Your myeloma – individualised treatment targets, where are we now

Chapters

[00:00] Introduction of Dr. Christian Bryant
[00:44] Presentation Aims: Focusing on Practical Patient Information
[01:49] Understanding ‘Risk’ in Myeloma: More Than Just a Number
[05:36] The International Staging System (ISS/R-ISS)
[09:14] Modern Genetic Testing: Cytogenetics, FISH & DNA Arrays
[12:40] New High-Risk Genetic Definitions (R2-ISS)
[14:37] Using Risk to Inform Treatment Choices (Transplant, Maintenance)
[19:11] Myeloma Response Criteria (sCR, CR, VGPR, PR)
[23:09] Going Deeper: Minimal Residual Disease (MRD) Explained
[26:09] How MRD Status Interacts with Risk & Outcomes
[28:17] Does MRD Negativity Mean You Can Stop Maintenance?
[30:44] Long-Term Maintenance & MRD Data (MYELOMA XI Study)
[32:25] Every Myeloma is Unique: Understanding Different Response Patterns
[35:10] The Role of PET Scans in Australia
[37:37] Summary & Key Takeaways: Democratising Information
[40:57] Q&A: Maintenance After Bispecifics & Marker Testing

Transcript

[00:00]
It’s now my absolute pleasure to welcome our first presenter. Dr. Christian Bryant currently works as a haematology staff specialist at the Institute of Haematology at the RPA Hospital, with a clinical focus on multiple myeloma and stem cell transplantation.

Christian does research in immunology and haematology. He’s currently researching T-cell biology, investigating novel approaches to use minimal residual disease testing, and setting up clinical trials for multiple myeloma patients under the ALLG. Dr. Bryant is a member of Myeloma Australia’s medical and scientific advisory group, and he is here today to talk to us about “My Myeloma: Individualised Treatment Targets.” Thank you, Dr. Bryant.

[00:44]
Thanks very much, Kath. Thanks for that kind introduction. It’s a real pleasure to be speaking here today and have the opportunity to talk to you about some of the things that I think are important for patients and families and caregivers to know about myeloma.

I have tried to make this applicable to individuals. I’m not going to throw thousands of clinical trials at you because I think doctors do that too much, and it makes us feel good because there’s lots of data to present. But I often worry that my talks in the past haven’t been palatable and haven’t delivered information that’s useful to individuals, to patients and their families.

So I’ve purposefully tried to have less data and more kind of synthesised content in this, and maybe at the end you can tell me whether I’ve been successful. But this is the overview of this talk.

I think the really important things that I wanted to discuss are how we approach myeloma from a clinical trial perspective and from a risk profile. What is risk? You know, when we’re talking about a disease that we can’t cure at the moment, it’s all high risk, right? There’s no good-risk myeloma. It’s a bad disease. We know that. So, if it’s all very difficult to treat, how do we split patients up into standard risk and high risk, and what does that mean? And what can that help you as a patient or you as a family member? How can that help you make decisions? And I’d like to try and address that.

I wanted to go through what state-of-the-art tests we have in Australia, because actually we’ve got really great diagnostic tests for myeloma that are all fully funded. And I think it’s good for patients to be aware of what’s available so you can be motivated to know that information to make sure you’ve had the right things done.

How can these new tests be used? Are there ways that they can help you to make decisions? I’m going to be talking about a special type of test we call MRD or minimal residual disease, which is a personal interest of mine, and I hope to explain that so that you could maybe talk to your doctor and say, “Can you run an MRD test on me if it was going to help you make a decision?”

And then I think it’s really important for us to acknowledge that myeloma is actually not one disease; it’s many. And it means that different patients will have very different experiences, and different treatments will have different efficacies. And each patient’s treatment decision needs to be highly individualised.

I think that’s important for doctors to know, but it’s really important for patients to know so that you don’t unfairly compare yourself to others and think that you’re getting the wrong treatment or different treatment to other people, because it’s likely that that treatment is different for very good reasons because it’s tailored to you.

And then briefly at the end, I’m going to talk about some of these targeted therapies (time providing) that I think are going to be the future of how we target treatments to myeloma patients.

[03:56]
So, I think the first thing to say is: what does risk mean in myeloma? And I think this always makes me feel really uncomfortable because when we’re talking about risk, we’re talking about people as groups. And you might say if there’s a thousand myeloma patients, 30% of them are predicted to have this outcome, 70% this outcome. And that’s horrible because you’re not a number. You’re a person.

So our patients with myeloma are not numbers. They are people. These are tools to help you make choices, but you should never be seen as a number. And I think it’s just really important to say that we deal with these numbers because we’re trying to make good choices about the future, but really they’re just tools for us to make choices. And your choice and your independent therapy for you will not be the same as all other people who’ve got high-risk or standard-risk myeloma.

But I think the importance of risk is that when we identify patients who’ve got a high risk, should they have different treatment to people who’ve got standard risk? Are the risk-benefits of different treatments different in those two groups of people? And which group might you lie in?

And then the other big question I wanted to address is: if you have high-risk myeloma, should you have more therapy and try and get to a point of deeper disease control? And that’s a big thing that we talk about a lot in trials at the moment. And there is some data that might help us.

[05:36]
So this is the International Staging System. This is the way we have been staging myeloma for the last 10 years. It uses some simple measurements like the amount of good protein in your blood, your albumin; this thing called beta-2 microglobulin, which really is kind of a measure of how much myeloma there is in the body; and it uses this other marker called lactate dehydrogenase, which is a marker of myeloma that’s growing really quickly. So it’s normal in most patients with myeloma, but when it’s high it shows growing myeloma, which we think is higher risk. And then these genetics.

Now, genetics in myeloma is constantly changing and getting better. But when this was designed 10 years ago, these three bad genetic features were thought to be important. And using this R-ISS or revised International Staging System, we can put myeloma patients in one of three groups.

Now they’re called stages. If you go back one… But actually, ‘stage’ is actually a really dumb word in myeloma. We think about stage with breast cancer and lung cancer and colon cancer when it moves outside of one organ into other organs, and that’s where you get, you know, stage one disease might be a localised tumour; stage three disease is when the tumour has spread more widely.

In myeloma that doesn’t really operate, because in most patients with myeloma when they’re diagnosed, they’ve already got myeloma in a lot of their bone marrow. And then I guess it’s possible for it to spread beyond the bone marrow, but that’s only the case in a minority of patients. So actually the stage one, two, and three is sometimes not very helpful, and when my patients ask me, “What stage am I?” I wonder whether it should not be called stage; it could be called something else, and it’s really risk group.

And if you have a look across at that diagram on the right, which is actually a Kaplan-Meier plot, what it shows is for each line, if you draw a line up from time in months and then to the left to the overall likelihood of being alive (a very confronting data), it shows that in the risk group three at 60 months, only about 40% of patients are alive, which is terrible.

Now this is old data. This is data from 10 years ago. This has changed now. So the outcome of patients in that three group is now much better than that. But it shows that in patients in risk group three, they have a lower chance of being alive than patients in risk group one. So it clearly is important, and it’s able to predict how patients may fare—not with 100% accuracy—but it suggests trends.

And the way that we now use this risk group one, two, and three is: if somebody’s in risk group three, we are worried that their outcome with standard treatment is not going to be good enough. And in our practice, we would worry that that patient may need to discuss availability of clinical trials or new treatments that might make that outcome in risk group three get better, because we would like all those lines to be a flat line that goes straight across the top. If that was a flat line, that would show that no patients were passing away from myeloma, and we’d managed to make even the patients in risk group three have good outcomes. Until there are three flat lines there, it’s not good enough. So we’ve got a long way to go.

[09:14]
Now if we move on to the next slide, this is from a talk I give to the junior doctors nationally about myeloma genetic techniques. And it can look a bit overwhelming, but I’ll try and explain to you what this data means.

So we now use three main techniques to assess the genetics of the bad cancer cells in myeloma. And we do that because we know that the genetics is probably the most powerful predictor of how myeloma is going to respond to treatment, how long it’s going to stay in remission, and whether it’s worth being exposed to more drugs or less drugs, and try and help with some of these decisions.

On the top left, you can see conventional cytogenetics. Now that is a test done by myeloma cells being removed from the bone marrow at a biopsy. The myeloma cells are then sent away to a laboratory where they grow in the test tube and get frozen at the point where the chromosomes are separating out as the cell divides. At that point, a very highly trained scientist can actually look with a microscope down at the chromosomes. And they’re so good at their jobs that they can see that that’s chromosome 1 and that’s chromosome 3.

And for example, in this example you can see before us is one of the commonest patterns for chromosomes to be abnormal in myeloma, and it’s called hyperdiploidy. And it means there are extra copies of chromosomes, and they are typically extra copies of odd-numbered chromosomes. No one knows why that is the case; it’s just a strange convenience of a fact that makes it easy to remember them.

But this pattern of hyperdiploidy without other genetic damages is actually one of the better genetic changes that can happen in myeloma, and it puts patients in a standard-risk group. For example, you might see bits broken off some of these chromosomes or additional bits, and some of those features are bad and some of those features are better.

This is the oldest technique that we’ve used to assess genetics in myeloma, and it usually doesn’t work. It works in about 10% of cases because most of the time when you take myeloma out of the body and you try and get it to grow, it doesn’t. One of the great strangenesses about myeloma is it’s very hard to kill in the body, but as soon as you take it out, it’s very difficult to keep it alive.

In fact, so conventional genetics has been replaced now by the bottom two tests that you can see there. One of them is called a DNA array, where we purify the myeloma cells from the bone marrow and look at their DNA against a comparison background. And the other is FISH: fluorescence in situ hybridisation, which detects very specific genetic changes which we know to be of high risk or of clinical significance.

And now if you had a diagnostic bone marrow biopsy for myeloma, you would most likely have those two bottom tests done. You’re only allowed to do them once. You’re not allowed to do them again and again, or you have to pay for them and they cost hundreds of dollars. But most patients in Australia get a DNA array and a FISH, and that’s very good state-of-the-art testing; actually can pick up most important features.

[12:40]
This is very new. This is not yet published, but this is just presented by Jesús San Miguel at the International Myeloma Society meeting last year and is about to be published in the Journal of Clinical Oncology. This is the new high-risk features for myeloma.

Now, what this means is if patients have these genetic changes, we’re very worried that standard treatment is not going to be good enough. That’s the decision that’s helping us make, so that we can think about what could be done to make patients who’ve got these genetic features do better and focus effort on these poor patients who have these high-risk changes.

And you can see there are things that we’ve known about before, like deletion 17p. There’s now this thing called TP53 mutation, which you need to do special testing called next-generation sequencing to pick up—hasn’t been there before. Two lost copies of chromosome 1p. And then all of the other high-risk features which we previously put patients in the high-risk group have been changed.

So having t(4;14) or t(14;20) used to be high-risk features. They’re now only high risk if they’re combined with other things. And that’s because over the last 10 years, our treatments have got better, and patients who have just those translocations are actually not doing worse than other patients because of the change in improvement in therapy. And it means that as the therapies get better, you have to reassess whether things are really high risk or make patients have a worse outcome.

So now you need to have extra copies of 1q or lost 1p if you’re going to have one of those translocations and have a high-risk phenotype.

[14:37]
And so, as I’ve said before, this concept of risk is important if it informs choices, and they need to be clinically relevant choices for patients. And I know there are patients listening today. This science is meant to help you and your doctors to make good choices about interventions which make you sick. You know, let’s be honest. Many of the treatments that we use for myeloma aren’t easy, and they’re not pleasant, and they make you sick. So they need to be worth it, and they need to be worth it as much as possible as we can figure out for an individual.

So on the left is a Kaplan-Meier plot once again. It shows the proportion of people over time who remain in remission. Right? So right at the beginning at the far left of this graph, everybody’s in remission. So the probability of people being in remission is one; it’s 100%. Over time, as patients unfortunately relapse after the treatment, these lines drop. And you can see that out at 8 years, there’s about 25% of patients in the blue line that remain in remission, and it’s about 45% in the red line.

Now the blue line and the red line are the same chemotherapy treatment, and that’s what we use in Australia now: lenalidomide, bortezomib, and dexamethasone, which we used to call RVD (Revlimid, Velcade, Dex). And the difference between these two lines is one group of patients had a transplant and one did not.

And this is looking in the high-risk patients from this big study called DETERMINATION and showing that there’s a big difference in length of remission in the patients with high-risk myeloma who had a transplant—actually a bigger benefit for the high-risk patients than there was in the standard-risk genetic and risk patients.

And this shows that if you’ve got high-risk genetics in myeloma and you have lenalidomide, bortezomib, and dex, you get a big benefit from having a transplant. So when you’re thinking about weighing up whether a transplant’s worth it or not, you should strongly think about the benefit of a transplant. In fact, the average or median remission without a transplant was 17 months, and with a transplant was 55 months. So it’s gone up more than three times.

So that’s one way of using risk to help us make decisions about whether something’s worth it. And in this case, it’s a melphalan stem cell transplant. It’s pretty heavy and makes you quite sick.

On the right, this is from another big study which was published a couple of years ago now called the MASTER study. This study was an “everything but the kitchen sink” study. Right? So they asked a different question. They said, let’s give all our patients every drug that we can justify giving together, and then stop if there’s no myeloma left, and let’s see if that works as well as continuing drugs on and on and on.

So it’s daratumumab, carfilzomib, lenalidomide, and dexamethasone—all four drugs, very strong—and it’s given until patients have no detectable myeloma in their bone marrow with a very sensitive test. And what it shows is that worked quite well if you had no high-risk genetic changes. That’s what that red line is. They’re patients who have none of those bad genetic features.

But in patients who had two or more high-risk genetic changes, they didn’t stay in remission after stopping therapy. And it suggests a really important kind of fundamental point, and something I wanted to get across today, is: if patients have higher genetic risk, it’s even more important that they stay on therapy and that they stay on as much therapy as you can tolerate. Whereas if patients have lower risk, particularly in this MASTER study, if they don’t have those high-risk genetic changes, it’s more justifiable for them to have some treatment and get into remission and then stop.

And that concept of trying to maintain responses if you’ve got higher risk, and maybe being a bit more prepared to stop therapy if it’s appropriate if you’ve got lower risk, is, I think, emerging as a fundamental decision-making tool for us.

[19:11]
So I’ll just summarise that last section of the talk then. So what can we do to improve outcomes if myeloma is high risk? Well, first thing is risk prediction isn’t accurate. It’s accurate if you take a thousand people, but it’s not accurate in one person. So if you are listening and you’re one person, do not despair.

And I think more important than what your risk is, is how you’re coping and how your myeloma is responding, because there will be people in that high-risk group who will do well. And that’s very well known, and I’ve got patients in that situation in my clinic. So don’t despair. Look at your own story and your own features and how you’re going first.

But I think there are still some principles, and I think if you’ve got higher-risk myeloma, you want to try and maximise your exposure to multiple effective drugs. There’s a very proven, in both standard-risk and high-risk myeloma, that maintenance therapy is very driven… maximize exposure to multiple effective drugs, and maintenance therapy has been shown to be useful in all myeloma, but I’m even more inclined to suggest ongoing maintenance therapy in higher-risk myeloma.

Of course, I think high-risk myeloma patients should be thinking about clinical trials and thinking about getting access to therapies which will change their outcome earlier in their therapy.

[20:44]
So, look, this is the old International Myeloma Working Group response criteria. It’s what we still use in clinical trials. I’m sure there are patients online who’ll be familiar with some of these terms. It’s actually pretty complicated. It’s difficult, I think, and not terribly accessible for patients.

But in short, what the IMWG did quite a few years ago now—more than 10 years—is they tried to use paraprotein and light chain responses in the blood (so simple blood tests everybody has access to) and, in some cases, urine and bone marrow testing to grade responses, because we’ve known for some time that in most situations, or in the majority of situations, getting a deeper response is better. But that’s not always the case.

And these four major response criteria are: stringent complete response, which means normal bone marrow and disappearance of paraprotein and normalisation of light chain in the blood. CR is complete response. That means there’s no paraprotein, no abnormalities in the urine, good response of any soft tissue masses, and less than 5% plasma cells in the bone marrow.

And a VGPR, which is often a very good depth of response to get, means you can detect but not measure the paraprotein, and there’s been a big change but not a complete change in light chains. And then a partial response is a 50% reduction in the paraprotein, and it’s a bit more complicated for light chains.

So going in reverse: it’s partial response (50%), VGPR (90%), CR (complete disappearance), stringent CR (complete disappearance and normal marrow).

[23:09]
Now these are the old criteria. On the next slide is the concept: can we get deeper than this? And yes, we can, and we can do this with MRD testing.

And so this picture is an iceberg because it says that really getting to a CR is just really the tip of the iceberg. Actually, you can detect myeloma using very sensitive tests down way, way, way deeper. And for example, the test that we run here at RPA—and samples can be sent to us—is called next-generation flow cytometry. And that can detect down to about 1 in 500,000 cells being abnormal. So one in 10 to the minus 5 cells being abnormal. And we’re designing a new test that’s going to get deeper than that even.

This is all data from myeloma.org that you can look up. This is the test that we run. This is a test called flow cytometry. What we do is we take bone marrow. We label that bone marrow with antibodies against markers we know are on myeloma and markers that are on non-myeloma cells. And we then run as many cells as we can, and we try to run 20 million through this very sensitive machine called a flow cytometer. And we look for abnormal cells. And we can call this if we see up to 20 abnormal cells.

In this example in front of you, you can see the red cells are abnormal because they shouldn’t have that CD56 marker on them in the light blue, and they shouldn’t have CD19 on them. So this allows us to detect abnormal cells down to very, very low levels. In this case, there’s 0.0036% abnormal cells. It actually looks like quite a lot, doesn’t it? But actually, it’s a very low number.

So these very sensitive tests allows us to tell our patients whether they’ve reached this state of what we called MRD negativity, or no detectable myeloma with a sensitive test. And that has lots of implications.

So, for example, we know that patients who get to MRD negativity after a transplant are likely to have a longer remission. We know that patients who remain MRD negative maybe a year after maintenance therapy after transplant have a lower risk of relapsing. And this doesn’t tell us what to do yet, but it’s just another bit of information which in some situations can help patients to make their best choice.

I think it’s really important to say that it doesn’t yet tell us what to do. And you should still make good decisions based on your disease as a whole, but it can be a tool that, if interpreted correctly, can help and empower patients to know what’s going on beneath the surface at the bottom of that iceberg.

[26:09]
So this might be then one question that we could ask: if I’m in a high-risk group like that stage three or risk group three, and I get to no detectable myeloma in the bone marrow on the left, do I do better? And the answer is yes.

So this is a trial where patients are given basically what we give a transplant-eligible patient under the age of 70 in Australia. They’ve had lenalidomide, bortezomib, and dexamethasone four times, and then a transplant, some consolidation, and lenalidomide maintenance.

And on the left in A, you can see the outcome or the likelihood of staying in remission in the patients who have no detectable myeloma using a sensitive MRD technique after their transplant. And what it shows is that the risk group three patients do the same as the risk group one patients. And that means that if you get to this MRD-negative state, you’re likely to do the same regardless of your risk, which is actually really reassuring and justifies being exposed to more intensive therapies like a transplant, for example, particularly if you’re in that risk group three group.

Whereas in B, unfortunately, in the patients who did not manage to get rid of that MRD after their transplant, there’s a big difference in outcome in the risk group three patients and the risk group one. And if you look in the green in the risk group three at two years, less than half of those patients remain in remission. So despite having all those drugs, despite having a transplant, those patients who don’t get to MRD negativity have had a worse outcome.

And that’s actually a big problem and something that we need to address. And there are numerous trials around the world that have been recently published and ongoing to try and address that problem of what you do if a patient continues to have minimal residual disease after their transplant.

[28:17]
I can… Yeah. So, but then what about this? What about asking a different question? And I’ll spend some time talking about this because it makes your brain hurt until it’s been explained.

One question might be: well, if I’ve had a transplant and I’ve had all of these drugs and I get to a very deep state of disease response where you can’t detect any myeloma in my bone marrow using an MRD test, do I really have to have lenalidomide maintenance therapy? I mean, we use lenalidomide maintenance therapy in almost all patients at the moment, and that’s because it’s shown unequivocally to lengthen remission length by about double.

And one of the questions that’s asked, particularly if patients are having side effects from lenalidomide like diarrhoea or low blood counts, is: well, if I’m MRD negative, can I stop the lenalidomide? And what this data shows—in the two red lines, so the hard red line is patients who have no detectable myeloma but stay on lenalidomide, and the dashed red line is patients who are MRD negative and don’t get lenalidomide—is you do better if you’re MRD negative and you have lenalidomide. In fact, that’s the group that has the longest remissions.

So just because you reach MRD negative doesn’t mean, unfortunately, you can stop maintenance therapy at the moment. What this line also shows is that if patients continue to have detectable myeloma in their bone marrow at these very low percentages like 0.00004%, those patients with those tiny bits of detectable myeloma definitely have a better remission length with lenalidomide. And that is the solid blue line, which has maybe at four years there’s 40-50% of people who are in remission, as opposed to the dashed blue line where about 10% of people are in remission after four years.

So what we can say from this is: yes, it’s nice to know what MRD is doing. It’s nice to know how deep your response is, but it doesn’t yet mean that you can stop lenalidomide. Maintenance doesn’t actually change your treatment. It might be part of the information you could use if you were really worried about drugs like lenalidomide, but we can’t yet say you’d be better off stopping lenalidomide, because the group that does best is the people who are MRD negative and stay on lenalidomide.

[30:44]
This is the most intriguing data so far about stopping lenalidomide after a long time. Right? So this is from a big study called the Myeloma XI study. In this study, patients had induction treatment, and then they were randomised to have either a placebo or lenalidomide. And the patients who stayed on lenalidomide long term—they then looked at 2 years, 3 years, 4 years, 5 years of lenalidomide—whether there was a big difference in the people who were MRD negative.

And what it showed is for the patients who are MRD negative on the top, there was less difference between the people who took lenalidomide for 5 years and the people who didn’t. And I think that’s kind of self-evident that if you’re in a very good, deep response, you’re maybe not going to get as much benefit, but it doesn’t actually tell you that you can stop lenalidomide. It might tell you that in a big group of people the benefit was a bit lower after four or five years of maintenance, but it doesn’t tell you that stopping is going to be better for you because probably if you’re tolerating it and you’re not getting unacceptable toxicity, staying on lenalidomide even if you’re MRD negative four years later is still going to be better.

But what it does show is in the MRD-positive patients who still have detectable myeloma in their marrow, the lenalidomide patients do much better than patients on placebo control. So once again, doesn’t really tell us what to do, but can be part of the information to help you make decisions out at this four- or five-year period if you’re getting toxicity from your drug lenalidomide.

[32:25]
I wanted to briefly talk about this, and I drew this by hand, but I think it’s really, really, really important. Not all myeloma is the same, right? So, yes, in a big trial, it’s best if everybody gets to MRD negativity and has no detectable myeloma, but actually some of my patients who’ve been in remission the longest don’t even get their paraproteins to go away.

They’re a different type of myeloma. They have lower aggressiveness myeloma that’s harder to get rid of, harder to get down to no detectable paraprotein or even way off having no detectable myeloma cells in the bone marrow. And they’re that group on the left.

And I think many of you would see these paraprotein graphs over time when you have treatment, and you might see on this graph that at the beginning the patient had a big paraprotein. It dropped with their induction treatment. Then they’ve had a transplant. It’s gone down to this first plateau. That remission has lasted for maybe four years on no drugs. They’ve slowly progressed and then started a second therapy like daratumumab and Velcade and remained. Once again, the paraprotein hasn’t gone away, but it’s remained at a low level and very stable for a long period of time.

This patient in this plot number one might feel really depressed when they go to their myeloma support group because they might talk to their friends and they say, “Oh, what’s your paraprotein? Oh, mine’s some small number, you know, five.” And the other people go, “Oh, mine went away straight away.” And so this poor person feels terrible. They feel like they haven’t done enough. They feel like they haven’t got their myeloma into a deeper response. And yet this person’s going to do exactly the same as the other person on the right, whose paraprotein goes away immediately but then comes back at a later stage and then goes away and comes back.

And really what I wanted to express to you is these are two different types of myeloma, but one is not worse than the other. And it is just a reminder to me that as patients, you need to learn your myeloma and be speaking to your doctor about what matters with your myeloma, because for some people getting to a plateau phase is a great response and actually a very stable and durable response. And if that patient kept adding drugs to try and drive it deeper and deeper, they actually probably make themselves sick without any added benefit in terms of controlling their myeloma long term. So I think horses for courses, but just be aware that there are these big differences between different groups of people.

[35:10]
And then almost finished, I just wanted to bring patients’ attention to the fact that PET scans are now fully funded in Australia for myeloma. There’s two item numbers down the bottom, 61612 and 61614. And you’re allowed to do PET scans at any stage where it’s going to inform treatment. So they don’t actually limit how many you can do. I mean, PET scans expose you to radiation, so you don’t want to have them all the time because of the risk to your body, but they can be used to help guide decisions.

And this is a picture of a PET scan in a myeloma patient showing a liver mass and then a PET scan afterwards showing lots of bony masses, unfortunately, but an improvement. So PET scans can be a really useful tool.

We’ve only had access to them for about, I’m guessing, about six months, I think, something like that. And so we’re still learning how we can deploy them best to help our patients. But I think if you’ve got a difficult question and your doctor doesn’t know whether your myeloma lesion is active, for example, this is a time when a PET scan can be useful.

And so I tried to write down here when we’re starting to think maybe you should perform a PET scan. This is just my ideas; this is not definitive. I think PET scans are very important when there are lumps outside of the bone marrow, which we call extramedullary myeloma. They’re important to measure those lumps, to direct things like radiotherapy to them, to make sure the treatment has worked on those extramedullary plasmacytomas.

PET scans are also really important, particularly in plasmablastic disease, to confirm that all areas of the disease are asleep when you’ve had induction treatment and confirm that you’re in remission. They’re really useful when blood tests aren’t working. So some patients don’t secrete a paraprotein or have very low-level paraproteins, and then PET scans are useful.

And I think what I’m finding more recently when they’re most useful is when CT scans or MRIs are inconclusive and you’re worried that a patient might have active disease or not. So we’re using them in those situations at the moment. They’re fully funded, so you don’t need to pay anything for them.

[37:37]
And then this is a summary, and I’m not going to get time to talk about BCMA-based therapy, but I think there are lots of talks about that, and I was more keen to talk about what practical skills are available right now for you to judge your myeloma and make good choices.

I think now in Australia we have really good state-of-the-art testing to generate that risk information. And we also have got growing access to MRD testing for bone marrows, and certainly at RPA on the eastern seaboard we can receive samples.

But it’s really important to know that, like that graph that I showed you of the patient who didn’t have the deep responses, that you are unique. Everyone’s myeloma is unique, and no one test is better than good sense. And your good sense and your doctor’s good sense in understanding things will beat all these risk tests, I think, every day.

Deep responses are important unless they’re not. So in some patients, reaching MRD negativity is just not appropriate. It’s not what’s needed. If they reach a plateau phase and stay in a stable plateau phase for 5 years, that’s a good result.

We know that risk can help making some decisions, but ultimately it’s going to be better treatments that deliver better outcomes to us. And there are a whole lot of trials going on at the moment to try and figure out how those better treatments like bispecific antibodies and CAR T therapies fit into treatment to give patients better outcomes.

And I’m passionate about MRD mainly because I like the democratisation of care. So, I think you should know what you want to know. Some of my colleagues criticise MRD testing because they say, “Well, we don’t know what to do if you remain positive, or what can you stop drugs if you’re MRD negative.” And I feel yes, that may be true, but actually, I want you to know because my patients have wanted to know. And if you want to know, I think you should have the opportunity to learn this data and then make your own decisions.

And I just think it’s really important to say at the end that every decision is actually a mixture of toxicity from treatment, patient wishes, risk of the myeloma at the beginning, and how deep and how your response has been. And you can’t make any of these decisions in isolation from all of that data. Which means you’ve got to get to know your doctor, get to know your myeloma support nurses, talk, ask questions, learn as much as you can, which is being here, I hope.

And hopefully that has given you some information, some of which you can understand, some of which will be a bit much. And it’s the start of a conversation about how we can help you to make your best choices.

And with that, I’d like to say thank you for asking me to talk. And the last slide is just some acknowledgements. I’d like to acknowledge my group—Professor Joy Ho and Tracy King and Edward Awe and all of the people in my research group in my hospital. And of course, our patients and our families, who we wouldn’t be here without. We’re here to serve them. Thank you very much.

[40:57]
Thank you, Christian. That was a really great start for our seminar series. I really loved early on how you identified that patients are people, not numbers. We get a lot of calls about prognosis and staging, and I really enjoyed how you could say that what matters is how they respond to treatment. So, thank you so much.

Apologies, we are having a slight technical issue with our live chat box. So, please email your questions through if you can. We did have a couple of email questions come through earlier, Christian. So I know you didn’t cover so much the bispecifics, but there were a couple of interesting questions.

One was: is maintenance suggested after successful bispecific treatment for high-risk patients? I know you talked about it in our current standard of care. Are you able to comment on that?

Yeah, absolutely. Look, that’s certainly what’s being proposed in trials and in current trial design like MajesTEC-7; that’s what’s happening. I think most of the current trials continue bispecifics, often with a big effect in terms of immunosuppression. I suspect that’s where we’ll get to: patients having induction therapy with bispecifics and then having maintenance with less toxic drugs like daratumumab and lenalidomide. I think that’s likely where things are going. But that will happen iteratively over the next couple of years as trials progress. They first need to show the combinations are safe and work, and then there’ll be modification and tweaking of those combinations.

Yeah, I think most patients need to stay on maintenance therapy. And I think otherwise you get emergent resistance, and unfortunately with myeloma, each time it comes back it has the chance to develop resistance, which makes it inherently harder to treat. So keeping it compressed, keeping it asleep if you like, with the least toxic agent is where most of our treatment paradigms are moving, particularly in that high-risk group like you identified.

I think that’s where the other question that I thought was interesting is: is testing available in Australia to actually identify any of the specific markers, so the BCMA, the GPRC5D, or the FcRH5, to know which specific would be most effective?

Yeah, really good question. Not routinely. Shirley Sim is setting up an ELISA to pick up soluble BCMA levels. I mean, the thing about BCMA—and I had slides about this; I just decided to focus on risk instead—it’s everywhere. So there is no myeloma that’s BCMA negative that I’m aware of. I think it’s 100% BCMA positive. And that’s because BCMA is not just a marker of myeloma; it’s a receptor that myeloma needs to survive. BCMA on the surface of myeloma cells receives critical life signals from other cells in the bone marrow to make it stay alive from molecules called BAFF and APRIL.

And that’s why you don’t become resistant to BCMA therapy very largely speaking by becoming BCMA negative, because cells that shed their BCMA completely or have no BCMA on the surface don’t get those life signals anymore. So to be able to do that, you have to be a very mutated cell. Most resistance doesn’t happen through that mechanism. It can happen by little mutations in the BCMA. But that means that it kind of wouldn’t be a point in measuring BCMA because everybody would be positive.

The other markers—FcRH5, I always always struggle with these complicated… GPRC5D—I don’t think there’s any testing available. I think that will happen once we get standard-of-care access to these agents. Just as we, for example, will set up an assay to measure CAR T from patients once it becomes a standard of care, which will also be another bit of important information. But yeah, not routinely available at the moment.