What is the definition of high risk multiple myeloma (HRMM)?

What is the definition of high risk multiple myeloma?

High risk multiple myeloma refers to a subgroup of people with multiple myeloma that may not respond well to standard therapies and have poor outcomes. Treating high risk multiple myeloma can be challenging, but some options are available.

So the high risk definition is always changing. And so part of that is because our treatments get better. So if something that might have been high risk before is not considered high risk. An example of that is deletion 13q, which is quite prevalent and used to be considered high risk, but now is no longer because modern therapeutics have made that obsolete. 4;14 translocations are another one that historically and is still sometimes considered high risk. But proteasome inhibitors seem to really specifically improve the outcomes of that.

So that's why the risk definition is inherently a little bit unstable, as it should be, because our therapeutics keep evolving, but also our technologies get better, right? So for example, in the US, there was a very interesting presentation that 50% of patients who get FISH testing done are not enriched on plasma cells. So what that means is when their bone marrow aspirate was tested, they looked at the entire aspirate, not just the myeloma cell.

So that's important because you want to know if somebody has a certain high risk feature such as deletion 17p. Is it in a few cells or many cells? Because some studies say that the amount matters. So you need to know the percentage of cells that have the abnormality. You need to know what's called allelic burden. So if you have 17p and you have two chromosomes, did you lose one or both? And there's also the mutational status. Right. So is it deletion or overexpression underexpression? So it's complicated.

So I think ultimately the purpose of these whatever you call high risks should be able to pull out the patients. That would be you'd be more worried about. High risk is a moving target. And so it is a hard thing to define. I think the presence of 17p deletion is clearly a high risk subset. Patients that have 14;16 translocation by FISH also are a high risk subset. The use now 1q amplification in combination with those high risk factors are also concerning for high risk disease and patients that have routine cytogenetics. So karyotyping abnormalities fall into a 15% of patients that are proliferating. And we call them high risk as well.

What is clinical high risk?

So the clinical high risk is really an interesting question. And I think that patients who present with true extramedullary disease at the time of initial presentation mean they have myeloma that's growing outside of a bone that well packed, like high risk disease patients with plasma cell leukemia. The definition of high risk is really evolving a lot. So we have some data that it's old data. And from the past that says p53 for 4;14, 14;16 this was discovered, I don't know if 10-15 years ago that they had high risk. But now we are now tuning this definition because we know that some p53 patients do not have high risk. They are not really high risk. And that depends on many things on the proportion of cells that they have or the type of mutation or deletion that it has.

We know that there are other patients by NGS or other metabolic that they may have other p53 abnormalities that are not captured by FISH. And the same happens with the 4;14 translocation, 14;16 and even novel and novel abnormalities. We are at discovery now with novel techniques. So this is really evolving. And and at the end, and as it is evolving, the treatment and the approach or the managing of these. So this is completely changing over time. What is good is that we make progress. We adapt treatment again. I mean the treatment adaptation based on that, because maybe we are now using it in novel mechanism, then we can overcome the high risk. So adapt treatment and change things.

Now regarding the biology of the patient. It's a broad definition because you have high risk, cytogenetic abnormalities. So aberrations and they are pretty standard. It's translocation 14;16, translocation 4;14, and deletion 17p, amplification 1q and maybe even also intermediate may be translocation 11;14 then you also have a high level at if you have a high level of LDH at diagnosis, it is a prognostic marker. Also, the ISS scoring system, which is pretty simple, is important.

And then again, if you have an early relapse after your transplant transplant, then you have a very poor prognosis. But this is more dynamic. Prognostic marker. The others can be assessed upfront at diagnosis. So this is high risk markers. It's a broad definition.

Who else is considered to be high risk?

Usually you talk about these high risk markers and also the blood test with ISS. But the thing is that comorbidities is just as important. And that's something you should really include, as a high risk because then you can't have the same treatment as others, and then you are at risk.