Hello, I'm Martin Kaiser.
I'm a professor of hematology at the Institute of Cancer Research in London.
And I also work as a specialist entomologist at the Royal Marsden Hospital in London.
I am going to speak about high-risk myeloma, which is the area of my research for many years now.
Many patients often get a lot of information when they get a new diagnosis of myeloma.
And also later down the line, it's difficult to understand what the technical terms mean. High-risk myeloma.
More people will hear about that and have to do with myeloma, have been affected by myeloma over the next two years because we're looking more closely at this as a research community, because we know now we get the first glimpses of how we can treat patients better and how we can personalize treatment on the basis of risk status.
There are many ways how treatment can be personalized.
Of course, there can include factors such as family factors, side effects of treatment, whether a patient can tolerate intensive therapy or not,
but another factor that is more difficult to determine and that we need laboratory tests for, is the risk stages.
And we mean by that effectively, how aggressive is the myeloma.
We cannot see that only by imaging tests or only by looking at the cells through a microscope.
We need to do very difficult and complicated genetic tests.
But that is not difficult for the patient, it is only for us in the lab to figure out how to do these tests.
That can actually all be done on the material that's taken from a bone marrow biopsy.
But it depends on how the lab is equipped and what tests can run as to whether a full set of results is available or not.
Now, next year there will be, in 2025, a new guideline by the International Myeloma Society and International Myeloma Working Group on High-risk myeloma.
And it will, I think, give more clarity on what we internationally consider high-risk myeloma, or as we call it, often standard-risk myeloma.
So people that don't have normal with these features.
These features will include genetic features.
And actually in particular through our work that we have done over many, many years, most of patients that have high-risk myeloma
are finding out about its rare genetic test, so-called FISH test.
But it can be done by newer methods such as next-generation sequencing as well.
And the feature is that some genetic operations in the tumor cells, not in the patient's genetic background, but in the tumor cells, have changed.
So the normal genome has been shuffled in certain ways, how they should not be shuffled.
And the tumor.
And it can mean that chromosomes.
So the areas where the genetic information sits break and are glued together in the wrong way, or that areas of chromosomes are missing and just getting lost, or actually they are gains to have more of it around than there should be.
And the errors that we're talking about are translocations.
There are three main translocations that are having to do with high-risk or more aggressive disease.
This is the t(4;14) translocation, the t(14;16) translocation and a t(14;20) translocation.
And then there are what we call copy number aberrations, which actually means that either part of the genes are lost or there's too many of them.
And there is, for example, the deletion of 1p chromosome.
1p is meant that an arm of chromosome 1p is missing or gain of 1q, so there are extra copies of the long arm of chromosome 1, or there are losses of the 17th chromosome 17p also called del17p.
And there is one gene that is playing a role in many tumors.
It's called TP53 that can also have mutations, as we call it.
So there are actually the genetic code is just changed in one place or several places.
And the main, group of patients I think that we now consider high risk are those that have two any two of these markers together.
Sometimes we call this constellation double hit as well.
And we also have kind of like introduced jargon in that if three of these lesions co-occur, we call it kind of they call it triplets.
These are of course terms that may not sound adequate for a patient, but it's important for us because we have to speak in the laboratories and on a technical side about how we categorize the disease.
So we need to have very technical terms.
There's another test that unfortunately is not as widely available.
Through our work.
We have found us is equally important.
It's called gene expression or risk testing.
There are only few manufacturers that produce such a test.
One of the signatures, for example, is called SKY92.
And what we found out is it's independent.
It's separate from the genetic information.
That's actually quite a lot of patients that we don't diagnose correctly.
If we don't add gene expression testing to the overall tests.
Now, I don't want to discourage people.
Many people cannot access to that moment.
But I think is an important thing that we get more access for patients to such a test because it tells us additional information, and it helps us
pick up patients that we would otherwise miss and simply not know about.
Now it's all a long story already, but how did we use this information?
We actually, several years back, thought about these patients deserve different treatments because we knew already through many trials they were never doing well with trials that we ran before, with treatments that we had around.
And to be fair, unfortunately, still today, many of them are not doing well.
So we thought, although for many other patients we might want to look at whether we can reduce the doses of treatments and maybe even be able to stop treatment.
This is probably a group where that will not work and where we actually need to find a way how to give treatments so that they don't cause too many side effects, but still are more intensive to keep the treatment controlled.
This is what we did in a trial called optimum MUKnine, and the trial will start a quite a while ago to find out where the patients have really done well long term, you need to wait for a long time follow up.
And this is what we're presenting at this meeting.
We're showing the five-year follow-up.
So patients have now been on average five years on the treatment.
Some were even on it for seven years already.
And we've compared the outcome of this trial to a treatment that is pretty similar to what we do in standard care today.
Now, the trick of this treatment is that the patients stay on three drugs for nearly one and a half years longer after a stem cell transplant than they do at the moment.
At the moment, we consider the start of treatment important. We do combine a lot of drugs at the start, then we do an autologous transplant for younger patients and then we drop the dose. We actually just go to one drug.
And that is the time when most patients with aggressive disease unfortunately already start to relapse.
That's why we actually intensified the treatment at that stage.
But we actually intentionally said, let's not give these doses, at the maximum dose. We actually want to find the right dose for every single patient and allowed dose reductions in the trial.
That worked very well.
What we have now seen with a five year follow up is that on the one hand side, still less than half of patients have had their relapse, whereas with standard of treatment only less than a quarter were still in remission.
So 75% of patients off the standard treatment already had their disease come back, whereas 60% were still in a remission in the optimum MuKnine trial after five years.
But what is even more important is that we now have an overall survival benefit.
So unfortunately, I had the majority of patients had already seen the disease not only come back, but a lot of patients already died with aggressive disease after five years
and we have probably reduced the risk by about 50% of overall survival for these patients.
So actually patients are living longer.
If we give such intensified treatment and not only a short duration, it might be that they live twice as long with this intensified first line treatment, then with standard of care treatment
now that is of course, a very hopeful message in a field that inherently is unfortunately, in the first instance, bad news for patients.
But there's a lot of hope in there because we're starting to understand how we can make patients life better?
How can we design even intensive treatments so that patients can continue them without having too much impact on their life?
The patients I'm looking after are doing really well on the ongoing treatment, I have to say.
And, I think it also allows patients to get all the benefits of treatments that are now in development that might come about in 3 or 4 years time, at the time when their disease then relapses to benefit from the new armamentarium of treatments that we have.
In that group of patients, we are still learning more through having done all of these tests, genetic tests, gene expression tests.
And we do see that some patients, for example, those with triple head genetics, still would benefit from other treatments.
That is, they still came back early.
But on the other hand, the patients that only had two genetic markers and no gene expression risk marker, they did phenomenally well.
Nearly all of them stayed in remission for over five years now.
So by doing more of these diagnostic tests, we can probably really give patients personalized advice in the future.
What is the right dose of treatment for your disease to stay in remission.
In the consolidation phase, we combined extra drugs that are very widely used daratumumab, bortezomib and lenalidomide.
So drugs that we normally use upfront in the induction treatment, but we, space them out more.
So for example, the bortezomib could be given once a week and people could dose reduce it.
I think it's more important what we learned through this trial that you stay on all three drugs, even if on lower doses, and maybe even if you have weeks break extra time between then stopping one of the drugs.
So our main message is rather stay on three drugs, even if that reduced doses then go down to two or only one drug.
So we are of course not leaving the result where they are. We actually writing guidelines.
We have published a guideline from the British Society of Hematology. And there was one global guidelines are on the way as well.
So I think if a patient is diagnosed with high risk disease, it would be really useful to speak with the doctors and their treating teams.
Ideally even earlier, think about whether as many diagnostic tests can be done when the first bone marrow biopsy is taken.
We found out it can sometimes make sense to have a second test if not, the right tests were done in the first round.
For as long as there is tumor around, we can still get a better diagnosis, but then we can give advice on how to treat better.
Not everyone will be able to access the triple consolidation therapy worldwide. We're working on better access and I think it's down to physician communities, patient communities, to advocates that everyone gets access.
But I think definitely have a conversation with your doctor and your treating team because your treatment could be personalized for you.