National myeloma update 2025

Chapters

[00:15] Introduction & Housekeeping
[03:14] Presentation Begins: Dedication & Aims
[06:24] Understanding Myeloma Biology & Treatment Principles
[10:53] Harnessing the Immune System: B-Cells, T-Cells & Antibodies
[15:55] The Evolution of Treatment & Why We Need New Drugs
[21:36] Overview of Modern Myeloma Drug Classes
[28:06] Deep Dive: Steroids, IMiDs, and Proteasome Inhibitors
[35:04] Monoclonal Antibodies & The ‘CD38’ Target
[37:22] Next-Generation Immune Therapies: ADCs, Bispecifics & CAR-T
[45:10] Choosing the Right Treatment Pathway
[48:48] Summary & The Road Ahead for 2025
[50:42] How Patients Can Help Advance Access
[51:45] Q&A Session Begins: Stem Cell Transplants vs. New Therapies
[1:03:30] Q&A: Compassionate Access, Personalised Medicine & IVIG
[1:12:01] Q&A: CAR-T vs. Bispecifics, Age Limits & Making Treatment Decisions
[1:19:10] Closing Remarks & Thanks

Transcript

[00:15]
Hello everyone. Thank you for joining us for the annual national myeloma update with Professor Miles Prince, who kindly volunteers his time to improve and update the knowledge of the myeloma community. My name is Danielle, and I’m one of the specialist myeloma nurses based in Victoria. My colleague Narrel from WA is helping with the behind the scenes today.

Firstly, I would like to begin today by acknowledging the traditional custodians of country throughout Australia and recognise their continuing connection to land, water, and culture. We pay our respects to their elders past, present, and emerging.

Just a few things before we get started. Miles will do his update, which will go from 10:05 to 10:45. We’ll then have a 15-minute break until 11:00. So, that’s time to stretch your legs, go to the bathroom, grab a cuppa, and then from 11 to 11:30, we’ll have our Q&A.

You can send in your questions via our email address, which is nurses@myeloma.org.au, or there is an interactive question box underneath where the webinar is being streamed on our website today. If you’re having any technical issues, please give us a call on our Telephone Support Line, which is 1800 693 566.

This session will be recorded and available for playback on our website a week or two following today’s event. And we also ask that if you can take some time to fill in our evaluation form, which is also on our website, and all feedback is always welcome.

I’m now going to introduce Professor Miles Prince, and then he will begin his presentation. Miles Prince is a professor of medicine at both Melbourne and Monash universities and professor director of molecular oncology and cancer immunology at Epworth Healthcare, and is a haematologist at the Peter MacCallum Cancer Centre in Melbourne. He trained in Melbourne, Sydney, and Toronto.

He has a very active research program involving clinical research and laboratory research involving stem cell research, cell engineering, and cancer immunology. He has been involved in dozens of clinical trials of new therapies for blood cancers such as leukaemia, lymphoma, and myeloma, and he has published over 550 peer-reviewed manuscripts.

He’s a previous chairman and current member of the medical scientific advisory group for Myeloma Australia and is on the steering committee of the International Myeloma Hub. He’s a member of the Australian Blood Cancer Taskforce, which has developed Australia’s first national strategic action plan for blood cancer.

In 2014, Miles was appointed as a member of the Order of Australia for distinguished service to medicine, particularly in the areas of blood cancer research, patient care, and philanthropic leadership. So would you please welcome Miles, who will now take you through his presentation. Thanks, Miles.

[03:14]
Thanks, Danielle, and thanks everybody for joining. I hope it’s an interactive session. As Danielle mentioned, we’ve got plenty of time for questions, which she will be able to walk us through at 11:00. I just like to thank all the team at Myeloma Australia, the ones who’ve been helping organising all of this, and Danielle and Katherine, and the team from CAPRI, and of course the hard work throughout the whole year from Myeloma Australia.

Good luck to you out there with getting into Zoom. Those of you who can hear me have done well so far. It’s always a difficult scenario, but as Danielle mentioned, this is recorded. So please don’t feel you have to take a flurry of notes. You can just listen in and listen to the recorded session later at your leisure.

I really want to dedicate this presentation to Brian Durie, who sadly died earlier this year. He started the International Myeloma Foundation, which was really important for the establishment of Myeloma Australia going back those years. He’d been out to Australia to present to both clinicians and carers for many years, and we have a great debt to what he’s done. He initially established the Durie-Salmon classification for myeloma, and that was just one of his many feats in myeloma.

The purpose of this talk is to talk about what’s new in the treatment of myeloma. So I’m really not going to focus on old drugs. I’m really going to focus on what’s been happening in the last few years. Although I need to talk about the drugs like lenalidomide and pomalidomide and bortezomib really in the context of where they sit with these new therapies.

It isn’t supposed to give you all the details about the drugs. I know all of you are desperate to hear about specific details that relate to you. I just can’t do that in the talk. And I can touch on some of those issues in the question time, but it is an overview, and it’s important to speak to your doctor about the details.

I know that there is always a carer involved, and it’s really important to bring your carer with you when you meet with your doctor. Not only to fact-check you, but also to remember the questions that you’ll forget under the stress of the moment of speaking to your doctor or nurse with regard to your treatment.

And this talk is complicated. It’s hard to take it all in. Please don’t think that you’re dumb or stupid because you don’t understand it all. It challenges the best of us. So, don’t be afraid to ask what you might think is a dumb question, because I bet you it’s not. And the details of the talk are not important. This talk is about giving you a bigger picture. And I just hope that you can walk away with some of the bigger issues rather than the tiny little points.

[06:24]
So we know myeloma is a bone disease—it is a disease that affects the bone, should I say—and it’s not a cancer of the bone, but it involves infiltrating into what you can see here in the middle there, predominantly the vertebrae, the bone marrow-containing spaces.

And what initially happens in myeloma is that you get small growths of these plasma cells, these little fried-egg cells. And then they can grow in little lakes within the vertebrae that you can see right in the middle there. And then to the bottom right-hand side, you can see they can, if they do grow, they can actually damage large parts of the bone. And I’m going to come back to that point a little bit later.

And ultimately, because of its bone effects, it can cause pain and increased calcium. It can affect the bone marrow function, leading to low blood counts. It can lead to infection, and sometimes it can result in kidney damage.

And I only make this point: myeloma, the average age is 65. So that means half the patients are below and half the patients are above 65 years of age. And it means that the treatments are designed for this age group. We’re not trying to squeeze treatments that are designed for 25-year-olds into 80-year-old people.

So it really is important that a lot of the trials have been done in patients of your age, younger or older. And so it is important to realise that these general treatments are considered safe in the age group of patients who have myeloma.

[08:10]
So we’re going to be talking about how we actually treat myeloma. And ultimately, we want to kill that abnormal plasma cell. But to understand how we kill it, we’ve got to just go back and, as I always do in this talk, just reflect on how this grows.

Just excuse this slide; it didn’t turn out. But this is really just to show you that when a cell is dividing, it splits into two. And so for cells like plasma cells to grow, it must double its DNA, and then it separates out, and the cells, one then becomes two, two then becomes four.

And for chemotherapy to work, what it basically does is get into that cell multiplication process. So chemotherapy is the classic, and it relies on cell multiplication. But can we kill cells that don’t multiply, that are not in the phase of multiplication? And the answer is now we can.

We used to rely just on chemotherapy, but now we can kill cells that are not multiplying. Why is that important? Because myeloma cells actually divide very rarely. They tend to stay in their current form. So when we use chemo, we’re only killing a certain population of cells. So all of the new treatments I’m going to talk about are able to kill the cell without it necessarily being in the multiplication phase.

So the second concept which relates to that is that for cancers to grow, they also fail to die. So most cancer cells have a programmed cell death, like a leaf; they should, after a certain period of time, die. And that’s called programmed cell death or apoptosis.

And so what happens is that these cancer cells subvert the survival process of a normal cell, and they become relatively immortal. So what they do is that they accumulate. They build up in your bone marrow, and then your bloods, and in certain blood cancers, but not in the lymph nodes in myeloma. And that gets back to that previous picture: what’s happening in those vertebrae is as those cells are growing in the vertebrae and other bones, they’re actually growing and increasing because they’re failing to die.

So a lot of our approaches for the treatment of myeloma is to try to revert that process and make those cells that were otherwise somewhat immortal subsequently commit suicide. So that’s one of the approaches.

[10:53]
The second big approach is to use the patient’s immune system. The immune system is primarily designed to fight infection and to survey the body for infection like viruses or bacteria, but it also surveys our body for cancer. And so it will pick up, if it picks up a cancer, it can then say that’s not normal and kill it.

And so we have different components of our immune system. And I tend to say that they’re a bit like the military. Along the bottom, there’s a navy, an air force, an army. All these different white cells that are measured on the blood test that you have: the neutrophils, the monocytes, the lymphocytes, the eosinophils, the basophils. These are all different types of white blood cells, and they kill in different ways.

Some are designed to kill bacteria, like the neutrophils. Some are designed to kill viruses better; for example, lymphocytes do that extremely well. So all of them are killing, but ultimately, like the military, they all kill in different ways. And we’re focusing in this talk on the lymphocytes and the plasma cells because they’re basically very closely related, lymphocytes and plasma cells.

The frontline soldiers are the neutrophils and macrophages. They produce pus. They’re very important cells, but ultimately they just work once, whereas the lymphocytes have a much longer role. And so these lymphocytes are what I call the central intelligence. And I’m mentioning two types: B-cells and T-cells.

B-cells produce antibodies. So if you have a tetanus jab, then your body will remember that. Ten years later, if you stand on a rusty nail, your B-cells turn into plasma cells and start to produce antibodies, and these antibodies can then bind specifically onto, in this case, tetanus and punch holes in it.

The importance of that is that the B-cell production and normal antibody production is affected in myeloma, and it’s affected by a number of the treatments. And if you don’t have enough normal antibodies, you’re at risk of infection. And this is one of the big issues that we face now with myeloma therapy: some of our drugs are so good at killing off the bad plasma cells, they also kill off the good plasma cells and the good B-cells that are producing these antibodies, and so we can’t fight infections as well as we normally could.

And these antibodies, as a separate issue, can also be produced as a benefit, because we can now produce antibodies outside the body to help treat disease, and I’ll come back to that later.

Another type of lymphocyte is the T-cells. And the T-cells are really the ones that directly kill the viruses and cancer cells. And these T-cells are divided up into a variety of different types that you can see listed there. And what they do is they’re part of this surveillance immune system that’s able to recognise and kill plasma cells.

The problem is that once myeloma is starting to grow, sadly it’s a pretty smart sort of cancer; it can start to suppress the normal T-cell function. So those cytotoxic T-cells, helper cells, the natural killer, etc., those cells are not working to their optimum because the myeloma cell is tricking them into being suppressed, and we’ll come back to that later.

So these lymphocytes are important. They started 500 million years ago. This is the Iguazu Falls in South America. And when this gives you an idea, 500 million years ago, this was just a creek. And what happened is that we changed from just being jellyfish; we moved on to having fish that had lymphocytes.

So a jellyfish can only recognise heat and cold and other sorts of irritants. Whereas what that lamprey was able to recognise was to recognise what was self and non-self. In other words, develop lymphocytes that were able to survey the body for invading viruses and cancers. And that’s obviously evolved over 500 million years to become very, very specific.

So the lymphocytes are critical. And how do these T-cells do it? Well, their target, as I’ve mentioned, could be viruses, could be bacteria, and importantly, cancer, and in what we’re talking about today, definitely in myeloma.

And the T-cell basically, if it sees it’s foreign, it locks onto it and causes this kiss of death. This is what is called that immune synapse, where that red T-cell is trying to bind on to the myeloma cell by immune recognition—a complex series of proteins on the cell surface that activates the T-cells, makes them multiply, and kill the plasma cell. And so the T-cell ends up killing this cancer cell very effectively.

And so just to recap, the T-cells on the right are the ones that are doing a lot of that direct killing. And the B-cells are like tanks, I suppose, indirect killing. They’re producing shells that are able to then shoot across and bind onto the cancer cell and kill it. And I’ll come back to that sort of picture in a second.

[15:55]
So let’s just go and summarise. You’ve got these plasma cells that are growing in the bone marrow, and then for them to grow, they need a conducive environment. They need the right sort of supplies to grow, and that’s important because drugs like thalidomide, lenalidomide, and pomalidomide work on that.

These cells need to be able to replicate, as I’ve mentioned before, and so if we can kill them during a replication phase, that’s important. They naturally should die. And they’ve also got the immune system which is trying to control these cells and control their growth.

So what we are trying to do in myeloma treatment is to ultimately boost up the immune control, boost up natural cell death, and reduce replication, and make the environment hostile to the cell, and in that way we can stop the growth of the myeloma cell.

So how do we use this immune system to our benefit? So as I’ve mentioned already, B-cells produce antibodies. So that’s normally happening in our body. But now we can actually make antibodies in a test tube. The pharmaceutical industry can produce antibodies that can be directed onto receptors on that cell surface, which you can see there.

We can also modify the T-cells, the ones that have been somewhat numbed in the process of the myeloma cell growth. So what you see in that diagram is in the centre of it is this abnormal plasma cell, and the T-cells are trying to attack it. They’re somewhat numbed in the process by the myeloma cells, but we can try and reset that so the T-cells become much more active.

And ultimately, one day we would like to stimulate the immune system and have vaccines that can be produced. We don’t have that in myeloma; we have it in things like cervical cancer, but we hope that will come. We won’t be talking about that any further today.

So what is the why is the approach changing? Well, we always want new drugs, and we want new drugs with less side effects. We want better drugs. We also are doing a really good job at predicting the future: the use of scanners like PET scanners, MRI scanners, special blood tests to determine how deep we’ve got response or whether disease is coming back, and better ways of following the disease—blood tests and scanning techniques.

And for example, the PET scanner is now being used commonly in myeloma. And this is an example, someone with myeloma. All the black spots in the arms, etc. The brain area at the top is normal. The bladder area at the bottom is normal. But all those bits in the bones are where the myeloma is growing, and that’s abnormal. And then after treatment, we hope to see this effect where we just see normal glucose activity in the body. And so these PET scanners and other sorts of imaging have really improved, and groups like Myeloma Australia have done a great job to try and get these funded.

So the new drugs we want to prolong survival, because relapse unfortunately is inevitable in everybody, and remissions, no matter how long, are always too short. And there are unfortunately some patients with very aggressive myeloma who don’t respond to standard chemotherapy or some of the standard upfront treatments.

And ultimately, we are aiming to cure this disease. And like lots of other cancers that we currently can cure today, they had to start somewhere. And myeloma, our treatment is getting better, and there is no doubt that we will have some patients cured with myeloma within the next few years.

And we want drugs that have a better side-effect profile, particularly given that the average age is 65, and we want to improve people’s quality of life.

[21:36]
So this is my diagram of how to kill a myeloma cell, and I just want you to remember the images: chemotherapy on the left, the so-called T-cells, the so-called apoptosis or programmed cell death where we’re trying to make these cells commit suicide. I really think of antibodies as a bit like cracking the shell from the outside. The antibodies, as you can see there, bind onto the surface of the myeloma cell and smash it. And then there are what we call small molecules. I won’t have much time to talk about those today, but they’re trying to get inside the cell and stop the normal signalling pathways.

So, this is a summary of the sorts of drugs, and you’ll hear these names over and over again. But I’ll mention chemotherapy and then just stop talking about it. We use chemotherapy drugs like cyclophosphamide and melphalan in patients that are undergoing stem cell transplant.

There are patients today who do not undergo a stem cell transplant because they’re older or not fit enough, and a lot of them go through their myeloma treatment without ever having had chemotherapy. Hard to believe in just 20 years. Chemotherapy still has an important role to play. We are trying to eradicate it because of its target, because of its side effects. But there’s no doubt we can’t eradicate things that will make people live many, many years. So stem cell transplants continue because, quite simply, they work, and they work in harmony with the other drugs that I’m talking about.

So the other drugs listed there: T-cell stimulators. So this is trying to stimulate those red T-cells there. And these drugs include thalidomide and its derivatives, lenalidomide and pomalidomide. They’re all part of the same family. And then there’s a direct descendance of those so-called IMiDs or immunomodulatory drugs to what are now called CELMoDs, which is iberdomide and mezigdomide. Those two drugs are not available on the PBS, but you may see them through clinical trials, and very exciting to see thalidomide to all of these daughter products over the last 25 years.

Then we can try and modify these T-cells, and I’ll be talking about what are called T-cell engagers and CAR T-cells in a few moments. There’s the two drugs that make the cells commit suicide, and that’s bortezomib or Velcade, very common drugs used, and a cousin of bortezomib called carfilzomib, which is also available on the PBS.

We have a variety of antibodies, and what I call ‘cold antibodies’, ones that just work by themselves. Daratumumab is the most common, and that’s the one that got publicity last week because it’s now available for frontline. We have been using it for subsequent for patients who’ve relapsed myeloma for the last few years.

There’s also ways of modifying those antibodies with what are called antibody-drug conjugates. That’s where we use these drugs to stealthfully get inside—use the antibodies to stealthfully get drugs inside the cell. And I’ll come to that in a second.

And then two drugs which are small molecules, selinexor and venetoclax, that work for the treatment of myeloma. And one of the issues around the problems that we face in the laboratory is that there’s a whole lot of pathways that are affected in myeloma, but we don’t know which pathways predominate in each individual patient.

And so lots of clinical trials have been done. We first start off with studies in the laboratory on the left, then small animal studies, and then ultimately studies in patients. And so I’m just pausing here for a second to remind you all that how we got to all of these places is through clinical trials, clinical trials and research. And I can’t emphasise the need to have ongoing treatment so the patient, and the patients who will develop myeloma in the future, benefit.

[25:57]
So this is just a summary in another way of what I have just mentioned. The first thing to say is that these new drugs are not the only treatment. We use surgery. We use radiation. We use the bisphosphonate drugs like zoledronic acid. We still use chemotherapy. And this is the ever-extending group of drugs that are non-chemotherapy that are listed there.

As I’ve mentioned, the IMiDs—lenalidomide, pomalidomide—I just want to mention that they’re the what we call generic names. A lot of these drugs have trade names as well, which are used commonly. So, for example, Revlimid is used for lenalidomide; pomalidomide was Pomalyst, but now there’s a lot of what we call generics. So the initial drug was owned by a company. Now, after a few years, it goes off patent, and unfortunately it becomes cheaper. It also tends to have a number of new names because it’s owned by different companies.

The CELMoDs are on trial. The proteasome inhibitors, these are the drugs that make the cells commit suicide, often known as Velcade or Kyprolis, of its cousin. The monoclonal antibodies and these other immune therapies.

[28:06]
So, it’s just a reminder to say thalidomide has been around for over 25 years. It’s not new anymore. And it’s really moved on because of its side effects, but we still see it in some situations where it can be combined with some other drugs. And the side effects of thalidomide are really, really challenging, and it just shows you how we’ve moved from the problems of thalidomide through to new drugs which are as effective but with less side effects. But I still have patients now, 25 years later, who have benefited from thalidomide, actually not relapsed.

I put this up because it has been—it’s always comes up in question time—which is: what about the steroids? Well, the most common steroids are prednisolone and dexamethasone. They’re really important because they work quickly. They have an anti-inflammatory effect. They often turbocharge the effects of other drugs, and they’re often used to maintain people in remission.

But the problem is that they cause a number of side effects, including hyperactivity. They can make your gut upset. They can increase the risk of infection. They can cause muscle weakness. They can cause thin bones, otherwise cause osteoporosis. And the side effects are very dependent on dose.

The short of it is that you’ll see these drugs still used because they do benefit the effects of some of the other treatments like Velcade and lenalidomide. They also can reduce some of the allergic-type side effects we see with the antibodies. And fortunately, we often find that we are able to stop or reduce the steroids. So an important question to ask your doctor is: “Can I reduce my steroids, or when can I reduce my steroids?” because they don’t always have to be used in high dose all along.

So we’ve moved beyond thalidomide to a new drug called lenalidomide. And lenalidomide is a very different tool. It’s still a very important drug. It doesn’t cause the nerve damage, but it can cause lower blood counts, it can cause blood clots, and diarrhoea can be a problem. So we watch it, use it cautiously. But the big thing about lenalidomide is that it can be combined with a whole lot of other drugs: the chemo drugs like cyclophosphamide, the Velcade, it can be combined with other antibodies. And most importantly, it’s now generic, and so we are using it a lot more, and we’re able to use it a lot more than previously.

Pomalidomide is the derivative of lenalidomide. It has similar activity. It’s often used in combination, and it works even when lenalidomide has failed to work. So they are different drugs. They’re not just an alternative. So it’s not uncommon to go from lenalidomide to pomalidomide and still for it to be effective.

I’ve mentioned these CELMoDs. They have a similar toxicity profile. You’ll see them out there. And they will eventually likely replace lenalidomide and pomalidomide over the next 5 to 10 years.

[31:25]
Velcade, I’ve mentioned, this is the cornerstone drug to make the cells commit suicide. It falls under the family of proteasome inhibitors, and it was initially used in relapsed disease but now is increasingly used up front. It’s often used with steroids. It’s often combined, and it’s generally well tolerated, but it can cause nerve damage, and that’s one of the important things to mention to your doctor. But we can use this drug over and over again.

And one of the things about it is that it can be given at home, and there are a number of hospital-in-the-home programmes because, although it’s just a jab under the skin, by the time you’ve come into the hospital and been processed and got your injection and gone home, it’s basically half a day. So ask about the use of hospital in the home for Velcade or even some of the other drugs that I’ve mentioned. But unfortunately it does have side effects. It’s got a wide range of what we call PBS indications where it can be used.

And really importantly, it’s combined with daratumumab, which is an antibody-based treatment. This daratumumab is now being used as second-line therapy, and we combine it with Velcade very frequently. And it adds—it’s a good example of two drugs working really well together.

We’ve moved on from Velcade to having another drug called carfilzomib; you can see the commonness about it is the so-called ‘-mib’. And they are very similar drugs, but carfilzomib has a different toxicity profile. It has less neuropathy, but it does cause some heart side effects. It can increase the blood pressure. It can’t be used in patients with cardiac disease. But it can be combined with other drugs.

And one of the good things about carfilzomib is that it allows ongoing treatment. And one of the big issues that we frequently get asked is, “Do I have to stay on this drug forever?” And I might leave that to talk about at question time. But one of the issues in myeloma is that it’s very important for the myeloma cells to have constant suppression of their growth. So stopping myeloma drugs can sometimes lead to the disease coming back earlier. But equally, there are times when we do want to stop it, and we feel very comfortable about stopping the therapy. And it really is an individual decision to make.

But sometimes your doctor will say to you, “No, you need to keep going because we know if we stop, the disease will come back quickly.” Or sometimes it’ll be, “Look, you’ve had a really great response; we can stop the drug because I don’t think continuing on is going to be additional benefit.”

[34:56]
So just switching gear, I’m going to talk to you about the immune system on the background of those drugs. So as I’ve mentioned, we predominantly use antibodies and T-cells. And these antibodies are about smashing the cells from the outside. They bind onto a receptor on the cell surface. You can see those little knobbins, and there are many different receptors on the cell surface.

And what happens is that they bind onto the receptors. You can see the antibodies coming in onto the myeloma cell, attaching on. And then what they do is that they then sort of pull these other T-cells, these so-called natural killer cells, towards the myeloma. And these natural killer cells are then able to kill off the myeloma cells.

And so the typical binding protein is so-called daratumumab, that is the anti-CD38 antibody binds on to the CD38 receptor. So the most common little knobbly receptor is CD38, and daratumumab and isatuximab bind onto it. And as I’ve mentioned before, they also benefit from using a partner drug, something that these antibodies can work with. And the most common is Velcade, the one that makes the cells commit suicide, and that’s used when patients relapse.

But as of last week on the PBS, lenalidomide and daratumumab combination has been approved for patients who are older who can’t undergo a stem cell transplant.

[36:51]
So this is an important slide because I’ve talked about the antibodies. If you look at 9:00 on the left-hand side, you can see we’ve got a ‘cold antibody’ there, a single antibody that binds on like I’ve described. But you can then modify these antibodies or the structure of the antibodies to produce subsequent drugs: so-called CAR T-cells, T-cell engagers, and antibody-drug conjugates. These are three next generations that derive from the concept of an antibody binding onto the cell surface. And I’m going to talk about each of these in turn.

First of all, what about those docking stations, those white little knobbins that I was talking about? Well, I’ve talked about CD38 and daratumumab, and that’s the star in the middle. But the other star is the one on the far left-hand side, and that’s called BCMA. And that’s another receptor on the cell surface for which we can use as a target. All of the other ones in orange and blue and bright green, they’re all for the future. And these sorts of—you will almost certainly into the future see new drugs developed against these different receptors on the cell surface.

[37:34]
So the first one I want to talk about in this new trick is the antibody-drug conjugate. And if you look at that small circle there, you can see here that on the antibody there’s a little hexagonal red product, and that is a drug. And what happens is that this drug binds onto the surface—the antibody binds onto the surface of the cell, and it gets sucked into the cell a bit like a Trojan horse, and it can then kill the cell.

So put another way, you’ve got BCMA on the cell surface. The antibody, which has now got this little drug on it called MMAF, binds onto the cell, is then sucked into the cell, and then can kill it. And this is given intravenously. And the little symbol I use is this Trojan horse, and the drug that’s out there is called belantamab mafodotin. And this drug is an important drug. It’s approved in the United States and is available in Australia, not through the PBS but through a compassionate scheme, because it’s likely to become an effective treatment in the next few years.

So building the antibody story: as I’ve said, we’ve got the cold antibodies, and the one that we have out there at the moment is daratumumab. We’ve now got these antibody-drug conjugates that I’ve just spoken about, and that’s belantamab mafodotin, and that drug is out there.

The next trick we can do is with bispecific T-cell engagers. These are molecules that specifically pull the T-cell and the plasma cell together. And so, as I’ve mentioned before, the myeloma cell is subverting the immune system. It’s pushing it away like two opposing ends of a magnet. So those blue cells are trying to attack that little yellow cell in the middle, but they’re being pushed away. What we can do is modify those antibodies and make them latch on to the T-cell and pull them together. And these are called engagers.

And if you look in the middle diagram, you see here that you’ve got the T-cell on the left in blue and the tumor cell, in this case myeloma, in green, and you’ve got these modified antibodies that are pulling it together. And on the right-hand side, you can see here how it’s pulling the two T-cells and the plasma cells together.

These are given as injections, usually subcutaneously, initially weekly, then second weekly, then once a month, and usually it’s ongoing. The problem is it can cause immune suppression or infection. And the big drugs that are out there: elranatamab is going to become available in early next year; it’s available through clinical trials. Teclistamab will hopefully be available sometime in 2025, government willing. And talquetamab is another antibody we hope will come, but probably not for a couple of years; it’s available through clinical trials.

So as I’ve said, building on the story, we’ve now got these T-cell engagers, which are often called bispecific antibodies because they’re binding onto two bits, and those are the drugs that are listed there, and we’ll see a lot more, and there are a number that are happening through clinical trials.

[41:40]
So, as I’ve said to you before, if you look at this diagram, by modifying the T-cells, we’ve got the T-cell engagers. On the right-hand side, the antibodies, by modifying it by putting a little drug in there, we’ve got belantamab. And the next one is the CAR T-cells.

And the CAR T-cells are about, instead of adding a drug that pulls the T-cell to the myeloma cell, we actually modify the T-cells themselves. And so in the middle there, you have a CAR T-cell bag where it’s been taken from the patient, modified, and then given back to the patient. And in this example, it was used for leukaemia, but we all know now it’s available for myeloma.

So I’ve told you before that the T-cell’s job is to bind on, but cancers suppress that. So they’re pushing those cells away. Why do they do that? Well, it’s a protection against autoimmunity. I won’t go in detail about that, but it’s a protective mechanism that the cancers can hijack and subvert. And so this balance of the immune system of attacking things that are viruses versus stopping autoimmunity is a delicate balance. And cancers subvert that process.

So how do we modify it to make it work? Well, what we do is, instead of having a normal T-cell, we modify those T-cells to put receptors on the surface. So, you can see on the right-hand side, we’ve modified that T-cell to then have special modified receptors that are able to bind onto that myeloma cell.

So if you look in the middle there, you’ve got the T-cell, and then you’ve got the plasma cell, and then we’ve modified it to have the good guys on this side and the bad guys on that side, the plasma cell. What happens is that these cells are modified and bind on. And this little film here shows you an example of how the cell comes in on that left-hand side and binds onto a plasma cell, and then punches holes in it, and its toxic substances get into the plasma cell and kill it.

And we’ve subsequently been able to show that these cells can be serial killers, that they can go from one cell to another. So if you look at the green cell, it binds on, then it comes off, binds onto another cell, kills it, binds onto another cell, and 8 to 11 of these cells can be progressively killed. So we finally call them serial killers. It’s a means of ultimately getting the same result that we would see with specific drugs.

So they are a living drug. They can cure leukaemia. In some cases, they’re replacing bone marrow transplants. They’re a one-off treatment, but they’re extremely expensive. And they’re used; they’ve been available in the US since 2017. They’re available in Australia for leukaemia, lymphoma, and we hope very soon myeloma. But they take quite a while to produce.

What happens if you look at the top diagram: of that patient, the cells are removed, and then they undergo about 14 days of modification, and then they get their spikes on their surface; that’s the receptor, and they go back into the patient.

[45:10]
So a big question, which we’ll talk about in a few minutes, is: which of these do we choose for which patient and why? And we have to choose often based on effectiveness but also toxicities, because these are not without their side effects. They can induce autoimmunity if we dial up the immune system too high. They can overstimulate the immune system, what we call cytokine release syndrome. They can cause neurological side effects, so-called ICANS. And they can suppress the immune system, causing infections and the need for immunoglobulin infusions.

So building on the story: as I’ve said, daratumumab, the cold antibody; the drug conjugates, the Trojan horses, belantamab mafodotin; the T-cell engagers, elranatamab, teclistamab, talquetamab are just a few of the first ones; and then CAR T-cells, so-called ciltacabtagene autoleucel, which is the one we hope to have here in Australia. And our job is to try and decide on the right treatment for you. So when you speak to your doctor, have a good fact-checker with you. And I like this little cartoon; you can have a little read.

So how do we decide on the right treatment for you? Well, first of all, transplant candidate, non-transplant candidate. And I’m not going to go through the treatments, except for a transplant candidate, it’s a combination of, you can see here, the diagrams on the left: the proteasome inhibitors, the lenalidomide, Velcade, a little bit of chemotherapy, and hopefully people will go into remission for many years. Then when they relapse, they often get Velcade and daratumab, and then there’s a variety of those treatments thereafter.

For people who are non-transplant candidates, we have to choose the treatment that’s best for them. And you can see across the top there, there’s a variety of treatments. And the most recent one is this lenalidomide and daratumab, which is using lenalidomide, thalidomide derivative, along with the monoclonal antibody. And then they again get the same sorts of treatments in second, third, fourth, fifth-line therapy as needed.

Most recently, there’s been a fight on between the Trojan horse and the daratumab-Velcade combination at relapse, and in fact what’s happened is that the winner was belantamab mafodotin, and that just seems to be a better drug when used early in the treatment. It hopefully will be available next year.

And so we’ve got a new future paradigm already happening, which is where do we place these antibody treatments versus these new next evolving therapies, and we can talk about that later.

[48:48]
So to summarise: the new treatments and the monoclonal antibodies, we’ve got daratumab at first line and at relapse. We’ve got belantamab, the Trojan horse, coming in next year, or actually available now. We’ve got these bispecific engagers. Elranatamab will be here in 2026 as fourth line. There’s a number on clinical trials. And we’re crossing our fingers that CAR T-cells will be available, and that’s likely to be fifth line. But a number of trials going on.

There’s a drug called selinexor which I haven’t got time to talk about today, but is very useful in myeloma, and it’s a tablet. But we tend to use these immune therapies a little bit earlier, but it’s still a good drug.

So, this has been complicated, this section. You can’t be expected to remember it at all. Don’t blame me for things that you may have heard because you could have heard them if I’ve said them wrong, or you may have misheard them. And you’ve always got a chance to go back and listen to the recording, and you can ask me questions in the next few minutes.

And really, just as a teaser, what’s next? Well, there’s a lot of receptors on the surface. There’s lots more things, as I’ve mentioned, that can be targeted, and that’s all for future development. But we’re left always with a problem of cost-benefit. The Pharmaceutical Benefits Scheme is around assessing the quality of the drug, what sort of trials have been done, and there’s always a cost for them to work out whether they should approve it or not. And unfortunately, we’re challenged with this all the time: the cost to the patient becomes a problem, and we’re facing that already with CAR T-cells.

But from my perspective, the cost of drugs will come down. High technology is high technology today; it’s standard of care and simple treatment in the future. And so we know that costs come down, and things will get better, and they will get cheaper.

[50:11]
So just in 2025, I said what do we want in the next 3 years? I said last year I said CAR T-cell therapy should be earlier in the disease course. I said we wanted daratumab first line. We wanted elranatamab and teclistamab, the engagers. And we wanted belantamab. And what’s happened? Unfortunately, we still awaiting CAR T. We’ve got daratumab first line. We’ve got elranatamab for relapsed disease. And we’ve got belantamab mafodotin.

[50:42]
So what can you do to get the new drugs? Always consider entering a trial. Question what you see in Google; this is complicated; it’s not always accurate, and not all treatments are suitable for you. Try to go to the myeloma website. Speak to a myeloma nurse. Contact a member of parliament; tell them we want these drugs because we never get them fast enough. And when you’re asked to provide feedback to our regulators, the PBAC, MSAC, please go online and tell them that you’re a patient.

So, I’m very much an optimist. I’m very much about what’s going to happen. We are changing the destiny of myeloma. And we need as much help as we possibly can get. So, thank you for listening. And I’ll hand back over, and Danielle will probably come back and tell you when we’re going to come back. Thanks very much.

[51:45]
Thank you, Miles. That was a really good comprehensive update on all the complex treatment options and the complexities around patients that have myeloma. So as mentioned at the beginning of the presentation, this presentation will be available on our website at a later date.

We will now have a short 10-minute break. So stretch your legs, grab a cuppa, and we’ll come back in about 10 minutes time for some Q&A with Miles. Thank you.

[1:03:23]
Thank you for joining us. Hope you’ve had time to stretch your legs and grab a cuppa. So, we’ve now got time for our Q&A with Miles and myself. So our first question is for Miles: “Do you think stem cell transplants will be stopped being used in the next few years?”

And let me give you a bit of background. I think the first thing to say is that stem cell transplants are still highly effective, and ultimately their goal is to try and get at the cells that are the seeds that are under the tree. In other words, we chop the tree off with our standard treatment, but the stem cells, the ones that lay dormant that grow back many years later, are the ones that we need to get out. And transplants are really good at that, and they continue to give us the best result.

The second bit of that is that there has been so-called randomised studies where standard treatment like Velcade and lenalidomide and ongoing therapy have been compared to transplant, and transplant is always shown to be most effective. So it’s a bigger hurdle to cover.

It’s fair to say, though, that the new drugs that we are having, the bispecifics, are giving us results that look very good, that look like we can get durable remissions. And there will be trials that will compare transplant to these drugs, and they’re literally happening in the next couple of years.

I feel very comfortable, from an ethical perspective, to randomise—ask my patients would they be happy to be randomised to a transplant versus a bispecific—because the results are looking very promising. The most important thing is that transplants can be done later as well.

So I think we are going to be addressing that question, and honestly I don’t know what the answer is, because we wouldn’t do randomised trials if we knew that they were most effective. There are swings and roundabouts, which are the potential side effects and the duration of effectiveness. And the big competitors to transplant are CAR T-cells and bispecifics.

The big unknown question is cost, because a transplant probably costs the healthcare provider about $100,000, whereas CAR T therapies cost $500,000 plus, and the bispecific treatments are not far off that cost as well when you look at ongoing therapy. So the regulators will push back against that and say show us the cost-benefit, because the cost-benefit may not only be around better outcomes but also around side effects.

So don’t know the answer. There’s all of those things factoring in it. But I do feel we’ve got to a point where I’m comfortable to ask the patient, “If there was a trial tomorrow, would you be happy to be randomised to transplant versus one of these other treatments?”

[1:06:58]
Thank you, Miles. And I guess it’s, you know, a great space that we can reiterate that there are so many options now for patients in their treatment, and not two patients’ journeys will be the same. But it’s really exciting that there are so many options out there for patients now, which is great.

The next question, which I’m going to answer, is: “Can you explain what compassionate access means and how do we know if this is an option for us to access treatment that isn’t on the PBS?” So compassionate access is when there is a treatment option that is in between approval and being made available on the PBS. And so your treating doctor will know if this is an option for you. So sometimes patients might access a treatment once they’ve finished a clinical trial and access it on compassionate grounds until it’s become available. But your treating team will know if this is an option for you, as our haematologists are always looking at ways to get the best treatment for our patients.

The next question for Miles is: “How far away do you think is personalised medicine where I can have genomic sequencing to know what treatments will work best for me?”

Yes. So let me put this into perspective. The genomic testing is about trying to get a more accurate picture of what your cancer is going to behave like. So genetic testing can, what I call, personality test it. We are already doing some forms of genomic testing to look at whether the myeloma has characteristics that are going to make it more susceptible to certain drugs. So we’re already doing that for certain types of chromosomal abnormalities that exist for myeloma.

Unfortunately, there’s certain myelomas that will never respond well to chemotherapy and will move to new treatments very quickly. And that’s, for example, 17p deletion chromosomal defect, etc. And we are profiling people all the time to work out whether they fit into a good prognosis or a poorer prognosis group. And so it is a question that you should consider asking your doctor: “Has my genomic testing been done, and what does my profile look like?”

But very specific genomic testing, we’ve been looking at that for a few years in myeloma, and there’s really no great single matches for genomic profile to this drug. There’s actually very few cancers that fit that, with a few exceptions. So I would say, but what they do is that they give us some idea of the personality of the myeloma: aggressive or belligerent and not want to respond. And that is already tailoring our treatments and getting better.

But there isn’t going to be a day in the foreseeable future where we can say this particular genomic problem requires this drug, because myeloma has a very complex genomic profile.

[1:10:49]
Thanks, Miles. The next question is: “With all the new treatments, a lot of patients are requiring IVIG, and this is an extra commitment on top of their treatment regime. Is this going to be ongoing for all new treatments?”

So that’s a really interesting question, and there are a lot of patients that are having IVIG. And this is to do with the immunoglobulin level. And a lot of patients are having IVIG that are getting recurrent infections or colds, just to boost up their immune system. There are a few options with IVIG. So it doesn’t always need to be given in hospital. There are lots of great programmes out there, and so patients are actually doing it themselves, giving it subcutaneously, so doing it in the comfort of their own home. And a lot of patients are enjoying having that flexibility. And then there’s others that are happy to go into the hospital.

So it is, as you know, part of having these new treatments, but it is tolerated well by most patients, and most patients are happy with that extra commitment because the treatment is keeping their myeloma at bay.

The next question for Miles is: “Do you think CAR T therapy is more effective than bispecifics?”

So I’m smiling because it’s a question that one, comes up all the time, and two, we don’t have an answer to, and three, it will keep evolving as we get these new treatments. So I have to turn that question around and say, well, what is the pros of a CAR T? Well, right now, CAR T-cells have the runs on the board. They’ve gone out on the first innings, and they put their score on the board. And the bispecifics are coming in for their first innings; we don’t have a score yet. We know what the responses are for the different bispecifics—in other words, how many people respond—but we really don’t know how long the responses go for. And we know that in some patients with CAR Ts, for example, they’re still in remission 7 to 10 years later, even with the earliest CAR Ts.

So we don’t have that data with the bispecifics. It’s fair to say that the general consensus is that CAR Ts, when used early around second or third line, are very effective and the best treatment that we have to date.

So the problem that we face in Australia is that CAR T-cells are only available for fifth line as standard of care, and it still hasn’t been approved. Realistically, when CAR Ts do get rolled out, they’re going to be in very short supply for the first 12 months. There’s only going to be a limited number of patients in limited states that are going to be approved. Now, that doesn’t mean it’s going to be state selective. People may actually have to travel interstate, for example, but there’s going to be less than 100 people treated in that first year simply because of supply.

So we’re not going to have a free tap for CAR Ts until midway through 2027 at the earliest. So that’s disappointing. And it means that the reality of that question outside the clinical trials for CAR Ts is that the drugs that are going to be easiest to get are the bispecifics.

And I would hasten to say there are probably some bispecifics that are as good as CAR T-cells. But it gets back to your original point, Danielle: every patient is different. CAR T-cells were a commitment for a long time. The bispecifics do require injections every month or potentially every three months, so it is more of a commitment than a CAR T in terms of the length of time. But in terms of getting the drug and having the initial therapy, they have benefits early on.

So the big benefit of the bispecific is that it’s off-the-shelf; it can be given straight away. So if a patient has run out of treatment options in, let’s say, March next year, then bispecific will be available, and CAR T-cells might be available through clinical trials, but they won’t be routinely available.

Thank you, Miles. And just on the back of that, is there an age cut-off for CAR T therapy similar to a stem cell transplant?

The answer is no, there isn’t. The CAR T-cells are being given to patients in their 80s, so mid-80s. So in fact, that is one of the benefits. We have found that scenario in lymphoma, where patients are unable to have a stem cell transplant for lymphoma above the age of a certain age, around the 70 mark, but are able to have CAR T-cells into their 80s. And I think we’ll find the same thing in myeloma. It’s not uncommon to give CAR T-cells in patients in their late 70s.

Thank you, Miles. And the next question: “With there being so many treatment options for myeloma, how do I know that I’m making the correct decision in terms of treatment path that I decide?”

So that’s a really great question, one that we get here at Myeloma Australia quite often on the Telephone Support Line and through our emails. And often that’s just chatting to patients about what the best option is for them and them having somebody to listen to what they’re thinking. And so it’s okay to ask your haematologist if there are other options as opposed to the one that they’re proposing to you. And often that is the case, and to always consider clinical trials.

The decision that you make is the correct decision for you, and you will be supported in what that decision is. But as we mentioned earlier, every patient with myeloma has a different journey. So it’s very individualised, and the decision that you make is the correct decision. And we are very lucky that there are so many different treatment options for patients these days, whether they’re wanting that commitment with the hospital, they’re happy just having something that they can take a tablet they can take at home. There are lots of different treatment options for patients. And Myeloma Australia is here to support all patients in the treatment options that they decide to take.

Miles, did you want to add anything on to that question?

No, I think you’ve summarised it. I think that some of the decisions unfortunately are made for us in terms of the availability of drugs. So there are some drugs on the PBS that are only available at certain points in the journey. And daratumumab, the antibody, is one of those. And so, for example, in someone who’s got newly diagnosed myeloma, daratumumab, it’s great to have it available first line, but that means that further down the track after first line, that drug won’t be available.

So in some ways, the doctors are having their decisions influenced by the time of availability. So it’s important to recognise that there’s that third dimension. There’s the, as you said, the patient factors, and then there’s the second, is the side effects, the tolerability, and effectiveness—the core of what clinical trials are about. And then the third is the regulatory landscape.

[1:19:10]
Thank you, Miles. Well, that now concludes today’s update from Professor Miles Prince. So, we’d like to thank Miles for giving up his valuable time on the weekend to present to the myeloma community. I’m sure we have all learned something new from today’s presentations. And if you have any questions, please reach out to our nurses by booking a call on our Telephone Support Line, or emailing our nurses, or alternatively, you can speak to your treating team in your next appointment.

Just a reminder: if you can, please complete the evaluation survey, which is located at the bottom of the web page where you are viewing today’s event. This feedback will help us plan and improve future events. Take care, and we hope to connect with you again soon. Thank you.