iwHRMM 2024 | CTCs in HRMM: their value in diagnosis, prognosis, and guiding treatment decisions

Gareth Morgan

Hello, my name is Gareth Morgan. I’m professor of medicine at New York University in New York City. We’re here at the International Workshop on High-Risk Myeloma in Charleston. I’m here with my colleagues.

Irene Ghobrial

I’m Irene Ghobrial. I’m a professor of medicine at Dana-Farber Cancer Institute in Boston.

Juan-José Garcés

I am Juan-José Garcés, I am a postdoctoral researcher in the Memorial Sloan Kettering in New York.

Gareth Morgan

And so we just had a great session on circulating tumor cells. And so I think that’s a very interesting prognostic vehicle. So Irene, tell us about your work sequencing these to get prognostic information.

Irene Ghobrial

Yeah. So for many years, we’ve known that if you do flow cytometry, if you count the cells, you definitely have a prognostic relevance of circulating tumor cells in multiple myeloma. And that happens as early as MGUS to smoldering to myeloma, but even as the patients relapse. The question that we are asking is, can we understand the genomic events that happen in those cells? So by doing DNA whole genome sequencing, and can that potentially replace FISH in the bone marrow biopsies, but also can we look at them at the single-cell level with single-cell RNA sequencing? So now looking at the transcriptional changes and not just the genomic events that happen in those patients.

Gareth Morgan

So if I understand this correctly, you’re saying that circulating tumor cells, prognostic just as a number, but using multiple types of genomics, you can generate important scores for prognostic factors that really have more clinical relevance for personalizing the therapy?

Irene Ghobrial

Absolutely. And I think what matters is it’s not only about understanding the prognostic relevance, but also understanding the true disease biology of those patients. Right now, we still do bone marrow biopsies, but bone marrow biopsies are patchy. They don’t give us the whole picture of the patient. So it’s not just the prognostic relevance of that circulating tumor cell is what kind of clones are circulating, why are they circulating, but also can I use it for the therapy for my patient? Can I define someone who is biallelic deletion of BCMA and I will not give them a BCMA CAR-T or a bispecific? So it is therapeutic, it’s prognostic, it’s also understanding the underlying biology, but it’s also very easy and simple. And if we can apply that in the clinic and give it to our patients, we can make a difference for our disease treatment for our own patients.

Gareth Morgan

So José, you gave a great presentation. I’ve seen some beautiful slides from you. Do you want to sum up what you were trying to say in your presentation?

Juan-José Garcés

Yeah, my presentation, I tried to do a global overview of everything from the clinical view to the biological and integrative view of everything. I started just saying that there is a conundrum of studies about the pronostic value of CTCs. There is a necessity of finding a standardization, a consensus between all these studies relating the technique, the sensitivity, the cutoff, because this is critical to establish a new non-invasive staging system in the clinic. On the other hand, I try to, especially from the transcriptomic point of view, I try to highlight some ideas, some results, trying to explain how the CTC is aggressive from the bone marrow, because it seems like there is a pro-inflammatory and [inaudible] environment that could help CTCs to go to the peripheral blood and disseminating the disease. So I think the transcriptomic is very important. And in the final section, I try to combine both aspects, especially making more…stressing the value of the immune system. The immune system has a very important role in helping the tumor cells to disseminate the disease, to protect them in the peripheral blood.

Gareth Morgan

So for any patients that are out there listening to this, what would you want to say to them about the value of this technology?

Juan-José Garcés

The peripheral blood is the future for developing new non-invasive staging systems. We can maybe in some years obviate repetitive bone marrow aspirates and maybe we can, based on more sequential peripheral blood assessment, to have a better view and forecast the disease behavior around the time.

Gareth Morgan

So one of the things that interests me is that the cost of whole genome sequencing has come down dramatically. I produced a slide which surprised myself that in 2014-15 we were talking about next-gen sequencing, the whole genome sequencing, and we’re 10 years on from that. And the cost has come down to not dollars, but like still a substantial amount, but a whole genome for $600, say. So I think that has serious clinical implications. And so my question for Irene is, how do you think that’s going to play out for patient diagnostics?

Irene Ghobrial

Yeah, I think we do need to bring it to the clinic. And actually, we owe it to our patients to bring it to the clinic. We think now that the cost is as much as FISH, potentially even cheaper than FISH. We think it gives you much more information. And that’s a valuable information for the patient to go on certain therapies or not. So it’s not just prognostic, it’s actually a decision making for your therapy. And that matters a lot for our patients, but also for all of the companies that are developing clinical trials and how to put certain populations. So again, personalizing therapy is very important because not all myeloma is the same and we should not be treating all the patients the same way.

Gareth Morgan

José?

Juan-José Garcés

Exactly. I’m seeing the same idea. And it’s especially important because whole genome sequencing can help us to track specific driver mutations or maybe drug-resistant associated mutations. And this is a very interesting way to track how the disease is evolving along the time, how the disease is responding to a specific treatment. For example, I mentioned the BCMA. Seeing the levels of BCMA can help us to to define the treatments.

Gareth Morgan

So for me, there’s a lot of work being done targeting BCMA with immunotherapy. But I think it’s still worth pointing out that myeloma, in 50% of the cases, has mutations of the RAS pathway. Some patients have even more than one mutation in different subclones. So targeting RAS, I think, is a really important therapeutic modality that we should pursue more. In particular, I think we’ve developed some ways of targeting drugs to RAS-activated cells, and there are now actually RAS-on pan-inhibitors. So what do you think about that mutational targeting of therapy?

Irene Ghobrial

Yeah, so you’re bringing on exactly personalized therapy, that every patient, you understand their genome, you understand their own mutation panel, and then you specifically pick the drugs that would work for them. And in the older days, we did not have RAS inhibitors or MYC inhibitors, but now we’re starting to get to that. I think protein degraders are starting to get for us what used to be undruggable. So now we’re starting to get to the level of potentially RAS therapeutics that will actually work very well in our patients. The ideas were there maybe five, seven years ago, but we’re not really with the right drugs. Now we potentially have the right drugs for the right patients.

Gareth Morgan

So an interesting concept for me is the immune cell death. And that kind of hovered around a bit in there. But if you could induce immune cell death, plus combining it with RAS inhibition, I think you have the potential to combine targeted drugs with immunotherapy.

Juan-José Garcés

Absolutely.

Gareth Morgan

So what do you think about that as an approach?

Irene Ghobrial

I mean, think of lung cancer. They’re doing EGFR inhibitors with immunotherapy. This is the trend now to understand that immunotherapy alone may not be enough. Targeting certain mutations may not be enough. But the combinations done in the right way will matter a lot for long-term remissions. and potentially cure for our patients.

Gareth Morgan

So I think you’ve heard it here. This is a very exciting time for patients. We’re developing multiple new therapeutic options. We’ll soon be able to move away from bone marrow testing to testing of the peripheral blood. Though for a while, I think we still have to stay with the bone marrow testing. But overall, I think this is a time of great momentum for patients where we’re seeing the development of cures. So thank you guys.

Irene Ghobrial

Thank you.