A session with experts Mohamad Mohty and Saad Usmani, who discuss key advances in myeloma treatment from the 2022 EHA Annual Meeting.

Welcome to The Myeloma Sessions brought to you by the Video Journal of Hematological Oncology (VJHemOnc). This exclusive session features leading experts Mohamad Mohty and Saad Usmani, who hold a fascinating discussion on myeloma treatment updates from EHA 2022. The experts highlight the DETERMINATION trial, the role of transplant, and exciting novel immunotherapies, including bispecifics, chimeric antigen receptor T-cell (CAR-T) therapy, and antibody-drug conjugates (ADCs).

The DETERMINATION trial & the role of transplant in treatment

 

“This question of early versus delayed transplant, I do not think it’s going to be answered. So this is where I think Joe Mikhael made the point, well, let’s have that discussion with the patient, give them the option, and also share with them what’s coming in the future and help them decide. I buy that argument for standard-risk patients. ”

– Saad Usmani

Novel immunotherapies: bispecifics

 

“They work amazingly in the relapsed/refractory setting. We know that even if you’ve been treated with a BCMA-targeting agent, you can still respond to a bispecific.”

– Mohamad Mohty

“The bispecifics in the relapsed setting are giving such high response rates in patients who are refractory to everything. I agree with you. There’s a lot of excitement about BCMA-directed bispecifics.”

– Saad Usmani

Novel immunotherapies: CAR-T cell therapy

 

“The reality is that we do not have access in a large fashion to CAR-T cells. So how do you see bispecifics and CAR-T cells? Because I think bispecifics can be a very nice bridge to CAR-T cells while waiting. They can be very useful.”

– Mohamad Mohty

Novel immunotherapies: antibody-drug conjugates

 

“I think there is still hope, because we are still figuring out the optimal partners, optimal dosing and schedule, and it looks like that 1.9 milligram per kilogram dose may be the sweet spot. And maybe giving it for every four or every eight weeks might be the way to go when you’re combining it with other mechanisms of actions.”

– Saad Usmani

Full transcript

Mohamad Mohty:

Hi, I’m Mohamad Mohty from the Sorbonne University and Saint-Antoine Hospital in Paris, and it is my great pleasure to be today in person at the EHA 2022 with my friend Saad Usmani. It’s so exciting to be together again, but also to see all of these advances ongoing in the field of multiple myeloma. Saad, I think we can spend hours and hours debating this. But, don’t worry, we’ll be on time. We’ll be only a few minutes about the key advances in this field.

Maybe I can start with the first line, and I think the major highlight is the DETERMINATION study, which was presented last week at ASCO by Dr Richardson. We’ll hear about it soon as a late-breaking abstract, but I think the news is all over the place. To make a long story short, it looks like a transplant gives you more PFS, but at the end of the day, overall survival is the same. And, well, the interpretation apparently is the glass is half full or half empty. What are your thoughts, my friend?

Saad Usmani:

I think there has been so much debate in social media, amongst ourselves, even over the past few days about how do we interpret these data. Now, DETERMINATION results have been long awaited because this was a sister study to the original IFM 2009 study. The only difference besides the early versus delayed transplant question was the DETERMINATION trial looked at Len continuously. So, there has always been-

Mohamad Mohty:

And this is true because the IFM study you’re referring to gave it only for 1 year and that’s a major difference.

Saad Usmani:

Yes. There is a camp of believers in autologous stem cell transplantation that they give you the best likelihood of the longest PFS frontline. And there is the other camp, well, we are having all of these advances in the field, so even if you get that PFS benefit, what if the overall survival is the same? So that’s kind of been the debate. With that in mind, the follow up on DETERMINATION is only 6 years, but you and I know that the median OS for myeloma has now advanced to 8 to 10 years.

Mohamad Mohty:

Which is good news.

Saad Usmani:

Which is excellent news. But then it also leads us to the question, is 6 years enough of a follow-up to start seeing the OS benefit? The way that I look at this data is, regardless of wherever you are in the world, the available therapies matter for that OS. So for us in US, in Europe where our patients have options, if it’s a standard risk patient, you still want to show them the PFS benefit if they opt out.

Mohamad Mohty:

20 months plus.

Saad Usmani:

21 months. That’s huge.

Mohamad Mohty:

That’s impressive.

Saad Usmani:

Yeah, that’s impressive. Almost 2 years of PFS benefit. So there are parts of the world where that may be the best bet for your patient, is that first-line. But with embarrasses of riches in the West, I think-

Mohamad Mohty:

It’s a luxury debate.

Saad Usmani:

Exactly. It’s a luxury debate. So if we’re thinking about, “Okay, if I’m going to treat my patient today, what will their options be 4 or 5 years from now?” And just looking at that pipeline, and we’ll talk about that too, bispecifics, CAR-Ts, new small molecules, does it matter?

Mohamad Mohty:

But one quick question, Saad, because you are alluding to the future. So let’s anticipate, how relevant are the DETERMINAITON data now that we are using quadruplets, and maybe doublet, maintenance.

Saad Usmani:

That is where I was going to.

Mohamad Mohty:

Okay.

Saad Usmani:

This is where I think the early versus delayed transplant comes into question. Because by the time the PFS is reading out, we already have all these advances.

Mohamad Mohty:

Absolutely.

Saad Usmani:

If we wait for OS to finally read out, because both the arms don’t have the median OS read out yet. So what you can say is, we don’t know, but they are similar at this time. This question of early versus delayed transplant, I do not think it’s going to be answered. So this is where I think Joe Mikhael made the point, well, let’s have that discussion with the patient, give them the option, and also share with them what’s coming in the future and help them decide. I buy that argument for standard risk patients. I’m okay with that argument, even though I’m a transplant person.

Mohamad Mohty:

I think we are roughly on the same line.

Saad Usmani:

Yes.

Mohamad Mohty:

But I like the issue that the question will never be answered.

Saad Usmani:

Yes.

Mohamad Mohty:

Because I don’t know if you remember, but in one of my first ASH in 1996, there was already a study from the IFM called the [inaudible 00:05:29] study. Never published, actually, looking into delayed versus early transplant. But that’s another story.

Saad Usmani:

High-risk patients, however, I would make the case that you can’t dilly dally there. Okay. That’s where studies have shown early intervention. What we do in that first year of diagnosis is important, trying to get them to as deep a response as possible. And that’s where I don’t think we can have that kind of a debate at this moment in time until we figure out what would be the best approach for high-risk enrichment design trials.

Mohamad Mohty:

So the keyword is DETERMINATION to cure.

Saad Usmani:

Yes.

Mohamad Mohty:

Let’s move now because you alluded to the bispecifics, and I would put this under the global picture of immune therapy. I think at this EHA, at ASCO, at ASH, bispecific is really the keyword. I’m not convinced that all of these bispecifics will make it maybe one day. Who knows, we’ll be lucky. Where do you see the field moving with these bispecifics? They work amazingly in the relapsed/refractory setting. We know that even if you’ve been treated with a BCMA-targeting agent, you can still respond to a bispecific. So, what’s your take on this?

Saad Usmani:

All right. I’m going to bring up our previous discussion into this. Okay. Up until this point, up until maybe 2 years ago, high-dose melphalan was our best single agent. That was our rationale to say, “Hey, there’s our call.”

Mohamad Mohty:

Backbone.

Saad Usmani:

Backbone. Right. We can no longer say it’s our best single agent, because the CAR-T cell therapies and the bispecifics in the relapsed setting are giving such high response rates in patients who are refractory to everything. I agree with you. There’s a lot of excitement about BCMA-directed bispecifics, their combinations with anti-CD38s, and the GPRC5D and cevostamab, which is the FcRH5, and both elran and teclistamab have shown that in prior ADC or CAR-T patients with BCMA, over 50% of the patients respond.

Mohamad Mohty:

Just to clarify. Elran, elranatamab, guys.

Saad Usmani:

Elranatamab. Yes.

Mohamad Mohty:

Yes. And this is really a great bispecific. Let me be provocative, Saad. You probably remember, we all remember, the daratumumab single-agent, with it’s history. Who speaks today about single-agent? So where is the future of bispecifics? Do you believe it’s single-agent or probably will move into combination?

Saad Usmani:

I think it will move into combination. So, in fact, there is some early data being combined with dara in dara-refractory patients, and there appears to be an overall response rate of 80%. So it’s not just single-agent, but if you’re throwing in daratumumab. Now, the caveat here is that dara may not be working on the myeloma, but maybe the immunomodulatory effects, because we’re-

Mohamad Mohty:

Getting rid of the immunosuppressive cells.

Saad Usmani:

There you go. So I think that mechanism of action is what is coming into play in that combination.

Mohamad Mohty:

It’s amazing. So, CAR-T cells. We’re talking about immune therapy. Lots of excitement. Every patient I meet, even the MGUS ones, to be honest, why don’t we get a CAR-T cell to eradicate the disease? Maybe it’s lots of hope, maybe some hype. The reality is that we do not have access in a large fashion to CAR-T cells. So how do you see bispecifics and CAR-T cells? Because I think bispecifics can be a very nice bridge to CAR-T cells while waiting. They can be very useful.

Saad Usmani:

I believe so. And teclistamab data is already published in the New England Journal of Medicine.

Mohamad Mohty:

Absolutely. Fantastic paper by Professor Moreau and colleagues, but it’s an international effort and you are a senior author.

Saad Usmani:

Yes.

Mohamad Mohty:

Congratulations.

Saad Usmani:

Thank you, thank you. We’re seeing a median PFS of almost a year and very similar kind of patient population to the KarMMa. Cilta-cel, probably, I don’t think those kind of results with CARTITUDE-1 will be replicated by its peers right now, but the future may change.

Mohamad Mohty:

But let’s be optimistic.

Saad Usmani:

Yeah. But let’s be optimistic. I do feel that as we shorten the duration of CAR production, as we marry the hype with the hope and create more slots that patients can get, yes, the one-and-done approach is still going to be preferred by a lot of patients.

Mohamad Mohty:

And shortening is going to be a reality.

Saad Usmani:

Yes.

Mohamad Mohty:

Our Chinese colleagues are already doing them in just a couple of days, so it’s going to happen.

Saad Usmani:

It’s going to happen, and then it will be up to whether we can replicate that at our individual institutions and do a point of care. In the meanwhile, however, if I have a patient in front of me and they need treatment right away, bispecifics would likely be the way to go.

Mohamad Mohty:

What do you think about antibody-drug conjugates, just to conclude?

Saad Usmani:

So antibody-drug conjugates, the big challenge has been the off-target side effects with belantamab. We’ve been talking about this for 3 or 4 years now. Some of the data that we are seeing at this congress right now is, if you back off of the dose, less frequent schedule, even in earlier lines of treatment. Professor Evangelos Terpos is-

Mohamad Mohty:

I know, in the elderly population, combining it with IMiDs. Actually, it reminds me the story of 20 years ago, it’s peripheral neuropathy to bortezomib. And we were very anxious, we were very worried. But progressively and rapidly, we learned how to deal with it, playing on the dose once weekly subcutaneous for bortezomib, but also maybe widening the duration between. Maybe it’s going to happen for belantamab. But I think we’ve been neglecting a little bit, belantamab.

Saad Usmani:

I think there is still hope, because we are still figuring out the optimal partners, optimal dosing and schedule, and it looks like that 1.9 milligram per kilogram dose may be the sweet spot. And maybe giving it for every four or every eight weeks might be the way to go when you’re combining it with other mechanisms of actions.

Mohamad Mohty:

Fantastic, the future looks brilliant.

Saad Usmani:

We have covered everything.

Mohamad Mohty:

I don’t know if we’ve covered everything but one thing for sure, that it is very exciting, and I’m so glad Saad, we met again in person. Thank you very much. Take care, guys.

 

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