A four-part session with experts Mohamad Mohty, Francesca Gay & Saad Usmani discussing updates from the COMy, ASCO & EHA 2020 Virtual Meetings

Welcome to The Myeloma Sessions, brought to you by The Video Journal of Hematological Oncology (VJHemOnc). This exclusive session features leading experts in multiple myeloma; Mohamad Mohty, Saint-Antoine Hospital, Paris, France, Francesca Gay, University of Turin, Italy, and Saad Usmani, Levine Cancer Institute, Charlotte, NC, who debate the key updates in the diagnosis and treatment of multiple myeloma from the recent COMy, ASCO and EHA 2020 Virtual Meetings.

The topics being discussed include the management of high-risk smoldering myeloma (part 1), evolution of induction strategies in transplant-eligible patients (part 2), impact and role of MRD & practical considerations and the latest advances in relapsed/refractory myeloma (part 4).

Part 1: Management of High-Risk Smoldering Myeloma

“In principle, if you identify those patients who are really at a high risk of developing asymptomatic disease and you treat them with a proper therapy at the time where the disease is still asymptomatic, then you probably have found the small population of patients that could be cured.”
– Francesca Gay

“We believe that in hematology you win when you intervene early.”
– Mohamad Mohty

 

Part 2: Evolution of Induction Strategies in Transplant-Eligible Patients 

” I honestly was quite surprised with the results of the ECOG trial (ENDURANCE) that was reported, which compared VRd to KRd in the frontline setting. Many first believed that KRd is a better regimen for high-risk multiple myeloma patients in the frontline setting based on the Phase II data that’s available.”
– Saad Usmani

“By adding a drug with a totally new mechanism of action, like the anti-CD38, is bringing much more added value than just by switching the same family of drugs, proteasome inhibitors, into first generation to second generation.”
– Mohamad Mohty

Part 3: Impact and Role of MRD – Practical Considerations 

“We can analyze and we can understand how can the outcome of patients who, for example, maintain a sustained MRD negativity, be affected.”
– Francesca Gay

I’ve never met a patient who has told me, “Oh, I love continuous therapy.” And MRD, I think, definitely is the right tool to help us to refine the duration of therapy and to identify, in a dynamic fashion, the high-risk patient versus maybe the standard-risk where our approaches can move away from this long-standing one-size-fits-all.
– Mohamad Mohty

 

Part 4: Latest Advances in Relapsed/Refractory Myeloma 

“Once the CAR-Ts and bispecifics move to earlier lines, there’s also possibility of utilizing bispecifics in consolidation and maintenance strategy for patients not achieving the best MRD negativity.”
– Saad Usmani

“This is really a very important message, that initially we used to think that the first line is really the most important but now we are able to achieve at the level of the second and even third line, a very important duration of response and progression-free survival.”
– Mohamad Mohty

Full Transcript
Part 1: Management of High-Risk Smoldering Myeloma

Mohamad:
Hi everybody, I'd like to welcome you all to this first Myeloma Sessions on The Video Journal of HemOnc. Today I'm very privileged because I'm joined by two wonderful friends and colleagues. Ladies first, Dr. Francesca Gay from the University of Torino, let's talk it in the Italian way, and by Dr. Saad Usmani from the Levine Cancer Institute and the Atrium Health in Charlotte in the United States.

Mohamad:
As you know, I think, over the last few weeks we have witnessed an amazing amount of new information in the field of multiple myeloma. I'm 100% convinced that we can spend the full day trying to summarize all the available new research evidence, however, for today, we will try to structure this into, I would say, four topics that I personally believe, and I hope my panellists would agree with me, into four major topics.

Mohamad:
One about smoldering multiple myeloma, which is really becoming a matter of concern these days, because probably we'll have to treat these patients. Then the transplant-eligible patient where things are moving quickly, especially when it comes to induction regimens. This will obviously lead us to the evaluation of minimal residual disease or measurable residual disease, and it's a true value not only in terms of a prognostic impact, but maybe to drive and guide the therapy of our patient.

Mohamad:
And finally the fourth topic, until we find a cure to everybody we'll still have to deal with the relapsed/refractory myeloma patient, and here we do have some very, very good news about new agents, new combinations, cellular therapy, T-cell engagers and we'll hear some very nice data. So, Francesca, Saad, welcome.

Saad:
Thank you.

Francesca:
Thank you.

Saad:
It's a pleasure to be here.

Mohamad:
Thank you for joining. So, let me start first by the management of high-risk smoldering multiple myeloma and my short, simple question, and let's start with the ladies, Francesca. What's your, I would say, feeling today about this topic based on what we heard recently from different groups?

Francesca:
I think that if you think about curing someone in myeloma, probably the tricky point is to define those patients who have these high-risk disease but that did not develop yet the CRABs, so where you can treat early. Probably you can have a disease that is more sensitive to therapy than later on where the disease is more aggressive. So then I think that, in principle, if you identify those patients who are really at a high risk of developing asymptomatic disease and you treat them with a proper therapy at the time where the disease is still asymptomatic, then you probably have found the small population of patients that could be cured.

Francesca:
So the first question, I think, is who are those patients that are really at high-risk? We have seen several definitions in the last years, from the myeloma-defining events, so the CRABs that actually are what we first defined as smoldering, to the most recent definitions, the 2020 definition, for example.

Francesca:
So, honestly, I don't know who are really these patients who are going to become symptomatic. There are several criteria and probably most of them are valid. But it is tricky for the research now to identify correctly these patients. And the other point is what is the current treatment approach, so you can have two type philosophy. One is treat and cure, so give them everything and use the high-dose therapy. The other one is just control the disease. To my opinion, I would honestly be more in favour of a more aggressive approach, if possible, in an attempt to cure the disease and to give treatment-free interval in this population. But this is just a personal opinion. I'm curious about what Saad and you think about it.

Mohamad:
I think, and Saad will confirm or not, we are all on the same line and we believe that in hematology you win when you intervene early. We also know, in oncology, in general, that you would try to detect the so-called in situ carcinoma. This is why we do breast cancer screening and we encourage all patients and all healthy people, whenever they have a risk factor related to family or age, to go into these screenings. Then one would wonder, philosophically, why, in multiple myeloma, this should be different.

Mohamad:
I have rarely heard that you would wait until acute leukemia before treating an MDS, a high-risk MDS. But now my question to you, Saad, how confidant do you feel about our capacity to detect or categorize these so-called high-risk smoldering multiple myeloma? Because this is the key issue.

Saad:
I think that this has been a key issue for a long time but the International Myeloma Working Group has recently taken a look at over 1,200 patients with smoldering myeloma and came up with the 2020 criteria, which is essentially an improvement on the previous clinical featured criteria. So patients who have 20% or more plasma cytosis on the bone marrow, two grams or more of M spike, abnormal to normal light-chain ratio of 20 or more. Those are identified as high-risk features and they characterize the high-risk smoldering myeloma patients.

Saad:
Which, in fact, is also the category of patients who benefited in that ECOG (ENDURANCE) trial the most. When lenalidomide was given, compared to observation, the Sagar Lonial study that was presented last year, and it's published now, but that group is the one that derived the most benefit. I'm still a little bit on the fence that that is the final answer because, again, we are only relying on burden of disease. We are not paying attention to disease biology or to what's happening to the immune microenvironment in those patients.

Saad:
I think our best guess is still we can give a 50-50 chance of identifying high-risk smoldering myeloma patients. I think when we account for biology and immune repertoire, we can potentially get to 100% but we're not there yet. So that's the other challenge. I'm kind of on the fence. And this is where the ECOG (ENDURANCE) study poses a challenge for me, personally when I'm sitting down with younger patients with high-risk smoldering myeloma and having discussion. Yes, you intervene but, just like Francesca said, you would like to intervene like it's active myeloma, like you're trying to push for a cure. And right now, we don't have any data to support that.

Mohamad:
So, should I understand that Francesca has given us a thought, like we can go into two directions? Either an early treatment but a mild, gentle treatment to delay disease progression, or either a very intensive, curative treatment to eradicate the disease. And probably the truth is in between. But what would be your current approach? Because we have to ECOG (ENDURANCE) trial, published in JCO, you mentioned. A very nice randomized trial. We do have also very nice trials from Dr. Mateos from Spain. Different philosophy. Highly intensive approach. So, if you have to design a third wave of trials today, what kind of approach would you take?

Saad:
Right now I don't think we need, how shall I put it, randomized trials for the high-risk smoldering myeloma patients. I think if we have strong Phase II data, at least two different data sets giving us the same message, I think that would be a reasonable approach for young patients. So, my approach is we do have the [SEN] trial that's ongoing, which has a very similar philosophy compared to what Marivi has said. We're enrolling younger, smoldering myeloma patients on that trial.

Saad:
And I would be totally onboard with that idea for patients. My issue is for patients who are 70 years and above who are presenting with high-risk smoldering myeloma. We know that half of those patients are going to progress to active disease, but the other half won't. That's the challenge. What do you intervene with on those patients? That's where we're going to need more clarity. I agree with Francesca's overall approach. I think we're going to have, I would say, three groups. Just like we do nowadays.

Saad:
One patient group we are going to treat gently, one we're going to be super aggressive and the other where things will be in between. You're to going to be giving them consolidation or multidrug maintenance. So, I think it's probably going to be three categories.

Mohamad:
Actually, you're making it even more complicated because actually it's already very difficult to identify the high-risk and it's likely you're proposing that we need to have the low-high risks and intermediate-high risk and the very-high risk.

Saad:
What I'm proposing is we will do away with this smoldering title. We'll treat this. It's myeloma. We are going to call it early myeloma or asymptomatic myeloma, but it will be myeloma. But, even today, for our patients, we have transplant-ineligible where we treat relatively gently with easier treatments. Patients can do very well with easy triple-drug regimens like DRd. But then we also have patients who are getting PI IMiD induction, transplant consolidation and then going on to maintenance.

Saad:
And then there are others who are kind of in between. So I think we are going to do away with the smoldering title and we are either going to have patients who have precursor disease and they're monitoring, or we're just going to treat them. I think that's where things are headed. So it will get simplified. I think in the next five years I can see the smoldering title going away, or category going away.

Mohamad:
Francesca, what is your practical approach today regarding this entity?

Francesca:
Well, actually, outside of clinical trial, we don't treat them because it's not allowed. We, as well, participate and have participated in trials exploring different approaches, more gentle or more aggressive. I totally agree with what Saad mentioned about this different approach that simply means that you have a patient that is in early myeloma. We can call it high-risk smoldering, but actually, it's myeloma at the early stage that is going to progress. And, of course, in a young patient, I think it's easy to give to the patient the whole burden of therapy with induction, transplant and so on.

Francesca:
In an elderly patient you modulate it according to the fitness, as you do in myeloma. And it's extremely important to me, also, in elderly patients, even the ones that are 70 and more of age, because think about the impact of quality of life of a bone fracture or a renal failure, also, in these patients. So maybe they are very elderly, you are improving, of course, their life expectancy, but also you are preventing the occurrence of the CRAB symptoms that can affect a loss to their quality of life. This is equally important in young and in elderly patients. Of course, the youngest are the ones for whom you can reach probably the longest duration of remission with intensive therapy and prolonged overall survival.

Mohamad:
Well, this is really fascinating and I would firstly consider that smoldering multiple myeloma is really work in progress. Obviously we all agree that, at the end of the day, our goal is to intervene early in order to eradicate the disease from the beginning and avoid any organ damage.

Part 2: Evolution of Induction Strategies in Transplant-Eligible Patients

Mohamad:
And that brings me to our second topic for today, which is about the progress that we have seen in the transplant-eligible patient, namely the changes or advances we've seen in induction.

Mohamad:
I believe VRd, maybe VTd in European countries, in some European countries, so bortezomib-lenalidomide-dexamethasone, bortezomib-thalidomide-dexamethasone, have been considered as standard of care regimens validated through randomized Phase III trials, from Italy, from Spain, from France and many other groups. Where do you view the future of induction, based now on the quadruplet coming, DARA VTd, DARA VRd, but also I would like to discuss with you in a few minutes the replacement of bortezomib by carfilzomib. And this is the famous KRd, or even DARA KRd. So, who wants to start?

Saad:
I think what we've seen in the frontline setting for transplant-eligible, as well as ineligible patients, is adding daratumumab as the anti-CD38 monoclonal antibody to the existing platforms has improved the depth of response, PFS, and in the transplant-ineligible setting, even overall survival. So, Maria-Victoria Mateos has shared these data with us, and it's published now on the ALCYONE study. And I suspect that we will see similar trends with other trials with DARA VTd and even with DARA RVd, that there is different trial data in the Phase II randomized setting but there are two Phase III trials looking at that combination, as well. And this will pan out.

Saad:
But I honestly was quite surprised with the results of the ECOG (ENDURANCE) trial that was reported, which compared VRd to KRd in the frontline setting. Many first believed that KRd is a better regimen for high-risk multiple myeloma patients in the frontline setting based on the Phase II data that's available. There are three datasets and Francesca can probably share her clinical trial experience, as well, in just a bit. But the ECOG (ENDURANCE) trial truly surprised us. I don't know whether it's the fact that stem cell transplant was deferred in this study, whether that had any role to play in it, or whether it was the discontinuation of the drug.

Saad:
But at least for the standard-risk patients, that's the population that ECOG (ENDURANCE) targeted, there were no differences in the primary endpoints of PFS. There was some improvement in depth of response but that really surprised me. So what I can share is that PI IMiD dexamethasone with a monoclonal antibody, that quadruplet schema is probably here to stay. I would still say that we need to explore the role of V versus K in high-risk patients. We don't have a clear answer.

Mohamad:
So you're alluding, Saad, to the ECOG trial, which is the ENDURANCE trial, which is Phase III randomized trial, 1,000-plus patients, reported by Dr. Shaji Kumar as a late-breaking abstract at the last ASCO, and showing no difference. I think the PFS, progression-free survival, in the VRd arm was 34 months and it was 34 months also in the KRd arm. My role as a moderator is to be also fair and defend the evidence, and we must admit that both arms were absolutely balanced. So, of course, the number of cycles nine versus 12 or the percentage going to transplant, but they are balanced.

Saad:
I agree with you.

Mohamad:
So maybe the story, the results, adding daratumumab to a triplet are quite impressive. We have the European trial, PERSEUS, led by Francesca and other European colleagues, which will come later, but we already know that DARA VTd CASSIOPEIA trial, DARA VRd, are very powerful. And my personal feeling is that maybe, by adding a drug with a totally new mechanism of action, like the anti-CD38, is bringing much more added value than just by switching same family of drugs, proteasome inhibitors, into first generation to second generation. So here I'll turn to Francesca because you are, since many years now, a strong believer in the triplet KRd using the second generation. Very effective. A highly potent drug. Very useful in myeloma, carfilzomib. So how did you view this ENDURANCE, I would say, negative results from ECOG ?

Francesca:
Well, I was surprised, as well, as Saad, because I really did not expect exactly the same results. It is true that, if we think about the comparison KMP and VMP, again, first versus second generation, I have to add comparison in the past first line and no difference. But then there was a clear signal of probably a higher toxicity with K. Here it seems that the toxicities are different but probably not so different to negatively affected the efficacy.

Francesca:
So it is a bit difficult for me to understand why, in the first-line setting, first generation, is not better than... Sorry, second generation is not better than first generation when, in the relapsed setting, K versus bortezomib comparison, you see this difference. And this is something that, honestly, I don't have an answer. I don't know if it's because here you used a combination and in the other, in the relapsed setting, you don't. So using a PI IMiD, maybe you don't need the more potent inhibition that you have with K. I think these results are clear because you cannot say, [inaudible] you are right, the PFS is absolutely equal and the number of patients getting into transplant is similar.

Francesca:
So it's a bit different, the proportion of patients that is stopping therapy and receiving an alternative therapy without specifying if this is transplant or not, if I remember right. But, anyway, there is nothing that can't probably be responsible of an equal PFS in the two arms with such a big trial. So, I think the conclusion is that, from this trial, when you don't use the transplant upfront and when you consider standard risk, the effectiveness in terms of PFS is the same.

Francesca:
I think you are right when you say that using a drug with a different mechanism of action can be better. Of course, if you add a fourth drug to a combination, either you have an extreme increase in the toxicity or four, if tolerable, should be better than three. So to me the real question is can we use VRd plus monoclonal antibodies in all patients or, since we have seen that in high risk, the results are not so strong as we expected. Here there is the role probably from a second generation protease inhibitor in a quadruplet and in a monoclonal antibody. We have the results presented from Katja Weisel that were nice at the ASCO meeting, also. So I think this is the question. We need to see if, in a high risk, it's the same or not, or if we can have a further benefit.

Mohamad:
But, again, my role is to be fair with everybody and to defend all those colleagues who are not able to be here to defend themselves. And, in the last ASCO, we have seen a very nice meta-analysis looking into all the daratumumab-based combinations, relapsed or frontline, showing that the addition of daratumumab is useful in the high-risk population. So, just to mention that we have this meta-analysis. So let me ask both of you because, again, what I like in these discussions, I think randomized trials are lovely. We need them to move the field, to get approval. But also, practical approach, routine practice, is very important. So today in your practice, Saad, what is your, let's call it, gold standard induction regimen in a standard risk transplant-eligible myeloma patient?

Saad:
We are utilizing DARA RVd as part of our frontline induction. Again, because our center led the GRIFFIN trial and when those initial data were reported, the NCC guidelines had already incorporated DARA VTd as a category I, based on the approval, and since we are already using VRd in the US, the insurance companies have been forthcoming and we have not faced any issues. For our standard-risk patients, that's our frontline.

Mohamad:
So, for the sake of the reference, you are referring to the GRIFFIN trial, which was published recently, pre-published in Blood by Dr. Voorhees and colleagues. Francesca, what is your current induction regimen, standard of care?

Francesca:
Well, I live in Italy and the only induction that is allowed is VTd.

Mohamad:
But we love Italy. Don't worry. You shouldn't be ashamed of it.

Francesca:
I know that this is suboptimal. We have data that a four-drug combination is better, that VRd is more tolerable. We don't have a randomized VRd versus VTd, but we have strong data on meta-analysis. Unfortunately, the truth is that in many countries, and mine is one, you can use just what is approved and the approval of the drugs is not fast. So, what we are currently using, except for clinical trials, is VTd.

Mohamad:
And, actually, here I would like the mention that, in terms of approval, we have daratumumab VTd, bortezomib-thalidomide-dexamethasone, which is approved only by FDA and EMA, which is slightly different from reimbursement, of course, in different countries.

Part 3: Impact and Role of MRD - Practical Considerations

So I'd like to hear briefly from both of you how are you using MRD today. Is it in routine practice? Is it in clinical research? And where do you view the utility, how useful is MRD in the near future?

Francesca:
In clinical research we use MRD routinely that now we start of all clinical trials. Most of the time with sequential monitoring in an attempt to gather a lot of data that then we can analyze and we can understand how can the outcome of patients who, for example, maintain a sustained MRD negativity, be affected. So that we can plan future trials that are MRD-driven when you decide the treatment strategy according to the response.

Francesca:
In clinical practice, at least, again, in my country, this is different because there are reimbursement issues that we have to face every day. So our decision is generally to perform MRD mainly in high-risk patients and in the post-transplant time point, where we decide how to modulate and intensify treatment according to response. We used to do this in standard and high-risk young patients. We are more keen in de-intensifying or stopping therapy after, let's say, a period of maintenance in standard-risk, and in high-risk at going on intensifying treatments, giving the second transplant, giving maybe a consolidation and so on. So, this is what we routinely do because we have to restrict the number of patients for whom we use the technique that is not reimbursed.

Mohamad:
I'm curious, Francesca, because you highlighted the high-risk population, let's say the deletion 17p patient. You said you looked to MRD negativity more frequently in this population. Is it frequent to achieve MRD negativity in this high-risk group? I thought that it's quite difficult.

Francesca:
No. But we have generally a definition of high-risk that is a bit broader than just the deletion 17p so we come from the data that deletion 17p is difficult, that they get MRD negativity, particularly with the regimens that we are using outside of a clinical trial. But there is a general definition of high-risk that can be clinical, that can include other abnormalities. For example, the gain 1q, so there are other abnormalities. And, in this population, maybe you can get it and then you can decide if the patient, that toxicity, if you really need to intensify more, or not.

Mohamad:
Saad, where do you see the future of MRD evaluation in myeloma?

Saad:
I think currently, I'm sure Francesca has already stated this, that we have the most information about MRD as a prognostic tool, but we are not ready to decide a treatment based on it. But that's where things are going to head. Especially for standard-risk patients, we've gone from this phase of having fixed-duration treatment to continuous-therapy model and now I think we are going to be coming back to a fixed-duration model, which will be dictated by sustained MRD negativity for standard-risk patients.

Saad:
For high-risk patients, I think maintaining MRD negativity is going to be a therapeutic goal, but we are not there yet for that patient population. I think that's the population where MRD will, at least now, stays as a prognostic tool. But until we develop therapies that can overcome high-risk, I don't think that high-risk patients, we will move away to a fixed-duration treatment schedule. I think many of us will feel uncomfortable taking the foot off the pedal for the high-risk patients. They should be on continuous therapy.

Mohamad:
When I think about MRD use in clinical practice to guide therapy, I always think now about the so-called MASTER trial by Dr. Costa and colleagues. It's quite amazing because he has used sort of a super quadruplet regimen, daratumumab and KRd, that we discussed a few minutes ago. How comfortable are you with such an approach outside a clinical trial?

Saad:
I think not outside a clinical trial yet, but I have to say that there are three other efforts beyond the MASTER trial that are asking the same question but with different schemas. There's a study that Andrzej Jakubowiak from the University of Chicago is doing with a very similar kind of a design, the PI IMiD and anti-CD38 monoclonal antibody as part of induction consolidation and then asking them the question. Ola Landgren actually presented some of his data and our center is doing something very similar.

Saad:
But all of us are trying to define when to stop. I think that's the trial that we need to do. With the MASTER protocol, yes, we are looking at MRDs at specific time points but everyone is getting high-dose melphalan. So, again, I think the right treatment trial should be one arm getting the standard of care treatment, and the other arm actually developing this response-adaptive strategy and seeing which one comes out on top.

Saad:
I think I would love to have a global trial where Francesca, you, and I and all of us, can sit down and design something. I don't think pharma will do this but I think all of us together can sit and design this study. The MASTER protocol, it's the first prototype but it can help us in designing this dream trial. And the number of sample size we'll need is probably more than 2,000 patients but if we put all our minds together, we can do this.

Mohamad:
Well, I think your last sentence sounds like music to my ears and hopefully we'll make it because I've never met a patient who was telling me, "Oh, I love continuous therapy." And MRD, I think, definitely is the right tool to help us to refine the duration of therapy and to identify, in a dynamic fashion, the high-risk patient versus maybe the standard-risk where our approaches can move away from this long-standing one-size-fits-all. So, we'll see how the future will be.

Part 4: Latest Advances in Relapsed/Refractory Myeloma

Mohamad:
Now let me move to our relapse refractory topic. Unfortunately, even the patient who achieves MRD negativity in myeloma, in contrast to ALL, for instance, or in contrast to lymphomas, many of these patients will continue to relapse. This is why we need more and more relapse options. So maybe both of you, you can give us about... There are plenty of options. We have CAR T-cells, we have drug conjugates, we have bi-specific T-cell engagers. And when I say CAR T-cells, we have also the NK, the gamma-delta, we have the bi-specific CAR T-cells. What's your favourite option? I know, Saad, you made a very nice presentation at ASCO about the new T-cell engager but maybe Francesca, you like something else. So, Francesca, what's your favorite one or two new tools these days?

Francesca:
Well, leaving the T-cell engagement to Saad, I think that he's the right person, given the wonderful presentation that he had. I think that when we think about immune therapy and I think about T-cell engagement, and CAR T-cells, of course, are the ones that have the most striking results, it would be nice if we can really understand which patient may benefit from one approach or the other. The advantage of the CAR-T, to me, is the one shot. If you can give that one shot and get the prolonged remission. If this is the case, probably now we are studying them in a population of patients where, of course, you cannot achieve a prolonged duration of remission, but if this will be the case, moving them early on, I think they are one of the most appealing treatments strategies at all.

Francesca:
On the other hand, all the other treatments are treatments that you need to administer for a prolonged time period and, as you said, there is no patient that wants a prolonged therapy. Even if, in the relapsed setting, they accept it more easily because, of course, the disease relapses several times. But the option of giving a fixed duration of therapy, and maybe with some immunotherapies we can have this. It's certainly appealing. Most of the other agents, small molecules and so on, everything is prolonged therapy and [inaudible].

Mohamad:
I think CAR-T cells are definitely very attractive and the results are really very nice. We've seen the results of the KarMMa trial by Dr. Munshi, multi-center, large scale, 140 patients, clearly reproducing the results achieved with smaller trials. And this is always good news because sometimes we have some disappointment between the smaller trials' results and the larger trials. We have the CARTITUDE trial, also very exciting. But then someone can challenge these cellular therapies by saying, "Oh, I prefer to have off-the-shelf antibody T-cell engager, maybe a drug conjugate, maybe a bispecific." Saad, can you give us a summary about your favourite topic these days?

Saad:
Sure, absolutely. First, I would like to start with agreeing with Francesca. I think the major advantage that CAR T-cell therapies have is it's a single shot and then patients can cruise without treatment for quite some time, at least at the current follow-up, we're seeing a lot of patients, unlike the CD19 CAR-Ts, we are seeing a higher degree of sustained responses for CAR-Ts. But you're right. I think the CAR T-cell therapy is restricted to centers that can administer cellular therapies, and you also require the bridging therapy and disease control to collect T-cells, manufacture them and deliver them to patients.

Saad:
So, if someone needs treatment right away, then I think CAR-Ts may not be the best modality to pick. This is where bispecifics and even ADCs may come into play. What I'm really liking about the bispecifics so far, there are three that have been reported, including the teclistamab data that I read at ASCO. With relapsed/refractory myeloma that is PI IMiD and anti-CD38 refractory, we are seeing sustained responses beyond 12 months with some of these bispecifics. So even though, yes, the patients are getting repeated treatment, but if I have an older patient or if I am a hematologist sitting in a geographic area that does not have access to cellular therapy or transplant centers, then I would go for a bispecific. I might feel more comfortable treating my 78-year-old patient with a bispecific rather than CAR-T.

Saad:
So, I think patient safety profile, faced with this disease relapsing, all of those things will dictate the treatments that we offer our patients. It's also quite possible that, for the frontline treatment, I'm actually moving ahead of where I should be thinking, but once the CAR-Ts and bispecifics move to earlier lines, there's also possibility of utilizing bispecifics in consolidation and maintenance strategy for patients not achieving the best MRD negativity, for example. So I think there's a lot of potential for each of these treatments. I think there will be patients who actually benefit from both as part of achieving MRD negativity as the goal.

Mohamad:
Well, I think we have a lot of hope, I think, for our relapsed/refractory patient. And I must emphasize, and I think this is really a very important message, that initially we used to think that the first line is really the most important but now we are able to achieve at the level of the second and even third line, a very important duration of response and progression-free survival. And, putting all this together, we have seen an amazing increase in the median survival of multiple myeloma patients.

Mohamad:
So, this has been absolutely fantastic. I'd like to thank you both for this lovely discussion. My take-home message, and I hope you'll agree me from this discussion, is that the field is moving more and more towards early intervention and with a dimension, for instance, the sub analysis of the slim CRAB criteria, slim CRAB group from CASSIOPEIA. These are patients who were included in the CASSIOPEIA trial, presented at ASCO.

Mohamad:
The induction, prior to transplant, is moving into quadruplet, apparently, and this will allow to deepen MRD negativity and, if you deepen MRD negativity, you will refine and further improve the outcome of the patient and, if patient relapse actually now we have a huge panel of different options, the usual three families, IMiDs, and we should not forget the new kid on the block, CELMoD, iberdomide, coming very soon. Very nice Phase I data. proteasome inhibitors, and we heard a lot about the impact of carfilzomib and how it can fit in the different scenarios.

Mohamad:
But we should not forget oral proteasome inhibitors which can be useful in many elderly patients. We didn't mention them but they can be very useful. Drugs like ixazomib. And, of course, immune therapy on a larger scale, whether cellular therapy or pharmacological immune therapy through drug conjugates. Belantamab has been really on the podium during ASCO. We didn't give all the details because we didn't have much time for this. And, of course, the T-cell engagers and the bispecific antibodies. Mohamad:
So, with this, thank you both and, wherever you are, I wish you a nice day, a nice evening, and I hope to see you soon.

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