Optimizing the Current Management of Multiple Myeloma (MM) — Joseph Mikhael, MD, MEd

DR MIKHAEL: Hello, my name is Dr Joseph Mikhael. I’m a Professor at the Translational Genomics Research Institute and the Chief Medical Officer of the International Myeloma Foundation. It’s a privilege to talk at year’s end a little bit about optimizing the current management of multiple myeloma. This is a disease that has just changed so much over the last few years. It’s mind-boggling trying to keep up with all of the things that are happening. But we’re going to hit some highlights of really what has been practice-changing over this last year.

And perhaps the first of them that is of particularly relevant has the DETERMINATION trial. So this was presented, in fact as Plenary at ASCO. I had the privilege of being the discussant of this same abstract and it was presented by Dr Paul Richardson. The short version is, this was the American version, if you will, of the IFM study that had looked at the role of transplant in modern therapy.

So patients were randomized to either receive RVd or lenalidomide/bortezomib and dexamethasone, or lenalidomide/bortezomib and dexamethasone plus a transplant, as you see here, in the figure. And then all patients actually were given lenalidomide maintenance until progression. Which was a little different than the IFM study where they gave it for a period of time.

What was the bottom line from this study? A major improvement in progression-free survival if you had had the stem cell transplant, an improvement of over 20 months in PFS. So, at first, this looks unequivocally clear that everyone’s going to be using a transplant. However, interestingly, albeit a secondary endpoint, there was really no difference in overall survival. And unlike the French study, we didn’t see quite as many patients cross over to get a transplant at first relapse — only about 28% of them versus almost 80% of them in the French study.

So what’s my take on this? Well, on the one hand, we could say the sheer magnitude of the PFS says we really want to do stem cell transplants. That should remain the standard of care. We do know, also, that that prolonged maintenance seems to make a difference, but it didn’t let those people that didn’t have the transplant catch up.

We’re in a modern day of thinking in myeloma. We don’t save the best for last. Let’s use our best upfront. So let’s be aggressive upfront. And it builds on other studies that continue to demonstrate the benefit of transplant. And lastly, if we don’t do transplant upfront, we may lose the chance.

However, the corollary arguments, or the opposite arguments, are saying, well, overall survival wasn’t improved. And we know that this was actually only in patients 65 years and younger, and everyone seems to apply this to patients 65 to 75 where we know the toxicity is higher. And there is a cost to toxicity, both short-term and long-term, including second primary malignancy.

So the bottom line here really, is that there’s still debate in the area. I think that it remains an option in my estimation. It’s not fixed at front-line. We can potentially use it later in patients who have a good response initially. And I do think in the future we won’t always be going to stem cell transplant.

DR LOVE: We could spend a whole hour talking about this, and we will in the webinar, but just a couple of things preliminarily. First of all, we see the data, but do you think that most investigators, including yourself, really do believe that there’s a survival benefit? And if you really think there’s no survival benefit, why would you want to do it?

DR MIKHAEL: That’s a great point. I think we typically, I personally don’t think that by itself, it is going to provide a survival benefit in everybody. If we’re going to see it, it is more likely going to be in the high-risk patient, those patients that really need that more intense therapy. And that’s a reflection of the fact, Neil, that we have so many great salvage options later. We’ve learned, even in transplant-ineligible patients, they can go 5 years on a first regimen.

So I do think that this is a step towards transplant frankly leaving us and not being standard of care across the board. But there are some patients in whom our more novel treatments aren’t as effective. And, in particular, the highest-risk patients that need that extra boost where I think in those people it still may remain a standard.

DR LOVE: Another just quick question. One of the things that was observed there that you comment on in your discussion was the lack of benefit in African-American patients. Do you think that’s for real? Or, maybe just a numbers thing?

DR MIKHAEL: It may just be a numbers thing for now. I think we need more data to prove it. Because most studies have demonstrated that African-Americans actually have superior outcomes when given equal therapies to White Americans. Although, we’re also see a little bit of that signal in CAR T that may not be as promising.

So I think it’s thought-provoking. It wasn’t powered enough to really answer that question. But I do think it is worth doing. And one thing I will commend the investigators of this study, is that we did see a significant participation of African-Americans in the study. And only when we see that, are we going to be able to understand these signals better.

DR LOVE: Yeah, that was really impressive. Okay, please continue.

DR MIKHAEL: We can’t look at 2022 and not comment on the GRIFFIN study, which was the study that is perhaps more than any other, moved us towards quadruplets in front-line therapy. And this was a study that compared the standard of care, now in many respects of VRd, to now adding D-RVd. So adding daratumumab to the bortezomib/lenalidomide and dexamethasone platform.

And this was a randomized, Phase II study, so it’s not a Phase III. It will not be what moves this combination to approval, but nonetheless, is very important. And what we saw interestingly in this study, at each cut of it, and this was the most recent cut presented at the International Myeloma Society this year’s annual meeting, was that at each level after induction, after consolidation, which included, by the way, a transplant and 2 more cycles of either RVd or D-VRd after 1 year of maintenance and at the end of the study, in each case the response deepened. So we are seeing the benefit of the 4 versus 3, if you will.

In addition to the deepening of response, we’ve now seen that response carry over into progression-free survival. And we’re finally seeing these curves indeed separate, interestingly not to almost 3 years, but we are seeing the benefit of this quadruplet over the triplet, with daratumumab being added to VRd. Obviously, with more time, we’ll see this. but with a hazard ratio of .45, this is a signal that we believe is real.

So what’s my take on this? Well, we really are already moving to quadruplet therapies, in particular in patients who are eligible for an autologous stem cell transplant. It’s already listed on NCCN. The justification of course, is that we see this continuing deepening. And even though transplant still has a role, we still see further deepening with using this thereafter.

What’s probably unclear yet from the GRIFFIN study, its design allowed the daratumumab in that arm, in the maintenance phase, to be given for 2 years, then just lenalidomide alone. Not everybody is doing that and we’re still unclear as to the value of that daratumumab in maintenance therapy. But that’s still to be determined. And also, as a segue to other quadruplets that we’re seeing now, where the carfilzomib is being switched out for the bortezomib or isatuximab, another CD38 antibody, is being switched out for the daratumumab.

On that vein, another very important quadruplet study, now not just so much seeing the value of the quadruplet, but starting to move us in a direction of can we stop therapy? This is the kind of study our patients are very keen to learn from because as I always say, Neil, my favorite drug is nada. I want to give nothing whenever I can, if I can stop treatment. And so the design of this study was to give what was felt to be the most intense quadruplet we have, daratumumab plus carfilzomib/lenalidomide and dexamethasone, along with a transplant, and then continue that quadruplet until someone reaches MRD-negativity, not just once but twice, at least 3 months apart. And then at that point, the drugs could be stopped and patients would continue just on lenalidomide maintenance, as you see here.

And the bottom line was that it did seem to be an effective strategy in patients that did not have high-risk cytogenetic abnormalities, or perhaps even patients that had 1 high-risk cytogenetic abnormality. But those higher-risk patients with 2 or more high-risk cytogenetic abnormalities defined below as you can see. Unfortunately, their outcomes were significantly inferior.

And so my take on this is, this really is an important first step moving us to stop therapy. And part of that is going to be using MRD, and not just MRD-negativity, but this concept of MRD “sure” — of having it more than once. Some kind of sustained MRD, although maybe 3 months is too little.

It is interesting to see that the patients with 0 or 1 high-risk cytogenetic abnormality seemed to perform very similarly, so maybe we’re overcoming some feature of high-risk disease with this approach. But it still isn’t the answer. And I think we all realize that, although this was an important study to do to start to set the lines of what we can and can’t do, it’s not yet the full answer, especially in high-risk patients. We definitely need more for them. And MRD “sure, as it stands in this study, was not sufficient to stop treatment.

The next study is the famous MAIA study that we saw really presented in large form last year, but now has been updated further. And I think it’s worthy of mentioning, Neil, because it really is incredibly influential in patients that are not going to an autologous stem cell transplant. And has really become the new standard of care for nearly all patients. Giving daratumumab/lenalidomide and dexamethasone continuously led to really impressive outcomes, outcomes we’ve never seen before in almost any myeloma patient.

And so, it really is impressive to see both a PFS and OS benefit that we saw with MAIA last year. And now it’s been updated further with really not a lot of change, in the sense that we’re still seeing with much longer-term follow-up, that we still have over 50% of patients not progressed at the 5-year mark and two thirds of them alive, a comparison to 30% PFS in just Rd, and just over half of them alive at 5 years.

So I think this is a critical study and really has become the standard of care in transplant-ineligible patients. We’re seeing a shift moving from the VRd strategy using bortezomib/lenalidomide/dexamethasone. It’s less toxic. We’re seeing better outcomes. We see less neuropathy. And these updated results are important because we’re seeing not only the PFS and the OS benefit, we are seeing that they’re literally quadrupling the MRD-negativity.

I think where there may still be a question, Neil, in our minds is, what do you do with that really high-risk patient? Do you still want to give them a proteasome inhibitor? And now we’re doing studies of saying, well, can we give that full quad, like we saw with the GRIFFIN study, to transplant ineligible patients by adding bortezomib, even if it’s only for this first 6 or so months, or maybe after 12 months. And that’s actually kind of what I’m doing in my highest-risk patients, is trying to give them low dose bortezomib, starting weekly, maybe even every other week. Because in the VRd study in SWOG, patients actually had an overall survival advantage just having had 6 months of bortezomib.

So I think there is something about even a short course of proteasome inhibition in these patients that are not eligible for transplant.

On the same subject of quadruplets, before we start looking at more relapse settings, we had the German study, the GMMG study of adding isatuximab to VRd. So in some way similar to what we saw in the GRIFFIN study, but here we have a quadruplet of Isa/RVd being compared to RVd. And last year we had an update of what happened before transplant. And now we’re seeing what comes later.

What’s interesting is, this is the first Phase III study in front-line myeloma, where the primary endpoint wasn’t just response rate, actually was MRD-negativity. And it’s remarkable, with 18 weeks of treatment, even before they had a transplant, with isatuximab/VRd, that 50% of people achieved MRD-negativity. Whereas there was only about 35% in those that had the RVd alone.

And so this is really important, I think, because even though we talk about GRIFFIN, it is only a Phase II study. This is the first Phase III study we’ve seen with quads, with MRD, as I’ve mentioned, as an endpoint, with obviously that depth of response even before someone gets to a transplant.

Right now there does seem to be no issue with collecting stem cells. This was a bit of a challenge in the GRIFFIN study, that it was a little bit more difficult to collect stem cells in patients that had a quad. Obviously, we need a bit more data to know this. And it will be more important to see the impact of that transplant after induction. But this is yet adding another brick to the wall of quadruplets where more and more we’re likely going to be using quadruplets across the board in the near future.

Similarly here, from our friends in Germany, again they have an Isa-KRd study. And now looking specifically at the highest-risk patients. And so, as we understand myeloma more and more, this is not one disease, this has a tremendous spectrum between standard risk and high risk. And so, they wanted to explore this actually in patients both who were eligible and ineligible for transplant — can we give them this arguably most intense quadruplet that we have now. And so, even as a concept, I think this is important because it’s pushing the envelope a little bit, helping us see what we could potentially do.

So, obviously in those eligible for transplant, they were going to have one, and those who were not eligible for transplant were actually going to have Isa-KRd for 12 cycles followed just by Isa-KR maintenance, where we drop the dexamethasone.

And so my take on this study, obviously it’s a little bit preliminary in getting a lot of results, but we all recognize that high-risk disease remains an unmet need, if you will, in myeloma. There are some patients whose disease just takes off like a bonfire. And I think we will be using more quadruplets in this group. I think we all recognize that carfilzomib is more potent than bortezomib and is actually more sustainably given over a long period of time. Know every drug drugs go through evolution and now carfilzomib, we’re typically using once-weekly and that has made it more sustainable to give over time. And I think what’s interesting about this study in particular is we really do see the feasibility of giving this intensive quadruplet as long as we give it carefully in patients that are ineligible for transplant.

Ultimately, as a Phase II study, we’ll need a Phase III for full proof. But again, it’s stepping us in the direction of understanding quadruplets, in particular in high-risk disease.

Another important proteasome inhibitor to include in our discussion was the update, or the final results actually, of the IFM 2013-06 study, which was just published this year, which looked at giving the triplet combination of ixazomib, lenalidomide and dexamethasone in newly diagnosed multiple myeloma patients.

This was meant to obviously see if we could supplant, at the time, current standard of care with VRd by switching out the bortezomib with ixazomib, which is an oral drug and also has considerably less neuropathy.

Interestingly, and encouragingly, there was an 92% response rate, but the PFS was 41 months. And the 3-year overall survival was 92%. And although these numbers historically better than what we’ve had in the past, are definitely inferior to what we have seen with both VRd and indeed now with the quadruplets. So, although it’s an attractive combination, it was given this small number of patients, it was also a little bit unusual that they had limited in the design of the study to give 1 year of ixazomib maintenance. And although the toxicities were very manageable and there obviously was not the kind of neuropathy that we might see with VRd, we definitely saw it as an inferior outcome to VRd and even DRd. And it’s unfortunate, because we’ve seen this history of ixazomib has really not performed in the way that we’ve perhaps wanted in front-line and maintenance therapy. But I do think it still has a role, Neil, in certain patients, patients who really could not tolerate bortezomib and patients who are older, more frail, and particularly in various combinations.

We also saw this year, now moving to a more relapse setting, we saw updates in the ICARIA trial, which was the study of isatuximab plus pomalidomide/dex versus pomalidomide/dex. This was the first indication for isatuximab. It was given in patients who had had 2 prior or more lines of therapy. And at our International Myeloma Society annual meeting, Paul Richardson updated the overall survival data of this study, demonstrating, as you can see here, with considerable follow-up, that there was a persistent, not only PFS benefit as we saw earlier on, but now an overall survival benefit of approximately 7 months. So you see here about 25 months versus 18 months in these patients.

So I think it’s good that even in later relapse we’re seeing overall survival advantage. And I think 7 months is clinically significant. Thankfully, we also, in the longer-term, didn’t see any unusual safety signals. I think what this raises though is further questions a little bit about what do we do in sequencing CD38 antibodies? We know that we shouldn’t use isatuximab immediately after daratumumab. I actually had the privilege of leading that study. We gave isatuximab to people who just failed daratumumab. It didn’t overcome its resistance. So it’s not like moving from a first- or a second-generation immunomodulatory drug or proteasome inhibitor where we know it can overcome resistance. They’re very similar.

And so most of us now have agreed until we have more data, that if you’re going to retreat with dara or use — go on to Isa in someone who’s already had dara or Isa, we should at least have a line of therapy without a CD38 antibody in between to see if that CD38 antigen can be re-invigored. But at this point ICARIA with isatuximab/pomalidomide/dexamethasone remains a very potent combination in relapse myeloma.

The subject of using isatuximab in relapse myeloma, I had the privilege of providing the most recent update in IKEMA at the Leukemia/Lymphoma Myeloma meeting in New York City in October, where we looked at now longer-term follow-up of the benefit of this combination in progression-free survival when compared to carfilzomib and dexamethasone. And I think this was important to include in the year-end evaluation, Neil, because this is the first relapse study in myeloma where we see 3-year progression-free survival in the intervention arm.

Now interestingly, carfilzomib/dex by itself performed quite well at 19 months. That’s not something to ignore either. But adding this third drug of isatuximab, and I think it speaks to the synergy of these 2 drugs, but also of using them early in relapse. I had commented earlier that we’re moving towards a more intense treatment earlier in the disease course of myeloma. I always say, saving the best for last is great for a Hallmark movie, but not for myeloma, right. We want to use what we have earlier on. And so, we’re seeing more and more studies using carfilzomib at first relapse. We had previously seen the KANDOR study and now we see this IKEMA study.

And so this was driven by a deepening of response, no surprise. In particular, if we look at the MRD-negativity, we’re getting a third of these patients who already have relapse myeloma, half of them had had more than 1 prior line of therapy and half of them had had 1 prior line of therapy. A third of them are getting to MRD-negativity, whereas only 15% in those patients that are receiving carfilzomib and dex.

So this is really an unprecedented progression-free survival. I think carfilzomib is a very attractive partner in early relapse. And this is one of the few studies that used carfilzomib indefinitely instead of just defining an endpoint of 12 or 18 months. And so we saw this impressive PFS driven by a deeper response. And although I didn’t show the data, we even had improved PFS-2 which, of course, is always an important concept to ensure that we’re not, if you will, burning bridges for the future if we use an intense combination like this in early relapse.

We had the final readout of COLUMBA as well this year on the subject of using a CD38 antibody. This is not brand new news in using subcutaneous daratumumab, but I think is a reminder to us now that it’s really penetrated more into community practice, that this has become really the new standard of care of giving fixed dose subcutaneous daratumumab versus IV. And so, when they had looked at the overall response rate, giving it subcutaneously was clearly non-inferior. If anything, it was close to superior in doing so. And that when we looked at the Max C_trough right before that third cycle, we saw that we still had enough penetration of the drug into a patient’s system giving it subcutaneously versus IV.

As you can see here, this non-inferiority outcome was there, if not even it appears to be superior, but that was not the design of the study. And so we can feel very comfortable giving this drug in this way. And the updated analysis that we saw compared to the primary analysis of 41% is now 44%. Earlier with IV 27%, now 40%. So very similar outcome. There wasn’t any late-term signal that made us concerned, whether it was in the response rate or in that C Max, as I mentioned.

So my take here is, this has been critical. I mean what a massive difference for patients. Whereas patients before came in for hours, now we schedule them for less than ½ hour because they come in, they’ll get their blood pressure checked. Check in with how they’re doing, and they get a 5-minute literal infusion subcutaneously. It’s really quite impressive that it’s really shortened our times of keeping patients in the clinic. It’s also had the added benefit of a dramatic reduction in infusional reactions from anywhere to 30- to 40%, depending on how they were being treated, now to less than 15%. And in fact, often even less 10% in real life now.

And so this is why we’re seeing pretty much everybody moving from IV to subcutaneous daratumumab.

On that subject of CD38 and subcutaneous use, I was happy to see that Hang Quach from Australia presented just at ASH recently, the updated analysis of using isatuximab subcutaneously. They have an interesting, as they call it, the OBDS, the On-body delivery system. So as opposed to a simple infusion, there’s almost like a little pump that gets put on the arm or the abdomen and is pushed into the patient by a — it’s an injector that has to be given a healthcare professional. So it’s not self-administered but it’s not as a drip infusion as we use daratumumab. And in this study, they treated 56 patients, and they tried different ways in which it was administered.

And the bottom line is that they had very infrequent infusion reactions. The duration of that injection was about 10 minutes for most patients. It seemed to be tolerable well. There were a few patients, no surprise, that had some local skin reactions and injection site reactions, but nothing that was by any means defining or exclusionary.

So we’ve been waiting for this. I mean I think it’s just so much more desirable to give a drug subcutaneously. Even though isatuximab had a shorter infusion than daratumumab, after the first 2 doses it only takes 75 minutes to infuse. Nonetheless, if you have a choice between 75 minutes and 10 minutes, I think I would take 10 minutes. That’s typically how we would look at it. And so, with similar efficacy to IV, I think we’re going to be seeing this in the future. it’s not quite ready for primetime but we are getting close to using isatuximab subcutaneously.

DR LOVE: Yeah, I was just going to ask how you would compare the data that you have for subQ isa versus dara? And any projections on when subQ Isa might be available?

DR MIKHAEL: So I would see them again, like I would seem them intravenously, very similarly. Neil, I’ve had the privilege of developing isatuximab and working with dara for years. I really don’t see a major difference between them. And now with this early results of subQ, I think similarly there isn’t really a major difference in efficacy. There’s some fine differences of course, in frequency of it being given and obviously cost sometimes, depending on someone’s region may influence them.

How soon are we going to see subQ Isa? It’s hard to get out my crystal ball, but my gut feeling is it’s still going to take well over a year before it’s going to be available in the clinic. But latest I’ve heard is that maybe in early 2024.

DR LOVE: Are there other trials that we’re waiting on data from? Or we’re just waiting for the FDA to process this data?

DR MIKHAEL: There are other trials moving forward with this dosing. I do not believe it’s been submitted yet to the FDA. But my understanding is that hopefully that’ll happen in the near future so that we can use it soon thereafter.

DR LOVE: Great. Please continue.

DR MIKHAEL: So another I think important article that was published this year that I think is valuable to us. It was published by Cristina Gasparetto. Was using once-weekly selinexor with carfilzomib and dexamethasone.

Selinexor has really gone through an evolution over this last year, in 2 years. It used to be given twice-weekly with dexamethasone alone. Lots of challenges with nausea in particular, fatigue and anorexia. But now as we’ve used the drug at a lower dose in a once-weekly setting, it’s been much more tolerable and much more easily combined with other agents. And although the Phase III trial was with bortezomib, it was very attractive to do this study in combining with carfilzomib because carfilzomib, as we noted earlier in the IKEMA study, is a very attractive target — a very attractive agent to use in early relapse.

And so, here as you can see, the selinexor is given weekly. The carfilzomib is given weekly. They enrolled patients at different dose levels here from as high as initially 100 mg of selinexor down to as low 60 mg of selinexor. The Phase II dose going forward, as you can see here, is 80 mg of selinexor.

And when we look at the response rates, obviously there’s a lot of different data here, but really across the board we see consistent response rates in these generally speaking, heavily pretreated, although not having had carfilzomib before. And whether patients were triple-class exposed or not, we saw a strong signal of response across the board.

The duration of that response was also, and those who of course were responders, was just under 2 years at 22.7 months, with the median PFS being 15 months.

So my take on this is, this is critical to the evolution of selinexor. As we mentioned to now be paired with multiple agents. Because we’ve not historically always wanted to use bortezomib in the early relapse setting. It’s so much better tolerated now when we give it with 2 antinauseants, typically a 5HT3 antagonist and a drug like olanzapine that can help with some of the anorexia feeling that patients get with it. This is actually my favorite combination to use selinexor with carfilzomib. And particularly in patients with high-risk disease, just by virtue of the mechanism of p53 deletion, for example, or other high-risk abnormalities that we see, respond well to both carfilzomib and selinexor independently. And now perhaps more so together. And seeing a 15-month PFS in this group of patients I think is significant.

Then, of course, this is reflective of the Phase III study as I indicated of the BOSTON study, which did look at weekly selinexor starting at 100 mg with weekly bortezomib in the intervention arm. And the control arm being given twice-weekly, where there was, of course, that roughly 4-month or 4-1/2 month improvement in progression-free of the triplet combination.

There was an update this year in looking at patients that ha d had renal impairment because there were patients included in this study even with creatinine clearance of less than 40. And we did see a reduced PFS in these patients, but there was still the preserved benefit over Vd alone.

And so it’s not a surprise that, unfortunately, patients with renal insufficiency, at least of that degree below 40, tend to have inferior outcomes. But we saw the feasibility of giving this triplet to them and how it was still better than the doublet.

And thankfully, one of the other features we typically see with patients and renal impairment, not only do they have reduced efficacy, they have considerably more toxicity. We didn’t see as much toxicity. And so the similarity of the AEs is encouraging. And this can be a preferred regimen in those patients.

Chimeric Antigen Receptor T-Cell Therapy, Bispecific Antibodies and Other Novel Approaches for MM — Ajay K Nooka, MD, MPH

DR NOOKA: My name is Ajay Nooka. I’m a Professor in the Department of Hematology and Oncology at the Emory University Winship Cancer Institute.

The Year in Review, I’ll be discussing the chimeric antigen receptor therapy, the bispecific antibodies and other novel approaches in multiple myeloma.

First I’ll discuss the MRD-based study, the early and sustained undetectable MRD after receiving ide-cel and patients defined, a subset of myeloma patients in KarMMa that achieved prolonged survival. This abstract was presented by Bruno Paiva. So the background for this abstract is we all understand that MRD is prognostic for multiple myeloma. However, the MRD is a bone marrow-based technique. So there is a discordance between the responses that are seen in the bone marrow versus the serological responses.

So the MRD post-treatments, like CAR T, may not be the best surrogate, is the biggest, or the serological response is the best surrogate for the real optimal assessment of responses.

So with that background, there were questions that were asked whether the marrow-based MRD testing is optimal? If it is optimal, which is the best test? Whether it’s a next-generation sequencing or next-generation flow? And if any of these are prognostic or optimal, what is optimal timing of these MRD testing to give us the best prognostic impact of the long-term outcomes.

So, Paiva’s group evaluated the prognostic value of the depth of serological responses and MRD responses among these patients receiving CAR T-cells, specifically ide-cel from the KarMMa-2 trial. So MRD had a threshold of 10-6. Both techniques were analyzed at month 1, 3, 6 and 12 after ide-cel infusion.

As you’re aware, 156 patients were screened for the trial, 128 patients receive the CAR T treatment. And among these 128 patients, MRD testing was done at least on one time point for 125 patients.

The results were astonishing. There was significant concordance between NGF and NGS at each of these time points that were tested, 1, 3, 6 and 12, at the values at 67%, 75%, 82% and 73%, respectively.

This may not seem like a lot, but if you look at the discordant samples, those are all related to either a hemodiluted sample or an undetectable sample by the NGS.

So the CR responses at 1 month are 11% with NGS — with next-generation flow. At month 3, they escalated to 23%. And at month 6, there were 26%; at month 12 at 13%. So these numbers were significantly higher at the MRD depths at 10^-6 and 10^-5, going back to the question that we had, MRD-negativity in the bone marrow biopsy were seen at 41% at month 1, increased to 45% at month 3. At month 6, they were 35% and month 12 at 18% at threshold of 10^-6.

So what did this really mean? So, patients who are MRD-positive at 10-6 in 8 of the patients that were tested had a negative prognostic impact, they had decreased progression-free survival. So specifically looking at month 1, so whether the patients got a CR or less than a CR serologically, the median PFS did not matter. They had 8 months versus 11 months. These are not statistically significant. But if you look another way, patients were MRD-positive at 10-6 at month 1, had a median PFS of 2 months versus those patients who were MRD-negative, their PFS was 11.5 months.

So as we went on with further months at 3, 6, 12, so those patients that had MRD-negative and those achieved — that garnered a CR had the longest progression-free survival reported.

So there was another piece of information that was shown by Paiva’s group about the reappearance of normal cells. So the normal plasma cells, if they’re reappearing post-CAR T, suggesting a loss of the copies of persistence or the copies of functionality and could this be used as a biomarker for us to see who are the patients that would be achieving long-term benefits or not achieving those long-term benefits. So they were able to show that the reappearance of normal plasma cells suggested inferior PFS. And the appearance of normal plasma cells, even among patients who are MRD-negative were able to show that inferior PFS.

So now the absence of normal plasma cells and MRD-negative group are the ones that had the best progression-free survival.

So to conclude, the NGS and the NGF have higher degrees of concordance. The MRD-positivity at 1 month is an early prognostic marker for PFS, not a serological response. And those patients who have achieved greater than a CR and MRD-negative to 10-6 at 12 months are prognostic for improved PFS.

So, again, the reappearance of normal plasma cells could suggest a negative impact on the long-term PFS. And early and sustained MRD-negative patients had improved PFS.

DR LOVE: Just a couple of clarifying questions. The reappearance of normal plasma cells, is that just the histologic visualization in the marrow?

DR NOOKA: So great question. It is a flow-based normal plasma cells. So it is a next-generation flow-based normal plasma cells when they’re reappearing.

DR LOVE: I mean it makes a lot of sense. And I don’t know, maybe it’s been reported a lot. I just missed it. But is this something that’s been looked at a lot, the reappearance? I mean it makes sense, but has it been reported a lot?

DR NOOKA: This is the first time it is being reported.

DR LOVE: That’s what I thought.

DR NOOKA: We all physiologically thought that that is not a good sign. But this is the first ever time that they’re able to show the reappearance of normal plasma cells identified under NGF is a bad prognostic marker.

DR LOVE: Really interesting. The other thing I wanted to ask you is, when you started out talking about this, I wasn’t sure whether there was some kind of theoretical concern that because of the way that CAR T works, in some way would interfere with the assay or something? Is that the case?

DR NOOKA: That’s not. So the lymphodepleting therapy and the copy, we are able to ablate the marrow very quickly. But the serological responses are the ones that typically take longer because there is a half-life of the antibody that needed to be cleared from the serum. So, historically, if you look at the bone marrow and assess the MRD-negativity, this is not the case. So that is the main reason for this discordance of hey, you’re seeing MRD-negativity in the marrow, so could this be the real prognostic factor or should we be looking at MRD-negativity in the marrow? And what Bruno’s group was able to show was achieving an MRD-negativity is not a big deal, but patients who are MRD-positive were the ones that had the poorest outcome.

So this is the next paper, the topline results for KarMMa-3 trial showing ide-cel significantly improves PFS versus standard regimens in relapsed/refractory multiple myeloma.

So what’s ide-cel? Ide-cel is a BCMA-targeting CAR T that has an extracellular single chain variable fragment with one heavy chain and one light chain targeting a single epitope of the BCMA.

So ide-cel for the treatment of relapsed/refractory multiple myeloma, is approved in 2021 by the US FDA for the treatment of adult patients with relapsed/refractory multiple myeloma after they had received more than or equal to 4 prior lines of therapy, including a PI, IMiD and an anti-CD38 antibody. So this is based on — this approval was based on the KarMMa-1 trial.

So, now that we have an approval, and just like how we saw the drug development in multiple myeloma, when a drug is approved in the later lines of therapy, you really want to show the efficacy in the earlier lines of therapy and that’s what KarMMa-3 trial had done. KarMMA-3 is a Phase III, global, randomized, multicenter trial evaluating ide-cel compared to the standard of care options in adult patients in relapsed/refractory multiple myeloma after 2 to 4 prior lines of therapy and refractory to the last regimen.

So the randomization was given 2:1 to received ide-cel versus standard of care. And the standard of care could be any 1 of the 5 regimens including daratumumab, pomalidomide and dexamethasone, daratumumab/bortezomib/dexamethasone, ixazomib/lenalidomide/dexamethasone, carfilzomib and dexamethasone, or elotuzumab/pomalidomide and dexamethasone.

So the primary endpoint for the trial is progression-free survival. And we received a press release that KarMMa-3 met its primary endpoint, demonstrating a statistically significant improvement in the PFS favoring the ide-cel CAR T. Again, the press release clearly shows that the safety results in the trial were consistent with the well-established and predictable safety profile of ide-cel.

And clinically, what the relevance of this specific study is we’re able to show for the first ever time if the CAR T has moved to earlier lines of therapy, it was able to show better outcomes compared to the standard of care options.

So the next one is cilta-cel, an anti-BCMA CAR T therapy for relapsed/refractory multiple myeloma. And cilta-cel, as opposed to ide-cel, is a differentiated CAR T therapy. It has 2 BCMA-targeting single-domain antibodies to confer avidity.

So, this was approved by the US FDA in 2022 for the treatment of adult patients with relapsed/refractory multiple myeloma, who had seen more than 4 prior lines of therapy, including a PI, IMiD and an anti-CD38 monoclonal antibody. This was based on the CARTITUDE-1 trial, which was a Phase Ib/II study.

So what Dr Martin’s group was able to do was to update the results of 2 years after the last patient in, with a median follow-up of 27 to 28 months. This was reported in the Journal of Clinical Oncology. It also included the high-risk patients subgroups. And what they were able to show was more than two thirds of the patients, 66 of the 97 patients, remained on the study.

Impressive response rates. Overall response rate of 98%, stringent complete response rates in 4 of the 5 people that were treated, with 82.5%. The median PFS, duration of response, not reached beyond the 2-year mark. The 27-month PFS rates and overall survival rates were 54.9% and 70.4%, respectively.

This is a group of patients who had seen 6 prior lines of therapy. And at 2-year mark, 70% of the patients were alive. So very impressive results for this group.

So if you look at the depths of responses of the 61 patients that had the evaluable samples of MRD at 10^-5 threshold, 91% achieved MRD-negativity, and this was sustained beyond the 6-month mark.

Here, the median time to response was very quick at 1.2 months. And what they were also able to show was the long-term safety profile from a hematological safety profile, Grade 3 or Grade 4 thrombocytopenia occurred in 2 out of 3 patients, that’s 60 patients. But these recovered to Grade 2 by day 30, and 60% of the patients recovered by day 60. So similarly, neutropenia, 90% of the patients recovered by day 60. And for lymphopenia, 90% of the patients recovered by day 60.

So whenever we’re using lymphodepletion therapy like fludarabine and cyclophosphamide, we always have a concern for the secondary primary malignancies. So at the 2-year mark, they reported 20 secondary primary malignancies in 16 patients; 9 had hematological secondary primary malignancies, 1 with low-grade lymphoma, 6 with MDS, and 4 cases with AML. And 11 had solid tumors of different kinds.

So the study also shows the long-term safety there was no further CRS beyond the 12-month mark. There was 1 case of Parkinsonism at day 914. This is close to the 3-year mark. And this is the patient that neurotoxicity while the patient was receiving CAR T. Don’t know about their attribution, whether this is related to CAR T.

So how does it change the clinical practice? This is transformative. As you are able to see, these patients, based on the MAMMOTH trial, based on the LocoMMotion trial, should have a lifespan of less than a year. However, this CAR T was able to show that at the 2-year mark, 70% of these patients are alive, which clearly shows the benefit of these treatments.

There are other ongoing treatments in the earlier lines to show the benefit of cilta-cel in the early relapsed patient population.

DR LOVE: So a couple of things. The second primary cancer seems kind of high. What was the take on that?

DR NOOKA: So patients had received a lot of prior lines of therapy and the majority of these patients have received a prior alkylating therapy. The majority of these patients had a prior transplant. So in such case, there is a signal that was seen, when patients are living longer, when the patients are receiving more treatments that potentially put them at a higher risk for therapy-related MDS and AML, you’re able to see these high SPMs in this patient population. Would this surprise me? This does surprise me that the rate is high. But in reality, these patients have received a lot of prior lines of therapy.

DR LOVE: Another question. If a patient gets an induction regimen like RVd, then they go to transplant, and then they go to maintenance, len maintenance, is that considered 1 prior therapy or 3?

DR NOOKA: It’s considered 1 prior line of therapy. So that’s one of the ongoing hard topics that we have this point of time. In 2 or 3 prior lines of therapy, you may have used all the agents that are existing out there. The indication of having more than or equal to 4 prior lines of therapy, does it really serve the purpose or serve the need of the patients is the biggest question that we have. And in my opinion, it should not be considered as early lines of therapy, even though they consider 3 — 1 line of therapy with 3 different agents that were given, these are 3 different agents given and in the indication should reflect on that.

DR LOVE: Do you think that makes sense to have the indication of simply PI, IMiD and anti-CD38-refaractory, period?

DR NOOKA: I agree, that should be the indication because that’s the patient population with the unmet need.

DR LOVE: Okay. Please continue.

DR NOOKA: So, number one, we had seen the results from the KarMMa-3 trial which was reviewed in the early relapse setting. So we also saw at the same time the CARTITUDE-1 trial showing the benefit of cilta-cel in the late relapse setting. And clearly, the avidity of the cilta-cel and the higher responses, make it a very promising drug.

Now, what this trial was clearly sowing presented by Einsele’s group, was look at the biological correlative analyses and the clinical data with CAR T among lenalidomide-refractory patients with multiple myeloma after 1 to 3 prior lines of therapy. This is Cohort A, a Cohort of CARTITUDE-2 trial. This was presented at ASCO 2022.

So Cohort A consisted of patients who are len-refractory with 1 to 3 prior lines of therapy. There are 20 patients. And this group is enriched for these high-risk patients. So, number one, 5 of these 20 patients had translocation 14;16, and 3 of these 20 patients had deletion 17p. So this is a group that is enriched for all these high-risk patients.

So Cohort A looked for the efficacy and safety, along with other markers, the T-cell and the cytokine analysis as well. So the patients are younger, median age is 60. Median time to response was 1 month. And as in the spirit from the CARTITUDE-1 trial, you’re seeing an overall response rate of 95%. The stringent complete response rate seen in 17 of these 20 patients with 85%. Except 1 patient, everybody got a VGPR, at least a VGPR.

What’s very impressive here is the MRD-negative rates at 100%, 16 of the 16 patients had an MRD-negative rate.

So we have to look at the patient population much more closely. These are early relapsed patients, that means patients with 1 to 3 prior lines of therapy. And you’re seeing Grade 3 and 4 cytopenias, not returning to baseline. And only 20% of the patients and 15% of the patients with thrombocytopenia did not return to baseline, and 5% for the lymphopenia.

Very happy from a safety profile, from a hematological profile.

From a CRS perspective, 95% of these patients had CRS. Grade 3 and 4 were seen in only 10%. And the median time to onset was 7 days, similar to what we saw with cilta-cel in CARTITUDE-1 as well. So ICANS were seen in 15% of the patients. And Grade 2 was seen in only 5%.

So, we talked about this in the early line of therapy. So, the 2 deaths from the disease progression does not surprise me because this is a very, very high-risk patient population. It is difficult to maintain that duration.

What is probably preventable are the 2 deaths, 1 from sepsis and 1 from COVID that occurred among the patients that were on as a part of this study. So, those are almost 10% of the patients where the death could have been prevented.

So, when you look at the biological correlates, in the early relapse patients who are len-refractory, the CAR T peak expansion happened at day 11, and the median persistence happened all the way until the 5-month mark.

So if you look at the pro-inflammatory cytokines, like IL-6, IFN-gamma, the ILT-R-alpha and IL-10, it peaked at the 1- to 2-week mark and they returned to baseline in 2 to 3 months. And these correlated with the severity of the CRS as well. So there was increased CD4 to CD8 ratio was associated with CRS and ICANS severity as well.

And they did not find any association of the CD8 plus enrichment with response at the peak CAR T expansion, probably because everybody got a response. There is nothing to compare with.

So, now how these results translate into clinical practice? These results support the evaluation of cilta-cel as earlier lines of therapy. This cohort did really, really well despite enrichment of all the high-risk patients like we talked about without any unexpected adverse events.

And the deaths that we talked about, including the COVID death as well as the sepsis death, really emphasize the need for using infectious prophylaxis. And the duration of this infectious prophylaxis needs to be very well described in many of these CAR T trials.

So there are ongoing Phase III trials, the CARTITUDE-4 comparing cilta-cel to standard of care regimens, pomalidomide/bortezomib/dexamethasone or daratumumab/pomalidomide and dexamethasone.

So the next one is the clinical activity of BMS-986393. This is a GPRC5D-targeting CAR T in patients with relapsed/refractory multiple myeloma. These are results presented by Susan Bal from UAB. And these are the first results from the Phase I, multicentered, open-label study. These results were in fact presented by the last author, Jesús Berdeja.

So GPRC5D is an orphan receptor that’s expressed on the myeloma cells. And it does not have much of an expression on normal cells. And it really serves as a promising therapy to target.

So, previously, the MCARH109, is a CAR T therapy that was published in The New England Journal of Medicine, showed that it has initial safety and promising — safety and efficacy results.

So the interim results from the dose escalation of study, where 33 patients were enrolled, is currently presented. Patients were younger, median age of 63, 4 prior lines of therapy. Half of the patients had high-risk disease. And most importantly, 54% had prior BCMA-directed therapy. This is very important right now in this space where we have a lot of BCMA-directed therapies, where what happens in the BCMA-refractory patient is an ongoing hard question.

So 5 cohorts were evaluated. The primary endpoint was to look for the maximum tolerated dose and the recommended Phase II dosing. The cohorts started with 25 million CAR T-cells, the second one is 75 million CAR T-cells. We had a third cohort at 150, fourth at 300 million cohort, and the fifth one at 450 million cohort.

There was one DLT. This was very prolonged, Grade 4 neutropenia — there were 2 DLTs, prolonged neutropenia. There were 2 DLTs, DLTs of prolonged duration of Grade 4 neutropenia and thrombocytopenia in 2 patients. And MTD has not been reached.

So similar to expected CRS, CRS was seen in 63% of the patients. The majority had a low grade. And mostly occurred with the higher CAR T dosing at 300 million or about.

Again, ICANS Grade 1-2 were seen in 6% of the patients. And there were unique toxicities that are specific to this target, the GPRC5D expressed in the keratinized tissues. So you’re seeing the skin toxicity in 30% of the patients, dysgeusia, which is altered taste, seen in 15% of the patients. Nail changes seen in 9% of the patients. So, what is very impressive is about the dosing of 300 million cells, almost 100% of the patients achieved a response. But if you look at overall response rate across all cohorts among these 19 patients that were evaluated, 90% overall response rate.

So what I’m interested more is the prior BMCA-exposed cohort where there were 9 patients of these 19 achieved an overall response rate of close to 80% and half of those are complete response rates. Very impressive data.

This is a promising drug, demonstrated safety profile across all the dosing that were tested. And the dose escalation is ongoing. And BMS-986393 had promising efficacy even among the BMCA-exposed patients.

So the expansion in Part B is on the way to define the recommended Phase II dosing.

DR LOVE: Am I correct in saying there’s also a bispecific with this same target?

DR NOOKA: That is correct. So there is a GPRC5D bispecific that is called talquetamab and there is a second one as well.

DR LOVE: Interesting. Please continue.

DR NOOKA: So teclistamab in relapsed/refractory multiple myeloma. Teclistamab is a bispecific antibody that targets BCMA and CD3. It recently received an approval for treatment in the United States, based on the Phase I/II MajesTEC-1 trial. There were 165 patients that were treated — that were enrolled in this trial. These are highly pretreated patients who have received more than 5 prior lines of therapy, 26% had high-risk disease. And the treatment is given as a weekly subcutaneous injection.

So, to start with, patients would receive a priming dose at 0.66 mg/kg. There is a second priming dose given at 0.3 mg/kg before the patients receive a targeted dose of 1.5 mg/kg. And the response rates across all cohorts was with an overall response rate of 63% and more than complete response rate was seen in close to 40% of the patients. Forty-four patients were found to have MRD-negativity, but if you look at those patients that achieved a CR, MRD-negativity 10^-6 was seen in close to half of them.

Very quick response. Median time to response was 1.2 months. The median PFS was 11.3 months. And those patients that achieved a response have a remission of a long, durable response. Among those patients that achieved a response, the median duration of response was 18.4 months.

So if you look at the CRS, all-grade toxicity with CRS was seen in 72%. But if you look specifically at the Grade 3 toxicity, there’s only 1 patient that had Grade 3 toxicity. And it’s counted at 0.6%.

Neurotoxic events, all grades, were seen in 14%. But ICANS was only seen in 3% of the patients. Again, all Grade 1 or 2.

So, bispecific antibodies given weekly with teclistamab resulted in neutropenia, all-grade of 70.9%, and Grade 3-4 were seen in 64.2%. Anemia, Grade 3-4 in 37%. And thrombocytopenia, Grade 4 in 1 of the 5 patients, it’s 20%.

So what I’d like to emphasizes is the infection rates. Infection rates are significantly higher. All-grade infections were seen in 3 out of the 4 patients that were treated with this drug. And Grade 3-4 toxicities were seen in half of the patients. So, fully understanding that teclistamab is a first-in-class BCMA-directed bispecific antibody that was approved for the treatment of triple-class exposed or refractory multiple myeloma, who had seen 4 prior lines of therapy, including a PI, IMiD and a CD38 antibody. We clearly need better infectious prophylaxis to be defined for this patient population.

So, given the risks of the CRS, a REMS program, a risk mitigation program, has been established for CRS and neurotoxicity monitoring where the patients have to be hospitalized for 48 hours after receiving the first priming dose, the second priming dose and the target dose for teclistamab.

So the next one is teclistamab in combination with subcutaneous daratumumab and lenalidomide in patients with multiple myeloma. These are the results from a cohort of MajesTEC-2 study, which is a Phase Ib, multicohort study going on.

So, just like how we talked about, teclistamab is approved for treatment of relapsed/refractory multiple myeloma patients who have received more than 4 prior lines of therapy. So, now in this specific study, tec is in combination with dara and len in a Phase Ib study at a weekly dosing of tec evaluated at 0.72 mg/kg and the second dose of 1.5 mg/kg in combination with dara of 1800 mg and len of 25 mg. So a total of 32 patients received those drugs. And of these 13, received the 0.72 mg/kg and 19 received the 1.5 mg/kg. Median age of the patients was 62. They’re young. These are early relapse patients. Prior lines of therapy were 2. And a third of the patients were anti-CD38 antibody exposed.

Here, the most frequent adverse events were the CRS seen in 80%. All of these are Grade 1 or 2. These all resolved. There’s no ICANS that were seen. Similar to what we had seen with the prior teclistamab experience, you see a lot of hematological toxicity: neutropenia, anemia, thrombocytopenia. Neutropenia was seen at Grade 3 and 4 in 68%. Febrile neutropenia was seen in 12%.

Again, from an infectious perspective, the same thing that we saw with teclistamab, infection occurred in 75% of the patients. Here Grade 3 or 4 infections seen in 28%.

So there is 1 patient that died due to COVID. And when you look at the overall response rate, 13 out of 13 evaluable patients had 0.72 mg/kg and 13 of the 16 evaluable patients at 1.5 mg/kg, all of these had responses.

So, there was good biological correlative data with tec/dara/len treatment leading to the enhancement of these proinflammatory cytokines and the T-cell activation.

So, clearly, the tec combinations have shown that the rates of infection are much, much higher. There is a clear possibility for us to evaluate alternate dosing strategy or alternate schedule strategy to minimize these risks of infections.

The next one is Anita D’Souza’s paper on the ABBV-383. This is another BCMA-directed bispecific antibody. And clearly, the study evaluating the safety and outcomes of the Phase I dose escalation and dose expansion study.

So contrary to what we heard about teclistamab given on a weekly basis, in this study, the drug ABBV-383 was given once every 3 weeks. There is not a step-up dosing. And this is a 3 + 3 design.

So a total of 124 patients, 73 in the escalation phase and 51 in the expansion phase, have received ABBV-383. So, what you see, compared to the other BCMA-directed treatment that was approved, teclistamab, you’re able to see there’s neutropenias, anemias and fatigue, all grades to be much lower. So this is half as much as you expect. And it also impacted the overall response rate at 10% lesser than what you would expect. Here the overall response rate if 57%, VGPR rates were 43%. And this, to me, is clearly saying, as a lesser dose with a better dosing schedule given every 3 weeks, is able to deliver us the benefits without causing a lot of hematological toxicity.

So at 60 mg in the 49 patients, you’re able to see that the responses to the VGPR rates of 59% — and the VGPR rates of 39% and the overall response rates of 59%. And the 60 mg expansion phase in the 49 patients, the overall response rate was 59% and greater than VPGR rate was 39%. Among those patients that received more than 40 mg, that means 40 mg or 60 mg, in a total of 79 patients, the overall response rate was 68% and the VGPR rates were 54%. These were similar to the teclistamab dosings.

Pete Vorhees presented the same exact compound, ABBV-383, in this cohort of patients who had 40 mg escalation and 60 mg escalation and expansion at ASH of 2022.

Again, as I alluded to before, the drug was administered every 3 weeks IV, and you’re able to see overall response rates at 40 mg in 83% of the patients, with greater than CR rates in 67% — greater than VGPR rates in 83%. These rates at 60 mg were 60% overall response rate. and greater than CR seen in 29% and greater than VGPR see in 43%.

So, the 40 mg expansion with an “n” of 42 was presented at ASH 2022.

The third one, which is alnuctamab, which is another BCMA-targeting bispecific antibody. This is BMS-986349, which used to be given IV. So alnuctamab used to be given IV in the past, and unfortunately was associated with very high rates of CRS. Any grade CRS was seen in 89%. Even though the Grade 3 or about, were seen in 5%, this led them to explore a subcutaneous formulation. This subcutaneous formulation was the one that was presented at ASH of 2022.

SubQ alnuctamab was given on days 1, 4, 8, 15 and 22 of cycle 1, q weekly in cycle 2 and cycle 3, q2weekly in cycles 4 to 6. And beyond cycle 7, patients would receive it q4wk. So 2 step-up doses, 3 mg on cycle 1, day 1 and 6 mg on cycle 1, day 4. And beyond cycle 1, day 8, there is a 10 mg target dose or higher were explored.

So, overall, there are 47 patients that received subcutaneous alnuctamab. Overall response rate was 51% across all dosing regimens. And 77% in patients that received a target dose of greater than 30 mg. So, similar to the others that we had seen, any-grade toxicities with the CRS were 53%. There were no Grade 3 or 4 toxicities that were seen with the CRS. And neutropenia, Grade 3 and 4, were seen in 30% and in any grade/Grade 3 or 4 was seen in 17% of the patients.

So with this specific compound, the subcutaneous administration definitely widen the therapeutic index and improved the safety profile compared with the IV formulation. And CRS was all limited to Grade 1 or 2 events. Even with IV formulation, Grade 3 events were seen in 5% of the patients. Here the number was 0.

So high numbers of MRD response rates. Again, this is another BCMA-directed option without much novelty — there are 2 other existing compounds there that we talked about. But what we’d seen from the long-term data from the ongoing cohort suggested that there’s a prolonged PFS, this is close to 36 months, the highest reported for any BCMA. There were no unexpected toxicities that were seen, including ICANS. So if you’re trying to choose which is the best one existing out there, we still don’t have an answer, but the jury’s out there.

Talquetamab, a GPRC5D CD3 bispecific antibody in patients with relapsed/refractory multiple myeloma. The Phase I/II results from the MonumenTAL-1 study was presented at ASH of 2022.

This is a bispecific antibody that targets an alternate target other than BCMA. This is GPRC5D, as we alluded to before. In the Phase I/II MonumenTAL-1 trial, there were a total of 288 heavily pretreated patients. These patients had 5 prior lines of therapy, 60% of the patients had high-risk disease. And had treatment with 2 doses, 1 is a weekly dose a 0.405 mg/kg subcutaneously weekly and an every other-week dose at .8 mg/kg subcutaneous every other week.

So response rates were 74% with weekly dosing and 73% with q other week dosing. Similarly, there was no difference in the greater than CR rates or the VGPR rates showing the safety or the efficacy of these 2 regimens or the 2 dosing schedules to be quite similar.

So in the 51 patients of these 288 patients, which this cohort comprised a fourth of the patient population, the overall response rates seen were 10% lesser. So this was rated at 62.7%, providing an option for post-BCMA patients. The median time to response here is again very quick, 1.2 months. And the median PFS reported was 7.5 months with a median duration of response of 9.2 months with q weekly dosing and 13 months with q other week dosing.

So, here the Grade 3-4 anemia was close to 30%. Neutropenia close to 30% and lymphopenia close to 25%.

Infections occurred in 57% of the patients at 0.4 mg/kg weekly dose. And the Grade 3-4 toxicities were seen in only 17% and 12%. So, very clearly you’re seeing a significant decrease in the higher grade infections with an alternated target than BCMA.

So, one toxicity that we talked about, which is unique and related to GPRC5D, was the skin and the nail toxicity and the dysgeusia, the altered taste. And these had very low grade and clearly manageable with a lot of supportive care.

CRS is low and it’s low grade and it is only confined to the first dose. And if you look at all the patients, all the 288 patients that were treated, less than 5% of the patients discontinued treatment due to an adverse event.

So now, what’s the take-home message for this specific compound? Compared to any other BCMA-targeting strategies is the significantly low rates of high-grade infections. And it makes it a feasible approach for patients who are heavily refractory and heavily pretreated.

So the next one is presented by Nizar Bahlis’ group. This is an updated safety and efficacy analysis of venetoclax plus daratumumab and dexamethasone in an expansion cohort, a Phase I/II study of patients with translocation 11;14 relapsed/refractory multiple myeloma.

So venetoclax is a Bcl-2 inhibitor. And in this specific study, it’s a 3-part study -- the part 3 evaluated venetoclax with daratumumab and dexamethasone with venetoclax at 2 doses, 400 mg daily and 800 mg daily. And a third cohort is almost like a comparator cohort with daratumumab/brentuximab/dexamethasone. These are all patients with translocation 11;14. And the overall response rates seen with daratumumab, with venetoclax at 400 mg, and dex, you’re able to see an overall response rate of 72.7%. And the dose is increased to 800 mg, you’re able to see the response rate at 100% compared to a similar patient population who received an approved combination of daratumumab/bortezomib/dexamethasone, you’re seeing a response rate of 31%.

So at ASH, the results were presented, which included 21 patients that received the 400 mg of ven dose, 10 patients that received the 800 mg of ven dose, and 24 patients that received dara/bortezomib and dexamethasone.

So again, the overall response rates were 95% and 100% with the venetoclax combinations. The VGPR rates at 86% and 100%. And the 24-month PFS rate is amazing at 94% of the patients and 83% of the patients not progressing at the 2-year mark.

The overall response rate for the combined venetoclax and dexamethasone and dara arms was 98%.

Here, the most common adverse events are not hematological, as you can see. The non-hematological side effects are insomnia, fatigue and diarrhea.

So in clinical practice, who do we offer this to? So this is a better biomarker defined strategy. If there’s a patient with translocation 11;14, this study provides a good safety established in combination with venetoclax, daratumumab and dexamethasone.

Next one is iberdomide plus dexamethasone in heavily pretreated late-line relapsed or refractory multiple myeloma patients.

So this was presented in Lancet Hematology. So to bring to the background, iberdomide is a novel cereblon E3 ligase modulator. We call them the CELMoDs. And it has 20 times more binding affinity to cereblon compared to the regular IMiDs and it has enhanced tumoricidal and immune-stimulatory effects.

In the CC-220-MM-001 trial, patients received escalating doses of oral iberdomide all the way from 0.3 mg to 1.6 mg on days 1 to 21 every 28-day cycle. This is similar to how we administered the IMiDs. And oral dexamethasone at 40 mg per week was administered as well.

So of more than 400 patients that were screened, a total of 197 patients received the dosing, 90 patients in the dose escalation cohort and 107 patients in the dose expansion cohort. The dose expansion cohort happened at the recommend Phase II dosing of 1.6 mg.

Median age of the patients was 65. Again, these are heavily refractory patients population. Patients had more than 5 to 6 prior lines of therapy. Overall response rate was seen in 32%.

To give it context, the approved agents in the same space, belantamab as well as selinexor, both had an overall response rate of 32%. Median PFS of 3 months and a median duration of 7 months.

Safety. So, mostly similar to what you see with the IMiDs, these are hematological and infection domain. A common theme as well.

So these are well tolerable oral agents and more likely to be used in combinations that single agents as the mechanism of CELMoDs is highly different than what you see with the other anti-myeloma agents. And as long as we don’t have overlapping toxicities, these could serve as good additive agents or synergistic agents.

The next one is by Paul Richardson’s group. This is mezigdomide, this is a next-generation CELMoD. So here this is CC-92480. This is a potent, novel cereblon E3 ligase modulator, combined with dexamethasone in patients with relapsed/refractory MM.

So mezigdomide, similar to iberdomide, as we talked about, has much more affinity to cereblon, and degrades the Ikaros and Aiolos, transcription factors, much more efficiently leading to the myeloma cell kill.

So in the Phase I/II trial, evaluating mezigdomide alone or in combination with dex, the recommended Phase II dosing of mezi was at 1 mg daily, similar to the dosing schedule of the IMiDs or iberdomide, at days 1 to 21 every 28 days.

A total of 101 patients were evaluated at mezi and dex. Median age is 67. A third of the patients had high-risk cytogenetics and the median prior lines of therapy at 6.

Overall response rate here is 39.6%. And median PFS was 4.6 months, median duration of response was 8.3 months.

So, again, these are options for combinations again as well. And given that we have a lot of bispecific antibodies targeting BCMA, CAR Ts targeting BCMA and alternate targets, the AE profile is likely to be safe with the combinations. And having an oral administration makes it much more convenient for both of these CELMoDs.

The hematological toxicities and the neutropenias are seen in this patient population. But if you look at the way of drug development in myeloma, if you move them to earlier lines of therapy probably the patients that have much more of a marrow reserve and we may not see the same kind of the cytopenias in those patient populations.

So again, in the clinical space, where would I fit them? A good option is post-CAR T as maintenance as well, as we move forward to earlier lines of therapy.

So one other thing that was clearly evident here is all the bispecific agents targeting BCMA, if you look at the subsets of patients who do not respond, the extramedullary disease patients are the ones that have the least kind of a response. And in this specific study, you’re able to see extramedullary disease patients have a response rate of 31%.

So the combination of an agent like this to a bispecific antibody would probably enhance those rates significantly and potentially could be used in these combinations in the future.

DR LOVE: That was great. Wow, that’s really a lot of great, new stuff. Just one final question. I want to ask you, right now if you have a patient that know — two things.

This came up, we did a symposium last week, Sagar was part of it, at ASH. And somebody said something and I didn’t pursue it but I wasn’t clear what they were saying, the idea that translocations are drivers. You don’t see more than 1 translocation? Is that right?

DR NOOKA: So the likelihood of having more translocations at the same time is very, very minimal. But do we see patients with translocation 4;14 and deletion 17? Yes, we see those are normalities together, but you don’t see the translocation of 4;14 and 11;14 happening at the same time.

DR LOVE: Hmm. Because we had a case where that was seen. Is that usually a lab error or something?

DR NOOKA: Not necessarily. These patients could have multiple translocation, but it’s not the most common thing that you see. These are early events, not acquired events.

DR LOVE: Okay. The other question I had is, just out of curiosity, if you have a patient who comes in today and you know upfront they have t(11;14) translocation, in what line of therapy are you likely to use venetoclax and with which regimen? Both on protocol and off protocol?

DR NOOKA: So as an institution, we’re very biased because we are basic scientists that really help to define the treatment among these patients. So my typical practice is, if they have early relapse disease, even after the first line of treatment, if they have translocation 11;14, I tend to use a venetoclax-based regimen.

DR LOVE: Which one.

DR NOOKA: Yeah, venetoclax and dexamethasone as a combination certainly will be my first choice. But there is more and more data that is coming in with venetoclax and dexamethasone in combination with a PI. And venetoclax and dexamethasone in combination with daratumumab, as you’ve seen previously.

So my choice would be a PI at this point of time.

DR LOVE: Really, the reason I ask is I thought that the daratumumab idea was pretty cool and the data looked good, but you don’t think there’s enough data yet to use that?

DR NOOKA: So the biggest challenge that I have when I’m using a regimen like this is, I’m always looking for the next line of regimen, trying to look for what is the best combo for dara. So if I’m using pomalidomide and daratumumab as a next line of treatment, I always have a backup plan.