Gareth Morgan

So we are at Myeloma 2022 in Scottsdale, Arizona. My name’s Gareth Morgan. I’m joined by three of my colleagues…

Rafael Fonsecca:

Rafael Fonseca from the Mayo Clinic in Arizona.

Leif Bergsagel:

Leif Bergsagel from the Mayo Clinic in Arizona.

Keith Stewart:

And I’m Keith Stewart from Princess Margaret Cancer Center in Toronto.

Gareth Morgan:

It’s been a great two days of science and interaction. And today we’re just going to wrap up the meeting and discuss some of the highlights of this morning.

Gareth Morgan:

So Rafael, what was the highlight for you?

Rafael Fonsecca:

Boy, there’s so much to talk about, but I have a special place in my heart for Venetoclax and Larry Boise did a fantastic presentation, as always, regarding the biology behind how we should think about BCL2 inhibitors. In particular the selection of patients, the prediction of those that might be more likely to respond versus not, but really a very deep understanding of the molecular mechanisms regarding the efficacy of this drug. So I hope to see a lot more like that, analogs. And also at some point interestingly he said, I won’t talk about MCL1 because it’s just been a path of frustration. So, but we couldn’t hope for something like an MCL1 equivalent to what we have for Venetoclax.

Gareth Morgan:

So do you think we can predict sensitivity to Venetoclax in the laboratory now?

Rafael Fonsecca:

I think to a large degree, I think if you take a very pragmatic approach, I would still say (11;14). You could expand that by lymphoid morphology, maybe cyclin D1 expression, but we need to get to the point that we’re more precise than that. So you need that last 15, 20% of patients. Dr. Gupta had the paper on flow cytometry. I think that some of the functional work that could be done as well, too. But for our audience, if they’re clinicians just (11;14) always think that Venetoclax is an important tool.

Gareth Morgan:

Yeah. And it gives you options in some of the earliest stages of disease, and amyloid as well.

Rafael Fonsecca:

Of course, there’s nothing more rewarding than seeing a second opinion in someone who you find in the record, an (11;14). I’ve actually used it now frontline in one patient who, not quite frontline, but the patient was given a couple of cycles for primary plasma cell leukemia. Total failure of therapy, sent to us so we actually used combinatorial strategy, but we added Venetoclax and the patient is in a stringent CR. So I hope to see more studies in that area.

Gareth Morgan:

And what did you think about what he said about African Americans?

Rafael Fonsecca:

Well, that was very interesting. One of the things that Dr Boise showed was that there might be a differential ability of patients that are African Americans to respond. Whether, even when they have this (11;14). It’s interesting that we have seen that there’s other aspects of (11;14) that still need to be sorted out. At ASH we saw the presentation that we know it’s slightly more common in younger people, and it might be associated with that genetic predisposition to develop multiple myeloma by the familial events, in about nine percent of myeloma patients. So I think the story still needs to be connected a little bit better.

Gareth Morgan:

Great.

Gareth Morgan:

Leif, what was the highlight for you today?

Leif Bergsagel:

Well, the big takeaway for me was T-cell exhaustion. So the second half of the session today dealt with the therapies that look so exciting, bispecific antibodies and CAR-T cells. And they’re really… I think the clue to making those therapies work better is to understand the mechanism of resistance. And we heard yesterday from Marta Chesi, that it looks like T-cell exhaustion in a preclinical model was an issue. And then we heard today from Paolo Neri, with elegant studies in patients really seeming to show that T-cell exhaustion was a major factor.

Leif Bergsagel:

And then Dr. Einsele with his keynote talk really dealt in how for both CAR-T cells and bispecific antibodies in patients, T-cell exhaustion is something that we’re going to need to understand better, and to overcome.

Leif Bergsagel:

So Dr. Einsele had some suggestions of one limiting the therapies for bispecifics, to he said maybe three months, as opposed to continuous. He also talked about checkpoint inhibitors maybe as a way of dealing with that. But I think understanding the mechanism of resistance and how best to use those therapies is the-

Gareth Morgan:

So a couple of interesting things came out of that, and so I was fascinated by the spectrum of infections that occur in these patients. And I wonder what you thought about that?

Leif Bergsagel:

Well, I had never really thought about what’s the difference between CAR-T cells and bispecific antibodies. And then Dr. Einsele sort of explained it to me really nicely. With CAR-T cells you’re exhausting all your T-cells or as with, sorry with bispecific antibodies you’re exhausting all your CAR-T cells. Whereas with CAR-T cells you’re just exhausting the one CAR-T cell. So if you exhaust all your CAR-T cells it appears that you get a profound T-cell immunosuppression, which is very different than what you’re seeing with CAR-T cells.

Gareth Morgan:

So what was the highlight for you, for us?

Keith Stewart:

You know, just to back to some things we haven’t talked about already, I think that the protein degrading drugs have huge promise, and Dr. Kumar discussed those. We haven’t seen any clinical results yet in myeloma we’re anxiously awaiting those, but the preclinical data looks very impressive.

Keith Stewart:

I think there were some important questions addressed about how much can one push Icarus degradation as the mechanisms of action versus other maybe bystander pathways. And then again, I think to reemphasize what Leif said, the world continues to be just transforming in front of our eyes with immunotherapies, T-cell engagers, CAR-T. And the focus now is clearly turning from their absolutely decimate myeloma on day one, but how do you sustain that over time? And there were a lot of different strategies talked about that potentially could make the initial blast better, there could be up regulation of the target with gamma secretase inhibitors, and there could be mechanisms to overcome T-cell exhaustion by-

Gareth Morgan:

So you’ve presented some stuff about targeted therapies and targeting protein tyrosine kinases. So, and we heard from Robert Orlowski about targeting RAS. So, he actually came over a little negative about targeting RAS. What do you think about targeted therapy now, in light of this amazing results with the immunotherapy?

Keith Stewart:

Well, targeting specific kinases, where there’s a kinase mutation, is not proven to be a very successful strategy, I think cause of clonal escape. And I always think back to, I think it was actually Larry Boise that first did the ying and yang curve, and the drugs that work in myeloma tend to target broad mechanisms of survival for plasma cells, as opposed to specific targeted kinases, so proteasome inhibition, [inaudible 00:06:38] degradation. Today I mentioned another plausible pathway, which is a targeting lysozyme as another, sort of broadly acting plasma cell survival strategy. So my guess is for now the very patient specific mutation targeting isn’t going to get us where we need to go to, but I think if we continue to look at things that plasma cells generically alive whether it’s NF-kappa B or whatever, that’s where we’ll have more success.

Gareth Morgan:

So I heard kind of terrific messages about understanding disease biology, targeting disease biology, targeting the immune system.

Gareth Morgan:

And so what I’d like to get a comment from each of you is around how do you think we’re going to go forward in the next couple of years to improve patient outcomes? What do you think is really going to make a difference?

Rafael Fonsecca:

I think I would say that a we’ve learned that combinations are the way to go, and that’s going to be true for targeted therapies. I think the overlap that you have by the various mechanisms of potential escape or clonal heterogeneity could be covering in a larger fraction of patients if we do that, but also very early introduction of the best therapies is going to be critical. So the designs that we saw for instance from the EMN, where they’re going to use bispecifics post-transplant, we’re seeing CAR-T cells up front, I think lining up all those players is going to be critical for our success. And I’ve always believed I’m being quite open about this. I do think myeloma is curable, only a small fraction, but it’s curable. But I think if you bring all these players together, that fraction is going to grow.

Gareth Morgan:

So we have great tools. How are you going to use them Leif?

Leif Bergsagel:

That’s exactly what I was going to say. You stole my thunder. I think maybe we’re all thinking the same, but I guess how else might the field change? I wonder if we’re maybe moving away from continuous therapy with the idea that we can… I mean when all you’ve got is melphalan, or thalidomide, you use it indefinitely, but now that we’ve got all these different therapies and we can get such deep responses. I think you didn’t mention MRD, there’s something. Really, going for the minimal residual disease, using that as an endpoint and using all of our therapies to get there.

Gareth Morgan:

So we heard a great talk from Dr. Martin.

Keith Stewart:

I thought Leif was honestly saying we didn’t need melphalan anymore.

Leif Bergsagel:

Going to be a historic.

Rafael Fonsecca:

And I’m going to say, we don’t need fish anymore. We’re going to go to MRD.

Keith Stewart:

I agree with that.

Gareth Morgan:

So like-

Keith Stewart:

I think these guys have covered it. I think we’re going to…

Gareth Morgan:

So, Tom gave a great talk. So is CAR-T the only winner that’s what he was implying the great multi log reduction in disease burden.

Keith Stewart:

There’s absolutely no doubt that the CAR-T therapy is the best thing we’ve seen ever in our lifetimes in terms of controlling myeloma in the acute setting. I think we need a longer follow up, we need to manage toxicity better, we need to figure out how to get it into more patients with the manufacturing delays. But as far as I can see right now, I’m kind of on Tom’s side, that there’s nothing been quite as powerful as CAR-T therapy, but particularly with the sort of bivalent CAR-T’s.

Gareth Morgan:

Okay. So, thank you guys-

Keith Stewart:

And I think it will replace transplant if you want to go-

Gareth Morgan:

So the days of autologous stem cell transplant are definitely limited, I believe.

Keith Stewart:

Yep.

Gareth Morgan:

So thank you guys. It’s been a great meeting. It’s never a great time to be a patient, but I think there’s more hope for cure at the end of this meeting after seeing these new tools that we have. And I think I’m very excited about the way forward and getting more people into deep, deep responses, and keeping people in those responses permanently.

Gareth Morgan:

So thank you guys, and thanks for your great answers to the questions.

Rafael Fonsecca:

Thank you.

Keith Stewart:

It’s been another fabulous meeting and we hope to see, any of you in the audience are interested, we’ll be back in Madrid next year, 2023.

Gareth Morgan:

Great. Thanks so much.