麻豆传媒

At the recent American Society of Hematology (ASH) virtual meeting, studies investigating chimeric antigen receptor (CAR) T-cell therapy products demonstrated unprecedented response rates with seemingly durable remissions in patients with relapsed/refractory multiple myeloma. However, questions surrounding management strategies, accessibility, and best timing of treatment still need to be fully answered.

麻豆传媒 has brought together three expert leaders in the field: moderator , is joined by , and , for a virtual roundtable discussion on the lingering questions of CAR-T in multiple myeloma, in this last of five exclusive roundtable episodes.

Episode one: Early Transplant or Delayed? Multiple Myeloma Experts Debate

Episode two: Selinexor OK'd for Myeloma, But Does That Make It a Good Drug?

Episode three: Many Questions Surround GRIFFIN Study

Episode four: FORTE Raises Question of Excessive Treatment in Myeloma

Episode five: CAR-T for Myeloma Excites at ASH, but Questions Remain

Following is a transcript of their remarks:

Vinay Prasad, MD: I'm back with Aaron Goodman and Al-Ola Abdallah, and we're talking about ASH abstracts. Gentlemen, the myeloma field is excited about CAR-T or cellular therapy and they are going after all sorts of targets. Of course, they start with BCMA [B-cell maturation antigen], but they've expanded from there, and CAR-T therapies are incredibly exciting.

Those of us who've used them in lymphoma, who have seen the ability to take a chemo-resistant patient and render them free of disease, folks who have used them in pediatric ALL [acute lymphocytic leukemia] have seen the impressive powers of CAR-T. It is not an easy therapy to administer. Often side effects are profound, including neurotoxicity.

But one of the things that I have noted, even in the early phase of the CAR-T studies in multiple myeloma, is that the excitement wasn't just that they have high response rates. In myeloma, we've been fortunate to have a number of drugs with pretty solid response rates of single agents.

Dara [daratumumab (Darzalex)] comes to mind. It's a pretty decent drug. But the hope, I think, of the CAR-Ts in myeloma was that there would be a fraction of people in whom the final cancer cell will be extinct, will be eradicated, and we will be curing some patients.

But all of the results I have been seeing over the last few years with myeloma have left me in a very sober phase, which is I don't think I see CAR-Ts curing patients, and it makes me ask the question of whether or not there is something about myeloma that is very difficult to eradicate the last cells. It's very difficult to cure. If we're not curing people with VRD [bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone], adding some dara might not do it. If we're not curing people with VRD and auto [autologous stem cell transplant], adding some CAR-T might not do it either.

Gentlemen, let's hear your thoughts. CAR-T, what has it shown and what has it yet to show? Aaron, let's start with you. What are your thoughts on CAR-Ts? Its still in its nascency in myeloma. We have no approved products. We have abstract after abstract. What do you think?

Aaron Goodman, MD: Like you, as a cellular therapist and transplanter, the enthusiasm's there. This is why we, at least I, went into this field. We are able to engineer patients' own T cells to fight their cancer and give it back to them. It's cool and we've shown in acute leukemia, lymphoblastic leukemia, and aggressive lymphomas that this approach can cure patients. At least, I'm about ready to use that word. There are some very durable remissions....

Prasad: In those cancers.

Goodman: ... I believe, here. When this got around to myeloma, our site, like many sites, opened up these studies and we accrued heavily on these studies. So what are the positives?

We have patients that are basically penta-refractory with no standard-of-care options. They can get a one-time treatment. There is something about ... CAR-T does have all of these issues with neurotoxicity, cytokine release. It's super-expensive, but unlike every other therapy, to my knowledge, in myeloma, it's like a one-time deal outside of auto transplant.

They get their cells collected, they get admitted to the hospital, they get them infused with a little bit of chemo before, and they're done. With that approach, I don't know the exact numbers off the top of my head, but many patients can have reasonable remissions in a setting where they wouldn't otherwise have. When I say reasonable, maybe 6 months to a year, to a year and a half, I think, at most.

That's the positive. A one-time treatment with a reasonable, durable remission with, I think, a quality of life that's good once they get through the acute setting of neurotoxicity and cytokine release. The bad is, like you said, I don't think we're ... we're not curing these patients. They seem to all be relapsing and there is something about that immortal plasma cell -- maybe it doesn't have enough BCMA on it or it's surrounded by all these cells protecting it -- that we cannot seem to eradicate it. Even allogeneic transplant for myeloma, this is a whole other discussion.

Prasad: Oh, that's a controversy, my friend.

Goodman: [LAUGHTER]

Prasad: That's a real controversy, but you're right. Whether or not it can eradicate the last cell has long been disputed. I think that that's just something that we have to state. I think the hope was that we'd eradicate the last cell. I don't think we see that. Dr. Abdallah, thoughts on the CAR-T cells?

Al-Ola Abdallah, MD: That's a great topic, and I think that's going to be a very hot topic, especially that it ... definitely with the FDA approving drugs with a 20% response rate, so with a 90% response rate I don't think they will second-question that.

But here is the problem about CAR-T cell. We have to agree that it's not perfect. That's number one. The clinical trials, unfortunately, as much as it's showing us great response, like up to 90%, we have to look at the number of patients who are candidates for the CAR-T cell.

If I want to put a patient ... I don't know exactly if Aaron is in the same boat, but we have a lot of clinical trials for CAR-T cell. Patients who are penta-refractory or triple-refractory, some of these patients, their myeloma, when they're aggressive, it actually moves very fast. We're talking about in a week.

If you don't do anything, or any treatment, or you stop the treatment, things can go south very fast. By the time they're going to get a CAR-T cell slot, I think there will be an end organ damage and they might not survive, so that's a very important note to say.

If you look at the best trial they have, it's the CAR-T trial that Janssen is proud about that they have a 96% response rate. If we look closely about these patients, 113 patients got apheresed. At the beginning, prior to the lymphodepletion, 12 discontinued the treatment, eight died, and two had progression disease, and for some reason, two withdrew from the treatment. After they did the lymphodepletion for the 101 patients, four discontinued, and one of their patients died and three actually withdrew.

There is at least 10% of patients that actually did not receive the CAR-T cell, and that's a big number. That's a huge number, and these are patients ... don't forget ... a clinical trial, not real-world, and that's my biggest fear about it, we're exaggerating the number -- 95%, 97%.

But are we giving the right myeloma patients? Which means those who are very aggressive, those who are progressing very fast. Or are we giving them those who are slowly progressing and they can actually wait for 3 months until they get the CAR-T cell?

Prasad: Yeah, that's a...

Abdallah: I'm just worried about those numbers, that it's really good. I'm not trying to doubt their numbers, but I'm worried about are we really seeing the real efficacy of the CAR-T cell, and real world we're going to start seeing like, "Oh, it's not really 90%. It's less than 70% and the progression-free survival, unfortunately, is not 1 and a half years. It's actually less than that."

Because now we're seeing what happened to the patients, because we're treating patients with extramedullary disease and CNS [central nervous system] myeloma more often, and that's where you're going to see the progression-free survival, and the survival is not going to be the same as the clinical trial.

We have to be very careful about our ... and I think the drug and I think the treatment can be approved, but we should not be just giving patients like 95% is going to respond while you have a CNS myeloma. I think there are a lot of question marks about how effective is this treatment.

Prasad: That's well put, and I think that (1), of course the FDA, 20% response rate that will certainly get your approval. They've approved some drugs with as low as 13% response rate, so soon that response rate will be a little bit lower still and we'll get even more approvals.

The next point I think you make is a terrific point, which is that unlike other products, here we use a denominator we don't normally use, which is people who receive the product. We don't use the intention-to-treat denominator, which is people who enrolled on your study and you collected cells in. That denominator would, of course, make these products look slightly less favorable, but still quite favorable.

But the unspoken bias that you're talking about is the trial bias, which is that many centers that are running CAR-T have a long waitlist of patients who are eagerly anticipating CAR-T therapy, but there's not always a spot available.

As they wait on that list, people will fall off. They will become ineligible because the liver enzymes may go through the roof, or renal dysfunction may happen, or their disease may explode. Those people are preferentially removed from the waiting list, leaving behind possibly, potentially, more indolent biology, slower biology in the setting of preserved organ function, which may exaggerate the therapeutic efficacy of these products, which we will learn more in future studies and in real-world experience.

Aaron Goodman, last thoughts on CAR-T? We are all to some degree excited about it. We're all believers, but there are these important caveats. Last thoughts?

Goodman: You are 100% correct, and this isn't unique to the myeloma CARs. It's to all CARs. The most indolent biology is just selected by the nature of the processing time for these therapies, weeks to sometimes months, and I've had many patients drop out for these various reasons.

The hope is maybe we'll have an off-the-shelf CAR, maybe, that would get around that, where we could give these therapies much faster. But you're right: When you're looking at this data that seems super-promising in refractory patients, by nature they have to be more indolent because they've managed to survive 3 to 4 weeks not needing myeloma therapy and be a contender to be on this study.

Prasad: That's well said. Gentlemen, it's been a pleasure to chat with you about all these topics. You know, I can't call you thought leaders because you don't so easily have your thoughts led. You have your own independent thoughts and so that puts you in a different category entirely. I don't think we have a word for that in oncology, so thank you for doing this.

Goodman: Thank you for having me.

Abdallah: Thank you very much for having me as well.

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