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Joseph Mikhael, MD, MEd: Hello, my name is Dr Joseph Mikhael, and welcome to season two of the Medscape InDiscussion multiple myeloma podcast series. Today, we will discuss the question: Should all patients be treated with a quadruplet in frontline therapy?
Let me introduce my dear friend and my guest, Dr Saad Usmani. Dr Usmani is the chief of the Myeloma Service at Memorial Sloan Kettering (MSK) Cancer Center in New York City. He leads over 14 investigators there. He is inordinately well known in the myeloma community, has led trials throughout the whole spectrum of multiple myeloma, and in particular, has led trials in frontline therapy regarding quadruplets — which is why I thought it would be great to have Dr Usmani as part of this podcast today. Saad, welcome to the Medscape InDiscussion Multiple Myeloma podcast.
Saad Usmani, MD, MBA: Thank you so much, Joe. It's a pleasure to be here.
Mikhael: Always good to see you, brother. I appreciate you so much personally and professionally, and let's just dive right into it. We have seen what I might call just a tidal wave of change from back in the early days when you and I were considerably younger, that we went from doublets to triplets and now really quadruplets. We've seen evidence both in transplant-ineligible and eligible patients. Hence, the title of our discussion today: Should all patients be treated with a quadruplet in frontline therapy? Maybe you can give us just a little bit of a background before I make you answer the question. What has led to this change? What studies have brought us to the point where we're now using these four drugs together?
Usmani: I think it's always important to look at where we are coming from to appreciate where we are going. We've come from a place where myeloma was a disease that was considered to be incurable to now thinking about even functional curability of the disease. During this journey, over the past two and a half decades, we've seen the incorporation of novel small molecules, proteasome inhibitors, monoclonal antibodies, and now novel immune therapies such as bispecifics and CAR-Ts. If we look at where the future is going, the goal has always been to get patients to the most efficacious regimens, making sure that you're balancing that efficacy with safety, of course, but getting more and more patients into complete responses that eventually translate into [minimal residual disease] negativity.
That is what is leading to better progression-free survival (PFS) and overall survival outcomes for our patients. In the last 15 years, we've seen monoclonal antibodies get incorporated into those initial regimens. We went from just using one mechanism of action with steroids, such as immunomodulatory drugs or proteasome inhibitors, to combining all three together into triplets, and now incorporating four drug regimens with those monoclonal antibodies, with the eventual goal that we want our patients to live longer, to get the most efficacious regimens, and have the best outcome.
Mikhael: I think you make such a critical point that historically it's not only that we've moved to giving more or that more is better, but it really is giving those different mechanisms of action together. I almost think of diseases like HIV. It wasn't really one antiretroviral that made the difference. It was that right combination. I think it reflects the biology of myeloma. Myeloma is a complicated disease, and it is always better to capture it in its entirety at the start as opposed to saying, “Well, let's sort of sequentially add more drugs as we go.” I think we've proven that. I think we've also proven that really the biology of myeloma is the same, whether you're so-called transplant eligible or ineligible. And I'm going to be asking you about those terms in a few minutes. But the biology of the disease is such that — whether the patient is younger, older, more frail, or less frail — the biology of the disease is the same. It has been remarkable to me that we've sort of proven this principle of more mechanisms of action that are, as you said, safely given together, can really help overcome the disease.
Without being redundant and mentioning all sorts of names, we've seen this in the PERSEUS study, where daratumumab was added to the typical bortezomib, lenalidomide, and dexamethasone. Then we saw it in transplant-ineligible patients, adding isatuximab to bortezomib, lenalidomide, and dexamethasone. And then the study that you led, that I'm going to be interested in understanding a little bit more, adding daratumumab to bortezomib, lenalidomide, and dexamethasone again, but this time in patients who are either transplant ineligible or transplant deferred. Now we're seeing a whole series of quadruplet studies that sometimes add carfilzomib instead of bortezomib, sometimes use isatuximab, and sometimes use daratumumab.
My question to you initially is, if I'm a community oncologist listening to this today, they may think to themselves, “Okay, that sounds nice in your academic center where you have all this support, and you carefully select patients, but can we really give four drugs together, even in older and more frail patients?” I mean, trying to get to the question at hand today, do all patients get quadruplets when they see you, Professor Usmani?
Usmani: This is such a timely question, because I had this discussion with five different patients yesterday, along with their families. As you know, myeloma is a disease with a median age of diagnosis of 69. But in the transplant-eligible clinical trials you mentioned, the median age of patients enrolled on the PERSEUS study was 60. This is a very different patient population from the average myeloma patient that you and I see in our clinics, who are either in their late 60s or early 70s. So, for both the IMROZ and the CEPHEUS trials, the median age of the patient population was in the low 70s, 71 and 72 years of age. And in that group of patients, there's a lot of different baggage that these patients bring. You can see patients who are fit who may have other health problems, but they are fit, they're active, and have a very different phenotype. But then you'll also see patients who actually have a lot of other health problems that compete for attention, and those patients we would consider intermediate fit or even frail. So our decision-making for those patients who are 70 or older is going to be different.
Going back to both the IMROZ and the CEPHEUS trials that were done in the 70-plus patient population, IMROZ specifically looked at just the patients who were not going for a transplant. But CEPHEUS included about 15% or 16% of the patients who were also deferred. They were deferring their stem cell transplant for later, but the rest were transplant ineligible. Both of these trials prove the point that if you have a quadruplet as part of your initial therapy, you can get patients to a good depth of response. And that is what translates into better PFS.
The second very important component is dual drug maintenance because the success of the myeloma story in the last two decades has been on the continuous therapy model. So the initial therapy gets you to a good response, but then you also deepen that response with that dual targeting mechanism, too.
Mikhael: Yes. I definitely want to come back to that maintenance towards the end, because I know that's often one of the most challenging questions that people ask us: Well, I started the quadruplet. How long do I keep it going? But I want to come back a little bit to the nitty gritty, because it really resonated with me the way you described that. Historically, we’ve seen that very often the first remission is the deepest and the longest remission. Now, maybe with time, things like CAR T will change that modality of thinking, but for now, in general, you have that first crack at it, where the disease is completely chemosensitive, where the patient is as young as they're ever going to be in their care, to really get a control of the disease.
It did fascinate me, as you demonstrated, that so many of those patients in IMROZ up to the age of 80 were included; it was feasible to do that. It makes me feel that it's even more feasible than it was in the clinical trial, though people always say, “Oh yes, we, we sort of cherry pick those individuals who go on to clinical trials.” But the clinical trials use doses of these drugs that we don't always apply immediately to, in particular, our older and more frail population. If we look at IMROZ, for example, they even gave the bortezomib twice weekly. They started lenalidomide at 25 milligrams, and they gave quite a bit of dexamethasone. I would suggest the devil is in the details that those three drugs, because we don't typically modify the monoclonal antibody, be it daratumumab or isatuximab, but those other three drugs, the bortezomib, how it's given the lenalidomide dosing and the tapering of dexamethasone, can make a massive difference between that person, as you said, who might be 71 years old and very fit, or a 78-year-old who's really unfit, where I still feel comfortable giving them that quadruplet, but I modify things. I start the lenalidomide at 10 or 15 mg. I give the bortezomib subcutaneously and only once weekly. In fact, as you know, the French study, the BENEFIT study, planned to do that, and I often plan to give them bortezomib for about a year, because I think that's where the maximal benefit is had. We're adding bortezomib to our standard daratumumab and lenalidomide. And then, of course, you know my sentiments about dexamethasone, that it's a drug we love and we hate, and that after the first few months, I really like to taper it down.
But my question to you is: When you're applying this quadruplet model, as it were, in your clinic at MSK, are you giving it exactly the way it was done in the trial with twice weekly bortezomib with 25 mg of lenalidomide with full dose dexamethasone whether the patients are going to transplant or not, or do you make modifications to match your patients' comorbidities and frailty?
Usmani: Joe, this is such a critical point. We do these randomized phase 3 studies for regulatory purposes. So we are going in a certain regimented way, but neither you nor I has treated patients with twice weekly bortezomib for well over a decade. I think one of the most understated studies is actually the RVD lite study that was originally led by Noopur Raje and eventually published by Betsy (Elizabeth) O'Donnell a few years ago, which has had the most profound impact on our clinical practices, where we found that while the SWOG S0777 trial that clearly showed that RVD induction therapy is better than RD for newly diagnosed multiple myeloma patients. That RVD lite trial, where you can come in with a lower dose of lenalidomide, weekly dosing of bortezomib for that older patient population, you can actually get the same type of response rates and PFS benefit. And that's how we practice in the clinic. Yes, those clinical trial data are important for regulatory purposes and getting us access to therapies. But when we are seeing patients in the clinic, we are using once weekly dosing of bortezomib, even tweaking the bortezomib dose for patients if they have other comorbidities and starting perhaps with a low dose of lenalidomide at 10 or 15 mg, as you stated. Just as you do in your practice, once we start seeing the responses in patients, typically getting to that second or third cycle, we start dialing down the dexamethasone dosing as well.
Mikhael: I think it's capturing what biologically makes sense. Sometimes I say it to patients this way: It takes more gas to get up on the highway than to cruise, right? And so if we can get that combination upfront, even at slightly lower doses, you know, the "Goldilocks phenomenon" of don't wait until it's too hot or too cold, try to get it right in the middle to begin with. I think we're not perfect at assessing our patients, but I think if we take some time to assess our patients to see if they are quadruplet eligible or not, and if so, what would be the right dosing for them? I really think we can make a big difference because if patients get more therapy upfront, paradoxically, they're going to get less later. Because we're going to keep them in that deep and durable remission.
It is so remarkable, and we'll come to the maintenance in just a minute, but help me understand your approach. You mentioned in the CEPHEUS study that most patients are transplant ineligible, but some were transplant deferred. What is your approach now? I know we're talking about whether all patients should get a quad, so let's say that now, the vast majority of our patients will get a quadruplet. There may be some for whom we may not give the fourth drug. Usually, for me, it's not giving the bortezomib if I'm particularly concerned about neuropathy or something. But what's guiding you to make the decision about transplant or no transplant? How are you thinking about that? Is it a more careful geriatric assessment? Is it kind of a Gestalt? When you look at your patient, how do you make that determination?
Usmani: I try to make this point with my colleagues, especially after all these quadruplet data came out, that we have to pay attention to the patient populations in which these clinical trials were studied. In the GRIFFIN and PERSEUS trials, the upper age limit was 70, and the median age of those patient populations was around 60 years. So, trying to utilize GRIFFIN or PERSEUS to have a transplant conversation with someone who's in their 70s when you have IMROZ and CEPHEUS data is not something that I'm doing anymore. If you had asked me this question, maybe 2 or 3 years ago, my answer would've been different. But we have to modify our practice based on the best available evidence.
I had two patients who were in their early 70s that I saw yesterday, and I had this conversation. One of them was actually fit, and came in with a pro-transplant approach, saying, “Dr Usmani, I'm in my fourth cycle of induction therapy, and this is the discussion I want to have.” I had someone else who was more on the borderline of fit, intermediate fit, frail, based on the International Myeloma Working Group frailty score. And I had a similar conversation in terms of presenting data. But my leaning for that latter patient was to favor more of the CEPHEUS or IMROZ kind of approach. My conversation was that if we go the PERSEUS route, the projected PFS — if you get a quadruplet induction transplant and then do this maintenance treatment, of course, with the caveats of adjusting the doses — we anticipate that the PFS for a standard-risk patient would be north of 10 years at the very least. The projection that was shared by Pieter Sonneveld was wild. It was almost 17 years.
But, even if our patients get to be 12 or 13 years of that benefit, that's fine. And I told that patient, by that time you'll be 85, the landscape of myeloma treatment would've changed. But if you choose to go the CEPHEUS or IMROZ route, guess what? You still get, probably, a median PFS of 7+ years out of that. So you are going to be close to 79 or 80, and even at that time, you'll have many more choices in the year 2032 or 2033. We have a lot of irons in the fire right now, and we'll have a lot more tools for you.
So really, the choice is up to you. If you are gung-ho about doing an autologous stem cell transplant, I'm not going to push you in that direction, but if you want to do it, I think we can do it safely. But if you go the other route, you'll be fine. It's quite possible that your PFS may be even longer than that. So, I have that conversation, and it has to be a two-way conversation with your patient. For that latter patient, I was more firm in my recommendation that maybe going with the CEPHEUS route is better for you because you won't have to take this 3 or 4-month period out of your life, which will impact your quality of life. It may worsen your diabetes, and you already have some neuropathy. You have heart disease, so it's really dependent on each individual patient.
Mikhael: I think you so beautifully captured, if you will, part of our shift in focus. Obviously, everyone has their own approach, and some people just love, love, love transplant no matter what. But I really like your approach, which is really to say, I could do a transplant, but should I do this transplant? I mean, you're going to have a very good outcome, and there are challenges with transplant. I know sometimes we become a bit callous to it, but like you said, it takes 3-4 months out of someone's life. They get quite sick sometimes. There are some long-lasting effects from it. I've taken a similar approach to you, where I really feel that the quad has allowed us now to potentially do less transplants in those patients in whom we knew the toxicity was going to be high. We could do it, but as they say, I'm not sure we absolutely have to or should do it. I think you've captured that beautifully. I think it's important for us, as you've underscored, and I try to say this at every podcast, every discussion, discussion with the patient is so important, that shared decision-making model where we involve the patient, because this is where it is a little bit more tricky.
One last comment about transplant eligibility for you, Saad, before we move on to talk about maintenance and wrap up here. Would that first patient you just described — fit, early 70s — debating should I transplant? Should I not? What if we knew that the patient was high-risk myeloma? Would that have influenced your thinking one way or another? Would you have said, “Ooh, maybe we should go to transplant?”
Usmani: Very important point. I mentioned standard risk, and I was hoping you would ask me about high risk. For a fit patient who is in their early 70s and has high-risk features, I think that is the patient whom I would encourage to have an autologous stem cell transplant to give them the best chance of staying in a good remission, even with having two drug maintenance treatment. And that's where I make the argument, that today is the youngest that they're going to get. If you want to stack the odds in your favor of staying in remission, then for that patient, autologous stem cell transplant may offer an additional benefit. So, I would agree with going for it.
Mikhael: I think that is important. I think that's where definitely the high-risk feature may fall in. For me, even if a patient is not going to transplant, and I'm trying to give them a quadruplet, if they have high-risk disease, I'm particularly careful to really try to deliver that bortezomib for a year, in the start of their therapy.
Usmani: Yeah.
Mikhael: Well, before we wrap up, Saad, you've mentioned a few times in the discussion today the importance of dual maintenance. We've sort of seen this for a long time in the patients who were historically getting daratumumab, lenalidomide, dexamethasone (DRD), the transplant-ineligible patients, daratumumab and lenalidomide, that they would continue those two indefinitely until progression. I think now with IMROZ and CEPHEUS, that's sort of been built into our mind. Maybe we drop the bortezomib at 6 months, 12 months, or 18 months based on risk and tolerability. But tell me your thoughts about dual maintenance for the transplant eligible, are you now giving daratumumab and lenalidomide to just about everybody, or are you risk-stratifying differently?
Usmani: We are risk-stratifying based on post-transplant response, and the threshold I'm thinking about is getting our patients to minimal residual disease (MRD) negativity at the 10-6 threshold. So even if our patients got the quad, got the transplant, and they are still MRD positive at 10-6, I would favor using a dual anti-CD38 lenalidomide-based maintenance to get them to MRD negativity at 10-6 and perhaps, you know, deescalate at that time. If our patients have achieved MRD negativity at 10-6 post-transplant after having had a quad induction, and there's standard risk, I'm comfortable using lenalidomide on its own. This is more art than science. All of us want to do the best for our patients, but not at the expense of incurring more safety concerns or financial toxicity for them. So, that's my general approach, and that's what our group has adopted here at MSK.
Mikhael: That sounds like a very reasonable approach. I think more and more of us are doing that. By the way, for your high-risk patient, are you putting them on daratumumab and lenalidomide, or are you using a proteasome inhibitor with lenalidomide?
Usmani: So that's where I think we have more data from all the Arkansas data, the Emory data sets, the FORTE, and the ISKIA studies. where I think having continued proteasome inhibition and maintenance is beneficial for high-risk patients. So we still prefer a proteosome inhibitor-IMiD-based maintenance for high-risk patients unless someone develops some issues with a proteasome inhibitor. In which case, an anti-CD38-lenalidomide maintenance is totally reasonable.
Mikhael: I think you've summarized that area well. I take a very similar approach. I tend to favor giving carfilzomib just because I think it's more sustainable in the long run than bortezomib in the high-risk scenario. But I think we're going to see more and more use of daratumumab in high-risk, especially if we see more readouts from PERSEUS about high-risk.
In summary, it sounds like we are answering the question: Should all patients be treated with a quadruplet in frontline therapy? Never use the word all in myeloma, but for the vast majority, I think, the answer is absolutely yes. Thank you for your input on that today, Saad.
Today we've talked to Dr Saad Usmani. Thank you for tuning in. Please take a moment to download the Medscape app to listen and subscribe to this podcast series on multiple myeloma. This is Dr Joseph Mikhael for the Medscape InDiscussion Multiple Myeloma podcast.
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Resources
Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma
Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma
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Cite this: Should All Newly Diagnosed Multiple Myeloma Patients Be Treated With a Quadruplet in Frontline Therapy? - Medscape - Aug 21, 2025.
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