iwHRMM 2025 | Circulating malignant plasma cell biology in HRMM: detecting PR cells at the single cell level

Gareth Morgan:

Hello, my name is Gareth Morgan. I’m Professor of Hematology at New York University in New York City. We’re here today at the International Workshop on high-risk myeloma. I’m here with my colleague, Paola, who will introduce herself now. 

Paola Neri:

Hello, everyone. My name is Paola Neri. I’m a clinician scientist at the University of Calgary, so I’m happy to be here with Gareth to discuss some of the topics of the session. 

Gareth Morgan:

So we’ve just come from a very interesting session on circulating tumor cells, and I think the interesting basic fact is that circulating tumor cell numbers go up with higher risk disease and they correlate with outcome. And so the question is, why does that happen? And you presented some fascinating data. 

Paola Neri:

Yeah, that is a great question. And I mean, there are some preliminary data. The new definition of high-risk myeloma, I think we all agree, is a starting point because we can better identify these patients, but we are far from getting the whole picture because, for example, the consensus guidelines didn’t even consider transcriptomics. And I showed that by looking at single-cell RNA-seq, we can identify this minor subclone, they have this PR, so proliferative disease, that unfortunately, if they are present even in newly diagnosed patients, even in standard-risk patients, they are the ones driving eventually poor outcome and eventually poor disease for patients. So it’s very important we look at that. 

Gareth Morgan:

So, I’m not sure it’s entirely clear to everybody why this was innovative, and it’s the application of transcriptomics in the context of single cells. Do you want to explain a bit more about that? 

Paola Neri:

Absolutely. So you’re right, the PR group, per se, was identified more than 20 years ago by microarray, affymetrix, or by bulk RNA-seq. The novelty is that if we do this bulk approach, we may miss the ability to detect minor clones, less than 10%. By single cell, we go so deep into every single cell that we’ll be able to detect this signature, which in our hands means poor prognosis. So the single cell gives us higher sensitivity, specificity, allows us to go down to one single cell and be able to capture this clone when it’s present. Because we know if we can treat or eventually try to deplete this minor clone in the disease, that can actually make a difference in the survival of the patient. 

Gareth Morgan:

So the fascinating thing for me is I’ve always been obsessed about the genetics and understanding what the genetics mean. Actually, when you see that the new definition incorporates these double hits, which basically means an adverse translocation with 1q, the question is, when you have both of those lesions, what is driving the abnormal transcriptional profile? So what do you think of that? 

Paola Neri:

Yeah, we actually got several questions in that regard. I think we need to see not just the tumor, we have to look at the microenvironment where the tumor is. I think we need to understand if we’re seeing a phenomenon caused by the fact the microenvironment is dysfunctional, or is that tumor per se, to your point, with that proliferative advantage changing in the microenvironment. I think we are all learning how additional omics approaches, that means looking at the spatial, looking at the microenvironment around the tumor, can help us understand what exactly happened there. 

Gareth Morgan:

So it all comes down to this question in high-risk disease. So you’ve written some great papers the last year on deletion of the target and mechanisms of resistance. But in essence, high-risk disease is intrinsically treatment-resistant. Even though it responds, it relapses early. And I’m sort of fascinated in what transcriptional rewiring at the epigenetic level is actually doing to the behavior of the clone. And at some level, you might think that the cells, when they start dividing, drop into the peripheral blood where you see this sort of correlation between the two, but I think you presented some cool data on that as well. 

Paola Neri:

Yeah, and actually, it was interesting to see even in the era of T-cell therapy that we thought could eventually deplete these high-risk PR cells, this PR still persists, and actually, we see an accumulation of that signature. So to your point, should we go now after two different targets instead of one target to go to remove that clone emerging? Or to your point, you actually present beautiful data on the epigenomic component of the tumor that can actually eventually help us to identify how to better personalize therapy for patients. 

Gareth Morgan:

So I think you’re making the key point. So Darwin presented some great ideas in the mid-1800s about survival of the fittest. And so if you’re treating cancer, you have to use combinations. Years have taught us that. And we’re using quad therapies now, which are highly effective, median PFS of somewhere between 10 and 17 years. And yet there is still this subgroup of patients that we can probably identify where we could change the treatment up front. So what do you think of that as an idea? 

Paola Neri:

So the combination is definitely the point that we probably can extrapolate. We are seeing, for example, when we look at the signature of these cells, we see a lot of, of course, proliferative signal is there, but we also see DNA repair. We see MYC, we see E2F. So I think these are signatures that we could explore further and say maybe we need to use an epigenetic drug or should we use a DNA repair inhibitor that could help rescue this patient. I think we are learning even more that we need to do more combinations to capture that population as well. 

Gareth Morgan:

So what you’re hearing today is that the myeloma community is focusing more on high-risk disease, there are better definitions, there are focused clinical trials, and we’re trying to develop new treatments that can target this high-risk biology that can be applied in the clinic to improve the outcome of this group. So I think we’re making lots of progress.

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