines of therapy, comparing it to standard of care. There's a significant need in the high-risk population, even from the first line of therapy in that high need population even early on.

But beyond that, there are now studies also looking at CAR T cells in the frontline setting. So, I think the future for CAR Ts is that these will be sort of implemented into the treatment paradigm of myeloma from the very beginning, and in at least certain patient populations. And hopefully, they will be used better than where we are now, where oftentimes patients’ myeloma is so aggressive that they can't get to the CAR T cells. So, there's a potential that it could be used in every aspect of myeloma, again, depending on the availability and some of these logistical challenges.

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