番茄社区

Findings from the phase I/II were presented at December's American Society of Hematology (ASH) annual meeting, showing that the B-cell maturation antigen (BCMA) × CD3 bispecific antibody continues to produce meaningful and durable responses in patients with heavily pretreated relapsed or refractory multiple myeloma, as well as a manageable safety profile at the recommended phase II dose.

番茄社区 brought together three expert leaders in their field: moderator , of the University of California San Francisco, is joined by , of the University of California San Diego, and , of the University of Utah in Salt Lake City, for a virtual roundtable discussion. This last of four exclusive episodes focuses on teclistamab and other similar bispecific drugs.

Following is a transcript of their remarks:

Prasad: I'm back. I'm joined by Aaron Goodman, UCSD; Manni Mohyuddin, Utah. We're talking about the breaking myeloma abstracts from ASH. We've got the updated results from the MajesTEC-1 trial, phase I/II study of teclistamab, a BCMA CD3 bispecific antibody, in relapsed/refractory multiple myeloma. This is exciting, this is exciting. Aaron, would you walk us through this new drug teclistamab, or however you say it.

Goodman: Teclistamab. I'm excited by it...

Prasad: Gesundheit, by the way. Sorry.

Goodman: I'm excited by teclistamab and drugs that are similar to the bispecifics. You know, we have one approved bispecific right now in B-cell ALL [acute lymphoblastic leukemia], blinatumomab [Blincyto], and it has its issues. So the MajesTEC-1 study, basically it was a phase I/II study, and it took this bispecific to BCMA CD3, and it gave it to relapsed/refractory multiple myeloma [patients]. They all had to be exposed to IMiDs [immunomodulatory drugs], proteasome inhibitors, and monoclonal antibodies to CD38.

And first, just reporting on the toxicity, what you fear with this type of drug is kind of what we see with CAR T-cells -- cytokine release syndrome and neurotoxicity. So, cytokine release syndrome was seen in about 66% of patients, so two-thirds. But just about all of them, I think other than, like, one or two cases, was just fevers. So there was no grade 3 or 4 -- or very few, one or two patients with grade 3 to 4 cytokine release syndrome. The other toxicity that we worry about, the neurotoxicity or ICANS. Only grade 1 or 2 was seen in a couple percent of patients. So, from those standpoints the drug appeared to be safe, at least compared to CAR-Ts.

Now, about the response rates in this heavily pretreated population. The overall response rate was 65%. And many of those responses were VGPRs [very good partial responses] and CRs [complete responses]. And as we'll see with the swimmer's plot, many of these responses at last follow-up, the majority were durable at last follow-up.

Prasad: So, this is promising. Now, Manni, I want to know your reaction to this drug, bispecific BCMA CD3 antibody.

Mohyuddin: So, I am quite excited. And I think the thing that excites me most about bispecifics are that they're available off the shelf. And I think that if you look at CAR-T, it's a highly selected type of patient that makes it to getting the product. They have to go through so many hurdles. But with bispecifics, it's off the shelf. It's easier.

And I will say that they're treating a fairly heavily relapsed/refractory population, and they are getting response rates that are in the 60s. Whereas, previously, a lot of our drugs were moved forward when their response rates was like in the 20s or 30s. If you look at selinexor [Xpovio], if you look at blinatumomab, melflufen, and all of these drugs were moved forward with very low response rates. So yes, we're seeing good response rates in a single-arm study for a drug that -- if it does get approved -- will be available over the shelf.

I will, however, say it sort of raises a good point where the phase III study of this is basically daratumumab [Darzalex] and teclistamab. Just two drugs -- they're not even relying on steroids -- versus two different types of dara-based triplets, so either dara-pom-dex [daratumumab-pomalidomide-dexamethasone] or dara-Velcade-dex. And I think that tells you how confident the sponsor is in their drug. They're not relying on steroids. Aaron Goodman and I have pointed out how melflufen was hiding behind a heavy dose of steroids for its activity.

Prasad: Yeah.

Mohyuddin: They're trying to get rid of steroids and our patients don't like steroids. So I'm really excited about the fact that if this dex-dara phase III combination works out, we can use a steroid-free regimen. So, it tells you about how confident the sponsor is in their drug. And I think that I'm excited about moving this forward.

Prasad: We have to applaud sponsors for running decent phase III trials with good control arms. We have to applaud that. My thoughts about this are the following. You know, there was a lot of enthusiasm of BCMA CAR-T. And BCMA appears to be a useful target in myeloma.

But one of the great disappointments about BCMA CAR-T is that BCMA CAR-T does not appear to cure any patients. It appears to generate a certain degree of response, but that response is always transient. And so if you're going to embark down a road as toxic as CAR-T , without the prospect of cure, I think there might be another way to hit the target that is off the shelf, easier potentially? We'll find out someday, maybe less toxic, and this might be the answer there. Thoughts, Aaron?

Goodman: I haven't given this specific bispecific, but similar ones including in patients that CAR-Ts didn't work. They're fairly easy to give, they're given to outpatients. Once they get through that first cycle, the CRS [cytokine release syndrome] doesn't seem to happen, and the responses are durable. And I do commend the sponsor. There's two versus three. I mean, think about it. We had selinexor first relapse versus SVd [selinexor-bortezomib-dexamethasone] versus Velcade-dex. That's clearly a company that has no faith in their drug. And this company's going to do two versus three, eliminating a drug. So, I am hopeful that these will move forward and be available to our patients.

Prasad: One thing I want to say is that they show a swim lane plot -- a swim lane plot shows you what happens to people once you enroll them in the study, what the response was, and whether it's ongoing. I much prefer a different plot. It's led by Mark Lythgoe and colleagues. It's called .

The iceberg plot is a plot we develop that adds a piece of information you don't see in a swimmer's plot. It shows you the best response prior to enrolling on this study. Because it's one thing to generate a long and durable response in someone who's had short and fleeting responses. That's where you have a little bit of ice under the water, and a lot of ice above the surface. But it's another thing entirely to take a patient who's always done well with therapies. They have incredibly pan sensitive tumor biology and indolent tumor biology, and to get a long response out of them. So the iceberg plot is the plot we propose as a better way to see what our drug is doing versus what the patient's cancer is doing. Manni, last thoughts on teclistamab.

Mohyuddin: Yeah, I think it's a step forward, undoubtedly, and I look forward to the phase III. I just had one minor comment on what you already said about BCMA CAR-T. It is very true that with ide-cel [idecabtagene vicleucel], almost everybody eventually progressed. The cilta-cel [ciltacabtagene autoleucel] data, again, it's a highly selected group of patients subject to the same selection bias as we spoke about. But with cilta-cel, those who actually went on to receive the product, at 2 years, 60% of them had still not progressed. So I think longer follow-up is needed.

But I do think that, conceptually, there may be a future where if it's maybe targeting different constructs on the BCMA receptor, or combining BCMA with something else, conceptually we may actually have a future where responses with CAR-Ts are durable. I think cilta-cel, at least updated follow-up, is a step forward, relative to what we saw with ide-cel.

Prasad: Well, Manni, I hope you're right. But as they say, hope springs eternal. Thank you, gentlemen, for this.

Mohyuddin: Thank you.

Goodman: Thank you.

Watch episode 1: The 'Messy' Data on Chromosome 1 Abnormalities and Multiple Myeloma Treatment

Watch episode 2: Any Role for Maintenance Ixazomib in Multiple Myeloma?

Watch episode 3: Isatuximab Plus RVd Induction in Newly Diagnosed Multiple Myeloma

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