What is risk stratification and why is knowing risk status important?

What is risk stratification?

Why is risk stratification important?

When we talk about risk in any disease, what we're really having is a professional conversation that people who have standard risk take 100 of them. On average, those patients actually appear to do better than 100 patients with increased risk.

So this is a way to compare aggregates of patients just to determine whether their outcomes will be as good as we might expect or whether it's going to be more challenging for them with lower response rates or shorter time before the myeloma recurs.

But individuals within that group of 100 can do anything. So there are patients who have high-risk disease who can do quite well, and patients with low-risk disease who can have very challenging clinical courses.

So it doesn't help us predict what a given individual will do, but it helps when we talk about large numbers of patients to try and understand: Are there groups where we might consider different approaches, different maintenance, greater number of drugs for induction?

And then we talk about higher risk. Then we have to decide, well, what criteria we’re going to use to determine who has an increased risk.

One way you can identify risk is by stage. In all cancers, there are staging systems that are in existence that give you some sense of how widespread the disease is and therefore infer what your expectations are for outcome.

Currently in myeloma, there are actually six big numbers that you need to know to try and calculate your risk. Those would be the blood albumin level, the blood beta-2 microglobulin level, the LDH level, and whether you have one of three, two of three, or three of three genetic abnormalities—Del (17p), 1q+, and t(4;14). You can take those six and actually give a risk profile in points that your doctor can help you with their online calculators.

To give you some sense about what your anticipated risk is. However, you have to remember that this applies to large numbers of patients and may not determine how you will do because it's all over the place. Everyone's an individual, and standard-risk patients can have challenges and high-risk patients can do exceptionally well.

Right now, most physicians are not using risk-stratified patients for therapeutic decision-making outside of a clinical trial, with the exception of one versus two transplants, perhaps, or the length and number of medications used during maintenance therapy.

So what is meant by risk stratification?

Risk stratification refers to testing that we do usually when a patient is first diagnosed with multiple myeloma. In order to help determine their overall prognosis and get some sense of the aggressiveness of their myeloma.

And it usually entails both laboratory tests, often done in the blood, such as beta-2 microglobulin, lactate dehydrogenase, or LDH, and albumin, as well as tests from the bone marrow biopsy called cytogenetics. These are looking for chromosome changes within the myeloma cells that can be predictive of the cells' behavior.

We've known for some time now that the myeloma cells can have certain chromosome changes that can predict either for more aggressive or less aggressive behavior.

And so based on all of those tests, we can come up with a risk status of the patient as either standard risk or high-risk myeloma.

Why is understanding risk stratification important?

Well, a couple of ways of answering why risk is important to a patient. First is that I think we're all striving for a cure. And I think to do that, we need to understand both extremes of the patient populations.

If somebody is a standard-risk or good-risk patient, there's a risk that we may be over-treating some of them. And in particular, if 10 to 20% of patients with myeloma are being cured, then why do we treat people forever?

Right? And maybe there's a subset of patients that should be discontinued therapies if we’ve achieved a long-term remission. And so that's one reason you want to know if somebody is a good-risk patient to ask those questions.

So, for example, in my standard-risk patients who are getting more than four years out from lenalidomide maintenance post-transplant, I always ask myself the question, is the patient doing well because of the lenalidomide maintenance or in spite of their lenalidomide maintenance? And if you don't ask that question, you would never discontinue therapy.

And so I think we're not there yet routinely, but we need to ask those. And at the other extreme, for high-risk patients, you can't be complacent just because the remissions, the high-risk patients do respond. And that's an important thing for patients to know.

Everybody responds. What we're interested ultimately is how long will people live? And short of that, how long this remission will last, and short of that, how deep the remission is. So you kind of work backwards.

And the most imminent thing is like, can you get rid of all the disease that's detectable? And that would be MRD negativity. And then sustaining that is the key.

What are some challenges of the risk stratification system?

What's challenging is we do a lot of prognostication in myeloma, so there's going to be low, medium, high-risk patients. But to me, I don't— I think it can be very disheartening as a patient to hear that you're high-risk, but that we don't have anything to really do about it.

So I don't spend too much time prognosticating because I always say that what's more important than what we think is going to happen to you is what actually happens. So let's acknowledge where your starting point is. But we have a lot of exciting new drugs and treatments that might change where you are.

And I think the problem with the risk at some of these diagnosis, it's not sensitive or specific, meaning there may be patients who are not called high-risk but behave high-risk. And conversely, there may be many patients who are high-risk with current technology and treatments may no longer be high-risk.

And so that's the limitation of, I think, our current risk stratification.