Listen to expert faculty discuss the evolving role of quadruplet therapy in newly diagnosed multiple myeloma, with an emphasis on treatment selection across transplant-eligible and transplant-ineligible populations, the incorporation of proteasome inhibitors, and the tailoring of treatment intensity. The experts also examine unresolved questions regarding the optimal use of bortezomib, the role of autologous stem cell transplantation in the quadruplet era, and the use of MRD status to inform treatment decisions. Maintenance strategies with lenalidomide alone or in combination with anti-CD38 therapy are also discussed.
In this podcast episode, Jesus G. Berdeja, MD, and Ajai Chari, MD, discuss evolving therapy in newly diagnosed multiple myeloma, including:
Presenters:
Jesus G. Berdeja, MD
Director of Myeloma Research
Greco-Hainsworth Centers for Research
Partner
Tennessee Oncology
Nashville, Tennessee
Ajai Chari, MD
Professor of Clinical Medicine
Director of Multiple Myeloma Program
UCSF Helen Diller Family Comprehensive Cancer Center
University of California, San Francisco (UCSF) Medical Center
San Francisco, California
Content based on an online CME program supported by an educational grant from GSK.
Link to full program:
https://bit.ly/4yTeLZD
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This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
Experts Discuss Key Topics in Treatment for Newly Diagnosed Multiple Myeloma
Dr. Chari: Okay. Newly diagnosed myeloma is changing significantly. It is really amazing.
Maybe we could start with our approach to initial therapy for those who are transplant‑eligible. Jesus, what are you doing these days?
Dr. Berdeja: It is really interesting because I have been treating myeloma patients for over 20 years now. We never say to a patient that we have a true standard of care. This is probably the closest we have ever gotten to a standard of care for the majority of patients. That is both for transplant‑eligible and transplant‑ineligible patients, where the initial question when a newly diagnosed patient comes used to be whether they are a transplant candidate or not. Now I feel like it is, are they quadruplet‑eligible or not? That should be the first question that is asked. For most patients, I would argue, the answer is yes.
Dr. Chari: Wow. I will agree. I mean, usually the joke two doctors will have five opinions, right? Maybe we can do drug by drug. I think CD38, everybody should get frontline. Agreed?
Dr. Berdeja: Agreed.
Dr. Chari: Lenalidomide? Yes.
Dr. Berdeja: Agreed.
Dr. Chari: Dexamethasone, at least at the beginning.
Dr. Berdeja: Agreed.
Dr. Chari: The one question is the PI. Yes, for fit younger patients, absolutely. The [inaudible 00:17:05] data set for the older patient population, which is technically transplant deferred or ineligible, so it is a little bit of a hodgepodge, but that showed the benefit of quadruplet. However, I am not totally convinced on that one, I will say, because I am not sure who these "transplant‑ineligible" patients are that are getting randomized to twice‑weekly bortezomib, like either pick and vote with your feet or do not. If you are truly transplant ineligible, I do not think these patients tolerate twice‑weekly bortezomib. I bring that up because, to me, the regimen to have beaten for this population was not VRd. To me, the scientific question is not VRd plus or minus CD38 because MAIA data with daratumumab + dexamethasone really beating Rd with a PFS of five years with OS benefit in a median age of 73. That is the regimen to beat. The question to me is, if you accept DRd for the older patient, do you need V? If so, how much? I am curious to hear what you think, especially I do not know particularly there is the BENEFIT study, but who needs the V?
Dr. Berdeja: No. I completely agree. I guess we can really just back up a little bit and say that we have two phase III randomized trials in transplant‑eligible and transplant‑ineligible patients with the triplet. However, in all of those studies, like you suggested, the triplet was the non‑anti‑CD38‑containing arm, which means everybody got bortezomib, lenalidomide, and dexamethasone, except for the benefit trial which was done by the French group that actually looked at isatuximab, lenalidomide, bortezomib, dexamethasone versus isatuximab, lenalidomide, dexamethasone. Very similar to daratumumab, lenalidomide, dexamethasone, which from the MAIA trial, which we all feel was the prior standard of care for especially elderly, frail patients, and may still be. We will argue that point later.
The BENEFIT study showed it is still early. Their primary endpoint was MRD negativity. They were able to show that by incorporating bortezomib, they got better MRD negativity compared to the triplet. They did meet their primary endpoint.
To your point, the bortezomib, I believe, was continued for 18 cycles. Was that it?
Dr. Chari: 18 months. Yes.
Dr. Berdeja: 18 months. Yes. That is a long time of bortezomib. That is one of my pet peeves, I have to say. With all these trials since the approved triplet combination was with twice‑weekly bortezomib, all of the control arms and ‑ actually all arms are done with twice‑weekly bortezomib, which, as we all know, is very difficult to tolerate and leads to significant peripheral neuropathy and poor quality of life, in my opinion.
The BENEFIT study did use weekly bortezomib instead of twice‑weekly bortezomib. That was a plus of that. The minus there is, unlike most other studies that could stop after eight cycles, here continued for 18 months. We are always left with, if we need proteasome inhibitor, how much do we need proteasome inhibitor?
I personally do think we need a proteasome inhibitor for all patients, but I do not think we need to be as aggressive with it as all of the clinical trials have been. The problem with my comment that I just made and that you are going to pounce on, is I do not know how much enough is enough to really ‑ how much was the benefit or how much of the proteasome inhibitors required for the perceived benefit or the actual benefit of the quadruplet, for example, versus the triplet.
The answer to that is, I do not know. I will say that I tend to be on the camp that ‑ in a standard risk patient that less is more. I tend to be less aggressive with the proteasome inhibitor and really try to deescalate if any toxicity is being seen to try and preserve that remission. I get the sense that in those patients, pushing the therapy is probably not in their best interest. That is very different for a high‑risk patient. I am curious as to what you think.
Dr. Chari: The two quick points I will make on this topic is, first, the reason this is so important is if you have to pick a fourth drug, make sure ‑ we have been talking about PI, but the frontline U.S. data suggests 30% of patients are not getting frontline CD38. That is unacceptable. Everybody should be getting a CD38, lenalidomide, and dexamethasone. The bortezomib, I have issue with the twice weekly, but what I do in my clinic, if it is a fit older patient, I can start with a quad. What I struggle with is when you are now decreasing the frequency of the CD38, you are going to every other week. Are you going to torture these people to come just for a squirt of bortezomib? I tend to back off, especially if they are having a great response. I will often just use the CD38 schedule as a backbone, and then unless the patient is very high risk or not responding well, I will minimize the bortezomib. Then, once they are going to, say, monthly CD38, I sometimes omit the bortezomib altogether. I do think that the limitation of the BENEFIT study that you mentioned, which yes, it was weekly for 12 months and then every other week for six months, and yes, they showed MRD negativity, the follow‑up is so short; it is only a few months after stopping the bortezomib. The question is not, is the MRD negativity better at, say, 24 months? Is it better at five years? Which is what MAIA showed. We just have to remind everybody that bortezomib for 18 months is a lot of toxicity risk and time risk for the patient.
I am curious, though, and I would say for the high risk, certainly we should be doing quads as much as possible. The big other question that we need to address is whether or not to transplant. To transplant or not. That is the question, as Shakespeare would say. Jesus, what say ye?
Dr. Berdeja: Yes. The first thing I will say is that those comments you just made are more apropos, in my opinion, to someone who is not going through transplant. In the transplant setting, we have actually, in a way, the transplant has become this big elephant, and the therapy around it has become actually much nicer than we do for patients who do not get transplant, which I always find a little bit ironic.
In the transplant patient, usually we do four, maybe six cycles of the quadruplet therapy, then we do transplant, and then we really back off and then go to maintenance, especially in a standard‑risk patient. Whether you do anti‑CD38 and lenalidomide maintenance versus just maintenance, something that we will discuss, I believe, in a second.
In terms of whether we transplant or not, that has become increasingly a patient choice in my opinion. I still think there is a benefit to transplant. I still think that they are definitely transplant results in deeper responses, higher MRD‑negative rates, which we know translate to a longer duration of remission with every single study that we do.
Where the caveat is happening now is that we have these incredible therapies waiting in the wings that are getting people into those very deep responses, perhaps even more so than their initial therapy, that are lasting for a long time. It is very likely that it will be very ‑ like the DETERMINATION study was done before the quadruple era, when the standard risk patient and overall survival benefit was not necessarily seen for patients with transplant. If that is the case, if the person is going to live just as long, then it becomes a question of, is the increased progression‑free survival benefit sufficient for someone to undergo this procedure, which, although very safe, is not a fun procedure?
I am curious. A lot of that is the discussion with the patient. "This is what it means. You are likely to stay in remission much longer if we do a transplant." Especially in a standard‑risk patient, it may not translate to you living longer. In a high‑risk patient, there we need all of our guns pointing in the same direction. We need to be aggressive there. I really do try to persuade my patients to incorporate transplant into their therapy. Curious what you think?
Dr. Chari: At a high level, the projected PFS of PERSEUS, which is quad plus transplant, I do not know if it is 17 years if I believe that, but it is the best projected PFS that we have to date. Then CEPHEUS, which is quad without transplant, is around eight years. Then MAIA is around, say, five years. What that tells us ‑ and, again, caution with cross‑study population comparisons because these are different regimens, but at least it shows that quad seems to do better than triplet and transplant still seems to add value.
Where the confusion is, is the devil is in the details. One thing one of our fellows presented at ASH, because no one is going to do this study, is for the 70‑plus‑year‑olds. Should you do a transplant or not? We did a retrospective analysis like every patient we treated at UCSF. Long story short, we did not see a difference in PFS between transplanted and not. I do not think the typical 70‑plus patient where the melphalan dose matters and can cause ‑ On the one hand, if you back off on melphalan for transplant, you get a little bit less toxicity, but you might also decrease the efficacy. In the typical 70‑plus patient who is tolerating therapy and responding to therapy and does not have high‑risk disease, I do not know that you need to do the transplant, and so I have stopped doing that, unless they are not getting a CR or they have some high‑risk feature.
For the transplant‑eligible patient population, let us say below 70, fit, the struggle is the data from the MIDAS study, which was quad induction. Then, based on MRD status, there was a randomization of either you do transplant or more chemo, whether or not you do a second transplant. The second transplant did not add value.
A lot of discussion is happening with the first randomization, which is continued chemo versus transplant did not show any difference in MRD negativity. For that reason, many people are saying, "Do we really need to do it at least in standard risk patients?" Fun side note that this showed for the first time, we are appreciating t(11;14) patients will get to MRD negativity slower than non‑t(11;14), and that is been shown over and over. Even though they do well in the long term, do not be surprised if your t(11;14) patient is MRD positive.
The problem with the MIDAS study, if you ask the French who did this study there have not changed their practice. They are still doing transplant. Why? Because it has short follow‑up. We do not know about the PFS readout. If you believe what we just said, that PERSEUS quad induction transplant maintenance has the best PFS, we need longer‑term data.
Another study that sheds light on why this is important, FORTE, which is KRd with or without transplant, did not show an initial difference in PFS. It took longer follow‑up to show that difference. If we are really going to use MRD as a surrogate, it needs to be supported, as the health authorities also require, by longer‑term PFS. I personally think it is reasonable to offer, but if a patient is MRD‑negative standard risk and they do not want to do it, if they understand the caveats that we just discussed, I do not think we can force anybody to do it because we do not have data that it is superior. The message should be transplant is not inferior, but it may not be superior. What do you think?
Dr. Berdeja: Yes. Those are excellent points. I completely agree with you that it is not just about the risk of the disease, but it is also the risk of myeloma being the potential cause of death. A lot of these patients who are older, they are going to do really well regardless of the therapy. They may not die from myeloma. They may die from alternate causes and reach their normal lifespan, so I agree with that. I think we do need to take it into account.
One of the things about the MIDAS that I did not change my practice I think was very intriguing, but part of it is a lot of patients, unfortunately, in the community, especially, are not getting the test done to be able to be MRD accessible. One of my biggest concerns is that when we look at the data that closely and say, if we reach this and this subset of patients, is that it gets translated to everybody with or without that data. Because I am seeing a lot of patients that are being sent for evaluation of either transplant, or they want to not do to transplant, or they want to stop maintenance, for example, but there is no MRD data. We do not have that at all. We are just going by the IMWG response assessment. We just need to ‑ since we are having this discussion, if you are listening to this ‑ just to be cautious that that is a very specific subset of patients that we are talking about that has had a very robust response to their initial quadruplet induction therapy. It does not necessarily mean the entire group of standard‑risk patients.
Dr. Chari: The other thing you also alluded to is that in both MIDAS and FORTE, which actually asked the question of whether or not to transplant, the non‑transplant patients got a year of chemotherapy. There is this tendency like, "Oh, four months and then you are done." These regimens were quite intensive, so it is easy to say you are not going to do transplant, but are you really going to bring your patient in for a full year of triplet to quad therapy, which is what these studies did? If we agree that transplant‑eligible patients are getting CD38‑based quads and PI, you can mention ‑ I personally think I use bortezomib. If they have neuropathy, I switch to the K, but I do not give everybody K upfront.
Let us say you can weigh in on that as well. After doing a quad, we do the transplant. I think we have all used lenalidomide maintenance for a long time now. I have also decided to incorporate CD38 in anybody who is high risk or MRD‑positive after transplant. I am not totally convinced that if you are MRD‑negative standard risk after induction and transplant, that you definitely need doublet therapy. What is your take on PI and maintenance?
Dr. Berdeja: PI and maintenance. Not [inaudible 00:32:46].
Dr. Chari: No, no. First PI and induction, and then if you want to throw a PI maintenance too, by all means, chat away.
Dr. Berdeja: Again, I am more simplistic. Part of that is because of my position, and the majority of the patients that I see are treated with my colleagues in the community, I do feel there is a benefit to having as much of our therapies being in a way that any one person can access and click a button and have the patient be treated ‑ which I think is the most optimal therapy ‑ and then make changes as you go along.
I have always felt the quadruplet absolutely is better than a triplet. From my standpoint, every patient should get a quadruplet until they are not able, and/or you have to stop the therapy for a particular reason. We have developed these pathways. As you know, most people in the community go by pathways now.
When you are developing a pathway, you have to put the onus on the practitioner to change the pathway that they are given, which they should do, for example, in a frail patient. I know that is not your question, but a very frail patient that is diabetic neuropathy. We are talking about the standard risks; do they really need that PI? Most likely, you are going to cause more harm than not. That is a patient where I would probably say no PI; the triplet will be fine.
From a standpoint of the PI and induction, I am a believer for now until proven otherwise. From a standpoint of maintenance ‑
Dr. Chari: P versus k. You did not mention. That was my question for the transplant‑eligible. Bortezomib or carfilzomib?
Dr. Berdeja: Bortezomib versus carfilzomib. I use bortezomib mostly. Carfilzomib is a better drug from a standpoint of it is more aggressive, it can induce a quicker response. However, I also think carfilzomib is a more difficult drug to give. It is IV; it can cause cardiotoxicity. You have to monitor for hypertension, you have to be much more aggressive with anticoagulation. As you know, there are higher risks to develop clotting issues, including things like atypical HUS.
From a standpoint of the ease, definitely the bortezomib is much easier than carfilzomib. There has been a few trials that have been done looking ‑ and again, in very different populations, and mostly in standard‑risk patients, so excluding high‑risk patients ‑ where bortezomib as a triplet with carfilzomib has been looked at. There appears to be no difference in outcomes. I think that was the ENDEAVOR study that looked at that. Then there was another study in Europe that I am blanking on right now, but it was in the relapsed/refractory setting.
The ENDEAVOR study looked at patients in the frontline setting, and they appear to be no difference, but with the caveat that they excluded high‑risk patients. That is an important distinction to make.
In a standard‑risk patient, I use bortezomib unless I cannot because of neuropathy or something, or the patient, for some reason, does not want to be poked and they have IV, which is rare, but I have had one patient.
Dr. Chari: Just in the interest of time, for maintenance, as I alluded to, I would say lenalidomide for everybody, doublet with CD38 for anybody with high risk or suboptimal, not attaining MRD. However, I put a caveat on that, per GRIFFIN and PERSEUS, that is two years of CD38. It is not indefinite CD38 because we do not know yet the OS data for these, but we know that the PFS seems to be better. I am curious to have your thoughts on that. Also, maybe weighing in on really exciting new future directions because we have heard some really cool data about bispecifics in this space. What are you doing for maintenance post‑transplant, currently?
Dr. Berdeja: Definitely, in a patient that did not receive a quadruplet, I am recommending ‑ they had a transplant, and for some reason, they got, let us say, they got CyBorD induction. That is the patient, for sure, I think they need the anti‑CD38 and lenalidomide. Just like I mentioned before, from a standpoint of keeping things as easy as possible, and I feel the data is robust enough, I do recommend that we do anti‑CD38 maintenance on all patients.
We do follow the clinical trials in stopping. The problem with what we have is that we have a built‑in stop at two years. In a patient that maybe is not MRD‑negative at that point, do we really stop? You keep it going. Again, there is caveats to some patients where you might not want to do that, but at least from my standpoint, the data from the phase III trials, data from the EUREKA study, which we have not really talked about, looking at daratumumab‑lenalidomide versus lenalidomide.
Now, granted those, most of those patients had not received an anti‑CD38 in induction. Definitely, there was a benefit to the doublet, so I decided to do the doublet and not singlet.
Dr. Chari: One of the nice things about CD38 is it is easy to give, for example, once a month daratumumab. One of the other principles for high‑risk maintenance is best if you can actually deliver it. It is fine to say you are going to do a parenteral drug every two weeks, but are patients really doing that at the real world?
The last quick point I wanted to make is that there is some really exciting BCMA bispecific data as either post‑induction or post‑transplant and showing really profound MRD negativity. We are going to have to see longer‑term data, but begging the question of do we really need a transplant? Because if you can get everybody to be MRD‑negative, how will that work? What will the ramifications be for sequencing? Hopefully, you will stay tuned to our next podcast on that topic. Any take‑home messages for the newly diagnosed, Jesus?
Dr. Berdeja: No. The only thing I would say is Aaron's[? 00:39:16] side of quad for everybody, and then peel away as needed for the individual patient, would be my takeaway from when you have a newly diagnosed patient in front of you.