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Jack Khouri, MD, hematologist oncologist at Cleveland Clinic Cancer Center, who specializes in rare plasma cell disorders joins the Cancer Advances podcast to discuss ide-CEL CAR T-cell therapy and its effectiveness in multiple myeloma patients. Listen as Dr. Khouri talks about the KarMMa trial and his retrospective study.

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Ide-CEL CAR T-Cell Therapy Effective in Multiple Myeloma Among Patients with Comorbidities

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances.

I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic overseeing our Taussig phase 1 and sarcoma programs. Today, I'm happy to be joined by Dr. Jack Khouri, a hematologist-oncologist at Cleveland Clinic who specializes in rare plasma cell disorders. He was here previously to talk about POEMS, and that episode is still available for you to listen to. Today, he's here to talk to us about ide-cel CAR T-cell therapy, effective in multiple myeloma among patients with comorbidities.

Jack, welcome to the podcast.

Jack Khouri, MD: Hi, Dale. Good to be here.

Dale Shepard, MD, PhD: Maybe to start, you've been here before, remind us of a little bit about what you do here at Cleveland Clinic.

Jack Khouri, MD: Yeah. I'm one of the hematologist-oncologists here at Taussig. I mostly treat patients with plasma cell disorders, such as multiple myeloma, amyloidosis and other rare plasma cell disorders. I also do bone marrow transplantation, CAR T-cell therapy, and apheresis procedures.

Dale Shepard, MD, PhD: Excellent. Well, we're going to focus a little bit on that CAR T part, and maybe we'll delve a little bit about other things you're interested in for treatment, but to start off, we're going to talk about this ide-cel CAR T-cell therapy and multiple myeloma. Maybe to start off, remind us of it a little bit. We've had some episodes. We've talked about CAR T therapy. Just give us a really brief, broad overview. What is CAR T-cell therapy?

Jack Khouri, MD: Right. CAR T-cell therapy is chimeric antigen cell receptor T-cell therapy. Basically, we try to engineer the patient's own immune cells, their own T-cells, make them smarter at fighting the cancer in their own body, so it's just harnessing the power of the immune system. The way we do it is we collect the patient's own T-cells with leukapheresis and then we manufacture the cells. We currently have two products approved for multiple myeloma, ide-cel CAR T-cell or idecabtagene vicleucel, and there's another product that's also approved, and then, after the cells are manufactured, they are shipped back, and they are infused into the patient after a little bit of chemotherapy. This is a kind of immunotherapy. It's cell-based though.

Dale Shepard, MD, PhD: Excellent. Well, we're going to talk a little bit about when there was a trial that was looking at patient's election, if I recall. It's something called the KarMMa trial. Tell us a little bit about that.

Jack Khouri, MD: The KarMMa study is a pivotal study that led to the FDA approval of idecabtagene vicleucel. The study included about 120 patients with heavily pre-treated multiple myelomas. A lot of these patients had already exhausted a lot of the standard-of-care options. Those patients had their CAR T-cells collected and manufactured and then they had them infused, and the majority of these patients responded and had great responses. More than 70 percent of the patients responded. The progression-free survival was close to nine months for the majority of the patients. CAR T-cell therapy works obviously, but the responses have not been as durable as we thought, so it's still not a cure as we're seeing with some of the lymphoma CAR Ts, but this is a great option for our patients who have had a lot of treatments.

Dale Shepard, MD, PhD: Do we have any early thoughts in terms of why they're not as durable for this population?

Jack Khouri, MD: Yeah. There is a lot of work that's currently being done on the mechanisms of resistance, and some of the thoughts are that the CAR T-cells are not really persistent in some of these patients. There's some senescence that happens. Another thought is that the myeloma cell gets very resistant, that it comes up with all kinds of biological approaches to resist the CAR T-cells. It's been mostly just the resistance of the myeloma cell and, potentially, lack of persistence of the T-cells.

Dale Shepard, MD, PhD: As you mentioned, these are all pretty heavily pre-treated patients, and so the approval of the drug is for that population specifically?

Jack Khouri, MD: Correct. More than four lines of treatments are currently approved by the FDA, so a lot of treatments before we can get people to CAR T unless on clinical trials.

Dale Shepard, MD, PhD: Now, CAR T as a therapy, particularly lymphoma has been around for a little while now, is it becoming more widespread in its availability or is it still a pretty specialized therapy?

Jack Khouri, MD: We used to have a lot of issues with slot allocation for CAR T-cell manufacturing. Many centers did not have it. Even centers like us, we were not really allocating enough slots to manufacture CAR T-cells. That's getting better. Pharma companies have more slots. They're offering more slots currently for our patients, so that's great. I think more centers are acquiring CAR T-cell therapy capabilities currently. It sounds like more centers are having CAR T-cells at this time, and we are having more slots being allocated to the majority of the centers, so there's more access for sure, and that's been in the span of the past month or so, so a lot of progress in that area.

Dale Shepard, MD, PhD: That's excellent. Tell me a little bit about the retrospective study that you were involved with.

Jack Khouri, MD: As you know, Dale, with a lot of the FDA approvals that we have, it's always good to take a look at what we're doing in the real world to make sure it matches up with the clinical trials. That's what we did. We formed a consortium with 11 other centers in the US and we looked at our data. We had about 150 patients that were infused with idecabtagene vicleucel in the real-world setting and we tried to study their outcomes. What was really important to note from that study was that 75 percent of the patients that were given CAR T-cell in the real-world setting would not have been eligible in clinical trials for CAR T-cell therapy.

Three quarters of the people that we treat in our daily life with CAR T-cell therapy would not have been eligible for clinical trials with CAR T-cell therapy. It was just very interesting to learn that. Those people were not eligible because their performance status was not adequate for this study, or their kidney function would not have been up to par. They had cytopenias like a low neutrophil count or low platelets that would've precluded them from going on study.

It's great to learn that a lot of patients that would've been excluded from clinical trials, we can actually treat them in real world, and the CAR T-cell therapy was really safe for those patients. They did not really have more toxicities, and it was pretty effective for a lot of the patients that we treated in the real-world setting. That's encouraging, which is why I always tell people in the region and elsewhere to always refer patients to us even if they think they don't really look as fit as they think they would for CAR T-cell therapy because a lot of these patients would end up actually being listed for CAR T and would get the therapy.

Dale Shepard, MD, PhD: I guess it's somewhat striking that 75 percent of patients wouldn't have been on the trial. I mean, it kind of speaks to not only how you can use the drug once it's available, but even earlier to trial design, and just imagine how much faster a trial could accrue if they had less restrictive criteria, how many things are we keeping from patients that might benefit from them.

Jack Khouri, MD: Exactly, and this is where the field is going. A lot of the trials currently on CAR T are using CAR T in the earlier lines of treatment, even in the first line setting where people's bone marrow is healthier, they're not as sick, their performance status is better. We're hoping that, in the next year or so, CAR T-cell will be approved for the earlier lines of treatment.

Dale Shepard, MD, PhD: I guess anytime you get new therapies, and particularly expensive therapies, there's sometimes a little more scrutiny from insurance companies. Has there been pushback for that or is it pretty easily overcome able?

Jack Khouri, MD: Not really. It's been very easy to get CAR T approved as long as you follow the actual indication after four lines of treatment, but, yeah, we have not really been getting pushback from insurance companies thankfully.

Dale Shepard, MD, PhD: Of the factors you mentioned, performance status, kidney function, cytopenias, age, are there any of those that give you the most pause when you see patients? If someone is referring to a patient, is there one factor over another that might end up maybe leading you not to go down a CAR T path?

Jack Khouri, MD: Yeah. The main thing has been kidney function for me, and this is because we have to give lymphodepleting chemotherapy to a lot of these patients before CAR T-cell therapy. This is mostly to make sure that the cells expand after infusion. It's more for the immunosuppressive role of lymphodepletion, and some of the drugs that we give for that are renally excreted and being on dialysis, can be a problem. Potentially, kidney dysfunction and being on dialysis have been the ones that I've been looking at the most in terms of saying no to CAR T-cell therapy. Otherwise, cytopenias have not been an issue, performance status, unless the patient can walk. Even if they're 83, we can still consider it. The upper range on the age in the study was 83, so there was a patient who was 83 that got treated.

The oldest patient that we've had here was 80, and he's done great, this is one of the case studies that we submitted for Consult QD where the patient did very well, and he's a year out from his CAR T and he's still in remission, never had any toxicities or anything. He was a real fit 80-year-old, didn't have any organ problems, no organ dysfunction, and he did very well.

Dale Shepard, MD, PhD: When we think about especially when you're using some of these more complex therapies and you're outside the PI norms if you will, is there more of a hesitancy on the patient part to get these therapies or on a provider, too, to send patients to you?

Jack Khouri, MD: No, it's not on the patient's part. It's always on the provider, I feel. Patients, actually, are very excited about CAR T. They know about it, and they ask their docs to refer them. I think we're seeing more and more referrals, so I think this stigma is fading away. Hopefully, we'll see more and more referrals with time.

Dale Shepard, MD, PhD: How do you think studies like these retrospective experiences, which 150 patients is pretty significant for this kind of therapy? Do you think there's a hope that this will affect how future trials are designed?

Jack Khouri, MD: Yes, I do think there will be hope. We're already talking to pharma about study design for future studies, and we are trying to drop some of the inclusion criteria and exclusion criteria that could preclude a lot of patients. Now, the good thing is CAR T-cell therapy will be moving ahead in the myeloma paradigm. We will be treating people with CAR T anyway in the earlier lines of treatment, but, yes, I always talk to pharma about it whenever I meet with them, and we talk about what are we talking about in terms of future trials, what are some things that you don't want to see in our design? We talk about all of those things, and they seem to be open to change. It will take time, but I think we're heading all in that way.

Dale Shepard, MD, PhD: Excellent. You say there's currently two therapies that are available moving into earlier lines. What are the other exciting things in either CAR T or cellular therapies for myeloma? What's exciting for you right now?

Jack Khouri, MD: Right. In myeloma, we currently target BCMA on the surface of the myeloma cells with CAR T-cell therapy. There are other CAR T-cell therapies out there that are targeting different proteins on the surface of the myeloma cell. Those will be really good for people after they relapse, after BCMA-targeted CAR T-cell therapy, so different targets for CAR T-cell therapy, these are very exciting.

Another exciting realm in myeloma care currently is bispecific antibodies. We've already had one bispecific antibody approved by the FDA that happened last year, and that's another option for our patients, especially those with the fast disease tempo who cannot really wait for CAR T-cell collection and manufacturing, that we have to do something right now for their disease. This is off the shelf and easy to give with very similar responses to CAR T-cells. We also have another bispecific antibody that will hopefully be approved later this year that targets a different target. We do have a lot of CAR T-cell products in the making, BCMA-targeting and other targets, and we have bispecific antibodies that are very promising, and we already have one approved by the FDA.

Dale Shepard, MD, PhD: Then just give us a rough idea. You mentioned it earlier and then you've mentioned it again. What kind of timeframe are we thinking about, so see a patient in the clinic, you need therapy, hey, how about CAR T? When can you get them treated typically?

Jack Khouri, MD: We used to have a waiting list where people would wait months to get to CAR T, but now it's getting better in terms of access and slot allocation. If I were to see somebody today, then in the next month or so we can collect their cells. It's getting a little bit easier to get people to the collection. It used to take three months to four months before, but now it's getting better, so I would say a month or so.

Dale Shepard, MD, PhD: It's a pretty significant change.

Jack Khouri, MD: Yeah, and it happened in the span of a month or so. It's all new, this transition. We're really hopeful that we'll get people access faster than before.

Dale Shepard, MD, PhD: Excellent. When we think about these therapies, certainly, we talk about how we don't need to be as concerned about some of these factors like age and performance status, do you think we're going to find any factors that are more or less likely to lead to resistance or people who might need a retreatment? How does the world work in terms of patient selection?

Jack Khouri, MD: I think the main thing will be prior treatment. Currently, we have BCMA-targeted CAR T-cell therapy approved in myeloma. Anybody who had prior BCMA-targeted therapy, they tend to have suboptimal responses to CAR T-cell therapy, so I think the main thing that's really important to note is prior BCMA-targeted therapy before CAR T is something where I have to stop and really think about whether I do need to do CAR T or not, because we do know that the responses tend to be more suboptimal and less durable if you do CAR T-cell therapy after prior BCMA-targeted therapy. As I said, kidney function is something that's really important. Currently, prior BCMA-targeted therapy is where I have to stop and really think about whether I need to do CAR T-cells or not.

Dale Shepard, MD, PhD: Gotcha, but it sounds like the most important take home message is, if there's a patient who you think might even remotely think is a candidate, get them evaluated.

Jack Khouri, MD: Correct.

Dale Shepard, MD, PhD: Well, it sounds like a really exciting field. It sounds like lots of exciting things are going on. As usual, how do we use the therapies in the best way? Thanks for your great insight today.

Jack Khouri, MD: Thank you. Thanks for having me.

Dale Shepard, MD, PhD: Thank you. To make a direct online referral to our Taussig Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You'll receive confirmation once the appointment is scheduled.

This concludes this episode of Cancer Advances. You'll find additional podcast episodes on our website, clevelandclinic.org/canceradvancespodcast. Subscribe to the podcast on iTunes, Google Play, Spotify, SoundCloud, or wherever you listen to podcasts. And don't forget, you can access real time updates from Cleveland Clinic's Cancer Center experts on our Consult QD website, at consultqd.clevelandclinic.org/cancer.

Thank you for listening. Please join us again soon.

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