Dr. Brian G.M. Durie:
Welcome everyone to today's IMWG conference series, which will be an overview of the IMWG Summit, which was just recently held live in-person in Vienna, Austria. Joining me today, very pleased that Maria V. Mateos from Salamanca in Spain is able to be with us today. So, welcome Maria V. Vincent Rajkumar from the Mayo Clinic in Rochester. So, welcome to both of them who will be able to comment on the presentations. We're very grateful to Janssen and Takeda for specifically sponsoring this conference series presentation today.
The 13th annual IMWG Summit was held June 7th to 9th in Vienna, Austria and we covered key questions. For the next five years, we tried to be more forward looking. I think, and you guys can perhaps comment on this. Everyone was so excited that we were back in person. I think that maybe you could both even comment on that. It was wonderful to see all of our colleagues, many of whom we hadn't seen for over two years and just great to have a chance to connect and it makes a big difference versus Zoom. Maria V, what was your reaction to that?
Dr. María V. Mateos:
Yeah, no, exactly what you said. It was great to see in person people since more than two years ago. On the other side is true, that this whole meeting is also feasible, is also possible, as we are doing PR today right now but it was great.
Dr. Brian G.M. Durie:
Yeah, Vincent?
Dr. S. Vincent Rajkumar:
Yeah, same here. I really was glad to be back and to meet all our friends again and made for some really good interactions as well.
Dr. Brian G.M. Durie:
Great. Just to highlight that during the Summit, there is an awards dinner, which was held on the Wednesday evening and it was wonderful that we were able to in-person give out the awards and have a special event in person. A special part of the award ceremony is the IMF Band with star members, Vincent and Maria V. You can see here, Vincent playing the guitar and Maria V, as one of our star singers, singing special words to the music of Hotel California. I think that several people have some video of that, which those interested might want to track down.
The main thing was for the group to get together at the Orangerie at the Schonbrunn Palace. You can see the large group connected there for dinner inside. Obviously the main thing was for the award, which is given out in my name. The achievement award this year, the award went to Bruno Paiva from Pamplona with his mentor and close friend, Jesus San-Miguel. Just wonderful to have this award go to such a dedicated and wonderful researcher.
And then with his family and colleagues, including Maria V in this picture. Just great for the whole Spanish team to get together and celebrate the achievements of Bruno within the Spanish team.
And then it was great to have Herve Avet-Loiseau from France. The IFM team received the Robert A. Kyle Lifetime Achievement Award. Again, great to see him with his colleagues and his friends. And then also with previous awardee's of the Kyle Award, just a great opportunity to celebrate in person.
The mission of the IMWG is to both conduct collaborative basic, clinical and translational research, and also to produce consensus guidelines for myeloma. So those two goals, to be able to conduct ongoing research but also to provide guidelines for the myeloma community. The chairperson's overseeing the development of the program and implementing the program are here, including myself and Vincent. I do believe that we had an innovative program focused on shorter presentations with more time for in-depth discussion, which I think we did achieve.
The overall sponsors for the Summit, you can see here. We are very grateful to all of these sponsors and that has been consistent even all over the last two years when we had Zoom activities. So very grateful to all of our sponsors. So the plenary sessions this year were as listed here, Early Disease, Minimal Residual Disease, Frontline Therapy, Early Relapse and Late Relapse. And so what I'm going to do is to touch on each of those plenary sessions, show you a couple of slides and then have input and reaction from our two guests today.
I chaired this first session on early disease, and it was a pleasure to have the initial presentation from Sigurdur Kristinsson, from the University of Iceland who leads the iStop MM effort, Iceland Screens Treats or Prevents Multiple Myeloma. The initial results from the screening of over 80,000 Iceland residents are coming in. There is a RCT, randomized control trial, which allocates patients identified as having MGUS or an M component into three groups. One with no further follow up. One with standard follow up, and one with intensive follow up, which would be over on the right arm three.
The very striking thing was the number of cases picked up in arms two and arms three of over 3000 individuals identified. Particularly some patients with active myeloma and very interestingly, many more cases in the olive green in the two right bands with the 92 and the 133, identified is smoldering myeloma.
If you exclude indolent disease individuals who might require intervention, the differences remained. The important initial observation at this time before the randomized trial is completed is that smoldering myeloma is more common than we had realized, and actually has a prevalence of about 0.5%, half a percentage point in those over the age of 50 and more common in men, which is the blue versus the pink, which is women.
So the first question which we can touch on is, should we screen for MGUS? It certainly does identify a higher number of individuals with both myeloma or smoldering myeloma. And then earlier intervention is achievable but although these findings are encouraging, the overall survival on the quality of life in the three arms remains to be fully evaluated in the next one to two years and maybe then there will be a statistical difference between the three arms.
So the first question Maria V is, if we look to the next five years, do you see screening as becoming the way forward? How do you view screening at this point?
Dr. María V. Mateos:
I can't say today that screening is recommended for the general population basically because Sigurdur Kristinsson clearly pointed out, maybe not yet. We have to wait in order to see how the iStop Multiple Myeloma study will evolve, especially in terms of overall survival. Also, I think that this is very important quality of life. We have to realize that we are going to do a diagnosis of ABCs to the patients and sometimes for the physician who is visiting the patient, it is very clear that MGUS or small, very low risk is maybe an indolent disease.
But this as well, we have to put in context the psychological impact in the patient. So I would say that not yet. On the other side, much more routine analysis are being done in the normal population. And of course, if whatever physician detects proteins elevated and M component is detected, my recommendation of course, is to move forward with the recommended work out in order to do the current diagnosis and to plan an appropriate management, follow up, clinical trials and so on.
Dr. Brian G.M. Durie:
Right. We definitely do need to wait. I mean, obviously the transition from MGUS to active myeloma is only at 1% per year, but one of the things that is being observed is that there are other things which are potentially linked to MGUS that could contribute to decreased or lesser outcomes. These details need to be evaluated to see what those are and what the implications are. So a little too soon to make a decision on screening. Vincent seems to have dropped off for the moment. Are you there, Vincent?
Dr. S. Vincent Rajkumar:
Yes, I am.
Dr. Brian G.M. Durie:
Oh, okay. Your picture dropped off. Any additional thoughts on this?
Dr. S. Vincent Rajkumar:
No, I agree with Maria V that we don't have data right now to recommend screening for the general population. If screening is indeed valuable, then we will see it in survival differences.
Dr. Brian G.M. Durie:
Right. So we're just waiting for another year to comment on that.
Dr. S. Vincent Rajkumar:
Years maybe.
Dr. Brian G.M. Durie:
Yes. So our next very interesting presentation came from Bruno who was looking at testing for high risk smoldering. Obviously the three of us on this webinar today spent a lot of time looking at what are identifiers of high risk smoldering myeloma? What are the factors that would allow us to predict disease progression? And so, Bruno presented some information and emphasized a couple of points.
One is that it's obviously extremely important to identify the subset of patients with no risk or very low risk of transformation. So those patients can be excluded from any type of interventional activities. The second thing that he emphasized, which has been a big emphasis within the Spanish teams, both in Salamanca, I think as well as Pamplona is CTCs. Basically this means clonal tumor cells, which is basically clonal plasma cells or basically myeloma cells in the blood. The detection of myeloma cells in the blood can replace the detection or quantification of bone marrow plasma cells in the different risk models.
And so he showed, for example on this slide here on the left, using very sensitive techniques. It seems like a very small number but with a cutoff of 0.015%, you can have a cutoff indicating the likelihood of progression or not. And so this is a new tool, which does seem as if it can be quite powerful. First of all, Maria V, do you agree that this really can be a tool that can be helpful moving forward? It's obviously a blood test, which is great.
Dr. María V. Mateos:
Definitely. I think that these models evaluating the circulating tumor cells is going to complement the current models. I think that we are building and we are generating a lot of markers predicting risk of population to multiple myeloma. I think that this is good for the patients because at the end of the day, we will be able to accurate much more the risk of progression to myeloma in every patient. As soon as we generate techniques available worldwide and even not painful for the patients like the bone marrow, I think that this is much more better.
Patients have to understand that there are different ways in order to evaluate the risk of progression to multiple myeloma and what we are doing right now is improving the accuracy for the identification of the risk.
Dr. Brian G.M. Durie:
Right. So obviously, we'd be using this 2/20/20 model based on the M component, the free light ratio and the bone marrow plasma cells, which has been good but room for improvement. Vincent, any reaction to blood clonal cells being evaluated at the Mayo Clinic by the myeloma team there?
Dr. S. Vincent Rajkumar:
Yeah, we do routinely. What Maria V said is the right thing, which is these things will augment or supplement the other models that we have developed.
Dr. Brian G.M. Durie:
Absolutely.
Dr. S. Vincent Rajkumar:
And so if you do the IMWG score, right now it has FISH on top of the 2/20/20, right. Then when you add the circulating plasma cells, you will get additional prediction. The key is to remember that we don't need to identify all of them. We don't need to identify the same patients. That's a misconception.
All we need to do is to use some combination, whatever is available to identify the people who have a 50/50 chance of progressing in two years. That's our goal. Sometimes we may be able to identify even higher risk of progression and give them more sense but the fact that they identify different people is okay, and it's actually good for us. I hope that this is something that is more widely available.
Dr. Brian G.M. Durie:
Exactly. It's very promising and needs to be standardized and widely available, which we'll touch on in just a moment, actually. Moving forward, obviously Maria V you presented, if you do have high risk smoldering myeloma and are comfortable with that, what should be done about it? And you presented again, the outcomes from your GEM- CESAR trial and I just show one set of graphs here.
I think that it's very important, how many patients over time have ultimately developed symptomatic disease? How many have actually lost their MRD status, but have not yet developed any symptomatic disease? Overall, it's obvious from the left hand graph is that overall patients have done very well with this intensive treatment, the KRD plus autologous stem cell transplant. What's your interpretation of the outcome so far? Are they kind of what you expected or what is your reaction to the results of your study?
Dr. María V. Mateos:
In terms of time to progression to symptomatic disease, I think that the curve is very good. The follow-up right now is 55 months, but you have to know that the primary endpoint was minimal residual disease negative sustained over time. The GEM-CESAR implied treatment for three years. Our idea, and this is the most intriguing question for me is to evaluate how many patients five years after autologous stem cell transplantation will be in sustained minimal disease negative. Because this could be a potential surrogate rate marker for cure.
Honestly, we are utilizing here minimal residual disease negative with a sensitivity level of 10 to the minus six. This is the reason why we are observing how some patients are losing the MRD negative when they finalize the treatment. To put it in context, that maybe high risk is moderately closer to myeloma but definitely we will see how many patients will reach this situation and we will see what happens. But in principle, the trial from my point of view is quite positive. As always, we are learning a lot of information.
Dr. Brian G.M. Durie:
Right, exactly. Obviously, we have the US trial led by Shaji Kumar and the full results of that have not been presented. Hopefully at ASH this year but a very similar study where daratumumab is added to the KRD with a similar endpoint of achieving MRD at one, three and five years, obviously looking at progression pre-survival.
But we also discussed the results of the study from the ECOG with [inaudible], which looked at using just lenalidomide versus observation, indicating with the blue line here. You can see that the patients receiving lenalidomide had a superior progression pre-survival.
So the question was really, what's next? I think Maria V you said very honestly, we don't know what's the best. I would just turn it over to Vincent now who was really emphasizing the difficulty in deciding what is next. Because we have good results with the aggressive approach from the CESAR and probably the ASCENT where we're expecting maybe even higher levels of MRD negative, but also in the short term, we have quite good results with very simple therapy, like lenalidomide alone.
Vincent, maybe you can expand on your comment, which is that really it's going to take us a long time to look at overall survival and understand truly what are the differences in some of the studies. There are randomized trials going on, looking at RD versus VRD, things like that. So how do you see the data evolving in this space? How will we understand what is the best thing to do?
Dr. S. Vincent Rajkumar:
I think a lot of the confusion comes by people who are not very clear on what we seek to achieve and not very clear on what we know and what we don't know. What we know for a fact is that if you have 100 patients with smoldering myeloma, about 35 have the high risk smoldering myeloma. We are only talking about those people. The remaining 65, we are comfortable with either observation or enrolling in some clinical trial.
Now, these 35 people who have high risk smoldering myeloma, we know that Len or Len/Dex for about two years will reduce the risk of progression to end organ damage by 90%. We know that they have better overall survival from one of the two trials, which has mature follow up. So at this point, that's what we know.
What we don't know is, will they do better if you add two or three more drugs and treat them more like myeloma? That's the subject of current randomized trials. There's the RD versus DRD going on. So until the results of that trial comes, I'm comfortable recommending Len or Len/Dex for the high risk smolders, or if there is a good clinical trial like CEASAR or ASCENT or something else, enrolling them on that. That's my judgment call.
Now, there might be some patients where you feel like they've had this high risk features for almost four or five years, and this is the first time I'm seeing them. So you could possibly watch them. But by and large, if I de novo see a new patient, I'm pretty clear that intervening with Len or Len/Dex will reduce the risk of end organ damage and that's what I would recommend. It's not indefinite therapy, it's two years. But more preferably, enroll them in a clinical trial, like CEASAR or ASCENT or one of those other things.
Dr. Brian G.M. Durie:
Right. Just to highlight that and what Maria V has on her slide here is something that is going to be happening I think, and we'll come to this later in our session today. We've had such exciting data with some of the newer therapies like CAR T-cell therapy and the bio-specifics producing excellent results in patients with relapse refractory disease. How about considering those in the high risk smoldering setting?
I do believe that some pilot studies with those will move forward in the coming year and so that's going to be interesting. Fortunately, we do have CAR-T and bio-specific therapy, which is reasonably well tolerated with not too high level of CRS. So it is the kind of option that can be considered. But anyway, we need to move forward. It was interesting. This is an area where it's going to take time to understand what is the best strategy for sure.
Moving ahead, minimal residual disease has obviously been a key topic for the last several years. MRD-negative is a key endpoint in clinical trials for which we're seeking surrogacy status from the FDA. We're asking the FDA to accept it as an endpoint that can be used to compare outcomes in clinical trials. There are a number of issues that need to be considered. One of them is standardizing MRD testing.
Alberto Orfao showed us that results with NGF flow versus sequencing NGF negativity at the 10th of minus five, 10th of minus six, show equal benefit prognostically for patients. Then Alberto showed us, where do we stand with the authorization of these assays? Now, the NGS test has actually been approved by the FDA.
One very important recent development is that the next generation flow product, the one on the right NGF product, has recently been approved on the European side with what's called IVDD, which means that this cocktail of antibodies in a kit has been approved and is available on the European side. This will be very helpful related to both availability and also the cost. It's estimated that the cost is in the range of $133 versus $950 for NGS. So this is an important development, which is because the company Beckton Dickinson took over the Spanish company.
Alberto emphasized one other thing, which is that with the flow, in addition to having a cheap and possibly now an approved test, you can simultaneously look at MRD CAR T-cells, which are circulating in the blood. Plus you can also monitor the immune status of the patient. So next generation flow does have a number of advantages. I know Maria V, you're very much involved with this. But maybe Vincent, you're not so much directly involved in the flow technology and results. How do you view the value of the next generation flow?
Dr. S. Vincent Rajkumar:
Brian, as we did in the MRD consensus guideline paper, really what we are looking for is deep, minimal residual disease negative. Whichever technique is available, that's okay as long as you get the deep level. It looks like both techniques can get to a very low level of detection. Both techniques miss some people and pick up some. I don't think that I'm wedded to one technique per se, whichever is available.
We actually use the flow more commonly in Rochester, for example. But even in Mayo Clinic, Arizona, they use the sequencing more. So it's what's available and it might vary across countries and places. I think the flow has the advantage, like you said, of in one single test you can also assess other components of the bone marrow and blood, which is something that we have to keep in mind.
Dr. Brian G.M. Durie:
Right. Obviously in Spain, a strong focus on the flow methodology, although I know that you also do NGS on many samples as well.
Dr. María V. Mateos:
Yeah, sure. In clinical research, we do both in order to compare but in clinical practice we do flow and especially we have the results immediately in 24 hours. We evaluate immediately if the quality of the sample is good or not. In addition, now it is possible to evaluate the CAR T-cells and the immune system and all cellularities. So this test is giving us a lot of information.
On the other side, its true that it requires from some expertise in the evaluation. But it's possible to do this tests in centralized labs. So it is not necessary every small hospital has to have access to all this technology. It's possible to centralize in some, two or three centers in each country.
Dr. Brian G.M. Durie:
Right. I don't want to go into it in great detail but it was somewhat distressing that Alberto pointed out that thus far, that broader standardization has not happened. It is a little bit disconcerting. I think that for patients to be aware is that this methodology is not fully well standardized yet in terms of everything from collecting the sample, transporting the sample and then processing and running the samples. At the patient level, we need to have a degree of caution in interpreting these results, just because some extra standardization is still required.
Dr. María V. Mateos:
That's true.
Dr. Brian G.M. Durie:
Herve Avet-Loiseau made some strong points about if you have MRD testing, what is the value of having a negative test? Obviously, he just emphasized once again, if you have a negative test, this patient the top blue curve here is going to stay in remission longer and so the PFS, the progression free survival is better. He showed something which was a little controversial. Maybe you guys can comment on this, is that he showed that in the Cassiopeia trial, which is the French DARA VTD trial, that for patients who had poor cytogenetics, deletion 17 or (4;14) who did achieve MRD negative, they did not have an improved outcome.
So he really was very negative about this particular point. His conclusions were that obviously having MRD in our trials very important, 10 to the minus five or 10 to the minus six if possible. A controversial point was whether we should look at it as a standalone endpoint or should we also want these patients to be in a traditional, complete remission?
He talked about where maybe it's not so important for patients with high risk cytogenetics. I don't know who'd like to go first? Maybe Vincent, you could go first. What about this idea that it could be a standalone endpoint separate from CR?
Dr. S. Vincent Rajkumar:
It could be. The issue is that we have defined MRD and I don't like to change definitions. Right or wrong, we made the rules. We published a paper in which we defined MRD negative as requiring a CR. What he's talking about is not really MRD. It is basically NGS or NGF should be performed independent of the CR. Yeah, sure. You could call it NGS negative or NGF negative, and then see if that alone predicts poor outcome and whether that's as good as MRD negative, or even better than MRD negative.
If we have such data, then we can go back and see if we need to revise the definition. But to tell regulators three hours after we defined MRD that we are going to change the definition of MRD, will not look good. And so that's why I feel like what people are talking about is the bone marrow test. The bone marrow does not capture the whole body. It's one single spot.
The monoclonal protein however, maybe something that could be derived from a spot that is different from where you put the needle in. It's something that I would agree if there's data but I don't think we should change definitions quickly.
Dr. Brian G.M. Durie:
Yeah, but we could have a category NGF negative or NGS negative?
Dr. S. Vincent Rajkumar:
Exactly.
Dr. Brian G.M. Durie:
So Maria V, what do you think?
Dr. María V. Mateos:
Yeah, I agree. We can't confound to our patients and patients are used to the physicians to follow the M component. It's quite confusing to say to a patient that he's in PR because the end component is visible. And at the same time to say, let's go to the bone marrow in order to evaluate the minimal residual disease and we can't potentially say the minimal residual disease is negative. This is something contradictory. A patient can't be MRD negative if you see the M component and I think that this is important.
In clinical research, I agree with Vincent. We can't do measurable disease after induction, transplant, the consolidation, regardless of the serological response. But the patients have to know that it's quite contradictory to be in MRD negative if they don't present at least complete response.
Concerning the possibility of a measurable residual disease to overcome or not the cytogenetics information, I think that this should be confirmed because we have some data indicating that the achievement of MRD negative is able to overcome the poor prognosis of the presence of high risk cytogenetics abnormality. I think that the situation is not black and white and maybe this should be confirmed in other studies.
Dr. Brian G.M. Durie:
Right, thank you. Yeah, I agree. We don't have too much time but I think that the consensus with regard to the cytogenetics is that it did seem to be the case in the Cassiopeia trial but the impact may vary from treatment to treatment. Maybe that was the case in Cassiopeia, but maybe achieving MRD negative with regard to cytogenetics could be different using a different treatment, perhaps. Would you agree that people felt like this is maybe still an open point? Is that fair?
Dr. María V. Mateos:
Yeah, it's true.
Dr. Brian G.M. Durie:
Okay. Jesus San Miguel talked about how should MRD positive patients be managed. He talked about some of the difficulties in assessing MRD that I was touching on, the quality of the bone marrow samples, patchy infiltration in the marrow, hemodilution and the like. And so sometimes it's hard to know if a sample is positive or truly negative. One thing that maybe we could talk about, which has been something discussed for a long time and it's true for patients who have a residual M component, as well as patients who appear to have a small amount of residual disease.
Patients who are MRD positive, maybe with a small amount of MRD positive but seem to do quite well. One aspect of that was the identification of an MGUS like phenotype, which we've known about for maybe 10 years, I guess. Maria V, maybe you can comment on this. Do you think that we should be looking at this subcategory of patients who maybe can have a favorable outcome based on a better immune profile, perhaps?
Dr. María V. Mateos:
Yeah, sure. The rational for this is all of us have had some patients they are not in MRD negative, they are not in complete response. They present a small M component and they are long term survivals and they never progress. We have to try to understand why and the immune profiling is a key element. We have to try to identify these patients throughout what you mentioned, the MGUS like profile. These patients are characterized by the presence of I would say, a positive immune profiling, able to control the small quantity of the disease these patients present in the bone marrow.
Why is it important to identify these patients? Point number one, because these patients will not be overtreated. They don't need additional treatment. Point number two, because the outcome is going to be comparable to those in minimal residual disease negative.
Dr. Brian G.M. Durie:
Absolutely. So there was a lot of discussion about that for that exact reason. We need to identify those patients because they are not appropriate for maybe an aggressive backup therapy for MRD positive patients. We need to look cautiously and maybe exclude these patients that maybe don't warrant an aggressive, second type of therapy.
Let's go ahead now to the session that was chaired by Vincent. The big question here is, are four drugs better than three, a quadruplet? Obviously we're used to VRD or VTD or VCD, but adding for example, daratumumab, or isatuximab to that to give us four drugs. Is that the new standard of care?
Vincent talked about different things we can do to improve it, the issues that we need to think about, including the cost, the toxicity, how do we evaluate if a quadruplet is better than a triplet, the level of evidence and the like. So really, a very fruitful discussion. But in the backdrop to all of this discussion was the results of the DETERMINATION trial, which were presented at ASCO and came out just at this exact same time.
This is a trial with the triplet plus or minus early transplant. It's basically early autologous stem cell transplant versus later autologous stem cell transplant with RVD as the central treatment with, or without early autologous stem cell transplant. So Paul Richardson presented this as a plenary at the ASCO meeting, and everyone was talking about it.
The main thing that they were talking about was the efficacy. The main thing that people were talking about was that there was definitely a longer first remission with the patients who received the early transplant, 55.6 months versus 41.5 months on this particular slide here. The orange bar versus the blue bar. But if you look at the middle bars, the overall survival, you can see that at the current time, there is no difference in the overall survival between the two arms and really no major difference in the level or depth of response.
So this is actually very similar to the results of the previous IFM trial. As usual, there were many efforts to provide the best explanation for what's going on here. Maria V, what is your interpretation of these data with the longer remission but no impact on overall survival? Should we be transplanting our patients?
Dr. María V. Mateos:
In principle, this study shows that early transplant is better than late transplant because of the benefit in progression for survival is evident but it's true that overall survival is comparable. I would introduce here, maybe the patient preferences in order to reserve a transplant at the moment of the relapse. Is this applicable to all patients? According to this analysis, all percentage of patients with high risk cytogenetics abnormalities benefited from autologous stem cell transplantation.
The subgroup of patients with high risk cytogenetics, when they didn't receive a transplant, the medium PFS was of approximately one and a half years. So for me, this is important. The third important message is the incorporation of the minimal residual disease because although more patients were in MRD negative when they received transplant, if they achieved MRD negative without a transplant, the outcome was comparable.
So maybe we are entering into an era in which we are going to individualize the treatment based on all list of things Vincent pointed out in his slide, but maybe risk status and measurable residual disease will be incorporated into the equation. Maybe in the future, there will be some patients to which we can say, "You don't need autologous stem cell transplantation."
Dr. Brian G.M. Durie:
Absolutely. Obviously Vincent, there has been detailed and extensive analysis of this study. What would be the high points of your comments here? I've seen you really emphasize that now this is something to talk over between the patient and the doctor in terms of the pros and cons of early transplant. How should we approach this?
Dr. María V. Mateos:
You are on mute, Vincent.
Dr. Brian G.M. Durie:
Oh no. Maybe Vincent has dropped off.
Dr. S. Vincent Rajkumar:
I completely agree with Maria V. This trial shows that transplant works. It gives you a very long PFS and the timing can be flexible. But people have to keep in mind, not everyone can do a delayed transplant. This is something that is not possible in many countries and so it's not possible to collect and store stem cells, even in the US in many centers.
So if it is truly possible to do early or delayed, and the patient is in an age group where you can truly do an early or delayed, for example somebody 70, you cannot do a delayed then you could go by patient choice provided they don't have high risk disease and all of that. So multiple factors come in.
The funny thing is that this like the IFM trial, the transplanters look at this and say, "We want transplant one." And the people who are not in favor of transplant look at the overall survival and say, "Enough, no more transplants." The truth is not in either extreme. It's right in the middle.
Dr. Brian G.M. Durie:
Right. I think from a patient perspective, having that longer first remission as you were emphasizing Maria V, is significant and quite important. Disease-free intervals are very important. Anyway, a lot of discussion about this particular study and its results.
Moving on to the topic of this session. Obviously, we have the GRIFFIN trial, which Vincent showed, which shows DARA VRD with improved PFS versus RD. And then we had some discussion. There's an echo happening now, of quadruplet, which was from Thierry Facon and he looked at it from transplant eligible patients. His conclusion was that the addition of anti-CD38 is a feasible, really an excellent option. And then he looked at it for transplant not eligible and then he was really looking here at DARA RD as the standard of care versus VRD. In some discussion with Vincent on this in terms of what would be the ideal treatment for patients who are not transplant eligible.
He raised the question, DRD is actually remarkably good for patients not eligible for transplant. Do we really need to improve on that, especially for elderly or frail patients? I think that there are different issues to consider for the transplant patients or the transplant ineligible patients. Vincent, where do you think we are in terms of quadruples as standard of care?
Dr. S. Vincent Rajkumar:
I agreed for the transplant ineligible patients, it's really not a quadruplet question at this point. It's either VRD or DARA RD or some other triplet, depending on what's available, what's cost effective for that particular setting. Both are great regimens. You have done one of the trials. He has done one of the trials.
For the transplant eligible patients, some might feel that the quadruplet has already shown better PFS, and therefore it is the standard for all patients. Some like me, might feel like it's not yet the standard because we haven't shown an overall survival benefit and I'd like to see some more data from the Griffin or some other trial on the overall survival. I'm comfortable giving the quadruplet to high risk patients. Will I be willing to give it to a standard risk, young patient?
At this point, we are doing a randomized trial to see whether everyone needs a quadruplet or if people are already MRD negative, maybe they can do with a triplet alone. So I'm a little bit more circumspect about the transplant eligible standard risk patient, for whom some patients a triplet might get them the MRD negative status and you can add the fourth drug when you need to. It's ultimately a question of cost and toxicity concerns. Otherwise, you could do five drugs and get better PFS too.
Dr. Brian G.M. Durie:
Right. I know these are complicated things but certainly cost and availability are big issues. Certainly for the elderly, a triplet does a pretty good job. So we're going to have to move ahead here just to touch on some of the really important things. A key question that came up, people are excited about using CAR T-cell therapy earlier, even in high risk smoldering.
Tom Martin highlighted the possibility of integrating CAR T-cell therapy, which are the kind of the maroon blocks in these two diagrams here with CARTITUDE-5 and CARTITUDE-6, in newly diagnosed myeloma transplant eligible or non-transplant eligible. So basically the idea is to see if CAR-T could end up maybe even a substitute for autologous stem cell transplant, and maybe give us not just improved PFS, but maybe improved overall survival.
So he was proposing a new paradigm where for the transplant eligible, we would slot in CAR T-cell therapy and for the transplant ineligible and then consider maintenance or no maintenance. So really the question to both of you is, do you really see that this is going to be the way forward that we should expect that CAR-T will represent an improvement in this early setting? What do you anticipate these trials to show?
Dr. María V. Mateos:
We will see. We have it to wait for the transplant ineligible...
Dr. Brian G.M. Durie:
Your crystal ball, yes.
Dr. María V. Mateos:
For the transplant ineligible, I think that this CARTITUDE-5 clinical trial is restricted to fit patients because very elderly patients definitely are not eligible for VRD followed by CAR-T. Concerning the CARTITUDE-6, it's definitely some interesting trial and we've just been discussing about early transplant versus late transplant and now we are going to remove transplant and we are going replace it by CAR-T.
We have to see the benefit in overall survival because a transplant is cheap and affordable basically in whatever country and in whatever hospital. This is not going to be the situation for CAR T-cell. So the magnitude of the benefit has to be very evident in order for CAR T-cell to replace the autologous stem cell transplantation. This is my point and we will see because in principle the trial is planned to win but we have to wait.
Dr. Brian G.M. Durie:
Yeah.
Dr. S. Vincent Rajkumar:
Yeah, and I think PFS alone for this trial will be enough, even though it's written as a primary endpoint. They can pick any primary endpoint they feel like but that doesn't make it right. I think like Maria V said, given the cost and the expense of this treatment at this point compared to say 10 years from now where it might be cheaper, you want to use this only if there's a huge overall survival level advantage to doing it instead of transplant at this point.
Dr. Brian G.M. Durie:
Right.
Dr. María V. Mateos:
Absolutely. Especially, audience has to know that we need a longer follow up in terms of safety profile for CAR-T's because we are starting. So definitely we need time in order to incorporate these in the first line of therapy, of course.
Dr. Brian G.M. Durie:
Yeah, absolutely. We need to look at efficacy but also toxicity, costs, availability, a lot of factors that would play out and how this could or maybe not move forward.
Dr. S. Vincent Rajkumar:
I think Brian, the main thing that Maria V said is, we are telling ahead of time now to adjudicate this trial. Maria V said two things, overall survival improvement of a sufficient magnitude. It's really important not to just dilute that five years from now when the trial reads out because of the long term effects, we have no idea.
Dr. Brian G.M. Durie:
Absolutely. All right. So what we're going to have to do now is just to skip forward over some of these points and I'll just touch on them. The main thing that Paul Richardson emphasized is that the BCMA- targeted agents do represent a fourth treatment pillar, which we were just talking about. He did emphasize that. He also touched upon some of the other newer therapies that we should be aware of.
Early relapse, Philippe gave quite a few suggestions of combinations to think about either involving proteasome inhibitors or pomalidomide if patients would be getting a quad in the frontline setting. It is quite tricky and interesting to look at what would be the backup options, especially related to traditional therapy. He looked at it both in the frontline and the transplant eligible and transplant ineligible.
Meletios Dimopoulos discussed, will we continue to use iMiD? There is this discussion right now because of cell mods and immune therapies. Maybe we will not be so reliant on iMiD anymore. He showed a whole list of ESMO and EHA recommendations, which do in fact continue to include for example, pomalidomide in a backup setting. Although it is possible to use daratumumab and a proteasome inhibitor, for example, as was done in the CANDOR study. Basically the bottom line is that iMiD will continue to be used because we're familiar with them.
The fourth bullet on this slide here, anti-BCMA based therapies, like belantamab combined with pomalidomide for example, turns out to be rather a good combination. So I think that everyone is feeling that iMiD will continue to be around for a long time and maybe combining iMiD with some of the newer immune therapies could end up being the way to go.
Saad talked about the best positioning for bio-specifics. One key thing about the bio-specifics that he touched upon, bio-specifics are off the shelf. That are available. This is great. However, fixed duration would make them much more accessible broadly and we really do need to look at that more strongly.
In the later relapse, Ken Anderson from the Dana-Farber gave a really elegant discussion about what he looks for in the future. Maybe you guys could comment on this in red, prediction for the future. Long term disease free survival and potential cure will be achieved with a combination of targeted and immune therapies and restore host memory, anti- myeloma immunity. So he was really emphasizing the importance of the immune system in achieving long term disease free status. Maria V, how did you react to that? What do you think about this?
Dr. María V. Mateos:
I completely agree. You were discussing previously about the role of IMiD's and definitely I think that IMiD's are well and ideal complimented to all immune therapies that are coming to the treatment of patients with multiple myeloma. We have to combine these elements in the minimal residual disease negative sustained over time. Definitely cure means disease free but also treatment free. My goal, and I think that what we have to do is to finalize with this sentence that reads in all manuscripts at the beginning. Myeloma remains an incurable disease. We have to challenge this stigma of incurability of myeloma and I agree with this prediction.
Dr. Brian G.M. Durie:
Yeah. I think we certainly need to pay much more attention to that. Restoring of the host immunity, that's for sure. So we could just touch on this. We had a very nice discussion about entry criteria for trials, and clearly this is an area where we need to push harder so that novel trials can be more broadly available and this will certainly be an IMWG initiative.
And then we move forward into our working group reports, which I just want to touch on for smoldering myeloma. Maria V, I think that we've touched on the major issues which are, what will be the best therapy is going to take time for us to get the best criteria for high risk smoldering and then sort out what would be the best therapy.
I think that in the Bone Disease, maybe Vincent you could talk about this. I think the main thing that came out of the Bone Disease Committee this year was that they're planning to have a virtual imaging database, which seemed very good. So to collect images from patients for joint analysis. I don't know if that caught your attention, Vincent.
Dr. S. Vincent Rajkumar:
Yes. They are planning that and de-identified images. If institutions provide IRB approval, they want to collect it and then be able to assess both the impact of bone imaging negativity, along with the MRD negativity on outcomes and things like that.
Dr. Brian G.M. Durie:
Yeah. This was a very important new thing, which is one of the things that we're always looking for at our Summit. Tom Martin and Yi Lin from the Mayo Clinic, they talked about the two things, which we've discussed a little bit, which is the immune therapy database, where Tom and Yi Lin have started a new database where they're collecting outcomes for patients who are on immune therapy. And so this is a very important new initiative. Linked with that is the establishment of a virtual tissue bank, which will be a very helpful companion piece.
And then a last comment that we can make in the Mass Spectrometry Committee, there was a proposal to evaluate low spikes, which occur on mass spectrometry. The key point about mass spectrometry is that it's more sensitive and so that you can pick up very small spikes. What has emerged is that at that very low level, some patients can have low spikes, particularly IGM spikes, which may be transient. These are spikes, which maybe are not persistent and maybe do not turn into MGUS and move forward in a significant way. Maria V, what was your reaction to the information about the low spikes that have showed up on mass spectrometry?
Dr. María V. Mateos:
This is extremely important because these lower spikes can represent the monoclonal antibodies that we use as therapeutic agents. Sometimes they were little clonal bands we see as part of the immune reconstitution, maybe they can be evaluated also by mass spec. I think that this is the great advantage of this sensitive technique that we are going to be able to identify the different spikes and to see what is specifically the spike corresponding to the disease and to put in context what is the rest of the spikes.
Dr. Brian G.M. Durie:
Absolutely. The high level of sensitivity is crucial to track known spikes. So if a patient has a known spike and you know the mass of that spike, you can track it to a very low level. But if you're screening a patient and you find a low spike, it might be one of these lower spikes, which may or may not persist. So this is a new initiative to try to figure that out.
I'm sorry to rush towards the end here but the big impact for our audience is that I've really just scratched the surface of these many discussions that were happening at our IMWG Annual Summit this year, and many more interesting details were presented and discussed. It was I would say one of our most fruitful, if not the most fruitful summit that we've had. Final comments Vincent, were you happy with the outcomes of our summit this year?
Dr. S. Vincent Rajkumar:
Yes, Brian I was. It was a great summit. I just also want to point out that I've been trying to answer all the audience questions on the chat. So people who are listening on the chat, I've been trying to go one by one and answer all the questions.
Dr. Brian G.M. Durie:
Thank you so much for that Vincent. We've been tracking them as well and just not enough time today but we will follow up. Thank you for doing that initial follow up and we'll reach out to people who have important questions and get back with you. Apologies for that. Any final words from you, Maria V?
Dr. María V. Mateos:
It has been a great pleasure to participate first in the summit and now in this webinar dedicated to the patients and hope to see you in the near future.
Dr. Brian G.M. Durie:
Absolutely, it is great. We will indeed most likely see you in the near future, which is great.
Dr. María V. Mateos:
Absolutely.
Dr. Brian G.M. Durie:
I hope that this was worthwhile for our audience today. I really tried to identify what were some of the high points and discussion points, and hopefully that was fruitful for all of you. Thanks to Maria V. Thanks to Vincent. I hope everyone has a good rest of the day. Thank you.
