What is considered high risk multiple myeloma (HRMM)? Is this a standardized definition?

What is considered high risk multiple myeloma (HRMM)?

Is this a standardized definition?

High risk multiple myeloma is a subgroup of individuals who may not respond well to standard therapies and often have poorer outcomes. So HRMM is high risk multiple myeloma, and the definitions are all over the place. The easiest way to assess risk is to know your stage. In the current second revision of the international staging system, which involved the categorization of 10,000 patients for outcome, there were genetic variables that were identified as risk, and there were variables that kind of looked at how rapidly the myeloma cells grow. That's indirectly measured by the LDH and how much myeloma there is, which is measured by the beta two microglobulin. So there's the disease burden, if you will. How much myeloma do you have? How fast is the myeloma growing and does the myeloma have genetic features that could lead to chemotherapy resistance over time?

Having said that, experienced clinicians know that there's a difference between treating an 85 year old and a 55 year old and treating someone with emphysema, insulin dependent diabetes, coronary artery disease with prior heart attack, those may not be high risk biologic features, but it's going to make treatment more complicated and more challenging and may limit which medications are safe for a patient. There are those variables that you can recognize at the time of diagnosis, and those variables there appear later on, such as you get treatment with a very effective regimen and it doesn't work that well. The response step isn't good. That's just some inherent resistance of your myeloma to the treatment, and that can be challenging going on or patients who have an extremely good response to treatment. But the disease is already starting to grow bad within 6 to 12 months of initial. Those patients also carry risks.

So there's not one standard definition for risk. There are guidelines that exist. I think probably the best for a given patient is know your stage. The definition of high risk is really evolving a lot. We have some data that is old data and from the past, that is p53, 4;14, 14;16. These are discovered, I don’t know, if 10 to 15 years ago that they had high risk, but we are now turning these definition because we know that some p53 patients do not have high risk. They are not really high risk. And it depends on many things on the portion of cells that they have, or the type of mutations or deletion that it has. We know that there are other patients by NGS or other methodologists 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 abnormalities. We are discovering now with novel techniques. So this is really evolving and at the end, it is evolving treatment and the approach or the managing of the, so this is completely changing over time.

Well, it’s good. We make progress. We adapt treatment again. I mean the treatment adaptation based on that because maybe if we are now using a novel mechanism, then we can overcome the high risk. So adapt treatment and change things about regarding actually this disease or the biology of the patient. It's a broad definition because you have high risk cytogenetic abnormalities or 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. But then you also have a high level of LDH at diagnosis, it is a poor 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, then you have a very poor prognosis. But this is more dynamic prognostic marker. The other, you all, have those, can be assessed upfront at diagnosis. So this is high risk markers. It's a broad definition.

Who else may be considered high risk?

I can add to that because usually you talk about these high risk markers and also the blood test with ISS. But the thing is that comorbidities 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 all of us. And then you at risk.

Why is the definition of high risk multiple myeloma evolving and changing?

So the high risk definition, it is always changing. And so part of that is because our treatments get better. So 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 translocation is 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 U.S., 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 features 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 whether what's called allele 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 under expression? 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. So it is a hard thing to define. I think the presence of 17p deletion is clearly a high risk subset of patients that have 14;16 translocation by FISH, also a high risk subset. The use now of 1q amplification in combination with those high risk factors are also concerning for high risk disease. In patients that have routine cytogenetics so carry a typical abnormalities fall into a 15% of patients that are proliferative and we call them high risk as well.

Is there a clinically high risk group of patients?

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, meaning they have myeloma, that's growing outside of a bone that will act like high risk disease patients with plasma cell leukemia.