Understanding smouldering myeloma

Chapters

[0:07] Introduction
[1:36] What is Smoldering Myeloma? Definitions and Context
[4:37] The Disease Spectrum: MGUS, SMM, and Active Myeloma
[9:54] Symptoms: Understanding “CRAB” and “SLiM” Criteria
[16:10] Explaining Free Light Chains and Ratios
[22:25] How is Smoldering Myeloma Diagnosed?
[29:01] Imaging and Bone Marrow Biopsies
[31:49] Risk Stratification and Prognosis
[40:50] The Critical Question: Should We Treat Smoldering Myeloma?
[45:01] Analysis of Treatment Trials and Data
[51:22] Current Research and Clinical Trials in Australia
[55:23] Practical Management: Monitoring and Watchful Waiting
[59:14] Conclusion

Transcript

[0:07]
Dr. Wojt Janowski is a clinical and laboratory hematologist with a focus on hematological malignancies, particularly multiple myeloma and lymphomas. After completing his physician and hematology training in Melbourne, Dr. Janowski joined the hematology team at the Calvary Mater in 2014 and commenced in private practice in 2015.

At the Calvary Mater, he is the lead for the trials in multiple myeloma and chronic lymphocytic leukemia. He works on protocol development and the rapid translation of cancer research into the clinical setting and is involved in every level of medical training from medical students to hematology advanced trainees. He is a conjoint lecturer with the University of Newcastle and sits on various research committees. So we’d like to welcome Boyd this morning. Thanks, Boyd. Thanks, Julia. I’ll just share my slides. Hopefully everybody can see that.

[1:00]
Thank you for the invitation, first of all, during the event to Myeloma Australia, and welcome to everybody listening in. It’s obviously everyone’s become very used to Zooms and I think this is actually great and a really good way for people from around Australia to be able to access the great resources that Myeloma Australia develops, and hopefully this can be added to them if you feel it is that good.

So today’s topic is smoldering myeloma, which in many ways can be a little bit of a strange entity to wrap your head around because you get told that you have this cancer and that we’re not going to do anything about it, which of course can be a little bit confronting for people, understandably, and also very, very confusing. The focus… and so we’re going to talk about various aspects of things.

You may wonder what Dwayne “The Rock” Johnson is doing on there. I have children who watch movies like Jumanji and apparently when you search Google images for the word “smoldering,” he comes up. So apparently what you’re seeing there is smoldering intensity, but that’s not quite what we mean by smoldering myeloma. It’s more like the previous picture with the slowly simmering away but not quite bursting into flames is kind of the way I think about it.

We’re going to talk a little bit about definitions so that some of the mumbo-jumbo that I talk about doesn’t confuse everybody. We’ll talk a bit about how we decide that someone has smoldering myeloma as opposed to its relatives. We’ll talk about how we decide what risk group that person may then fall into, have a discussion about whether we should be treating smoldering myeloma and in what sort of situations, and then talk about really what is practical management in most cases in Australia in 2021.

[2:58]
So this is a bit of a busy slide and, knowing that this was recorded, I thought I’d actually put the slide in there so that later on you can rewind and come back to some of these definitions. But I know that there will be people in the audience who have had smoldering myeloma for a while now and there will be people in the audience who’ve only just heard about this diagnosis and for whom a lot of the terminology of myeloma is still very much mumbo-jumbo. So I’m not going to go through this in detail because this is not meant to be death by PowerPoint, but just the things we’ll be talking about.

Of course, are paraproteins. Most people in Australia refer to the myeloma protein that’s produced and detectable in blood as the paraprotein, but certainly there are other names for it that you will come across. And that’s just the abnormal antibody protein that’s being produced by the broken plasma cells—so by the myeloma cells. We will also talk about serum free light chains. This can be also quite hard to wrap your head around and I’ll go through that in a little bit more detail in the relevant section.

Plasma cells: what we’re talking about are the cells that become myeloma cells. So plasma cells are a normal part of your immune system, happily sitting in your bone marrow producing antibodies. But when they break, they can become MGUS or eventually myeloma cells. We’ll talk about MGUS in a second, as well as some other things. As I said, this isn’t a lecture on the terminology; come back to the slide later if some of the other things I’ve mentioned are a bit confusing from that perspective.

[4:37]
So what I want to talk about first is where smoldering myeloma fits into this disease group. Because really, MGUS (monoclonal gammopathy of uncertain significance), smoldering multiple myeloma, and symptomatic or what’s probably better called active myeloma all exist in the same sphere. And we are pretty confident that everybody who has myeloma that’s causing damage to their organs, or symptomatic myeloma—and that’s the one we traditionally would always treat—that everybody goes through a phase before that where the myeloma is just simmering but not yet causing damage. And even before that, goes through what’s called an MGUS phase, a monoclonal gammopathy of uncertain significance. And we assume that everybody with active myeloma has evolved through that process, be it slowly over decades or quickly over a matter of months.

However, what we also know is that not everybody with MGUS is going to evolve to having myeloma, and not everybody with smoldering myeloma is going to evolve to having active disease that needs treatment. The reason we draw these lines in the sand is to try and give people an idea of how closely they need to be monitored, but also what are the realistic chances that something is going to happen in their future.

So if you have monoclonal gammopathy of uncertain significance—so what that basically means is that you’ve got a small little paraprotein floating around in your blood, usually discovered by accident by the GP—and that’s not doing anything, and if you were to do a bone marrow biopsy, there’s really not much to find. It’s just this protein sitting there. People in that group have roughly a one in 100 chance every year of progressing to myeloma. So, if you’re in your 70s when you’re diagnosed with that, you know, a four out of five chance that if you live to your 90s, nothing at all happens.

We’ve known for a long time that that’s not everybody’s story, and we’ve also known that there are people where the myeloma is not yet directly causing damage who are much more likely to progress to needing treatment, and hence this group of smoldering myeloma. We’ll talk about that, how we define that in a second, and why we differentiate them as well.

[7:19]
Now, how we differentiate them can be a little bit complicated, but if you break it down really, really simply, it’s to do with: first of all, is this currently causing you damage? Are the broken plasma cells causing damage to the organs? And we’ll go through these a little bit later as well. And if there is damage to the organs as a result of the broken plasma cells, the broken antibody-producing cells, then you have active myeloma and we need to treat it because if we don’t treat it, that damage to the organs will become progressive.

On the other hand, if we have very little evidence of myeloma cells—very little protein and no damage to any of the organs—that’s when we say you have monoclonal gammopathy. So that means that the protein is less than 30 grams per liter and that the number of plasma cells or myeloma cells in the bone marrow are less than one in ten. Then we call that MGUS. So the risk of progression in those people, as I mentioned, is 1% per year.

The in-between group, the smoldering myeloma group, basically what we’re saying is there’s too many of these myeloma cells to say that it’s MGUS, but there isn’t any organ damage yet. So you’re in this in-between group called smoldering myeloma. The idea being—smoldering, if you go with the concept of this being sort of smoldering coals—is that they can burst into flames, start causing damage, and need treatment. And if you’re in that smoldering group, that means you either have a high paraprotein in the blood of greater than 30 grams per liter, or that there is myeloma protein that’s being lost through the kidneys, or that there’s more than 10% myeloma cells in your bone marrow.

And the people in that group—we’ll talk about a better stratification—but overall, the risk of progressing to myeloma and needing treatment is about one in ten every year for the first five years. And if it hasn’t happened by then—if you haven’t progressed to active myeloma by the end of five years from diagnosis—the risk drops off. In other words, most people that progress progress reasonably early.

And a really simple way to think about smoldering myeloma is: it is myeloma, but it doesn’t have symptoms and there’s no imminent risk of those symptoms. It’s not causing any harm to you at the moment, but it has a higher potential to cause you harm in the future than MGUS, than monoclonal gammopathy. And as a result of that, it needs closer monitoring with blood tests, with clinic visits, and sometimes CT scans or MRIs. We’ll talk about how that happens.

[10:25]
So, when we’re talking about symptoms of myeloma, doctors have to learn thousands of these collections of symptoms that define things, so we always use acronyms. And so the traditional symptoms of myeloma are abbreviated to “CRAB,” hence the picture of a crab. And so what we’re talking about is these are the things that myeloma can do to you that causes you damage, and if you have any of these then you’ll definitely be receiving treatment.

The “C” is that the calcium level in your blood can be too high, and that’s because of the myeloma; the calcium is being leached out of the bones and into the blood, and that can damage the kidneys, it can make you very muddled and confused, and usually you’ll land in hospital fairly quickly because you’ll know something is up. It’s not usually subtle. It can cause kidney failure. Lots of things can cause kidney failure; having high blood pressure for decades can cause kidney failure, having type 2 diabetes for a long time can cause kidney failure. And so you do have to be very specific and work out whether the kidney failure is due to the myeloma or not. But someone with myeloma proteins in their blood or the history of smoldering myeloma who suddenly has kidney damage on their blood tests, you would be very quickly assuming that it’s myeloma and wanting to work that out. Sometimes it does need a kidney biopsy to be absolutely sure.

The “A” in the CRAB is for anemia. Anemia—so a low hemoglobin. Hemoglobin is the molecule in your blood that carries the oxygen around. So anemia is often responsible for feelings of profound tiredness, but a thousand other things can cause tiredness as well. But anemia in myeloma can be because the number of plasma cells in the bone marrow is so large that it squashes out the normal healthy bone marrow, and also the myeloma cells themselves, they kind of have a suppressive effect on the normal bone marrow. So they not just cause the direct damage, they also cause a problem in their local—what we call the micro-environment—of the bone marrow, and that can stop your bone marrow from functioning properly.

And then the bone lesions of myeloma, often called lytic lesions—and I’ll show you some pictures of these later—but these are basically lumps of myeloma cells that are damaging the hard cortex, the hard outside of the bones. So if any of those things happen at any point, people need treatment for their myeloma.

[13:02]
A few years ago, myeloma doctors decided to confuse everything and basically realized that there was a group of people who didn’t have CRAB, didn’t have those symptoms of myeloma, and so therefore had smoldering myeloma. But if you watched what happened to those people without treatment for the next couple of years, there was a very, very high chance that something would happen—that one of those CRAB symptoms would occur.

And a few years ago, there was a big discussion saying, “Hey, look, our treatments have gotten better, our treatments are better tolerated. We know that these people, you know, there’s a four out of five times in the next two years that they either break a bone or their kidneys fail or something horrible happens. Why are we sitting on our hands? Why are we not doing something about this early?” And those people used to be termed as having ultra-high-risk smoldering myeloma. Now, there’s a scary-sounding diagnosis if you ever wanted one: you have something that’s ultra-high risk and I’m not treating it.

So, the international consensus was that in these people that fall into this ultra-high-risk group, we should go ahead and treat them properly as if they had that myeloma damage already. And by doing that, we prevent people from breaking those bones; we prevent that kidney failure in the first place. So what used to be called ultra-high-risk smoldering myeloma is actually now just active disease.

What do we use to define that? We all like acronyms, as I mentioned. Apologies to Slim Dusty, who did not have myeloma as far as I know, but the acronym we use for those myeloma-defining events is called “SLiM.” And so the “S” is 60% plasma cells in the bone marrow. You can see there was a bit of a stretch to come up with a nice acronym for this. But 60 percent plasma cells in the bone marrow means that when you have your bone marrow biopsy—which people with smoldering myeloma generally have had—when we look under the microscope, for every hundred cells we look at, 60 of them are myeloma cells and 40 of them are normal bone marrow cells. So we know that people that have that much myeloma on their bone marrow biopsy are at very high risk of something happening.

The light chain ratio is probably the most confusing for people, and I’ll come and explain that in a second. And then this other confusing one, which doesn’t confuse patients so much but definitely confuses radiologists who interpret MRI scans, is that if we do an MRI scan of your whole spine and your pelvis—we’re not looking for bone damage, we’re just looking for a slight difference in the what we call the signal or the intensity of the bone marrow—and what we know is that if we do an MRI scan on someone with smoldering myeloma and we see lots of these patches of different intensity in the bone marrow, then for some reason that predicts something happening soon. And what they probably are are early lytic lesions, but we’re not sure about that at the moment.

[16:10]
So, what’s a light chain ratio and what’s a light chain? I’m sorry, this is a mini biology lecture, so I apologize for anybody who falls asleep. Turn off your camera and make me feel better if you’re about to fall asleep if you don’t mind. But basically, when we’re talking about myeloma, we’re always talking either about free light chains or about paraproteins.

And the reason for this is, as I said at the beginning, is that myeloma cells are broken plasma cells, and plasma cells are antibody-producing cells. So when plasma cells become myeloma cells, what they tend to produce is a lot of identical but broken or abnormal antibody. Okay? And that’s the paraprotein. So, antibody-producing cells—plasma cells—break, become myeloma cells, they still produce antibodies, but it’s a broken antibody and usually producing lots of it, which they’re not meant to do. And that’s what causes that detectable paraprotein in your blood.

Now, an antibody—or an immunoglobulin, which is the other word for it—has two main building blocks. It’s composed of two identical heavy chains (which is the bit in blue here) and then two identical light chains. So every normal antibody looks like that, and most paraproteins produced by plasma cells are that whole molecule—the two heavy chains, the two light chains, all connected together into an antibody protein.

Now, in some people, the plasma cell is broken, as we know. And in some people, the plasma cell is broken in such a way that it no longer produces this whole antibody properly. Instead of producing this whole antibody properly, it’s just producing lots of these free light chains—so this free light chain component of the antibody. That’s all it’s doing. It’s probably making the heavy chains as well; it just doesn’t put them together anymore. So it doesn’t put the pieces of the IKEA furniture together into a whole piece; it just has lots of pieces scattered around. And that’s what we talk about as being free light chains because these free light chains spill out into the blood and they can be measured.

So, roughly 10% of patients with myeloma, if we look in their blood, we’re not going to see any paraprotein, but we are going to find lots of extra free light chains floating around. Our body in normal life always produces some free light chains. It’s like one of the immunologists I work with likes to describe it as: it’s the leftover bits from the furniture box after you’ve finished assembling it. So in normal life, everybody has a few spare light chains, and we all produce both kappa light chains and lambda light chains—just called that because you needed to give them some sort of name.

Now, what happens in myeloma is that in these plasma cells that are producing light chains, they’re always producing one type of them. So if you have myeloma that’s producing free light chains, that will only ever produce kappa light chains or only ever produce lambda light chains. You won’t have myeloma that switches, and you won’t have myeloma that produces both. And the reason for that is that if you think about how this process started months or years or decades ago, it started with one single broken plasma cell. One single broken plasma cell that then divided into two into an identical copy of itself, and those two identical ones then became four identical ones, and so it grew over time. And so you always—if you have myeloma that produces, and this is some of the terminology you’ll hear, an IgG or an IgA, it’s very, very, very strange for it to ever switch to being something else. And so if your myeloma produces kappa or lambda, it’s always going to produce kappa or lambda. And if it doesn’t, it’s going to be rare as hen’s teeth for it to switch.

And as I mentioned, we normally produce these light chains in normal life. And generally speaking, our body will produce roughly twice as many kappa light chains as lambda light chains, and that’s normal. So when we look at your light chain blood tests, we always look at the proportion of one to the other because there are some situations where our production of light chains normally increases. And so we’re always looking at the proportion of one to the other.

This is where it gets a bit complicated because in myeloma, only one of them is being produced in excess, and we call that one the involved light chain—that’s the light chain involved in the myeloma—and we call the other one that’s just a bystander the uninvolved light chain. And when doctors are talking about light chain ratios, they’re not talking about a ratio of kappa to lambda; they’re talking about the ratio of the involved light chain to the uninvolved one. So that can either be the kappa to the lambda ratio, or the lambda to the kappa ratio. I’ll show you what I mean by that.

That’s important because laboratories only ever report the proportion of the kappa to the lambda. So when we talk about a free light chain ratio of 100, the laboratory may be reporting that as 0.001. This is where it gets confusing, not just for patients; it gets confusing for a lot of doctors who aren’t hematologists. So if you think about it: the upper end of normal for kappa is about 20-odd. And so, just as some extreme examples, if you have myeloma that produces kappa light chains and that kappa light chain is, say, 2,000 and the normal lambda is 10, then the ratio is 200. If, on the other hand, your myeloma is the type that produces lambda light chains and your lambdas are 2,000 and your kappa is 10, the ratio is still 200 because it’s the ratio of the involved one (being produced by the myeloma) to the uninvolved one. Does that make sense? Hopefully that makes sense. I know that always confuses people; hopefully it doesn’t anymore, but it might still. So we can talk about that in a Q&A if we need to.

[22:25]
So, how do we diagnose smoldering myeloma? How do we decide? How did we decide that you had smoldering myeloma rather than MGUS? How did we decide that you had smoldering myeloma and not active disease? It’s through a combination of things. Blood tests are obviously where it all starts. It’s usually why you ended up in a hematologist’s office, because someone did a blood test for some reason and noticed something abnormal. And in that, specifically, we’re looking at the levels of those paraproteins and free light chains. We’re also looking at your blood counts and kidney function and a few other things to make sure that it’s not causing any damage at the time.

Urine tests are still important. They are not done universally in Australia anymore because most people argue that the myeloma protein that we could sometimes detect in urine is actually just free light chains anyway, and so we can measure it on blood. So what’s the point? That is largely true. I still think that there is a reason why you should have at least one urine sample at the beginning to look for protein, but we don’t do very many urine tests for people with myeloma anymore unless you’re on a clinical trial. And if you’re on a clinical trial, for reasons I won’t go into today, you get introduced to this lovely concept called the 24-hour urine collection, where you get a nice big bucket from the laboratory and you’re asked to collect every drop of urine that you produce for 24 hours. It cramps your social life a little bit, having to do that once a month. And you can always spot the person on the myeloma clinical trial wandering around a hospital with a huge big bucket of urine.

We also do some form of looking at your bones, and this is probably the bit in Australia at the moment that has the greatest amount of variation. But either way, what we want is a very detailed look at all of your bones that the myeloma can affect to make sure there is no sign at all that the myeloma is causing damage. Because early on, these bone lesions can be completely without symptoms. And you don’t want to find them if they’re without symptoms because you want to treat them before they start causing symptoms.

And so the recommendations these days are: if you have access to a whole-skeleton CT scan, then that’s probably the preferred option, and I suggest it’s probably the most common option in Australia at the moment. There is a recommendation that you add to that an MRI scan of the whole spine and the pelvis if you can swing it. The MRI of the whole spine we can usually get done in Australia without too much trouble under Medicare. The pelvis is a little bit trickier; Medicare has got all these strange rules. So in my practice, people with smoldering myeloma will get a CT scan of the whole skeleton and then an MRI of the whole spine, and we just accept that if the pelvis is the only place to find something, we might miss it for now and find it later.

In the past, we would just use skeletal x-rays—so plain x-rays of the skeleton—and I’ll show you a little picture in a second of why that’s not the preferred option anymore. Unfortunately, again because of the weirdness of Medicare and how different radiology companies interpret Medicare, not everybody can get a CT scan of the skeleton in Australia at the moment, in which case the x-ray of the skeleton is considered good enough. But certainly, at least a CT scan is the preferred option.

And then everybody’s favorite test: bone marrow biopsy. And just saying those words, I can imagine about 29 people on the call wincing. No one likes bone marrow biopsies. I’ll let you in on a secret: I don’t even like performing bone marrow biopsies, and I certainly wouldn’t like having one. Most bone marrow biopsies in Australia are performed under local anesthetic. Some places use sedation, but most places don’t use full general anesthetics anymore.

In case you were wondering what it was that was happening during the bone marrow biopsy since it’s all happening behind you: all it actually is is a fairly large needle put into the back of the pelvic bone where there is a nice big flat piece of bone that’s close to the skin. And so it’s easy for us to make sure we’re in the right place. There is also nothing nearby that we can accidentally put the needle into, like a blood vessel that will cause a big problem. So that’s why we like that spot.

And when we’re talking about the marrow itself, we need to get through the hard outer bit of bone called the cortex or the cortical bone into the spongy stuff in the middle, and that’s where the marrow is. The problem is that our bones have lots of pain nerve endings on the outside, something called the periosteum, which lines the bone. So we can anesthetize that, which stings a fair bit when that needle hits the bone and they inject the local anesthetic. But unfortunately, you can’t anesthetize the whole sensation, and particularly once you get into the bone and you suck some of the bone marrow out—which you have to do fairly quickly and sharply because otherwise all you get is blood, and what you want is bits of marrow—what happens is you’ve got a very solid structure with the bone, and you’re suddenly sucking a teaspoon out of it, which changes the pressure inside that bone very suddenly. And it’s the change in pressure that you feel as that very sudden sting in the back of the pelvic bone. Now, that only lasts a second or two, but it’s still very uncomfortable. But that’s what’s been happening.

And then they use the same needle in a slightly different spot and take an entire piece of the marrow itself, rather than just sucking it up. And that, of course, is when we go back to some of those earlier slides and we were talking about the number of plasma cells in your bone marrow. That’s the really, really important test for people with smoldering myeloma.

[29:01]
So, why are we doing CT scans of the spine and MRI scans of the spine if we’ve already done a CT scan? A number of reasons. The main thing to remember is that myeloma, mostly when it comes to affecting bones, mostly affects bones where there is bone marrow. And so it’s unusual to get myeloma in places where we don’t have bone marrow. As adults, we have very, very little bone marrow beyond our elbows; we have very, very little bone marrow beyond our lower thighs. But everywhere else is full of rich marrow.

And if you look at this picture—this sort of, in people with myeloma and bone lesions from myeloma—this picture sort of outlines where we find those lesions. And what will jump out at you is that, you know, 50% of people with myeloma bone disease will have it in the spine. The problem with the spine, apart from being an incredibly important structure, is it’s also the bit that plain old-fashioned x-rays are really, really, really bad at looking at because there’s so much stuff in the way. Old-fashioned x-rays aren’t that good at picking up myeloma lesions in the spine, and that’s where we want CT scans.

Because some of them can be as subtle as this picture on the right with the red arrows on it: they can be very, very small in the beginning, and you can just see that there’s an area of darkness that’s very, very small. And those are the small little ones we’d really like to pick up because if you pick those up at the beginning, then we know we need to get on and treat the myeloma and stop those from becoming big ones.

If you want to see big ones, you know, this is somebody’s thigh bone, and that area of blackness on the left in the middle of the bone—that’s all bone that’s been eroded away and eaten away by the myeloma. And so if you were to stick a needle into that, you’d just find lots of myeloma cells; what you’re not going to find is the nice hard cortex that I showed you on the previous slide—a nice hard bit of bone holding it together. And lesions like that are at a very, very high risk of breaking. And you know, that’s we really obviously don’t want that happening to anyone ever.

Skull x-rays—just, you know, this is what, unfortunately, some people have: lots of these tiny, tiny little holes of these lesions in the skull. And these usually are painless, believe it or not, but that’s how advanced the myeloma bone disease can get in some people.

[31:49]
So, we’ve made the diagnosis of smoldering myeloma. You’ve been given the good news that you don’t need chemotherapy treatment right now; in fact, all we need to do is watch you closely. But we do need to watch you closely because there is a reasonable chance that you will develop myeloma at some point in your life. And how do we predict this?

The picture on the left, the sword of Damocles—this is kind of what, from my early days in hematology training when thinking about smoldering myeloma, I almost felt that this is sort of how people must feel. You know that there’s this potential disease out there somewhere; you know there’s a sword hanging over your head at some point; you don’t know if and when that might drop. And that is really, really hard to wrap your head around. I’m sure I don’t have to tell this audience that concept—that you have something that may progress, that at your next visit with the hematologist you may be told, “Okay, it’s time to go, it’s time to do something”—can be really hard to wrap your head around.

And believe me, on our side of the table, it creates an incredible amount of anxiety. I don’t want to treat people any earlier than I absolutely have to because I know the treatment is hard work and treatment has its risks. And I would be lying to say that I haven’t been lying awake at night or waking up at three o’clock in the morning sometimes and going, “Geez, I’ve got a bad feeling about this person. But why do I have a bad feeling that they’re about to go wrong?” And so we try and be a little bit more scientific than three o’clock in the morning, sleepless nights.

And so we’ve tried to come up with prognostic models. The problem with prognostic models is that they aren’t crystal balls. And when we develop a risk model to try and work out what are the chances of this developing into active myeloma in the future, what you have to realize is what we’re doing is looking at what has happened to large groups of people, and then looking at all of the information we have about those people and trying to work out, “Well, what makes, what sort of helps identify someone who may progress a bit sooner?” And so that’s really, really helpful when you’re looking at a group of people and you say, “Well, if you have 100 people with smoldering myeloma with these features, so many of them are going to need treatment in the next whatever.”

On an individual level, what does it really mean to say you have a 20% chance or a 40% chance of something? It’s really hard to interpret and to translate into a number that you can actually do something with. And none of our models are perfect, as I’ll show you in a second, but they are getting better with time.

[34:20]
I’ll take you through this bit by bit. And this is the most commonly used risk model for defining if we’re trying to divide people into risk groups today. And so this comes from the Mayo Clinic in the US, which is one of the big myeloma research centers globally. And what they looked at is they looked at over a thousand of their patients with smoldering myeloma, and they looked at all of the information that they’d collected from their blood tests, from their scans, from their genetic tests on their bone marrows, and basically teased that out and how you could pull the people apart into different risk groups.

And what they found is that there are three—you can come up with a very simple risk score: zero, one, two, or three, depending on how many of these features you have. So: a paraprotein level of greater than 20 g/L (that’s the M-spike); a free light chain ratio of greater than 20; or a bone marrow plasma cell number—so the percentage of plasma cells in bone marrow—of greater than 20%. Gosh, that’s neat and tidy, isn’t it? Nice lines in the sand, trying to make things easy to remember. But this works really, really well.

Now, Americans always have to be different, and as you know, they like to measure everything differently. They use a slightly different way of measuring paraproteins. So, a paraprotein of 20 grams per liter in Australian is 2 grams per deciliter in American. So that’s how you translate between American and Australian. And so while the Americans call it the 2-20-20 model, from Australia it’s the 20-20-20 model because we like to keep things simple. Anyway, so you see how many of those features you have, add up that number, and then you can divide people into either having low-risk smoldering myeloma at the bottom, intermediate-risk, or high-risk.

And then what you can say is that people with a low-risk smoldering myeloma, their chances of needing treatment in the next two years are one in twenty-five (4%). If you have only one of those features, then the chances of needing treatment are just under one in five (20%) in the next two years. So that’s pretty good; it means a four out of five chance two years down the track nothing’s happened yet. And if you have two or three of those features, then the chances of something happening in the next two years are almost one in two (50%).

I’ll bring you to this graph now. Think about this graph. We’ve got three different curves, and I’ll explain how these work in a second. But the blue one is the high-risk group… this is actually the colors are the wrong way around. The green one is the intermediate-risk group, and the orange one is the low-risk group. So apologies, that’s a mistake on the slide. So I will credit Clinical Options for the slide, but I’ll also credit them for their mistake.

And what this slide has on the two different axes: if you look along the bottom, what we’re talking about here is the number of years until needing treatment—what we call “years to progression.” So two years, four years, six years, eight years, ten years. And then on the Y-axis, the likelihood that by that point in time that the myeloma has progressed to needing treatment—so it’s gone from smoldering disease to active disease.

So the way you would read that chart is: if you look two years down the track, draw a line up, and if you’re in the high-risk group, you would find that that crosses that high-risk line at about 46%. For the high-risk group, but is, you know, 5% for the low-risk group. You’ll also notice that in that even in that high-risk group of patients, there’s still a fair chunk—one in five people—ten years down the track have not needed treatment despite having high-risk smoldering myeloma. And that’s what I mean by it’s not guaranteed. In the low-risk group, look ten years