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I know that’s a bit of a data dump there, so I’m going to pause for a minute and turn to my colleagues in our last 10 minutes and say, what do you think of this? Do you see much of a difference, frankly, between isatuximab, carfilzomib, dexamethasone [Isa-Kd] vs daratumumab, carfilzomib, dexamethasone [DKd]? What is your sentiment? Why might you choose one over the other? I’ll start with you, Sikander.

Sure. When I look at these data, the thing that stands out to me is the median follow-up. To me, that is impressive, a 44-month follow-up and results standing out with that doubling of the PFS [progression-free survival]. Of course, when we look at these trials, there will always be questions. Why did Kd [carfilzomib, dexamethasone] behave one way in one study and the other way in the other study? Those kinds of things happen, that’s why rather than making cross-trial comparisons, to me, the long follow-up is very impressive. I think that somehow stands out to me when I look at all these studies and compare all these, or look through all these data.

I look at them and say there’s 5 months lower PFS in the CANDOR study than in the IKEMA study, so let’s add 5 months to the PFS for the daratumumab arm, and they look pretty similar to me. I don’t know, maybe I’m wrong, maybe there’s a difference, but I would say that these drugs are pretty equivalent in my head.

That’s a good point because that’s one of our questions in the question boxes, are they pretty much interchangeable? I think there is a bit of a different target, there are differences, but I would suggest that they are very similar. We did a study where we gave isatuximab immediately after daratumumab progression, and there really was no response rate. So I think one of the important messages is, interchangeable or not, I wouldn’t think that one overcomes immediately the resistance of the other, so try not to sequence them one after the other.

I think a lot of times people’s choice is based on, right now, we can give daratumumab subcutaneously, and we have to give isatuximab IV [intravenously]. Daratumumab is given a little more intensely for the first few months, weekly for 8 weeks, whereas isatuximab is given weekly for 4 weeks. But in the long run, isatuximab is given every other week, as opposed to ultimately going down to once a month with daratumumab. So, there are some subtle differences, sometimes financial considerations, etc. But it’s hard for me to conclude that there’s a massive difference between the two. I don’t know, Elisabet, what’s your take on that?

I think that overall, I agree with what you all are saying. Just the caveat on the subanalysis of the IKEMA study with chromosomal abnormalities showing there’s a big benefit for these patients with isatuximab. So, with this patient with a chromosomal abnormality, I may go with isatuximab, especially also carfilzomib is given IV. It’s not so difficult, the patients already have an IV, and they have to get carfilzomib anyway. I would agree with the approach, the treatment of this patient with isatuximab. I would agree, usually a patient like this could get an IV with this regimen. But yes, I think that the choice of using one agent or the other is very setting specific and depends on several considerations, which you have mentioned very well, Joe, already.

I can’t resist saying that they’re both very good, 44 months. They are both excellent.

Yes, to go over 3 years in the relapsed setting is unprecedented, really. To think a few years ago, we were wishing for 3 years at frontline therapy, let alone at relapse, so thanks, Keith, for the caveat there. A couple more questions before we wrap up, and some other ones are coming in. someone asked an interesting question, that Sikander, I’ll ask you to answer quickly. When do you choose DRd [daratumumab, lenalidomide, dexamethasone] vs VRd [bortezomib, lenalidomide, dexamethasone] in patients not going to transplant? Do you have a strategy there?

I don’t think I have a very specific strategy. I present the data to the patient, risk categories, high risk, proteasome inhibitors, those kinds of thoughts come to mind. But that is exactly the clinical trial that’s going to be starting very soon through cooperative groups, which should be hopefully going live this month. That is comparing DRd vs VRd-lite, and then the maintenance would be either DR [daratumumab, lenalidomide] or R [lenalidomide] as a single agent. Exactly trying to answer that question of which of the two is superior, because both of them have shown overall survival benefit. The caveat being that we end up using VRd-lite in those patients, and the SWOG S0777 trial’s overall survival benefit was with regular VRd. So, there are some caveats there, but hopefully, this forthcoming study will help clarify that a little better.

I love that you used it as a commercial for the trial. Well done, certainly good. Let’s look at this patient, what if the patient hadn’t had VRd? Keith, let’s say the patient had DVRd [daratumumab, bortezomib, lenalidomide, dexamethasone]. Would your thoughts have been any different in the relapse? What if they were on DR maintenance? Or what if they were just on R maintenance? Would that have influenced your choice?

 If they’d had daratumumab up front, and they stopped it and progressed off of it, I would use it again. If they’re still on it, obviously, we’re not going to use that. If they’ve gone through daratumumab therapy and are now relapsing, we’re looking at a carfilzomib-based regimen, most likely I’m increasingly looking to the T-cell engagers on clinical trials for this kind of a patient at this stage.

Excellent, really well said. I think your point is well taken, that if someone had had daratumumab but is not currently progressing on it, it may be reasonable to introduce the CD38 inhibitor, but not going from one CD38 inhibitor to another.

To close off as we come toward the end, and Keith, you just indicated, it was a perfect segue. Do we think that bispecific antibodies and CAR [chimeric antigen receptor] T-cell therapy, which are now approved much later in the disease course, Elisabet, do you feel that they’re coming earlier? Do you feel that we’re going to be doing those in early relapse in the near future?

I think so, I don’t know if everybody would agree. But there are certainly clinical trials being planned, being done in early relapse for bispecifics. And even for maintenance, for treatment of first relapse, from negative MRD [minimal residual disease] to positive MRD. There is a lot of research ongoing in this area; I am looking forward to seeing the results. But I do think there is an opportunity to use certain bispecifics. Even here, for example, the slide is mentioning teclistamab. But even some of the newer bispecifics that we’re seeing with newer targets, it seems plausible that those would also move forward in earlier lines of therapy.

I do have to say that some of these, and how agents are developed, depends a lot on how companies are developing these products. We don’t always have a say, when we look for example at pomalidomide, it was never in the front line. I think it depends a lot on how the companies are developing these drugs, sometimes they’ll have our help. There are other interests as well in these, so I’m just looking forward to seeing what happens with some of these agents, and which ones we can use earlier. But I do think it’s feasible and possible.

I agree with you. I think most of us would agree, this is how myeloma has been developed. You prove it in the very heavily relapsed setting and move forward. So, as we try to wrap up things today, it’s amazing how much we could discuss further, but I would give a few takeaways as follows. First, we have more options than ever before, and you have the opportunity to tailor them to your individual patient. And each of these regimens has flexibility within themselves.

We have a few questions coming in about the dosing of carfilzomib, and I think we have options to give it either once weekly or twice weekly. I tend to favor, for example, giving it once weekly. We have the opportunity, maybe we don’t have a phase 3 trial, but we can put carfilzomib and pomalidomide together. I think understanding the cytogenetics of your patient becomes important in individualized therapy.

Someone asked, are we comfortable using venetoclax in patients with translocation 11;14? Obviously, we don’t have time to get to that today, but absolutely. It’s not yet formally FDA approved in this indication, it’s being pursued, but it does speak of a different biology. I think the key takeaways are, we have more choice than ever, and this massive distinction between transplant eligible and ineligible is less of a major distinction. I think we are trying to treat myeloma a little more aggressively in the early relapsed setting with triplet combinations, if you will, jumping on the disease relatively early, not waiting for extensive progression. Lastly, many of these newer immunotherapies, bispecifics, CAR T, with all the different targets—BCMA, GPRC5D, FcRH5—I think are going to come earlier into the disease.

Someone asked, are we on the verge of curing myeloma? Well, I’m always careful to use that term, but I think a simple way to put it is, we’re closer now than we were before, and we’re working toward improving patient’s quality of life with the disease until we absolutely have a cure.

I want to take a moment to thank our 3 extraordinary panelists today. Thank you so much for your time, your wisdom, and your efforts. It’s been great to host this event with you. I trust that we’ve gotten to just about all the questions in the audience. Sorry, there are a couple that we haven’t had a chance to get to, but we can work on that thereafter. But thanks very much for your participation today. Thanks 

® for putting this together, and we’ll close the show. Thank you very much and have a great rest of the day.

Videos

Dr Joseph Mikhael and expert panel re-visit the patient case and offer their final thoughts on the impact of clinical trial updates in the treatment landscape of multiple myeloma.

Final Thoughts on Case Study and Treating Multiple Myeloma 

Excellent. We have a lot of commonalities in thinking. And I will go through this in tremendous detail, but just to remind people, if you're going to get a category 1 designation in the NCCN [National Comprehensive Cancer Network] guidelines, it's usually driven by a phase 3 trial. And it’s remarkable how many phase 3 trials we have now. Keith led one of the first ones when we saw carfilzomib/lenalidomide and dexamethasone when we weren't using as much continuous lenalidomide in the maintenance setting. But now look. We have a proteasome inhibitor in carfilzomib phase 3 trials with the IKEMA and CANDOR studies. And as Elisabet noted, IKEMA has really shown quite an impressive progression-free survival.

But we also have the proteasome inhibitor using bortezomib with DVd [daratumumab, bortezomib, and dexamethasone] and the CASTOR study and most recently, with a totally new mechanism of action with selinexor with the BOSTON study.

We have a question here where someone asks if there is really a difference between a 17p deletion and a p53 mutation? I'm going to ask you, Keith, because I know that this may be relevant to selinexor in the mechanism of action of that drug as being an export inhibitor. Could you clarify a little bit about the difference between having 17p deleted and having a mutation in the p53 gene?

Well, they have 2 copies of the gene. If one is deleted, which is what we test for with the FISH [fluorescence in situ hybridization] scale, that's usually a bad thing. But it turns out that if you do mutation tests, then you really need both to make yourself ultra-ultra-high risk. Most of us don't do p53 mutation testing, so it's a bit of a moot point. And in my opinion, any p53 deletion is bad. But clearly, I think one day we will be screening for mutation as well, and we probably should be.

Yeah, I completely agree with you, I think the key message for the clinician is that p53 deletion independent of whether the mutation has been looked for, and detected, is an adverse prognostic marker. And then, as we've mentioned, and I know Keith made comments about travel, so we also have now the pomalidomide combinations with phase 3 studies with isatuximab/pomalidomide and dexamethasone [IsaPd], as well as daratumumab/pomalidomide and dexamethasone [DPd].

We've talked a little bit about this question, so I'm going to come back to the patient and remind ourselves when someone is relapsing, it is important for us to look at the big picture. I've often said myeloma is like a crime scene where 1 piece of evidence doesn't tell you the whole story, and when someone relapses like that, it is wise to get the whole picture, and in a particular, repeating the marrow for cytogenetics, because some of these things are acquired, most of the translocations are not going to be acquired per se, but we can see this p53 deletion as a new de novo abnormality. And so, it really does become important for us.

And I would also put a plug in here for the importance of advanced imaging. Myeloma, especially with subsequent relapses, has a greater preponderance towards extramedullary disease, and so we can end up being in a situation where what you see in the blood in the marrow may not tell you the full picture, and you're going to want to know if there's evidence of extramedullary disease because that is not only going to be a way to follow the patient, but it could cause more damage and organ toxicity to patients when we see that. And it also speaks of higher-risk diseases.

So, in this patient, we did see that there was a PET [positron emission tomography]/CT [computed tomography] done and the patient was treated with isatuximab, carfilzomib, and dexamethasone [IsaKd]. And why is that? And I'm not going to spend a lot of time on this, because this was recently updated. In the design of this study, back in the day, we were still giving carfilzomib twice weekly. Isatuximab is a CD38 [cluster of differentiation 38] antibody that's given once weekly for the first cycle, then every other week there afterward. And in this phase 3 study, there was a 3-to-2 design of 3 IsaKd vs 2 receiving Kd [carfilzomib/daratumumab]. And these patients, I would suggest, reflecting on what we're seeing in early relapse, we didn't have a large fraction, but there were around 10% of patients over the age of 75. Interestingly, also, as Elisabet noted, we have about 40% of people that have a 1q abnormality in this study, and we can see that about half of these patients have had 1 prior line of therapy. The study was involving patients with 1 to 3 prior lines, and the other half had had either 2 or 3 prior lines.

And this is probably the key result to leave with you. That when we had FDA censoring rules applied to the PFS [progression-free survival], notice that Kd alone gives a progression-free survival of 21 months, which is pretty impressive for a doublet. But look at how that is improved, literally doubled, to 41.7 months in IsaKd. And there are different ways to cut this, if we do it without the censoring rules, it's 36 months instead of 42 months, roughly. But nonetheless, we're seeing patients on this regimen with a 3-year progression-free survival, which is really impressive. And we see it pretty much across the board and all the subgroups as we would have anticipated. And although, as Sikander mentioned, it's not yet necessarily guiding our therapy, we are very careful to capture MRD [minimal residual disease] status, as it is a greater indication, obviously, of the depth of response.

Safety-wise, we have to be careful as every drug comes with risk. We saw that the safety findings here were, if you will, consistent with what we've seen in the interim analysis and consistent with using a CD38 antibody where there's an increased risk of infection, and using carfilzomib where there's an increased risk of cardiac issues. We do see here that the discontinuation rate was lower in the triplet arm than in the control arm. There was this ongoing signal, Keith first demonstrated this in the ASPIRE trial, with carfilzomib, lenalidomide, and dexamethasone, that there is a signal of about 4% to 5% cardiac failure of grade 3 or higher, and so this does have to be monitored in the early phases of an individual's treatment. And this follows nicely after what we had already seen before in the CANDOR study, which is a very similarly designed study, phase 3 looking at daratumumab, carfilzomib, dexamethasone vs. carfilzomib and dexamethasone, where there are some absolute differences, so we're careful not to compare across trials.

But again, we saw a near doubling of the progression-free survival, from 15 months to 29 months in patients who received daratumumab plus carfilzomib, dexamethasone vs carfilzomib and dexamethasone alone. And then lastly, which we had seen previously, typically in the United States, we're not using as much bortezomib in early relapse, but we saw, again, if you will, a doubling of progression free-survival and DVd vs Vd [bortezomib and dexamethasone]. Although I must say that we have not typically used this regimen as frequently, especially in the way that it's given by virtue of the fact that the bortezomib has stopped after 6 months. And I do think that, in general, here in the United States, we are seeking to have deeper and more durable responses with more continuous therapy that hopefully can be tolerated a little bit better.

Dr Joseph Mikhael and expert panel discuss key efficacy and safety outcomes of pivotal clinical trials evaluating treatment regimens in patients with R/R multiple myeloma. 

Clinical Trials in R/R Multiple Myeloma 

The NCCN [National Comprehensive Cancer Network] guidelines have almost turned into a laundry list. It's hard to be a guideline when you give 30 options, but here we do have preferred options and noticed this one. If a relapse is greater than 6 months, the regimen used for the primary therapy may be repeated. But I must say that very few of us really follow that. We have several options that are listed here. I would note that in those category 1 designations, we have, carfilzomib/daratumumab and dexamethasone [KdD], as well as isatuximab/carfilzomib and dexamethasone [IsaKd], which both fit with our audience. We do have some other ones, including daratumumab/pomalidomide and dexamethasone [DPd] and isatuximab/pomalidomide and dexamethasone [IsaPd], typically after 1 therapy that includes lenalidomide for DPd and 2 therapies that include lenalidomide and a PI [proteasome inhibitor] as well for IsaPd.

Now we also have those who are true lenalidomide refractory. And I think, in this case, this slide is perhaps the most relevant because we have a patient here who is in lenalidomide refractory within a year of transplant. And I'm going to ask our experts here does that influence you if, let's say you are going to choose a CD30 [TNF receptor superfamily member 8] antibody, be it DARA [daratumumab] or Isa [isatuximab], are you leaning more toward carfilzomib, like the audience seems to be because this person only relapsed within a year of being on lenalidomide maintenance? As opposed to, let's say, this is happening 4 or 5 years later, while on lenalidomide maintenance. Elisabet, let me ask you first. Does that fit a little bit more with your thinking? Are you wanting to class switch here because the person is progressing within a year of being on lenalidomide maintenance?

 I think we compare bortezomib to carfilzomib, but you have to choose either one or the other. Carfilzomib usually tends to give higher responses early on so this patient needs a very fast-acting regimen. And she also has this abnormality in chromosome 1. And so, we have the IKEMA study that shows that isatuximab, carfilzomib, and dexamethasone give a very good and long progression-free survival. Being free of disease doesn’t happen to everyone, but it's a good start and it is well-tolerated.

So, I think in this patient, an option that includes carfilzomib with dexamethasone is very good because this is a very fast-acting medication that reduces myeloma very quickly. And maybe the addition of isatuximab because of the chromosomal abnormalities and the data from this study on the patients that have chromosome 1 abnormalities. And so, I think that that's what I would probably do for this patient. But I think the options presented were all very good and I agree with the audience in the choosing of the preferred regimens for this patient.

That's really helpful. And just to round out the NCCN guidelines, I'll show that there were other treatment options here. And this is where we have to tailor it to the individual. I think we all feel that this person is a little bit more aggressive in their relapse and we probably want to use that but there are other options as well. I'll just quickly give Sikander and Keith a quick vote. Assuming all availability of those options, Sikander what would have been your selection for this patient?

Joe, I think I would also go with IsaKd. In addition to the timing of the progression, I think for me, this being a clinical progression rather than just a slow biochemical change is another reason that I would go for the class switch.

I think one thing we haven't mentioned is geography. Carfilzomib requires coming into the clinic once a week, but if you live far away, Pomalyst [pomalidomide] would be a good alternative. Having said that, like the others, I would go with an anti-CD38 [cluster of differentiation 38] in carfilzomib. I would probably lean toward daratumumab because of the convenience of subcutaneous injection.

Dr Joseph Mikhael and expert panel review current treatment options for patients with early relapse multiple myeloma, in accordance with current NCCN guidelines. 

Treatment Options in Early Relapse Multiple Myeloma

Now, we're going to turn our thinking a little bit more to relapse because that's the focus of today. And in particular, early relapse. I think sometimes we get very excited to talk about frontline therapy and very late relapse with all the new modalities of CAR [chimeric antigen receptor] T-cell therapies and bispecific therapies, but we sometimes forget that most patients land in that 1 to 3 prior line space. To introduce this, I'm going to ask Elisabet if you could just walk us through this first case to get us primed a little bit. I will note to the audience that you do have the option to enter questions into the Q&A box and we'll make sure that we address those, so feel free to do so as we go.

Thank you, Joe. So, we're going to go over a very interesting and well-presented case of a patient that could have been treated in an academic center or in the community perfectly with this regimen, a very difficult patient. The patient is a 63-year-old Caucasian female that was diagnosed with stage 2 multiple myeloma. She has a history of being a heavy smoker. In the cytogenetics, in FISH [fluorescence in situ hybridization], what is remarkable is she has a gain of 1q21, she has a very good performance ECOG PS [Eastern Cooperative Oncology Group Performance Status Scale] of 0. Then the patient is treated with a standard regimen for newly diagnosed myeloma, very well accepted, bortezomib, lenalidomide, dexamethasone, and then she follows with an autonomous stem cell transplant, which is what our patients still do these days.

The patient then has a partial remission after this treatment, and she is placed in lenalidomide maintenance therapy. And in the next slide, you can see some of the genes and biological processes that are driven through these gains or amplifications of chromosome 1. And some of these are basically pro-oncogenic biological features. And what we know is that the abnormalities of chromosome 1 in general, in particular 1q, are a very common abnormality. It is found in about 40% of the myeloma patients through FISH, and it's reported as a 1q class, of a 1q21, and when we talk about the gain of 1q, it means that we have 3 copies of this particular area of the chromosome, and if it's an amplification, we have 4 or more copies.

Great. So that's perfect, thank you for that. That's a fantastic description. And we wanted to focus on chromosome 1 a little bit because as you mentioned, it is so common in 40% of patients. As we used to say, if you don't take the temperature, the patient doesn't have a fever. I think when we weren't looking for this, we didn't recognize how common it was. Now, before I get the take from my 3 colleagues on what this means and what they consider to be high risk, we're now going to go to a polling question from the audience. And I saw that some great questions have come in from the audience. The question is as follows: do you consider gain or amplification in chromosome 1q as a high-risk abnormality at its initial assessment? And it's not just a simple yes or no answer. It's yes for any gain or amplification. So, as Dr Manasanch described, gain means 3 copies, and amplification has 4 or more copies. So yes, to any of that, or only yes if there's amplification, meaning that 3 copies are not enough for you to consider it high risk.

All right, we get more votes in. So, it looks like 70% of the audience thinks that any of this is a risk. So, whether you have the gain or the amplification. About 20% of the audience thinks only if you have the amplification, and 10% to 12% of the audience are saying it's not a high-risk feature at all. So, this is great. Thank you for your answers to that, it's shifting a little bit but still in that same vein, about two-thirds of the audience think that either a gain or an amplification is high risk.

So when we look at the mSMART [stratification for myeloma and risk-adapted therapy] guidelines, which our colleagues at Mayo Clinic have touted for many years, and Keith and I were involved in this in the past, and Sikander is still in the middle of it, we can see that they've listed high-risk features that include the classic translocations of 4;14, 14;16, 14;20, the known deletion 17p or a specific mutation within the p53 gene, but also have listed gain 1q. Now, what colors this a little bit, in addition to those other more clinical features, you see they have Revised ISS [International Staging System] stage 3 plasma cell, a high plasma cell S [synthesis]-phase, and a high-risk signature on gene expression profiling, is this notion below that we have what is sometimes referred to as double hit or triple hit myeloma, where I think we're coming to appreciate that any one of these abnormalities carries some risk, but when you start adding them together, that risk goes up. I just want to pause for a moment here because I know that Keith is a particular expert in the genetics of myeloma. Keith, I know we're going to come back to it in a group discussion in a moment, but if you were an audience member today, how would you answer that question?

I would have selected none of the above because you're right, Joe, the bottom box is the key one. First of all, I'll say that the FISH scale does a terrible job of reporting the adverse applications, that is a totally unreliable and probably community practice, even worse than what is in our academic centers. So, I think that presence is a high-risk feature on its own. It's not in my mind high-risk if that's all you find, because it's 45% of our patients. However, if it's present, it would be additive to any of the other mutations so 1q plus something else in my mind is high risk. On its own, I tend to treat it as an intermediate risk.

Any other thoughts from our other 2 colleagues here?

I think that sometimes the evaluation of the abnormalities in chromosome 1 is difficult. I completely agree with Keith, if you have a high-risk abnormality and abnormalities in chromosome 1, it can be not just a gain on 1q. That is a patient that we treat as high-risk. But I think that it's true that we don't have such a reliable method to test this. But I think if you're in the community and you ask your pathologist or the companies that are doing the FISH testing to include probes that would measure this area, for example, in some of the probes sometimes it's reported paths that can use 1p, some gene in chromosome 1. But chromosome 1 abnormalities I think overall are not good in myeloma and they're very common and that also includes deletions and again, gains or amplifications of basically extra copies of parts of the chromosome or the entire chromosome are usually not good in myeloma.

With maybe the exception of a true hyperdiploid state where we do see these chess pieces in the standard risk.

I havea couple of thoughts. Obviously, Keith and Elisabet pointed out the most important things. I think especially what we discussed with our community partners that it's very important for, first of all, the lab, whatever the pathology specimens send, to include probes for chromosome 1. I think we get it done routinely and obviously with mSMART we've had a gain in 1q included as a high risk forever and ever. But the thought is that if you don't look for it, you don't find it. Just like you mentioned, Joe. And so, knowing whether abnormalities exist or not, 1q gain exists or not, is extremely important. Linking it with other abnormalities is, again, very important.

What I can say is whenever we look at large databases, registries, etc, it comes out clear that chromosome 1 patients do behave differently and that's where, when we start breaking them apart into one with 13, one with this, one double hip, one with a triple hip. I think we break it down into smaller subsets, so it does play an important role. But I agree that by itself it may not be that important. But we really need to look for it. We need to understand our patients need to be aware as well.

Great questions. Great comments from all of you about ensuring that the testing is done better. I think Keith raised that in particular. But I hope that we'll have a bit of an evolution where we'll be able to more clearly distinguish amplification from just a gain. Because I do think that probably in and of itself may be a high-risk feature. But I totally agree with all the comments you made.

Let me just quickly remind us of the case. So the patient that Elisabet shared with us got their VRd [Velcade, Revlimid, and dexamethasone], and got maintenance therapy with lenalidomide. But now here, unfortunately, 1 year after lenalidomide, we're running into trouble. So, before I even go into the details, someone asked a good question here which was, “How long do you plan to give lenalidomide? Do you plan to give it indefinitely?” As some of us know, coming up at the ASH [American Society of Hematology] annual meeting, there's some discussion and some studies looking at do we stop lenalidomide at 3 years. Do we stop it at 4 years? Do we stop it at 5 years? Do you, if someone is tolerating it, plan to prescribe lenalidomide forever? Or do you prescribe lenalidomide for 3, 4, or 5 years? Or what is your approach? I'll start with you, Elisabet.

I think that what you were saying is very important and I think that this is a patient that is relapsing seemingly quite quickly, has creatinine that is increasing, has a fracture in L2 second lumbar vertebrae. And so we want to give a treatment that is off the shelf, and we can get very quickly that is going to also reduce most of the myeloma very quickly, and that within 2 weeks can cut this down by quite a lot.

Absolutely. Sorry, I was asking you before you knew about this relapse, what is your plan for lenalidomide maintenance? Are you giving it for a defined period of time or indefinitely?

We usually continue it indefinitely unless there's some tolerance issue, or if the patient starts relapsing, we need a biochemical relapse or relapse like this patient is experiencing, which is with some symptoms.

I have almost no patients that take it forever. I tend to find a reason to stop around 2 or 3 years, such as rising MCP [medical care plan], dropping platelets, tolerance, and complete remission. I can't think of very many patients I've treated that go more than 3 or 4 years maximum taking lenalidomide.

I don't go with a time-limited treatment. Either ongoing, if the patient is tolerating and none of these issues show up like Keith is bringing up. Or most recently, with larger studies that are looking at maintenance, MRD [measurable residual disease]-driven maintenance, etc. Those data are not yet prime, but those studies are not yet ready. But we've started toying with the idea of looking for MRD-negative. Again, if there's sustained MRD-negative, it would be 6 months to 12 months. Should we be stopping lenalidomide? I feel comfortable with those kinds of discussions. I don't think there is one size that fits all, but those discussions have started happening more and more frequently with patients now.

Excellent. I believe hopefully we’ll go towards stopping lenalidomide. If it's an opportunity to give patients nothing for a period of time, then that's very good. There’s one other question I want to address from the Q&A box. Keith, I'll get you to answer this one because I know you've written about this and talked about this before. Someone is saying, in light of what we said for frontline therapy, that the exposure to melphalan in the transplants can potentially yield other genetic mutations. Is that something that you're considering in your mind now? Do you think that's going to play a feature in the future, whether or not we continue doing transplants?

You know, it clearly causes genetic damage throughout the cancer cell and the normal cells of a human to give high dose melphalan. However, it hasn't really translated into a very significant problem, as most of our patients end up dying of their myeloma, not something else. There is a background of acute leukemia that comes on later, but I think it's still small enough that we've tended to think the good for the bad transplant outweighs that.

Having said that, as our therapies improve, I'm all for getting rid of high-dose melphalan. I think it is genotoxic and at the end of the day, we'd be much better off without it. But for now, we're still transplanting, and the background DNA damage doesn't seem to be as important as controlling the myeloma.

Great. Thanks so much, Keith. I also appreciated your comment of when that person is on lenalidomide maintenance, we do have to be a little bit on higher alert for any potential second primary malignancy, which would include MDS [myelodysplastic syndromes]. So, watching that MCV [mean corpuscular volume], watching the blood counts. But also, any particular GU [genitourinary] malignancy, any evidence of blood in the urine, or urinary symptoms that may be consistent with that.

There was one other question that I'll quickly address, which was what about dexamethasone? We keep talking about always using dexamethasone and I have to say that I try to tell my patients that dexamethasone is like the booster rockets on the shuttle. Really helpful for those first few cycles but there is a very strong impetus now to have a reduction. I've even joked this week that our clinic is going to be renamed, instead of The Myeloma Clinic, The Dexamethasone Reduction Service. I think we do find ourselves so often doing that and we are now even embarking on protocols where people are only given dexamethasone for the first 2 or 3 cycles. So, I would encourage, particularly our colleagues in the community, to assess how much you’re starting dose should be but also to have a plan in most patients to have that dexamethasone reduced, if not discontinued, within 2 to 6 months of the beginning of that therapy.

Coming back to our patient; as Elisabet noted, this patient unfortunately is relapsing rather aggressively. The M [monoclonal] spike has reappeared. The white chain is going up. They're anemic. Their creatinine is now up to 1.5 with a GFR [glomerular filtration rate] of less than 50 and they do have a fracture at L2, based on a PET [positron emission tomography] scan, with a performance status of 1. We've talked a little bit about this, but the gist is a discussion. In general, I think with this patient, it's obvious that we've got to treat them. But Sikander, are you, at the first hint of any biochemical relapse, tending to jump in and treat? Or are you more of a wait-and-watch kind of individual? Or does risk status influence that decision?

Joe, absolutely. All of the above. I would say the very fact that this patient is progressing so soon after transplant and on maintenance, I think I would feel a little uncomfortable waiting and watching. So even if this was a slow progression but soon after transplant, I think I would be very concerned, because that is giving us an idea about the biological behavior of this case. In fact, just yesterday I had a patient who's about 160 days out of the transplant. Has, incidentally, 1q positive with a 13 deletion, and he was on dual agent maintenance and is progressing literally 5 months, 6 months, after the transplant. So, although that is a slow progression that patient was at, I'm very concerned. On the other hand, if the patient's been on treatment for 2 or 3 years with the regimen and now has a slow biochemical progression, I think that is a different disease. I think that's a different case. That's how we handle it. But with this one, I'm quite concerned. And I think it's the biological behavior that I'm most concerned about.

What concerns you, Keith, the most in early relapse? Sikander noted the fact that it happened within a year, about a year after the transplant. What other features might make you think that this is more of an aggressive or a high-risk relapse?

Obviously, one is worried about kidney function as a predominant thing so this is a pretty clear-cut case where the treatment needs to get started. I am very quick to move to new therapies when things start to rise. In some ways, the treatments we have available today are better than the treatments people started with in terms of the use of daratumumab if they haven't received it. The use of carfilzomib. The use of T [thymus]-cell engaging therapies. So, I very quickly switch gears and move on to the next thing. And in terms of this patient, I think just the fact they're relapsing so quickly is ominous. I think this patient's declaring themselves, despite their genetics being neutral, to be a high-risk patient.

This is really helpful. I'm hearing lots of themes from you, which are all really important. I do think there is a general trend in the myeloma community, to be more aggressive at early relapse than we used to be in the sense that now we have better treatments. We don't necessarily just go back and give this person VRd again. Now we have new treatments and new options.

This leads us to our next polling question. which says: what regimen are you most likely to recommend for this patient with early relapse while on lenalidomide maintenance after VRd induction and transplant? So, they're relapsing 1 year afterward. Will you go to daratumumab plus carfilzomib and dexamethasone [DaraKd]? Will you go to isatuximab plus carfilzomib and dexamethasone [IsaKd]? Will you go to daratumumab/pomalidomide and dexamethasone [DPd]? Will you go to isatuximab/pomalidomide and dexamethasone [IsaPD]? Or option number 5, will you go to selinexor/bortezomib and dexamethasone [selinexorVd]? Or perhaps there is another option. I will show you some of the results of the data of the studies that are behind these 5 options, but let's first see what the audience thinks with respect to the next line of therapy. And then I'm going to ask our presenters here what they think.

As it's starting to come in, no surprise. There's quite a spread here. It looks like there's no 1 major winner, but we do have a little over half of the people going to daratumumab plus carfilzomib and dexamethasone. And another 25-30% saying isatuximab/carfilzomib and dexamethasone. So, there definitely seems to be an endorsement here of carfilzomib and a CD38 [cluster of differentiation 38] antibody, be it daratumumab or isatuximab. There are a few votes for DPd, very few, if any, for IsaPD, and just very few also for selinexorVd. And no one has chosen the other.

So the bottom line here, it looks like DaraKd is at the top of the chain but there's considerable support for IsaKd, which I'm going to suggest is not surprising. And I'll share with you now a little bit about what we have in our NCCN [National Comprehensive Cancer Network] guidelines.

Dr Joseph Mikhael and expert panel review a case study in early relapse multiple myeloma and the impact of cytogenetics in risk assessment for patients with early relapse multiple myeloma. 

Case Study: Myeloma at Early Relapse

Hello and welcome everyone. It's a privilege to have you join us today in this educational session entitled, “The Evolving Treatment Landscape in Multiple Myeloma: An Expert Case-Based Discussion.” There is a lot of evolution in the myeloma world right now, and so we're going to talk a little bit about that not only upfront but in relapsed myeloma.

It's my pleasure to serve as our moderator today. My name is Dr Joseph Mikhael, I'm a professor at the Translational Genomics Research Institute in Phoenix, Arizona, and the chief medical officer of the International Myeloma Foundation. I have 3 outstanding faculty and friends who have joined me today, and I will have each of them introduce themselves. We'll start with you, Elisabet.

Thank you so much, Joseph, for that great introduction. My name is Dr Elisabet Manasanch, I'm an associate professor at the University of Texas MD Anderson Cancer Center in Houston, Texas where I treat multiple myeloma patients.

Wonderful. Welcome. It's good to see you. Next, we have not only a friend, but a mentor to me. Keith, could you introduce yourself?

Yes. Good morning, everybody. I'm Dr Keith Stewart, I'm a myeloma physician at Ontario Health in Toronto, Ontario, Canada and the director of the Princess Margaret Cancer Centre.

Wonderful. Thanks so much for joining us, Keith. And last but not least, a former colleague and dear friend, Sikander. Could you introduce yourself?

Thanks. Yes, absolutely. Hello to everybody watching this great program. I'm Dr Sikander Ailawadhi, I'm one of the hematologist oncologists at the Mayo Clinic in Jacksonville, Florida, and my practice is focused mostly on multiple myeloma.

OK, great. Yeah, we have a bit of a Mayo Clinic theme here, with 3 of us either presently or previously practiced at the Mayo Clinic. And of course, MD Anderson for Dr Elisabet Manasanch. It's so great to have each of you here.

So just a quick review, I know that many of our audience members are familiar with this already, but I do think it's important to highlight this because it's hard to believe now it's been 8 years since we changed the definition of myeloma. We used to say, "Show me the CRAB," meaning, as I always give the analogy to patients, if I'm running towards a cliff, you'd have to wait until someone was falling off the cliff to be diagnosed with myeloma. Hopefully, Sikander, who probably runs faster than I do anyway, would stop me from falling off the cliff, but we used to define myeloma as the presence of that true CRAB criteria: calcium elevation, renal insufficiency, anemia, and bone disease, obviously related to the underlying plasma cell disorder, with a monoclonal protein of greater than 10%. But we've now added 3 more features to that almost as if we drew a line, let's say 50 feet short of the cliff so that we knew when the disease was soon to progress and cause organ damage.

And so, we added those 3 features of 60% plasma cells, light chain ratio over uninvolved of greater than 100. And if there was more than 1 focal lesion on the MRI [magnetic resonance imaging] of the bone marrow, which is typically a homogenous picture, that's indicative of active disease. And so that has now been the new definition of active or symptomatic multiple myeloma, which of course is typically preceded by MGUS, or monoclonal gammopathy of undetermined significance, and perhaps a phase of smoldering myeloma. And still, we are treating the active myeloma, smoldering myeloma ... we're not typically treating, although there are some studies that may indicate that, and it's an area of investigation to determine which fraction of the highest risk patients in smoldering myeloma should be treated.

We’re going to talk a little bit today about patients who are eligible and ineligible for autologous stem cell transplant because indeed, that still seems to be the agreement that we divide patients into that category. And I'm going to ask the experts here for their opinions about how they make that distinction. But if we take for a moment that we are going to plan to have patients going towards an autologous stem cell transplant, we're not going to focus too much on frontline myeloma today, but just as a reminder that the general recommendation is that patients have a 3 drug or now perhaps a 4-drug induction regimen, which typically will include different mechanisms of action from a proteasome inhibitor, an immunomodulatory drug, and a monoclonal antibody, along with dexamethasone, followed by an autologous stem cell transplant, followed then by maintenance therapy, knowing that the goal is a deep response, which generally would translate into a longer duration of response.

Typically speaking, we use lenalidomide as the maintenance therapy, although, and we're going to be talking about the distinction of high-risk patients shortly and I know all 3 of our expert faculty here are experts in defining high risk, but we've come to appreciate that high-risk disease is probably not best served by lenalidomide alone. And so, we're still trying to find what is the best combination for patients. Many will use both a proteasome inhibitor and lenalidomide, and we have evidence for both bortezomib and carfilzomib in that light, and of course, exploring the addition of the CD38 [cluster of differentiation 38] antibody to maintenance therapy. And so the optimal treatment and strategy for a high-risk disease is still unknown, but generally speaking, as I say, we're going to need more than just lenalidomide.

When we now think of patients that are ineligible for an autologous stem cell transplant, the other evolution that we have seen is that we've gone primarily from doublets to triplets and the way in which we administer triplets are feasible in the majority of patients. Fit patients are typically given a triplet combination, the most commonly used combination now would be daratumumab plus lenalidomide and dexamethasone, but we also use versions of VRd [voltage reduction device] or bortezomib, lenalidomide and dexamethasone, sometimes called VRd-lite, if we use lower doses and a less aggressive strategy, but there are maybe particularly frail or unfit patients in whom we may still be using a doublet.

I would suggest that one of the greatest emerging areas in myeloma today is appropriate geriatric assessment. I think we have historically not done this particularly well as hematologists. We pretty much look at the date of birth and suspect that that tells us a probable diagnosis, and what we've come to appreciate is that age alone is not sufficient. And so, I do think it is important as we go forward that we have some kind of validated assessment, of which there are over 10 in myeloma, that can help distinguish as to whether or not they are fit or unfit for transplant, but also what would be the optimal regimen for those patients, which may include dose adjustment for renal insufficiency.

We may take into consideration the risks, if someone has cardiac dysfunction, to use carfilzomib, and that we're careful in using thromboprophylaxis, and that we monitor patients more carefully for potential adverse risks. And furthermore, for the presence already of peripheral neuropathy, let alone the development of it, we've routinely always used bortezomib in a subcutaneous method, and inweekly dosing, there may be some exceptions in that first cycle with very active myeloma, but in general, we're doing that to minimize that risk. And if a patient has pre-existing neuropathy, we may consider not using bortezomib, either to use daratumumab, with lenalidomide and dexamethasone, or perhaps even ixazomib.

So that's frontline therapy in a nutshell, I'm going to pause there for a moment to see if any of our expert faculty, Drs Manasanch, Ailawadhi, and Stuart, have any comments about what we've said before we dive in a little bit more to think about early relapse, which is our focus today. Any thoughts, Sikander?

Yeah, Joe, thanks for setting it up extremely well for the audience. The only thing I wanted to add to that was, I heard you mention transplant eligibility and ineligibility, and while that is still a term used all the time in myeloma and guidelines, etc, personally, I tried to make that assessment with the patient after they have received a couple of cycles of induction therapy, just to see where they lie physiologically, because like you've absolutely rightly said, it is not the chronological age, it's the physiological age that is important.

And the other piece that helps determine that is taking that history about what the patient was doing prior to their myeloma diagnosis. So that gives us a goal where to get them back from a quality-of-life standpoint. I think that's the only other thing that comes to my mind, that maybe we should not label the transplant as eligible or ineligible right off the bat and treat the patient, control the symptoms, and see where they land.

I totally agree with you. I think that notion is critical, especially in the old days, when we had to make that distinction upfront because we were giving such a different regimen to patients who were transplant-ineligible, that included oral melphalan, that would potentially prevent someone from going to transplant. But I agree with you, now that we're so close, VRd [Velcade, Revlimid, and dexamethasone], DRd [Dara-Rd; daratumumab lenalidomide dexamethasone], [DVRd] [Dara-VRd; lenalidomide, bortezomib, and dexamethasone], and all these combinations are so similar that that it makes a lot of sense and a very good point. I don't know if there are other comments from Keith or Elisabet.

Yeah, I think the decision has become much more fluid. I think the high efficiency of Dara-Rd with a long survival outcome has also become more than just age and fitness, it's also become expectations of, if you're doing really well on Dara-Rd or Dara-RVd, is really a transplant all right for a low-risk patient, for example. But I'm sure we'll talk about that during the case.

I agree with you, Keith, very much. Absolutely, I still transplant, but I have to say, a lot of times I find myself giving permission for patients to not go to transplant because they are doing so well, and they don't necessarily want to go through that process. Elisabet, I know you do both and you do so much with transplant. The University of Texas MD Anderson Cancer Center has been known as one of the biggest transplant centers in the world. What are your thoughts here?

Yeah, typically, we have transplanted more than 70% of our patients. And most of the patients that were not transplanted traditionally, it's because the patients chose not to be transplanted with a delayed transplant approach. And this has been the case for the past 10 years. Now, recently, over the last 2 to 3 years, with the addition of daratumumab upfront, I think that has made a big difference in terms of how we reach a very deep response early on in a lot of the patients. So, I think even in these patients they’re transplant-ineligible by choice, or they just don't want to do it. And they're still fit, I think we still use VRd-daratumumab quite a lot with the VRd-lite, so that once we do bortezomib, and if necessary, we reduce the lenalidomide. It's a very well-tolerated regimen as well and we find that at the end of a certain number of cycles, and I think it depends on the patient's physician to ... how many cycles are given initially. But patients do very well, a lot of them are in complete remission, MRD [measurable residual disease] negative, and so I think that that could be also a valid option in some selected patients. But I completely agree with everything that you are saying that this is very fluid and that the treatment of newly diagnosed patients is not as rigid as it used to be with 4 cycles and the transplant. It's a lot more fluid right now, which is good for patients, we have more choices.

All 3 of you have just summarized that beautifully, absolutely. I think that fluidity is a great word, that flexibility that we have, and I think that's the way the field is moving. And I know that some of you have discussed this in other venues before, that thinking ahead in the future, there may come a day where, frankly, we won't be doing transplants for patients because we have other options. But that's beyond the scope of today, I'm going to refocus us back now. But this is great, thank you for your comments regarding frontline therapy.

Joseph Mikhael, MD, discusses diagnosis criteria and treatment considerations for patients with multiple myeloma in the frontline setting.

Frontline Therapy in Multiple Myeloma 

	A. Keith Stewart, MB ChB, from the Mayo Clinic, discusses the safety profile of carfilzomib (Kyprolis) when used in combination with lenalidomide and dexamethasone for patients with relapsed multiple myeloma.

	In other studies, carfilzomib has been linked to heart-related adverse events, including swelling, shortness of breath, and cardiac failure, according to Stewart.  However,  in the phase III ASPIRE trial, which studied carfilzomib in combination with lenalidomide and dexamethasone, it was shown that the addition of the carfilzomib did not significantly change the frequency or severity of adverse events. 

	With carfilzomib, the number of adverse events was slightly higher, but there was only a modest increase in cardiac failure. Also, serious events did not increase significantly in the trial.

A. Keith Stewart, MBChB, from the Mayo Clinic, discusses the safety profile of carfilzomib (Kyprolis) when used in combination with lenalidomide and dexamethasone for patients with relapsed multiple myeloma.


Dr. Stewart on the Safety Profile of Carfilzomib in Multiple Myeloma Patients 

A. Keith Stewart, MBChB, from the Mayo Clinic in Scottsdale, Arizona, discusses findings from the phase III ASPIRE trial that evaluated the novel proteasome inhibitor carfilzomib (Kyprolis) in combination with lenalidomide and dexamethasone for patients with relapsed multiple myeloma.

The phase III study randomized 792 patients with relapsed multiple myeloma to receive carfilzomib, lenalidomide, and dexamethasone or lenalidomide and dexamethasone alone. The primary endpoint of the study was progression-free survival (PFS).

The study was overwhelmingly positive, Stewart notes. Patients receiving carfilzomib experienced an 8.7-month extension in PFS compared with lenalidomide and dexamethasone alone. The median PFS was 26.3 with carfilzomib versus 17.6 months without (HR = 0.69; 95% CI, 0.57-0.83; 

 <.0001). At this point, data on overall survival are immature.

View more from the 2014 ASH Annual Meeting

A. Keith Stewart, MBChB, from the Mayo Clinic in Scottsdale, Arizona, discusses findings from the phase III ASPIRE trial that evaluated the novel proteasome inhibitor carfilzomib in combination with lenalidomide and dexamethasone for patients with relapsed multiple myeloma.

A. Keith Stewart, MB ChB

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