Dr. Brian Durie:
Welcome everyone, to the IMWG Conference Series. Coming this year, or reporting from the recent ASH meeting, the 2022 ASH meeting held in New Orleans. And so, joining me today to discuss the very exciting abstracts this year presented at ASH is, Dr. Maria V. Mateos, from Salamanca in Spain. So, thank you, Maria V., for setting aside time to join us today.
Dr. Maria V. Mateos:
Thank you, Brian.
Dr. Brian Durie:
And Dr. Tom Martin, from UCSF in San Francisco. So, thank you, Tom, for joining, as it says, help us make sense of these different treatments that we were hearing about at ASH.
Dr. Thomas Martin:
Hi, Brian.
Dr. Brian Durie:
Okay. So obviously, all these kinds of activities are supported by sponsors, and we're very pleased that this activity today is supported by our sponsors at Janssen Oncology, Sanofi and Takeda Oncology. So, out of the many different topics that were covered at ASH this year, I selected six different areas which I think were particularly important and interesting, especially from the patient perspective. And so, there was a big, big focus this year on the bispecfic antibodies, that we'll talk about in some detail.
At previous ASH meetings, there has been a big focus on the CAR T therapies, not so much this year, although, I do touch on one CAR T abstract, which was using CAR T therapy, a new CAR T product in the frontline setting. And then this year there were actually 10 abstracts that were presented from the Iceland project, pretty remarkable. The iStopMM, and we'll touch on several of those. And it was very nice to see the presentations from the ASCENT Trial.
And Maria V., you updated a little bit the results from your CESAR Trial, and we'll touch on that a little bit. Some of the Spanish colleagues presented very interesting work related to MRD testing. Bruno Paiva, from Pamplona, presented details of a ultra sensitive method. And Naomi Pugh, looked at comparative data related to mass spectrometry, with next generation flow, with some really interesting cross-correlations.
And a number of people were quite interested in the French, randomized study, the IFM study, looking at a dex sparing regimen. And so, I'll be interested in my colleagues' thoughts about that. So if we can start with the bispecifics, I think the biggest excitement was the abstract presented by A.J. Cherry. And in fact, there were I think five overflow rooms from people who were trying to listen to this particular abstract. So a lot of interest in this abstract.
And this obviously focused on a novel antigen target, the GPRC5D, combined with the CD3 on the T-cell. So a bispecfic, and with the double target of the myeloma and the T-cells, to enhance the myeloma cell killing. And obviously this is important, because most of the other bispecfics have been targeting BCMA, B-cell maturation antigen. And so it's quite important and quite interesting to see what could be achieved, using an alternate target in this bispecfic setting.
And the results presented, included results in patients who had previously had T directed therapy. So this was quite interesting to see the efficacy in these kind of refractory patients. So, several important points, and you guys will be able to comment in detail about these. And so, on this slide here, we see the overall response rate, which was in the 73, 74% overall response rate range.
Interesting for me, is that in the two doses, the 400 milligram and the 800 milligram, the response is very similar, so that there was not a strong dose difference here, which was potentially important. Also looking at the once a week and every two weeks. And looking at the duration of response, a clearly excellent duration of response on average in about the nine-month range, so that a high level of efficacy and a sustained benefit. So quite interesting. And so, the summary with talquetamab, from the update of the MonumenTAL-1 trial, a 73 to 74% response rate.
In those with the prior T-cell redirection therapy, 63% overall response rate, and really rather safe. A.J. Cherry, he emphasized the ability to continue with the therapy, with dose reductions. He also touched upon, and maybe you guys can comment on this part, is that we have a concern about ongoing infections or maybe a cumulative tendency to infections with the bispecifics, but this did seem to be less of an issue with this particular product. And so, there is hope that it's a bispecfic that could be combined, used in combination, perhaps.
And some of those trials are ongoing, or just getting started. But a 70% overall response rate in patients who were heavily pretreated, really pretty impressive, I would say. And so, Tom, you did a summary for our IMWG breakfast, with this slide here, to compare the talquetamab with a number of the other bispecfics presented at ASH, mostly the BCMA directed, and obviously the overall response rate in that same range, although obviously the talquetamab is really quite good, a important level of infection in the BCMA directed product.
The one slight difference is for the AbbVie product, the top one, 383, there was no step-up dosing required, which is quite important related to the practical use of the bispecfic, but I think collectively, a very exciting group of new, off-the-shelf products as compared to CAR T, and some that really are looking rather promising. And so maybe, Tom, first, what was your takeaway from the ASH presentations, talquetamab, and the others?
Dr. Thomas Martin:
Well, I would say that is really unprecedented to see these level of responses in patients that have truly relapsed to refractory disease, when they've had median lines of therapy of four, five, and six prior lines, that really, we couldn't have asked for more for an off-the-shelf product. I would say the 60 to 70% response rate for the off-the-shelf, is very close to equivalent in my mind to the CAR T-cell therapies, where you kind of select the patients who are going to go on CAR, maybe take a less aggressive patient population to the CARs. So I think they're working in some regards as good as CARs. The response rate from talquetamab, of 73 to 74%, that's truly amazing. And over 60% for people who've had prior BCMA targeted therapy.
Dr. Brian Durie:
Right.
Dr. Thomas Martin:
That's also, I would say, quite impressive. And I would say the two best things that I heard also about talquetamab is, number one, that it was published in The New England Journal on the same time. And two, that the company, Janssen, has submitted the package of all the data to the FDA, and hopefully will soon start the countdown that this could potentially be available for us, for clinicians to treat patients, hopefully in the next six months or so.
Dr. Brian Durie:
Yeah, pretty remarkable. I made a note of that as well. That just happened two or three days ago. So Maria V., what was your takeaway hearing these data?
Dr. Maria V. Mateos:
Well, definitely I agree with what Tom has previously said. I think that we have a long list of BCMA and CD3 bispecfic monoclonal antibodies with excellent efficacy results in the patients with myeloma who had been previously exposed to the three main drug classes, [inaudible 00:10:51] inhibitors and immunomodulatory drugs, anti-CD38. And indeed, the majority of the patients were refractory to the three main drug classes.
And now we have talquetamab, with a similar mechanism of action, but a different target, GPRC5D. The data are outstanding, not only in the overall population, but also in the patients already exposed to the BCMA targeted therapy, either CAR T or bispecfic monoclonal antibodies. And I consider this extremely important, because at the end we had to learn how to sequence these different approaches in our patients with myeloma. And all of the data are a bit preliminary, we are learning more and more about these potential sequencing.
Dr. Brian Durie:
Yes, yes. Thank you for that. Maybe you guys could comment upon this aspect of infection, related to also what A.J. Cherry talked about, is the importance of dosing and scheduling, and maybe a fixed duration of therapy, things like that. But was your sense that there is less infection with the talquetamab?
Dr. Maria V. Mateos:
Sure. I want to know what Tom thinks, but I participate in these clinical trials since [inaudible 00:12:17], and this is something that we see. The infection rate is lower, than with the BCMA, CD3 bispecfic monoclonal antibodies. The reason is, because we know that BCMA is involved within the production of the normal immunoglobulin, so we don't see so severe, hypogammaglobulinemia, and definitely the infection rate is lower than with the BCMA targeted therapy.
In addition, and I think that this common is generally applicable to all bispecfic monoclonal antibodies. Now we are given this as continuous therapy until progressive disease, maybe we have to plan maybe some stopping rules, in order to stop therapy in the future, based on the response, based on minimal residual disease negativity achievement.
Because I think that as soon as all these bispecfic monoclonal antibodies move earlier on to earlier lines of therapy, or even to the [inaudible 00:13:20], we have to try to protect as much as possible to our patients. And I think that because of the efficacy we've seen, it would make sense to plan in the future, a fixed duration of therapy.
Dr. Brian Durie:
Absolutely. So Tom, what is your thought? I mean, we already have the approval of the talquetamab, for example. Do you see the need to really work closely with the doctors, to make sure that they're aware of these aspects?
Dr. Thomas Martin:
Absolutely. We're very excited about the efficacy, and how well these perform in terms of the anti-myeloma effects, but we do have to keep into consideration the safety behind these drugs. And there's a different safety signal between the BCMA targeted therapies and the GPRC5D targeted therapies. So ketumab and the GPRC5D targeted, they actually have a unique group of side effects, including you can have GPRC expression in the nail beds and in the oral mucocele, and on the skin.
So upwards of a third of patients or more, can have a skin rash and can have dry and peeling skin. Many people have changes in the nail beds, and the nails can become fractured and can become very sensitive. And also, there's what's called ageusia, the loss of taste. And I'd say in the patients that we've treated here at UCSF, we've seen relative changes in body mass, mostly on average, about a 10% loss of weight. So patients do experience weight loss, so we have to really encourage them to keep their weight up, and to make sure they're eating, and et cetera.
And so, those side effects in my mind push us towards what we want to do in that is, is to do time-dependent therapy, so that we're not on these drugs forever, that we're going to give a set duration of therapy, hopefully drive the disease to maximum response CR, or even sustain MRD negative, which would be okay, and to take them off. In the BCMA, the same thing, except we're taking them off because we want the immune system to grow back. I do think BCMA does suppress the immune system a little bit more than GPRC. You still have to worry about both, but it does suppress it a little bit more.
Dr. Brian Durie:
Yeah, so absolutely, these are not trivial side effects, with either one, the BCMA or not. Yeah, I think that fixed duration could be a solution, if you've achieved an excellent response. Yeah. Okay. So I think tremendous excitement about that, great potential. And as you said, Tom, moving forward pretty quickly, so we'll have access rather soon. The CAR T therapy that has been developed in China, and with this study led by Juan Du, in Shanghai, very interesting in several respects.
So the first little bit of a difference here is that this CAR T is double targeted against BCMA and CD19. And so, this may contribute potentially to enhanced efficacy. The other thing which was pretty intriguing, was the fast manufacturing time, which could be pretty amazing to really speed up access and availability. So I think that I sensed a number of people were taking note of that.
And then obviously, the efficacy, pretty dramatic, patients were achieving 100% overall response rate, and also deep responses, basically of these frontline patients. 17 out of 17 achieved MRD negative. Now, the way that this was used is that basically these patients received standard of care induction basically. So they received VRD for two cycles, all but one of them received VRD for two cycles, and then they received the CAR T product.
And one, they selected to start with patients who have high risk, newly diagnosed high risk myeloma, which I think was interesting, and obviously very good that these patients did achieve excellent results. And the safety profile pretty favorable with low grade CRS. So this really is intriguing. And Tom, this is something that you've talked about for a long time, bringing in CAR Ts earlier, and what could possibly be achieved. So Maria V., maybe if you want to comment first. So how did this information strike you about the potential for CAR T?
Dr. Maria V. Mateos:
Well, the information we have is actually also very exciting. It's true that we have to realize that the sample size is rather small, only 17 patients. But it's true that all patients were newly diagnosed with high risk features, and this dual CAR T targeting, CD19 and BCMA, seems to be very effective.
And what you remarked for me, it's quite impressive to see how the manufacturing process was done in less than three days, for all patients. What can potentially enhance the phenotype of the T-cells? What can potentially impact in the fact that 100% of the patient responded, that the minimal residual disease negativity rate is also very high, and we needed to wait in order to see the follow-up.
Dr. Brian Durie:
Absolutely.
Dr. Maria V. Mateos:
Another important thing to evaluate, that I think that it was not presented during the presentation, was induction therapy, and what was the response at the moment of the lymphodepletion, because maybe these patients were with a very low tumor burden, and we will see if this can impact into the outcome, as well as into the safety profile.
Because it's true that also the incidence of cytokine release syndrome is actually lower than expected, only 29%, and all of them grade one and two with no outcomes and no neurotoxicity. So I would say that this is a good starting point, and we need a longer follow-up and more patients in order to confirm this data.
Dr. Brian Durie:
Yes, yes, yes. Very, very good points there. So Tom, what's your takeaway from this, how do you see this information?
Dr. Thomas Martin:
Well, I would say some of the early data from CAR T-cells has obviously emanated from researchers in China, and they've been really on the forefront of all this, which is amazing. If this was in a lab in the U.S., we would all be calling this lab and saying, "Hey, can we do this at our center?"
Dr. Maria V. Mateos:
Yes.
Dr. Brian Durie:
Right. Right away.
Dr. Thomas Martin:
Yeah. Right away, we want it right away. This is amazing. And like Maria V. said, it's good initial data, we want to see if it's sustained, and this kind of one-and-done phenomenon that you can get induction therapy and then a CAR T-cell, and then maybe be off therapy, would really be a huge advantage to obvious patients with newly diagnosed multiple myeloma. And maybe targeting both CD19, maybe an earlier myeloma cell and BCMA at the same time, will give a more durable response, we'll just have to see on that. But this is obviously really exciting.
Dr. Brian Durie:
Okay. Yeah, and I think we need to see the follow-up. We need to see a few more details, but maybe it will be possible for some people in the U.S. or elsewhere to have access to the details of this fast prep technique. I think that's pretty interesting.
Dr. Thomas Martin:
I will add to that, Brian, is that we're having manufacturing issues in the U.S., I'm sure they're having the same thing in Europe also. And this shortened timeframe for the manufacturing, hopefully will make it so that we're not having so many manufacturing difficulties here, in the throughput for when somebody gets their cells collected from their arm, into when we get a successful product back, and then get it back into the patient, is shorter but also more successful.
Dr. Brian Durie:
Right, right, right. And obviously, I don't think they showed a lot of data, but using T-cells from earlier in the disease course, is going to give you a healthier product.
Dr. Maria V. Mateos:
Correct.
Dr. Brian Durie:
Okay. So I'm moving forward now to talk a little bit about the data from Iceland. I hope that you'll agree with me, of all the different abstracts from Iceland, I thought the most interesting one was predicting the need for upfront bone marrow sampling, which was, I would say pretty cool from my perspective. So this project comes as part of the iStopMM cohort, and utilized over 75,000 individuals who had sampling of the blood available, to see if they had a monoclonal protein.
And out of that cohort, 3358 new cases of MGUS were detected, and of which 2542 were randomized. So this is a randomized follow-up. And so these individuals were available to assess the value of using a calculator method to predict what would be the likely percentage of bone marrow plasma cells. And so this just shows you the follow-up to sort through the various individuals who were part of those newly diagnosed MGUS patients.
And so, the key part of this analysis was in the bottom right-hand bullet here, where it was selected to use predictors, which were the type of the MGUS, the level of the M-protein, the free light ratio, and then the total levels of IgG, IgA and IgM. So looking for hypogamma effects or not. And it turned out that this was a magic combination, a very intuitive combination which gave a remarkable correlation between the predicted percentage of plasma cells, and the actual percentage of plasma cells.
And so the curves here, looking at the probability of having more than 10% plasma cells, is basically overlapping, with I think it was a 97% predictability. And so this is quite important. So just to go ahead here, they've already set this up as an app, where you can load in the numbers, and it will give you the percentage. And this just shows you, can set the threshold, and the bottom line was here, that based on the results, 366, 36.1% of the individuals could avoid doing a bone marrow, because the predicted numbers were low.
So I think that it's an evidence-based approach to really limit the need for bone marrow sampling, and for me at least, I think it does help solve one of the big concerns about the screening approach. So the screening gives you a large number of people with MGUS, but it also potentially gives you a large number of people needing to have bone marrows done. And so, I think that this is very, very helpful to try to sift through those individuals, and do this in an organized way. So Maria V., what was your take on this?
Dr. Maria V. Mateos:
Well, I think that this is extremely important, especially for patients, because we know that MGUS is very frequent and basically every week, I don't know, but maybe we can receive between eight and 10 patients with a monoclonal component. I think that every physician's attending process, should have this calculator in a day, the phone, mobile or in their computer, because definitely this is going to save many bone marrows.
And this is not the problem of saving the bone marrow, saving resources, but this is extremely important for the patients, because with the end component, the free light chain and the levels of immunoglobulin, basically one out of the three patients will not require the bone marrow. So for me, it's extremely important from the patient's perspective.
Dr. Brian Durie:
Tom, I would assume you agree?
Dr. Thomas Martin:
Yes, I completely agree. And anything that has an app to save people from going through a bone marrow biopsy, is completely worthwhile.
Dr. Brian Durie:
Okay. So Maria V., can you validate this in your dataset? I was thinking that you may be able to do this rather quickly.
Dr. Maria V. Mateos:
Yeah. And I was going to say that, I think that this is going to validate in the real world, maybe it seems the day before yesterday, because I think that everybody should be in applying this model. But definitely, this is something that we can do.
Dr. Brian Durie:
Yeah. Anyway, so it was one of several exciting abstracts from the Iceland team. They also had one where they showed that autoimmune disease is not really so linked with MGUS, for example, I think were a very important observation.
Dr. Maria V. Mateos:
Exactly.
Dr. Brian Durie:
Yes. And then also, the idea that in some cases, a spike may not really actually be MGUS, it may just be a transient spike.
Dr. Maria V. Mateos:
Yes. As well as the higher sensitivity for mass spectrometry versus electrophoresis, especially in terms of this transient end component. So I think that all the studies that are being done from this iStopMM, or multiple myeloma project, are really with a great impact in our clinical practice, and with a clear impact for the patients.
Dr. Brian Durie:
Absolutely, absolutely. Very much patient-focused. Yeah. Okay. So the next topic is to look at the results from the two rather similar trials, the ASCENT Trial, and then Maria V., your update of the CESAR Trial. And so Shaji Kumar, presented the results of the ASCENT Trial for the first time. And so this is a trial in which daratumumab, carfilzomib, lenalidomide and dexamethasone, Dara-KRd, was given in this case, to 87 patients with high-risk smoldering myeloma using the two 20-20 system, or a risk score of nine or greater.
And so, as was the case with your trial, the CESAR Trial, this was a limited fixed duration therapy, two years induction, consolidation and maintenance. In your case you had KRd plus the transplant, in this case the Dara-KRd, with the Dara, continuing on through the maintenance phase. And so response is pretty remarkable, 97% overall response rate, the best response rate. And at this point, now about 20, 30% of the patients have not completed the two years yet.
And so, there could be a few more patients who will achieve MRD negative, as we go forward. But it was pretty impressive that 84% are already showing bone marrows, which are MRD negative. And you can see some of that was happening during the consolidation and the maintenance, as you would expect. So I think pretty encouraging early results with this. And then as you would expect, the PFS, right around 90%. And so there were no new toxicity signals.
Patients with high-risk smoldering, tolerated this as you might expect. I would have to say it was a little bit tricky, this was going on during the COVID pandemic, so it was actually quite challenging to get the study completed. But despite that, patients really did quite well, and it's going to be some time until we know if there are going to be sustained MRD negativity, and if any of these patients might end up being cured. And so Maria V., you can comment on your data, that obviously very, very similar data where you have improvement in the response and MRD over time.
And that with the follow-up survival, you have data out to basically six years now, 70.1 months with the PFS and the overall survival data. Really, really good. Five patients progressed with symptomatic disease, and thus far only seven patients have died. And so Maria V., maybe you can comment first, I mean, what's your take on the ASCENT Trial, and what is your take on the value of these pilot studies overall? Because obviously, these pilot studies are one type of study along with a variety of trials that are going on for smoldering myeloma patients.
Dr. Maria V. Mateos:
Yeah, sure. I think that both clinical trials are complementary, because they had been conducted in high-risk smoldering myeloma. Different combinations, this included the total assistance of transplantation, they asked them to do that. Important to mention that the models for the identification of high-risk were different, because they asked them to utilize the two 20-20, and the first study was designed before 2014.
And this means that we utilized the conventional model risk. And in spite of this, we can see how the results are quite similar, in terms of overall response rate, the majority of the patients responded, and over 60% of the patients achieved complete response. We have so far evaluated the minimal residual disease negative, and more than 60% of the patients after transplant, achieved minimal residual disease negative.
And in the evaluable population, four years after transplant, approximately 45% of the patients do remain with the MRD negative. It's true that I have to say that we observed once patients finalize the treatment, some biochemical progressions, some politicization of the minimal residual disease, or just some reappearance of the end component. And we decided to plan an early rescue intervention in these patients, if they accepted with daratumumab, pomalidomide and dexamethasone.
And the final results is here, after the median follow-up of six years, the time to progression at 70 months was 94%, indicating that it's true that with the first strategy, and the first early rescue intervention, we maintain the majority of the patients without any myeloma defining event, any [inaudible 00:35:58] symptomatology. And I think that again, this is something extremely important for the patients, because I have to say that the safety profile, as [inaudible 00:36:08] said, also in his study is quite good, acceptable, and the same experience than we have with our previous study with len, dex, patients with asymptomatic and multiple myeloma, tolerate better the treatment.
Dr. Brian Durie:
Yep, yep, yep. So Tom, what's your reaction to this? Do you think that this can end up being the way to go, to use something like this to treat high-risk smoldering?
Dr. Thomas Martin:
Yeah, I think I'm growing more and more towards the treatment side of smoldering myeloma. These are amazing data. Both studies are quite impressive, especially Maria V's study. Six to seven years down the road, people are still in remission. That's pretty amazing, when you would've expected them to progress at this point in time. And I actually think the next generation studies are even going to be better. They're going to compliment these and even be better.
Dr. Brian Durie:
Absolutely.
Dr. Thomas Martin:
And so, what's being tested now obviously are the bispecfic T-cell engagers. And it'll be nice when we can combine some of these strategies, and maybe even bring that number up to 100%. I don't think that's out of the realm of possibility. So a very exciting time for smoldering myeloma.
Dr. Brian Durie:
Right, right, right. Yeah.
Dr. Maria V. Mateos:
Just to mention, that the trials with the bispecifics are ongoing, as well as also trials with the CAR T-cell, and [inaudible 00:37:42] will be evaluated in 20 patients in Spain, 20 patients in the U.S. So I completely agree with you, Tom, and we will see how the treatment will evolve in this asymptomatic population.
Dr. Brian Durie:
Right, right. So I think that it's a proof of principle that can be improved upon, and even to 100%. I agree, I think that we're pretty close, and pretty remarkable. Yeah. All right, so let's go forward with some of these other data that were interesting. So Naomi Pugh, her analysis and comparison of using next generation flow and the quantitative mass spec, to look at minimal residual disease. This she did in a Spanish trial, the GEM2014MAIN Trial, Rd versus Ixa Rd, looking at MRD testing.
And interesting, that what we've relied upon for so many years to assess response, immunofixation performs pretty poorly, versus quantitative mass spec and next generation flow. Pretty disappointing, really. And look here, if you try to predict progression-free survival, immunofixation is not doing a good job at all. So I think that's the first takeaway. The second takeaway, is that the mass spec is actually doing really, really well, and this can be or become an important tool in this sort of monitoring, particularly since it's a very simple, rapid blood test.
And then it can allow us to assess sustained MRD, which is important. This is what we're interested in, is it MRD achieved, but also, is it sustained? And so having a precise blood testing can really make that a lot easier to monitor, and see what is the status of the patient. So I found this very interesting. Maybe we can just start with that point right there. So do you feel that the mass spec is really going to have an impact here in terms of our ability to monitor? Maria V., I guess you can continue.
Dr. Maria V. Mateos:
Yeah, I think so. And this is something absolutely necessary. And I realized, especially when I did the analysis of the [inaudible 00:40:33], in which we had to evaluate the sustained undetectable measurable residual disease, and we realized that some bone marrows were not done, sometimes because of the [inaudible 00:40:45], sometimes because the patient didn't want to.
Some patients sometimes, because the physician did forget to ask for the bone marrow. So I think that this is going to be a clear solution, because this minimal residual disease assessment can be done or is done in the peripheral bladder. And in addition, this type of monitoring for the minimal residual disease in peripheral bladder, will allow us to monitor more frequently the measurable residual disease.
Dr. Brian Durie:
Exactly.
Dr. Maria V. Mateos:
When we do bone marrow every year, the majority of the biochemical progerations were detected because of the appearance of the end component. But with this technique, we are going to be able to detect the biochemical relapse earlier on. So I think that this is something extremely important, is too, that this technique is not approved yet.
And today, I would say that it is highly complimentary to the bone marrow. The negative predictive value of mass spectrometry is almost 90%. This means that if we do mass spectrometry and it is negative, well, we cannot wait because we are going to be almost sure that the bone marrow is going to be negative for minimal residual disease.
So I think definitely this is the way in which we have to move forward, already considering a standard of care, minimal residual disease by flow or by next generation sequencing. And we will see if it is possible to replace completely, maybe no, because the bone marrow is going to give us other information, but it's something to compliment, for sure.
Dr. Brian Durie:
Right, right. And just for our listeners, we are hopeful that the mass spec will become commercially available, maybe sometime later this coming year. One piece of good news is that, this very large company, Thermo Fisher, will be taking over the binding site, and has rather an aggressive approach to try to move the commercialization process forward. So I think that will be good for patients and good for everyone. Your reaction, Tom, any?
Dr. Thomas Martin:
Well, I think it's great that Thermo Fisher has taken over, because hopefully that will expedite our use of this as a blood test. We've always been talking about a blood test that can limit the number of bone marrow biopsies that we have to do, and I think this is going to limit the number of bone marrows. They are going to be complimentary, but we're going to be able to do many fewer bone marrow biopsies, thankfully. And I think your next abstract might knock bone marrow biopsies off the palate.
Dr. Brian Durie:
Right. Right, right, right. And then, one other thing that can maybe help us just use the blood, was the data from Bruno's Lab, presented by Laura. And I think that using an ultra-sensitive method, again, a pretty remarkable result. And this was an idea that Bruno had, at least I think it was Bruno's idea, to use the magnetic beads to enhance the capture of the myeloma cells in the blood.
And so then, to use this so that blood testing, peripheral blood could be used for NGF assessment. And so, this is just a summary of what he calls the new blood flow test, in which he has a cocktail of monoclonal antibodies there, with the magnetic beads and the separation, and allowing sensitivity to 10 minus seven, or 10 or minus eight. And so, it doesn't need a large volume of blood, it's possibly not something that you would want to do for every patient or every time.
However, it does give that higher level of sensitivity, and again, would avoid the need for a bone marrow. This is just to show you over time that this negativity with this new method was certainly easily prognostic of a very good PFS. So clearly, a meaningful test result. So I guess Maria V., first, so do you see this as something that we might consider starting to use in a certain way or different patients?
Dr. Maria V. Mateos:
Yeah, sure. Maybe in the future [inaudible 00:45:46], and both abstracts are taking part of be it a project we have here in Spain, in which we are going to monitor the minimal residual disease in peripheral blood by mass spectrometry, by next generation flow, and also the circulating free DNA in the [inaudible 00:46:06].
So I think that the idea is to combine the information we will have from all these techniques, evaluated in a homogeneous patient population, in order to take conclusions. And, well, personally I consider that the possibility of doing this concentration of the peripheral blood in order to reach a sensitivity level of at least 10 to the minor seven or 10 to the minor eight, in the peripheral blood is great.
You can see here how the prognostic value is very evident, and as I previously said, I think that this is going to be the future, because this will allow us to monitor more frequently the measurable residual disease, and will plan maybe even early rescue intervention. So I think that this will be the future, although the research is ongoing.
Dr. Brian Durie:
Yeah. Yes. Any added comments, Tom? No. I think we need to see how things play out, but it looks like it can be part of a blood testing protocol that we're moving toward.
Dr. Maria V. Mateos:
Exactly.
Dr. Brian Durie:
Okay. So a final area of comment, and I don't know if you guys heard this presentation, but there was quite a bit of interest. There has been this constant feeling that maybe we could have a good regimen that works, which doesn't have dex. And so I think that people were particularly interested in this study, which is basically the mye regimen. So it's the daratumumab, lenalidomide but without the dex. So it's the mye regimen, but without the dex. And so the study was to compare that with traditional len and low dose dex.
And so I think this is a kind of cool idea, and this was for frail, elderly patients. So the best response with the Dara, Revlimid, really quite good overall response rate, 96%, versus 85% for just the Rd. One comment that was made is that, and obviously this is not a direct comparison, but the depth of the response with the Dara, Rev, was probably not quite as much as you get with the additional of the dex. But certainly well-tolerated, and it's certainly something to consider for an older or a frail patient population.
It was not a head to comparison either, a favorable safety profile, and it was also early, we're just starting to see the early results. So as you guys know, one of the very impressive things about the full mye regimen, is how long that first PFS is. I mean, it's out four or five years, a very impressive PFS. And so we'll have to see what will be the PFS if you drop the dex. So Tom, what was your reaction to this, do you have patients who want to get away from the dex?
Dr. Thomas Martin:
So yeah, we call it, Tyrannosaurus dex, here. And I would say that there have been a lot of comments about this, this is great, done in frail patients. Really nice to show the doublet, if it's Dara, plus lenalidomide is better than lenalidomide dex. But maybe it would've been better to do a triplet of the DRD versus DR, to see.
And this is where I think quality of life metrics really probably would matter, because it'd be nice to see if patients were happier off the dex than the patients who are on the dex, and that their quality of life was better. Not only do they have a good response, but they actually have really good quality of life. And also we should have the quality of life measures be done in the spouse also, so that the spouse's quality of life is better.
Dr. Brian Durie:
Yeah, actually some patients like the dex, I mean they get a boost from the dex and they want the dex. Maria V., what's your reaction to this?
Dr. Maria V. Mateos:
Well, I think that the most important thing that the disease, a Phase III clinical trial dedicated it to frail patients, what they did is extremely important, because we have to move on this direction and to distinguish fit versus frail patients, and to plan clinical trials with different approaches. So this is the first point. The second point, I agree with Tom, the ideal comparison would be Dara, len, dex, versus Dara, len.
And the only caveat I see in this study is, well, we are attributing that the [inaudible 00:51:25] is affecting this combination, is only coming from dexamethasone. But maybe many patients are here in this webinar and maybe they can ask, and what about lenalidomide? Because lenalidomide sometimes is not very well tolerated, and indeed in the mye study, a significant proportion of patients in the Dara, len, dex, had to reduce the dose of lenalidomide.
So maybe the management of frail patients with this extremely effective combination, Dara, len, dex, is not maybe only to eliminate dexamethasone, but maybe to reduce dose of dexamethasone, to reduce the dose of lenalidomide, and maybe we can have a similar efficacy to the mye, because at the end of the day this is the main objective.
And as you pointed out in principle the follow-up is quite shorter, but the overall response rate, not, but the complete response rate, and the minimal residual negativity rate are lower than that observed in the mye study, in which 40% of the patients were older than 75. So I would like to wait in order to have a longer follow-up data on outcomes, and really to put in context this data with mye. And maybe this is not while everybody, Dara, len, without dexamethasone for everybody, because maybe some patients will benefit from the addition of small doses of dexamethasone, so maybe no more than eight or 10 milligrams.
Dr. Brian Durie:
Right, exactly. Yeah. My feeling I think is rather similar. I think that zero dex, every one wants this idea of zero dex, but actually if you watch the dose of dex carefully, I mean, you can have a small amount of dex, which is really quite well-tolerated, and I think does contribute to a deeper response, and maybe a more sustained response. And so, I don't think we should throw away the baby with the bathwater, as they say, maybe a little bit of dex could be okay.
And as I mentioned, some patients do like dex, it gives them a boost for a few days. We need some further follow-up on that. But it did trigger a lot of discussion. So I have left a little bit of time here at the end. What I did was I selected abstracts. This year, there were really a lot of exciting, different things that were presented. And so, maybe Tom, maybe you could start first on this. Were there other abstracts where you would say, "This was really interesting and important," that caught your attention?
Dr. Thomas Martin:
Well, I think a couple of things. So in the field of CAR T-cells, there was a GPRC5D CAR T-cell therapy, that was presented by Jesus Berdeja. And this actually came out of the Memorial Sloan Kettering lab, from Eric Smith. And it's a CAR T-cell, not a bispecfic, but again targets the antigen of GPRC5D. And it was a dose escalation trial, and they started off with 25 million and went up to 300 million CAR T-cells, that were infused. And this was in the relapse or refractory space. So it was three or more prior lines of therapy. And at the higher doses of therapy, the overall response rate actually was 100%, in the GPRC.
Dr. Brian Durie:
Wow.
Dr. Thomas Martin:
And there was less toxicity in terms of the nail bed toxicities and the skin toxicities, and the dysgeusia and the weight loss, when you did a one-and-done treatment with CAR T-cell rather than you did continuous therapy with a bispecfic T-cell engager. Now this study is going to expand and they're going to enroll many more patients, I think overts of hundreds of patients on the higher dose levels, to further assess response in this patient population and toxicity.
But this is a very exciting result from a CAR T-cell therapy that targets a different antigen. And some of the patients in this trial also had received prior BCMA targeted therapy. So even in the BCMA targeted therapy group, the response rate was over 70%, which was really great. So that actually was one of my favorite CAR T-cell abstracts.
Dr. Brian Durie:
Okay. All right. So Maria V., did you have a favorite that came to your attention?
Dr. Maria V. Mateos:
Well, I think that the GPRC5D has been maybe the winner, this ASCENT 2022, throughout the bispecfic monoclonal antibody or the CAR T [inaudible 00:56:29]. But I would like to mention some biological studies in order to understand the mechanism or resistance to both, the BCMA and GPRC5D. And I think that the group of [inaudible 00:56:41] presented excellent studies evaluating the potential [inaudible 00:56:51], the potential loss of both expressing BCMA, GPRC5D, but also mutations in the genes and coding for BCMA or GPRC5D.
And maybe in the future, well, it is almost sure that all these approaches will move rapidly to every lines of therapy. And these therapeutic options are going to be definitely very expensive. So we have to select very well the adequate patient for this specific therapeutic approaches, and especially to plan an optimal sequencing. And maybe we have to incorporate immune profilings, in order to evaluate the quantity and the quality of the [inaudible 00:57:38], as well as the potential mutations in these genes in, order to select the appropriate therapy.
And another thing that I would like to remark is also combinations, talquetamab in combination with the daratumumab and lenalidomide, was reported in relapse and refractory myeloma patients after one to three prior lines of therapy, with a great efficacy data, acceptable toxicity profile. And this is going to be the rationale for moving with this combination to first-line of therapy. So I think that these two considerations were relevant also for me.
Dr. Brian Durie:
Yeah, very, very good points. Okay. So I think that we've covered a lot of ground today, and I think that we'll be able to bring it to a close here. So thanks again to our sponsors, but thanks to you guys, after a hugely busy ASH, where there were so many interesting and exciting abstracts, taking the time to join us today and give your perspective for our listeners. So, thank you so much, Maria V., and thank you so much, Tom.
Dr. Maria V. Mateos:
Thank you.
Dr. Brian Durie:
And look forward to seeing you guys soon. And we have, I think, bright prospects for 2023. I mean, all of this information is so hopeful for patients and for investigators. I mean, we just have so many new ideas, new options, but be expecting to have continued improved outcomes for our patients. It really is remarkable. So, thank you.
