Keith Stewart:

We’re here at Myeloma 2022 in Scottsdale, Arizona. I’m Keith Stewart. I’m one of the organizers of the meeting and currently working in Toronto Canada. I’m joined by Professor Gareth Morgan, our core organizer with me from New York University Langone Cancer Center and Dr. Faith Davies, who has also been chairing one of the sessions today and presented.

Keith Stewart:

So, we’re going to just have a recap of today’s event and what the highlights were for those of you who are listening. And we’ll maybe start backwards because I thought the last session we had today was probably one of the most interesting, which was talk about minimal residual disease in myeloma and the different technologies that are being employed. Gareth, what were your reactions to that?

Gareth Morgan:

So, I just see the utility of using mass spec going forward. We’ve been addicted to molecular tests and next generation flow. But, going forward, it looks like within a year, we’ll start to have a technology that’s applicable to the peripheral blood that has great sensitivity and if you measure at key time points like three or nine months after a transplant, you can predict how people are going to do long term and adjust therapy appropriately to make outcomes better. It’s great news.

Keith Stewart:

And it’s just a blood test. It’s not bone marrow.

Gareth Morgan:

It’s just a blood test.

Keith Stewart:

And I remember when I was at Mayo Clinic and it was first being developed, the other thing is it takes 15 minutes to run the test. So, really incredibly efficient and simple. Faith, what were you taken by in that session?

Faith Davies:

I really enjoyed Rafael Fonseca’s talk. He put some really good thoughts out there along the lines of, we’re all getting worked up about is MRD formally approved for all of these things, and he pointed out that we’re all very comfortable using serum free light chains to measure response and that we’re very comfortable using those to change our therapies and so on. So, why are we getting so upset and so concerned about using MRD as a test? And so, I thought that was really…

Keith Stewart:

Some people are really quite slow to adopt the technology. Irrationally reluctant to adopt it. Are you using it in your own practice?

Faith Davies:

Yeah. We use it a lot. I think it’s really informative.

Keith Stewart:

For cytometry or sequencing?

Faith Davies:

So, we’ve been mainly using the sequencing method and we’ve got the flow cytometry up and running too. And for us, the flow is probably a little easier because sometimes, because of our referral systems, we have issues getting the diagnostic bone marrow and so the flow method seems to be quite a good one. But yeah, very happy with it.

Keith Stewart:

Of course that still requires bone marrow, and the beauty of today’s talks towards the end, were that you can do this on a peripheral blood sample which… People challenge the sensitivity and specificity of that, but one of the things I always think about is if that’s paused, if you don’t need to do a bone marrow, if it’s negative, you can still go into a bone marrow…

Gareth Morgan:

Absolutely.

Keith Stewart:

If you’re worried about sensitivity. So what did you think about using whole genome scanning as a technology Gareth?

Gareth Morgan:

So, I really like the idea about measuring the number of genomes in the blood using a scanning technology. The issue is that in a disease like myeloma, the sensitivity is going to be limited by the number of genomes that are in the blood. So, my suspicion is that’s not going to work out as sensitive as mass spec. And so I actually think mass spec is going to come to dominate and be the routine diagnostic approach for looking for MRD.

Keith Stewart:

[inaudible] saw some other advantages, which were you could distinguish the drugs, the antibody drugs, from the tumor. You can distinguish the tumor colon from regenerating Crohns after transplant. And she didn’t talk about today, but I know that they’re working on forms of the protein that are amyloid… That cause amyloid [crosstalk] related forms of it. So, that’s also going to be very interesting. So, the session before that was on new drugs and for the audience, what did we learn there Faith?

Faith Davies:

So, we had a couple of talks in now. So, we had a number of talks about image resistance and how that [crosstalk].

Keith Stewart:

For the audience are Revlimid pomalidomide.

Faith Davies:

Yeah. Revlimid pomalidomide, but they’re also talking about some of the newer IMiD’s, MCC220 and 91248?

Keith Stewart:

248. Yeah.

Faith Davies:

Right. Nearly there. And so, that was very interesting. Had a great talk about immunogenic cell death and how important that is for many of the drugs we’ve been using for years like proteasome inhibitors, but also for some of the newer drugs. And I found that particularly interesting because Ken Anderson was saying that in the high risk patients, it may be that those cases are unable to use immunogenic cell death, and that might be why they’re more high risk. So, that was great. We had a really nice talk from Suzanne Lentzsch about new therapy therapies for amyloid and how they’re using similar approaches with bispecific antibodies and also reprogramming macrophages to kill off amyloid cells. So, that was good.

Keith Stewart:

Seems to be more and more amounting evidence that what we’ve always thought of as being directly cytotoxic drugs, may in fact, work in large part through the immune system, including the immune modulators and maybe proteasome inhibitors, which we never really thought about in the context of immunity. What do you think?

Gareth Morgan:

That was a great point of today, that a lot of the drugs that we use are actually utilized in the immune system and building on that with these newer drugs makes every bit of sense. But, I really was taken with Susie Lentzsch’s talk about modifying monocyte macrophages with chimeric antigen receptors in those cells to have them recognize amyloid deposits and go to those and eat up the deposits and then have people’s organs get better. And I thought that was really a novel…

Keith Stewart:

We’ll hear more about new drugs tomorrow of course. The last session in the morning was about single cell sequencing. So, it was probably the most technology focused, but what were the clinical perils that you took away from that? Either of you that wants to answer.

Gareth Morgan:

[crosstalk] I thought it was a great session, all of the single cell data was presented. It’s still got a long way to go. Dr. Ghobrial’s 200 patient samples is going to be a useful data set, but currently it’s not delivering what it should be delivering. I think we have to really work hard to understand what’s going on and not just have correlations between points of disease, the number of bad cells, and the number of immune cells. There was quite a lot of that correlative science and we really need to do investigative science where you change something and see…

Keith Stewart:

One thing that struck me as quite new, was Rodger Tiedemann’s talk where he talked about oxidative phosphorylation and the reactive oxygen species as being a dominant feature driven by application of chromosome one, which we have struggled to understand what the significance of that is. Did you buy into the story there or…?

Faith Davies:

Yeah. So, I mean, I’d actually been to a different meeting last week at our cancer center and the oxidative phosphorylation is the buzz area now in solid tumors and in radiation oncology as well. And so, there’s a lot of work now going on about metabolic reprogramming and metabolomics. And so, I’m really interested, not only in what Rodger’s doing at the moment, but that next step of looking at what the difference is in the metabolomic profiles between those two [crosstalk].

Keith Stewart:

Well, I was going to come to that. So, the last session we should discuss briefly was the opening one, which was on the genomics of myeloma. I guess I’ve asked you this before Gareth, do you think we’ve tapped out what we can learn from genomics? Is it time from metabolomics now?

Gareth Morgan:

I think that would be a bad move to give up on genomics about now. I think it’s just starting to deliver and as we introduce new treatments, exploring the molecular impacts of those treatments is going to be really important.

Keith Stewart:

The first session of today was on genomics. And we… just given what Faith just said about the importance of metabolisms in cancer in general and myeloma, do you think we’ve exhausted what we’ll learn from genomics Gareth?

Gareth Morgan:

I think we’re only just beginning to tap into what genomics can teach us and the use of signatures and timing of origin of the mutations. I think there’s a lot to learn in that. And I think the next year or two, we’ll see a number of new stories emerging like the role of APOBEC signatures and how that modulates disease in different ethnic groups and different risk strata of disease. So, I think we’re at the beginning rather than the end.

Keith Stewart:

What did you take away from that session Faith?

Faith Davies:

So one of the talks I really enjoyed was from Leo Rasche from Wurzburg, and he essentially was talking about the genomics of myeloma and comparing it to how the coronavirus has emerged over the last few years. And he was looking at parallels and similarities between the two. And number one, it was a real cool way to think about myeloma, but his thought process was incredible. And one of the stories he was talking about was, he was able to give examples where he felt there was a patient went into more or less MRD, but there was one single cell that was left and then came back to really take over [crosstalk].

Keith Stewart:

I feel like Gareth’s been talking about this for a decade. The evolution of the cell and this small clones emerging under drug selective pressure. Do you think it’s that new or…?

Gareth Morgan:

I think we’ve both been talking about it for a decade, but this was a good spin on it which really showed that it works.

Keith Stewart:

Especially when you’re explaining to a non expert, like parallels with the emerging variants of the COVID virus.

Faith Davies:

It’s always much more interesting when somebody other than your other half says something, isn’t it?

Gareth Morgan:

Yeah. Well, he’s usually wrong.

Keith Stewart:

Thank you everybody for paying attention. This is the end of day one of our Myeloma 2022 meeting on the innovation of biology and myeloma. We’ll be back tomorrow on day two, and thank you for listening.