Unpacking the Implications of CAR T-cell Therapy for Patients With Multiple Myeloma

Although patients with relapsed/refractory multiple myeloma have 2 FDA-approved CAR T-cell therapy options with idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti), limitations are prevalent regarding timely access to these therapies and sequencing questions for those who have experienced relapse, according to Abhinav Deol, MD.

“From the CAR T-cell standpoint, having more manufacturing slots to get patients who qualify on early, having trials utilizing CAR T-cell therapy earlier in the course of disease, [and] having the availability of allogeneic CAR T-cells, are 3 important things that are being looked at in BCMA-directed CAR T-cell therapy,” Deol said following a presentation he gave at an OncLive^® State of the Science Summit^™.

“There are also new targets that are being evaluated that can be targeted using CAR T-cell therapy [and] hopefully that will give us more products that we can use to try to target other markers on multiple myeloma cells utilizing the CAR T-cell platform,” he said.

Deol noted the agents have not been compared head-to-head at this point and longer-term follow-up will aid in determining which treatments may be more durable. Leaked data from an abstract scheduled to be presented at the 2023 European Hematology Association Hybrid Congress in June showed that patients receiving cilta-cel experienced an overall response rate (ORR) of 88% with a complete response (CR) rate of 73%.¹ Additionally, data from the phase 2 KarMMa-2 trial (NCT03601078) demonstrated patients receiving ide-cel (n = 31) experienced an ORR of 71% (95% CI, 66%-77%) and a CR rate of 39%.²

In an interview with OncLive, Deol, a medical oncologist and associate professor at the Karmanos Cancer Institute, gave insight on CAR T-cell therapy’s future role in the treatment landscape and what needs to be done to push the needle forward.

Onclive: What message were you hoping to convey to colleagues with your presentation?

The important thing to remember is to make sure that the patients are referred to a center that is able to provide CAR T-cell therapy, that needs to be done at the appropriate time. Currently, the FDA has approved CAR T-cell therapy for use in patients with multiple myeloma who failed 4 lines of [prior] treatment.

We do occasionally have patients who are referred after the first- [or] second-line failure anticipating that they will be able to get CAR T-cell therapy, but [outside of] clinical trials we’re not able to offer that at the current time. For the commercially approved CAR T-cell therapy, having the appropriate time for referral would be very important.

The second thing to remember for patients who are getting CAR T-cell therapy is to have that time lag, I refer to [as] brain to wane time in my presentation, because we might see patients who we think are appropriate candidates or different physicians think are appropriate candidates, but [with] the limitation of the manufacturing slots that are available it might take a few months before those patients are able to get apheresis to start the process of making CAR T-cell therapy. [In] that period of time the teams have to work together from the center that’s providing CAR T-cell therapy and the physicians who are taking care of the patients, to have a cohesive plan to be able to manage the patient [for] those few months [between] treatment so that the disease can be under control.

Subsequently, the other thing to know is that it does require [an] initial time period [where] patients will have to stay close to the center that has provided CAR T-cell therapy. Most of the patients who get CAR T-cell therapies may qualify for patient assistance programs they can use to stay close to the cancer center along with their caregiver. [Patients] need to have a caregiver [because] they can’t drive themselves even after they're discharged from the hospital.

This is definitely a great therapy for our patients, but there are still some limitations in terms of getting it in a timely manner for some patients.

What anti-BCMA CAR T-cell therapies are FDA approved for multiple myeloma?

There are 2 FDA approved therapies that are currently available, ide-cel and cilta-cel. Ide-cel was approved in 2021 and cilta-cel was approved in 2022. Both therapies are autologous products, so the T cells have to be collected, shipped off to the manufacturing company, and then it usually takes approximately 6 to 8 weeks for the cells to [return from manufacturing].

Patients will then undergo a short period of lymphodepleting chemotherapy, usually it’s mild chemotherapy to get the patient’s body to a place where these T cells can expand fully once they’re infused. That’s usually done [over] 3 days starting approximately 5 days before the planned infusion of the CAR T cells. Then the cells are infused, and the patients are monitored daily anywhere from 7 to 10 days [after transfusion] for signs of [cytokine release syndrome] CRS and neurotoxicity after which we can transition some of these patients to [the] outpatient [setting].

We have started a pilot program to try [administer] some of these CAR T-cell therapies in the outpatient setting…. Patients can be admitted if they develop CRS or neurological toxicity. The response rates for both these products are approximately 82% to 97%, so the majority of the patients will have a response. We are still looking at the long-term potential for keeping the disease under control. On the ide-cel study, even in the patients who had [an] [minimal residual disease] MRD-negative CR by approximately 1 year, and a half of patients had relapse, the other half were still in remission.

With the cilta-cel study with a median follow up of approximately 27 months, approximately [half of] of the patients had the disease control. We’ll see whether there are going to be some patients who stay in remission long term after these therapies, but at the current time our understanding is that this is not curative, and patients will have disease relapse. Then we have to think about what options are available at that point for these patients.

How do you decide between these 2 CAR T-cell treatments that are available when treating patients?

We don’t have any data comparing these 2 products head-to-head to see if one works better than the other, but we do have a long waiting list for our patients who are eligible for CAR T-cell therapy, [so] it’s the availability of the manufacturing slot [that can determine what product a patient receives]. Once we are informed that there’s a manufacturing slot available, we’ll go through our patient list and approach the next patient who’s eligible to assess and see whether they will be candidates.

There is no clear-cut distinction right now to separate between one or the other. The toxicities are similar, the response rates with different trials were in the 80% to 90% range, so we’ll see if long-term data point toward early signs [better efficacy]. [It] seems like cilta-cel might provide a bit more durable response as we have long-term follow up data, but we’ll see if that pans out.

Please expand on sequencing therapies past CAR T-cell treatment.

That’s an area of great interest for all the clinicians who are involved in treating multiple myeloma because luckily there has been a lot of research and there’s a lot of new therapies that are available. One of those therapies is trying to direct toxicity at BCMA using bispecific T-cell engaging antibodies.

Currently, the CAR T-cell therapy was studied in a group of patients, a majority of whom had progressed on lenalidomide [Revlimid], pomalidomide [Pomalyst], carfilzomib [Kyprolis], [and] bortezomib [Velcade] and daratumumab [Darzalex]. [For] those patients, CAR T-cell therapy worked well, but now patients have another option with recent approval of teclistamab [Tecvayli]. [Teclistamab] is a BCMA-directed bispecific T-cell engaging antibody, which in short is basically 2 headed antibody—1 head attaches to the BCMA on the multiple myeloma [and] the other head attaches to the CD3 on the T cells and bring those cells together so that there can be cellular toxicity that can get rid of the myeloma cells.

Most of the studies looking at both the BCMA directed bispecific T-cell engaging antibodies and CAR T-cell therapies, excluded patients [who had] prior BCMA-directed therapy, so data are very limited as to what happens if patients have had some other [therapy] targeting BCMA prior to CAR T-cell therapy. We have some real-world data that has been published now which shows that responses can still be seen, but the response rates are a little bit lower when BCMA has been previously targeted. In terms of teclistamab, [investigators] also looked at a cohort of patients that had prior BCMA targeted therapy to see what the response rates were, and those patients do respond, but the response rates are lower than we would have expected if they had not received any BCMA therapy.

The other question that comes up is when the disease relapses after CAR T-cell therapy. Will a second round of CAR T-cell therapy be effective? That has very limited data. In the ide-cel study, few patients were treated at a lower dose and [retreated] at a higher dose some of them had a response. On the cilta-cel study, there were only 3 patients who were retreated and 2 of them had stable disease and 1 patient had a partial response for a short period of time. So, [data] are limited right now [on] whether we can retreat patients with CAR T-cell therapy. Learning a little bit more about how patients relapse [and] what the mechanism of relapse is—whether it’s because of loss of T cells vs change in expression of the BCMA—might help us determine which next line of treatment might be better.

But with that said, most of the patients in the clinical world will be getting both these therapies hopefully and they will be sequenced one after the other. It’s important to remember that when talking to patients [to set] expectations that the second round with BCMA-targeted therapy would probably be less effective compared with if they never received any BCMA-directed therapy before.

Looking to the future what unmet needs within this landscape are you hoping to see addressed?

One of the important things is to help shorten the period of time that is required to get CAR T-cell therapies. There’s a lot of patients who may qualify for CAR T-cell therapy, but they’re limited by the number of manufacturing slots that are available. That’s one of the unmet needs in this field that needs to be focused on and hopefully with the availability of teclistamab some of those patients will be able to get therapies.

The second thing that researchers are working on is seeing if we use CAR T-cell therapy earlier in the course of the disease and whether that can help improve outcomes even more. So far, we have data for patients who have had relapsed or refractory disease and have run out of other options. But if we can use [CAR T-cell therapy] earlier to try to get a deeper response, can [that] help these patients stay in remission or have the disease under control for a longer period of time? That will be another area of interest that we will start seeing some results from clinical trials.

There are interesting data in terms of allogenic CAR T-cells. These are off-the-shelf CAR T-cell [products] that are available, ready to be infused when the patient needs the infusion, and they seem to be safe—they don’t cause any graft vs host disease. There are some responses that are seen, so we’ll see if that data pans out as we move to develop some strategies to help improve the lymphodepletion before [patients] get allogenic CAR T-cells. There’s a little bit more persistence of these allogeneic CAR T-cells.

What key takeaway message would you like to impart to colleagues?

The important thing is to have a multiteam approach for these patients. Some of these therapies are not available in multiple places in a state, there might be 1 or 2 centers that have it available. Having open channels of communication between the teams that are able to provide CAR T-cell therapy so that…plans can be made to get these therapies is imperative.

From the patient perspective, the first month or 2 they might requir more intensive follow-up, [and need] to stay close to a center that is able to provide CAR T-cell therapy, [and they] need to have a caregiver support. But there is a possibility that if the disease responds they can [experience] a long period of time [where] they might not require any treatment because currently we don’t recommend any kind of maintenance or any other strategies post CAR T-cell therapy. Some patients are able to be off of treatment for a period of time after the disease has responded to CAR T-cell therapy.

References

1. Legend Biotech: leaked EHA abstract shows outstanding CARTITUDE-4 results. Legend Biotech Corporation. April 19, 2023. Accessed May 1, 2023. https://seekingalpha.com/article/
2. Rodriguez-Ortero P, Ailawadhi S, Arnulf B, et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. N Engl J Med. 2023;388(11):1002-1014. doi:10.1056/NEJMoa2213614