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A session with experts Graham Jackson and Martin Kaiser, who discuss the treatment of multiple myeloma and pivotal clinical trials from a UK perspective.

Welcome to The Myeloma Sessions brought to you by the Video Journal of Hematological Oncology (VJHemOnc). This exclusive discussion features leading experts Graham Jackson and Martin Kaiser, who discuss myeloma treatment from a UK perspective. In this session, our experts will discuss updates from several clinical trials, including the MUK Nine b: OPTIMUM trial, the Myeloma XI trial, the importance of genetic testing in myeloma, and the management of high-risk patients.

Updates from Muk Nine b: OPTIMUM & the importance of genomics

 

“So I think we are fortunate in the UK that we have a standard guideline that genetics are possible for many people. Unfortunately, not for everyone. I think that was part of the argument that we wanted to make in the trial as well. That it’s really important to look for genetics, especially in the younger patients.”

– Martin Kaiser

“I think one of the interesting things about the OPTIMUM data is that there is an overlap between gene expression profiling and ultra-high-risk disease, but there are also patients that are defined as high-risk by either having one or the other.”

– Graham Jackson

Updates from the Myeloma XI and MASTER trials

 

“I think the data clearly shows, actually, the treatment in Myeloma XI was very good anyway, KCRD, but it was particularly the induction that had more intensive treatment. And actually, at that point from the data that we have at the moment, the outcome of the two groups are relatively similar. If you look at the survival curve, the progression-free survival curves between OPTIMUM and Myeloma XI, up to 12 months, they are relatively similar.”

– Martin Kaiser

Updates from the German CONCEPT study

 

“I think it’s brilliant and it shows what the rich culture, in terms of running investigator initiated trials, especially in these public healthcare countries, can really bring. Because in many respects, the two trials, I think, are confirming each other. I think there are, of course, subtleties in how the treatment was given and how the genetics were assessed that will allow, probably even in a richer way, to look at the results even more as they mature.”

– Martin Kaiser

The FORTE trial & the importance of chromosome 1q

 

“But one of the interesting things in the FORTE study is that KR versus R randomization for maintenance and that interesting data about amplification of 1q.”

– Graham Jackson

“1q is a very, very interesting genetic area, or region, in myeloma because it is one of the regions that we also see has more gain at relapse, so we see more patients. So it is, in some sense, a driver of resistance or disease re-emerging again. I think what the complexity is that it co-occurs with various other markers as well. ”

– Martin Kaiser

Full transcript

Graham Jackson:
Hello, my name’s Graham Jackson, and here we are at COMy 2022 in Paris, and I’m joined by my esteemed colleague, Dr Martin Kaiser. We’ve just come from the session around treating initial therapy in high-risk multiple myeloma. And Martin, you’ve been presenting your OPTIMUM data. Would you like to give, for our audience, some of the highlights of that fantastic trial that you’ve led on?

Martin Kaiser:
So, we ran a trial that we designed dedicated for ultra-high-risk patients and patients with plasma cell leukemia, and we wanted to be really inclusive, but also to the point to really address the need of the patients that have the worst outcomes currently with treatment. I mean, in the UK, many other countries as well, we are treating all newly diagnosed patients very similarly. We know that, unfortunately, 20% will relapse early. The question is, how do you identify those?

So I think we are fortunate in the UK that we have a standard guideline that genetics are possible for many people. Unfortunately, not for everyone. I think that was part of the argument that we wanted to make in the trial as well. That it’s really important to look for genetics, especially in the younger patients, but also that we are missing some of the information with genetics. So, gene expression, for example, is something that picks up a group of patients with fast growing tumors, and also, surprisingly, that was one of the findings in plasma cell leukemia.

The plasma leukemias nearly all have high proliferation rates. So, with a new cutoff between 5% and 20%, we can probably pick up most of them as well. And then we were asking the question, if we treat them differently with new treatments and monoclonal antibodies, making combinations now possible, like dara-VRd, in the UK we can even add cyclo. How is their outcome, randomizing was difficult, and we’re lucky that the Myeloma XI trial had just been run and Graham, you as chief investigator, know that was already a trial that was leading to far better outcomes than before, especially with the KCRD induction therapy and then Revlimid maintenance.

But we thought, “Okay, within that trial, the ultra-high-risk patients, same type of features at genetic high risk.” And we defined them here by double-hit. So two chromosomal abnormalities co-occurring, or more, two or three or four in some even, or gene expression high-risk. In Myeloma XI, how do they compare against patients that get more novel therapy with Dara-CVRD before transplant, a transplant with Velcade in there as well, but unusual, but then, most importantly, after transplant not dropping the intensity, but actually keeping them on intensive therapy with Dara-VRd for another six cycles. And that was actually the follow-up, up to which point we had data now, and we could compare. So 18 months progression-free survival between these two trials. An ultra-high-risk group from Myeloma XI and an ultra-high-risk group from OPTIMUM. And we could see that the progression-free survival at that 18 months time point was markedly higher for the new regimen. It was around 80%, whereas in Myeloma XI, it was significantly lower. And that’s, of course, a really important finding for the use of such novel treatments, and especially the monoclonal antibodies.

 

Graham Jackson:
You were unique as well. I think two things you deserve huge credit for was, first of all, trial design. You are pretty much the first person to really look at that really difficult group of patients separately and treat them more intensively. And also, I think gene expression profiling, which isn’t a standard assessment of high-risk disease, you’ve brought that into the mainstream. And I think one of the interesting things about the OPTIMUM data is that there is an overlap between gene expression profiling and ultra-high-risk disease, but there is also patients that are defined as high-risk by either having one or the other. Do you think gene expression profiling should be done for all patients now?

Martin Kaiser:
Yeah, I think we are all, at the moment, knowing about that frustration that we think we know a patient, we believe to think, “Okay, there is no genetic abnormality, patients should be doing well.” And then they come back. Unfortunately, a year after transplant their disease, it’s becoming detectable again. And I think it leads to frustration on all sides. And this is the group where we found many of those, actually the majority of those, do have gene expression, high-risk profile at the beginning. So we are just missing, in our current diagnostics, that group of patients, which I think then, in turn, by us feeling, “Okay, what we can do at the moment maybe means we shouldn’t do any genetics.”

I think the opposite is true. We should be doing more to learn more about our patients. And that’s both for us to know and for our teams to know, but I think it’s so important for the patient, because if we want to tell the patient, “Actually, maybe you shouldn’t be going. As much as we want patients to go on holiday, but maybe before the transplant, you shouldn’t have a 3-month trip without treatment just to have a break. Your disease is high-risk.” Even if we cannot change the type of treatment, just keeping, for example, treatment more to the point and more timely can be important information that we can derive from the risk status.

Graham Jackson:
Yeah. And again, that concept, and we heard the MASTER study today and we saw some of the data in standard risk single-hit disease and double-hit disease, one of the things that struck me about the MASTER study compared with OPTIMUM is that those double-hit patients in MASTER did not do as well. I wonder if you’d like to comment on that continuation of therapy in OPTIMUM makes a difference in those difficult to treat patients?

 

Martin Kaiser:
Yeah. I think the data clearly shows, actually, the treatment in Myeloma XI was very good anyway, KCRD, but it was particularly the induction that had more intensive treatment. And actually, at that point from the data that we have at the moment, the outcome of the two groups are relatively similar. If you look at the survival curve, the progression-free survival curves between OPTIMUM and Myeloma XI, up to 12 months, they are relatively similar. It starts, really, at the point when everyone has been through their transplant, when they normally start the lower intensity regimen or even follow-up in Myeloma XI, that the drop in the curve of progression-free survival starts. And this is where the OPTIMUM curve actually continues to be really showing people are staying in remission, they’re maintaining their responses, which can be sometimes even deep responses, as we have seen with MRD.

Graham Jackson:
Yeah, it is that point, isn’t it, after the transplant, when Myeloma XI patients kind of went on to Revlimid maintenance no matter what the risk, versus your strategy of really continuing that intensification through six cycles, and then a further 12 cycles of what would be regarded as triple therapy too. And that clearly makes a difference. I think the other thing I’d like to ask you is, comparing and contrasting with the German CONCEPT study, Katja delivered a very interesting study there, do you think that your study and Katja’s study have really changed the approach for clinical trials in newly diagnosed high-risk disease?

Martin Kaiser:
I think it’s brilliant and it shows what the rich culture, in terms of running investigator initiated trials, especially in these public healthcare countries, can really bring. Because in many respects, the two trials, I think, are confirming each other. I think there are, of course, subtleties in how the treatment was given and how the genetics were assessed that will allow, probably even in a richer way, to look at the results even more as they mature, because I think what will be important is to understand, which were the patients that were relapsing early, for example. Despite this very intensive treatment, there were a few, but there were some.

But I think, as such, the concepts, because it was so similar, I think, has been backed up by the two trials, which is actually, yes, an intensive induction therapy including monoclonal antibody, but then, in particular, the CONCEPT study as well, an intensified consolidation regimen after transplant. I think that’s where the thinking has to be very similar and the design, and it is fortunate that, despite some drugs being different, the outcome likewise looks good for both. So I think that is a very strong argument, especially if putting it next to, and I think that trial deserves a lot of credit for many reasons, but putting it next to MASTER, where patients received a very intensive induction, but then, based on MRD, were de-escalating therapy. I think in some sense that this trio of trials now is more or less emerging in parallel, I think, can inform us about what we should be doing.

 

Graham Jackson:
And presumably, working with Katja to do that sort of analysis of outcomes in these patients is another rich vein of data that we should be able to look at to help us, even more, make the best of these patients.

Martin Kaiser:
I think, absolutely. Internationally, I think we all realizing we learn more the more we learn from each other, and I think we have a history already of collaborations. We did a great collaboration that was another focus on chromosome 1 abnormalities here yesterday, we did a large meta-analysis with the German group already, over 2,500 patients just last year, and I think we are all set up to do more of that.

Graham Jackson:
That brings me onto maybe the last question, the FORTE data, which we haven’t discussed very much because it’s slightly different trial design. But one of the interesting things in the FORTE study is that KR versus R randomization for maintenance and that interesting data about amplification of 1q. What do you think is going on there versus gain 1q?

Martin Kaiser:
I mean, 1q is a very, very interesting genetic area, of course, or region in myeloma because it is one of the regions that we also see has more gain at relapse, so we see more patients. So it is, in some sense, a driver of resistance or disease re-emerging again. I think what the complexity is that it co-occurs with various other markers as well. So I think the data is very interesting, but what will be particularly interesting is digging into similar data tapes more deeply, because it could be that there are disease types that not only had the amplification of 1q, often that actually comes as well with having a t(4;14) or a deletion 17p. So I think that will be very informative to know more about, what else did these 1-amplified tumors have.

Graham Jackson:
I’d like to say, thank you. I think, as I said during the talk, a great trial. You deserve a huge credit for what is ground-breaking study and with ground-breaking results. Thank you.

Martin Kaiser:
Thank you very much.

 

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Disclosures

Graham Jackson – Speaker honoraria engagements: Amgen, Takeda, Johnson & Johnson, Sanofi, Celgene and Roche; Research funding: Takeda, Onyx and Celgene; Advisory Boards: Amgen, Takeda, Johnson & Johnson, Oncopeptides, Pfizer, Sanofi, Celgene, GSK and Roche; Board of directors Myeloma UK.

Martin Kaiser –