What are abnormalities of chromosome 1? Are these abnormalities considered high risk?

Chromosome one, the largest human chromosome, is packed with essential genes that play crucial roles in DNA repair, cell growth, and metabolism. In this HealthTree University lesson, you'll explore chromosome one abnormalities in myeloma and discover whether they are considered high risk.

Which chromosome one abnormalities are becoming part of the high risk discussion? When you drill down into chromosome one, the new high risk definition allows for these chromosome one abnormalities to be considered part of the discussion. Chromosome one, as with all chromosomes, have a short arm and a long arm p and q, and so it's the loss of p and the gain of q that makes somebody high risk. So either one of those can be bad. And the more 1q amplification and gain you have, the more copies you have, the higher the risk. And so some studies have been all over the place, whether three copies versus four or more. I think the other big problem with 1q is it seems to also matter whether it's in isolation or with other translocation. So we now talk about these terms like double hit and triple hit. So when you have chromosome one abnormalities with these other genetic abnormalities, that confers a worse prognosis in terms of risk status. So I think that's the new definition will include these chromosome one into high risk.

In lesson three of this course, we covered the new definition of high risk multiple myeloma. You may want to rewatch that lesson to understand where chromosome one abnormalities fit into the discussion.

What is the difference between a 1q gain and a 1q amplification? How does this affect risk? One of the mutations that is often seen in multiple myeloma is 1q gain, or a mutation in the chromosome one, and specifically in the portion of the q so it's a chromosome, it's almost like an X, and it has short arms and long arms and the short arm is called p. And the long arm of the chromosome is called q. So when you hear the word 1q gain, it means that that that cell that that cancer cell has an extra copy of that part of the chromosome 1q. Now, some people will say 1q gain and others will say 1q amplification. 1q gain, if we look at the strict sense of the word, means that you just have one extra copy. So three copies of that chromosome. If you have amplification, it means that you have four or more copies of that chromosome. We use that a lot of times interchangeably, but the more copies you have at that chromosome, the more effect it's going to have, depending on what chromosome it is that you have in excess is what genes it contains, and the functions that those genes have are going to impact your cell and specifically the myeloma cell.

So we have now discovered that, you know, we have our kind of historic FISH results that have captured some of these translocations, which basically means two parts of the chromosomes have swapped with each other. Some of those are standard risk. Some of those are high risk, depending on what we've learned, you know, over the last ten plus years or so with some of the genetics of myeloma. And then came this discovery that if you have an extra copy or two or several of chromosome one, that could have potential high risk behavior. Now I see it like that because I don't think the story gets fully clear yet with this space. So we have a lot of patients actually, that have this 1q gain, which means they have an extra copy of this chromosome. 1q in some studies, as high as 40% of patients that have these abnormalities have a 1q gain. So we all know that not all those patients are truly high risk. What we have learned is that if you have four or more copies, that's called amplification. And in that case that particular phenotype is associated with high risk myeloma. But we also have patients that have three or less copies of this extra chromosome. And in that case, not all those patients are truly high risk unless it's associated with another high risk abnormality. In that case we do consider those to be high risk.

In June 2025, the International Myeloma Working Group published a consensus statement on defining high-risk genetics in myeloma. In the new guidelines, 1q abnormalities need to occur alongside t(4;14), t(14;16), t(14;20), or with a monoallelic deletion of 1p to be considered as high-risk.

What is a biallelic deletion of chromosome 1p? For each chromosome, you should have two. Okay. And so if you lose one or get a problem with one, the theory is the other one will still work. Okay. However, if you lose the other one as well, then you don't have any to do the work. And so that is what we call biallelic. And it's two. So that bi means two.

What are some explanations as to why mutations in chromosome one are particularly high risk? What the thinking is, is that there are lots of genes on chromosome one that actually help the cell divide faster, adapt faster to changes in its environment. So the thinking is that the more of these genes, the more copies of these genes around, the more these cells are fit to survive in the bone marrow space. Now, we do see, and we do see that even in longitudinal analyzes, that some of the tumor cells seem to be really addicted to these genes on the 1q area. And some tumors start with just three copies, so just one extra copy, but they then acquire yet an extra copy later on so the same material copies itself yet once more to four copies or even 5 or 6 copies. That is on the one hand side, of course, very exciting, because it shows that this is a biologically important region, but from a testing perspective or how we talk about it, it makes it a little bit more difficult because 1q gain or 1q copy change doesn't mean necessarily the same thing. So we do see with some of the analysis that the more copies that cell has already acquired, the more aggressive the tumor may be. So if there is a higher copy number, it may mean that the tumor can grow and proliferate yet faster than one with three copies. But we do see as well that some of the strategies such as maintenance therapy, for example, just with Revlimid can help for those with just one copy number change already quite dramatically. It can extend the progression free time really, really quite substantially for those with just one high risk operation.

Are there any treatments that target chromosome 1 abnormalities? We think there's some conjecture that there's a protein there called MCL1, and so there's some thought that MCL1 inhibitors might be of interest. And also cevostamab FCRH5 target is also expressed on chromosome one. But we don't yet know whether certain drugs work better or not in that setting.

Can chromosome abnormalities be acquired over time? You can definitely acquire some of these abnormalities as time goes on for sure. So that is one that frequently patients have not had, for example, at the time of diagnosis, but then have acquired it similar to what we see with 17p deletion than some of the other abnormalities. So in general, we think about 20 to 30% of newly diagnosed patients are high risk. We kind of divide the risk into translocations and non-translocations because if you have a high risk translocation such as for t(4;14), t(14;16), it tends to be present when you're diagnosed and it stays with you. Unlike that, those translocations, other abnormalities such as chromosome one abnormalities and 17p abnormalities can develop during a patient's journey. Because as you treat myeloma, it's like killing weeds. You kill one weed, but then you have a new, more resistant weed, so that resistant weed can manifest these other changes that were present at the beginning.

Once you acquire a chromosomal abnormality, would it ever completely go away? We don't know of high risk completely going away per se. I think it's whether you can detect it or not. Right. And in terms of the clones. So if you're sustained MRD negative, then that bodes very well. But what we now know is that a single time point of MRD negativity, where you think you predicated it all, is not the same in standard risk and high risk, right? That persistence of MRD negativity is the most important for all patients, but particularly for high risk, because it's the ability to keep that clone in remission.

To learn more about high risk chromosomal abnormalities in multiple myeloma and their impact, be sure to watch the other video lessons in HealthTree University's chromosomal and gene abnormalities in myeloma course on HealthTree.org, or check out the playlist on YouTube.

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