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Multiple Myeloma Awareness Month 2024: What Patients Need to Know

For Multiple Myeloma Awareness Month this March, Oncology Data Advisor hosted a live panel discussion geared towards patients living with multiple myeloma. Dr. Rahul Banerjee, Dr. Alankrita Taneja, Dr. Richa Thakur, and Dr. Gurbakhash Kaur helped put the myriad of new developments in multiple myeloma treatment into perspective for patients and answered questions from the audience regarding current and future treatment strategies for multiple myeloma.  

Keira Smith: Thank you to everybody for joining today and tuning into this Multiple Myeloma Awareness Month panel. Today we're doing something a little bit different from our usual content and having a discussion geared towards patients who are living with multiple myeloma. I'm joined today by our Editor in Chief, Dr. Rahul Banerjee, as well as our Editorial Board and Fellows Forum members, Dr. Gurbakash Kaur, Dr. Alankrita Taneja, and Dr. Richa Thakur. We have some really interesting updates in store for Multiple Myeloma Awareness Month, and we're excited to cover them today. We'll also have some time at the end for questions, so if anybody has any comments or questions you'd like to ask our panelists, feel free to type them into the chat on YouTube and we can pivot to those at the end. Without further ado, I will turn it over to our panelists to start the discussion.

Alankrita Taneja: Sounds good, thank you so much, Keira. I'll just start with introductions. My name is Alankrita Taneja. I'm a third-year Hematology/Oncology (Heme/Onc) Fellow at Roswell Park Cancer Institute. I was wondering if all of you could also introduce yourselves.

Richa Thakur: Sure, hi, I'm Richa Tucker. I'm a second-year Heme/Onc Fellow at Northwell, and I'm really interested in hematologic malignancies. I'll hand it over to Rahul.

Rahul Banerjee, MD, FACP: Hi everyone, my name is Rahul Banerjee—call me Rahul, please, for this podcast. I'm an Assistant Professor of Medicine at the Fred Hutchinson Cancer in Seattle, Washington. I think Dr. Kaur will beat me, but it's 65 right now in Seattle, so we may win weather-wise. We'll see how Dallas is doing.

Gurbakhash Kaur, MD: Hi everyone, my name's Gurbakhash Kaur. I'm an Assistant Professor here at the University of Texas (UT) Southwestern Simmons Cancer Center. My focus is mostly in plasma cell disorders, including amyloidosis and myeloma. I've actually been in clinic all day, so I don't think I've even paid attention to the weather, but you're probably right, Rahul, the weather may be better over there than here today.

Dr. Banerjee: The one day of the year where that's true.

Dr. Taneja: We are definitely losing for weather in Buffalo, because I think I saw some snow. Having made those introductions, Rahul, I'll start with asking you what your approach is for newly diagnosed multiple myeloma patients. I know for the longest time, even when I started my training three years ago, we would bring in the patients and have them evaluated for transplant over time, dynamically, and we can talk about that. But our first-line treatment used to be a triplet therapy, a combination of three drugs. Over time, we saw some studies showing benefit of a quadruplet regimen, or four-drug regimen, starting with the GRIFFIN trial. In my second year of fellowship, we saw that the addition of anti-CD38 daratumumab to the front-line improved responses. This was followed by some more studies at the last American Society of Hematology (ASH) Meeting, such as the PERSEUS trial, which showed a longer duration of treatment and progression-free survival benefit. So what is your take for a newly diagnosed multiple myeloma patient in your clinic at this time?

Dr. Banerjee: Absolutely, and I'll be curious to hear Gurbakhash's take on this afterward too. I think for patients listening to this, as Alankrita just mentioned, a triplet is something plus something with dexamethasone ,and a quadruplet is something plus something plus something with dexamethasone. The question really is that new fourth drug, the new kid on the block, daratumumab—or Darzalex® or Darzalex Faspro®, it goes by many names. This is a targeted therapy that we typically use in later lines of therapy and have increasingly used in the frontline, meaning for a patient who's newly diagnosed. There's another version called isatuximab, or Sarclisa®. Some of you who have Kaiser insurance, for example, on the West Coast, may have gotten that instead or will in coming years.

My bottom line is I prefer for everybody to get a CD38 monoclonal antibody at presentation. That's either daratumumab or isatuximab—doesn't matter to me which one, and the triple versus quadruplet question we can come back to. I think in the GRIFFIN study, we saw very clear results. GRIFFIN was a phase 2 study, which means it was designed to see if adding that drug makes patients get deeper remissions or get the myeloma numbers down deeper, not necessarily to make them stay in remission for longer or live longer, for example. The GRIFFIN study showed that adding a drug like daratumumab in the frontline setting got deeper responses. It happened to show that patients actually were in remission for longer, but it wasn't designed to show that.

Then this bigger study, the PERSEUS study, which got presented at our big meeting in San Diego last December, showed—without a doubt, no statistical qualms or methodologic issues about it—that adding a drug like this means that patients are in remission. They're harder, faster, deeper, stronger, is what I tell patients. They get into remission faster and have deeper levels of remission. Some are even measurable residual disease (MRD)­–negative, meaning we can't see any myeloma there. Importantly, they're in remission for longer, which I think is really, really important for patients. That's technically for patients who are supposed to get a transplant, which I'm sure come back to as well as we talk about that.

For patients who are not planning to get transplants, there are two commonly used options that are triplets. One is VRd, which is Bortezomib (Velcade®), lenalidomide (Revlimid®), and dexamethasone (dex). The other is DRd, daratumumab, the drug I just mentioned, plus lenalidomide and dex. I tend to use the latter. Again, that same principle as a targeted therapy gets people into remission very quickly. I've had many patients have their light chains and M-spikes start to come down within a month, which is wonderful to see, but that hasn't been compared in a randomized manner for DRd versus VRd. Certainly, I think the trend in the US is moving towards more people getting daratumumab upfront. Gurbakhash, anything you would add?

Dr. Kaur: No, I think I have a very similar approach. Many people are adopting the four-drug regimen right now, which is a monoclonal antibody plus a proteasome inhibitor and an immunomodulatory drug (IMiD). But I think we sort of started doing that roughly three years ago. For all comers, it used to be that you reserve this regimen for the high-risk patients—whose genetics of their cancer plasma cells have features such as translocation (4;14) gain 1q or TP53 deletion. Those patients ended up getting a quadruplet therapy, but I think now, the standard is that everybody gets a quadruplet.

I think, Rahul, I'll also add to this, many people question, "Why are we giving all the big guns upfront? Why are we not saving some of this stuff for later?" I think we have to keep in mind that there is a very high attrition rate. There was a retrospective study done a few years ago that showed that with each subsequent therapy, we lose about 15% to 30% of patients. We want to capture all of them, and we want to keep those patients in remission, but 15% to 30% of patients don't make it to the next line of therapy. We do want to give them the big guns in a safe and effective manner upfront. So, I think that's what I'd like to add. I agree with you that the trend in the US is that for transplant-ineligible patients, we are doing more of the MAIA regimen, which is DRD, versus the SWOG S0777 regimen, which is VRd. I agree with you on those; my practice is very similar.

Dr. Banerjee: Agreed. One other thing I'll add to piggyback on Gurbakhash's point that came up at ASH, there were a lot of talks around dynamic frailty, which means that patients actually get better with treatment. Many of you listening to this may remember a time when you were diagnosed when you probably assumed, "All right, as soon as I start therapy, I'm going to feel worse." That's very reasonable, and I often counsel patients, "You may start to feel worse; you may have a rash with the lenalidomide, the dex is going to make you feel miserable," et cetera, et cetera.

But there was at least one oral abstract at this big meeting last December that showed that especially with these modern therapies that Gurbakhash is alluding to where patients are getting into remission faster, that's not just numbers on a page. That's a patient feeling better and walking more. Their pain is better controlled, and they no longer have to use a walker, and that's wonderful. What they actually found was that for those patients with dynamic frailty—I don't love the word "frail," but it is important to note that in the medical field, we're not using it as a binary, like "Oh, you're frail, you're not frail." It's different ways of looking at how fit people feel and how physically able they are to function.

One's destination level of frailty is a better predictor of how one does than one's original frailty, meaning that for patients who were diagnosed and felt really crummy, weren't able to get much treatment, and were barely able to walk, then they got a regimen like daratumumab and all of a sudden felt more fit and less frail, they do just as well as those patients who had that level of fitness all along. I think that's another example of using our big guns, so to speak, as you said earlier. They get people into remission faster, and that gets them feeling better. That's better both for that line of treatment, and Dr. Kaur alluded to, in future lines with therapy. That's helpful.

Dr. Taneja: I think one other benefit of daratumumab that we also often overlook is it's given as a subcutaneous injection as opposed to an infusion. At least in our clinic, the number one thing I always hear patients complain about is the wait times of having to sit in the chemo chairs to get their chemotherapy. With an injection, you can get it in a couple of minutes. It doesn't really add much time for the patient to be sitting and waiting for treatment, but it adds so much more improved efficacy for their disease control.

Dr. Thakur: Definitely, from my experience, I've seen patients tolerate it really well too as compared to some of the other therapies. That's very exciting information about attrition, and I would just like to elaborate on what we mean by that. Do you mean, Dr. Kaur, that patients are just lost to follow-up in the further lines of treatment?

Dr. Kaur: No, I think they succumb to the disease, or they have toxicity and don't make it to the next line of therapy. This concept of saving the best till the last doesn't hold true in that setting. There's a balance between safety—how safe the drugs are—and efficacy, the effectiveness of the medication. You do want to give your best drugs upfront in order to make sure that patients stay in remission longer.

Dr. Banerjee: I'll add one level to that—and Gurbakhash, tell me if you've heard the same thing. Many of my patients, when they were diagnosed, there was this belief 10 years ago—and at the time, it was correct—that every medication had a shelf life, and as soon as someone had gotten bortezomib and the myeloma started to grow despite it, they were refractory to the bortezomib and could never get it again. At that point, that kind of made sense in some way or form. Now, as patients are living longer and longer with myeloma, I routinely recycle old therapies again. Just because someone got daratumumab, for example, doesn't mean they can never get it again. Let's say they get daratumumab, and now they get a transplant, or don't, and end up on lenalidomide maintenance for years. Then the myeloma decides to creep back up again. I can very easily give them daratumumab.

I've had some patients come back after chimeric antigen receptor (CAR) T. As I'm sure we'll discuss in the second half of this podcast, we've had a lot of updates at ASH. Just last week—three days ago—we had a lot of big updates in the myeloma field. I've had patients where the CAR T stops working, so three years after CAR T, now they're having the myeloma numbers come back up again. I give them that same daratumumab from years ago, and it works just like that, because the myeloma cells have forgotten about it. I think people sometimes get nervous about using the big guns because they're like, "What do we have five years from now?" One, five years from now, I hope we'll have better options regardless for patients with myeloma. And two, it's very reasonable to recycle some of these medications.

Dr. Kaur: I think theoretical and practical are two different things, right? In theory, we cannot recycle them, but practically, oftentimes we read the clinical trials and say the median prior lines of therapy were seven or eight, and that just means how many different regimens patients got each time their myeloma relapsed. Oftentimes, in between those regimens is recirculation of older drugs. We end up recirculating drugs, and even by today's standards, we are talking about CAR T. Maybe I'm going to jump into this early, and we can also save this for later, but the drive-home point is that why is there a need to have CAR T moved up earlier? There's a gap where we don't have effective options between second and fourth line or fifth line of therapy, because we end up using many of these medications. So, where we have a gap, we recirculate a lot of the older drugs, as Rahul alluded to.

Dr. Taneja: I believe that there was also a concern regarding the CD38 antibodies—that the CD38 receptor, which is on the cell on which these drugs act apart from other mechanisms, especially for dara, could be downregulated or they could be removed from the surface, and subsequent therapy with the same drugor maybe other CD38 antibodies like isatuximab would not be active. Maybe some studies also did not show that there were any problems with repeating daratumumab. What is your take

Dr. Kaur: I can go. I think exposure and refractory are two different things. It could be that when somebody gets daratumumab upfront, and then like Rahul said, undergoes a stem cell transplant and then is on lenalidomide, it means they're daratumumab-exposed, but their myeloma didn't stop responding to it and the removal of daratumumab from the treatment plan wasn't because there was some sort of resistance mechanism. Exposure and refractory are two concepts that we often as oncologists discuss. If somebody just has an exposure to a drug and there's a break for some reason, whether the patient prefers to have a treatment holiday or because they went on to have a different treatment plan, you can recirculate that. Now, if they're truly refractory, you can always reuse it. We use it in combinations because it'll provide synergy, meaning two drugs working very collectively to deepen each other's response. By itself, you might be a little bit hesitant, so I think we should talk about that.

Dr. Taneja: We have a question from the audience—"How long typically do you stay in remission after being on daratumumab? I've been on it for a year and a half. My diagnosis was 11 years ago, I've various treatments, and the longest remission has been a little over two years."

Dr. Banerjee: I can take that one. It's an excellent question, Kathy, thank you for sharing that. You've passed the 10 years and are now 11 years living with myeloma, which is wonderful to hear. It is true that over time, I often find that each individual line of therapy doesn't seem to last as long as it might've before. For a newly diagnosed patient who's getting daratumumab today, for example in the MAIA study, even if you take out transplant and just give dara/lenalidomide/dex, on average, I typically tell patients about five years of mileage out of that. As the myeloma has been around for longer and longer, the cells start to get a little bit wilder and wilder. Here, I would say that two to three years is probably very reasonable depending on your medical situation and what you've gotten.

For example, this would be a scenario where I do think newer therapies like CAR T therapy, bispecific antibodies—there'll be a newer version of lenalidomide or a newer version of pomalidomide, I should say, or both really, called cereblon E3 ligand modulatory drugs (CELMoDs) that should be hopefully approved this year—that might be really nice. This would be a scenario where these newer therapies may actually end up having the most mileage, but the existing therapies do have some roles, especially as they're helping to keep disease control while we wait for something new to emerge.

Dr. Thakur: I think one more thing we should probably talk about regarding general paradigms for treating myeloma is how we usually started with doublets decades ago and then we've transferred to triplets and quadruplets as the better, bigger guns are moving frontline—all of the new drugs we usually give after patients have tried multiple lines, but they do better the earlier we bring them to the treatment timeline for patients. But the thing is, as we do this, it's also really difficult to know how each of the newer drugs will respond in a different sequence. Especially with myeloma, for most of the treatments we have today, the goal is really to get better disease control. It's not necessarily to cure, although with such great improvements with bispecific T-cell engagers (BiTEs) and CAR T, I really think the cure is on the horizon very soon.

When we're focused on trying to make sure that we keep patients with symptoms very well-controlled and keep their disease controlled for much longer, our bigger take-home point is not necessarily that we're worried about overall survival, it's really quality of life, symptom control, and getting the best bang for our buck as we can. With each of these new trials that comes out, we keep changing the order of how we give different treatments to patients, with the goal of seeing how we can do this better than we've done it in the past. Especially nowadays, what a patient would get coming in today isn't what a patient would've gotten even one to two years ago. This is probably true everywhere in cancer just because the research is so rapidly involving.

Dr. Banerjee: Completely agree, and I will just add to the Richa's point that we're constantly making newer therapies that work better, not just in terms of efficacy, but also better safety. A topic that'll come back again and again is this word that I like, calling it "time toxicity"—basically meaning visits to clinic that don't add that much benefit in terms how long patients live or how good they feel. The PERSEUS study that we were just talking about, how wonderful it was, that was a study that just got published. It was a big phase 3 multinational study done mainly in Europe, and it showed that adding daratumumab seems to definitely help us in terms of efficacy. It was far from a perfect trial. I think Gurbakhash and I have many bones to pick with it, because our research focuses on how we can take those trial regimens and actually make them work better for patients. In that trial, they dosed bortezomib twice per week, which is one of Gurbakhash's my core research areas. Twice-per-week bortezomib has been shown to give people more neuropathy and more nerve pain but does not add anything in terms of how long they live or how long they're in remission for, plus more time toxicity and more time in clinic.

The PERSEUS study actually also used dexamethasone daily for four days in a row, so not once a week the way that we typically do it in the US. That's something that we're working on improving with a lot of our other research interests. All of you who are listening to this probably have been on dexamethasone one way or another in the modern era. Probably one of the biggest things I do once patients are in remission is I drop the dex anyway possible. In the era of daratumumab and isatuximab and carfilzomib and CAR T and bispecifics, the oldest drug that has probably the least mileage added, but the most toxicity that it's causing, is 100% those five pills or 10 pills a week of steroids, meaning dexamethasone. Trying to improve that is better.

Dr. Taneja: We also have some more questions in the chat here. The next one is, "How do you inform your patients about these updates in myeloma treatment? What can they stay hopeful for in a positive and helpful way for them to understand?"

Dr. Kaur: I can take that one. This sort of live panel is a way to do that. We're very fortunate that with the advent of social media and the Internet, information is now available at patients' fingertips. I remember when I was a fellow, not too long ago, and we were still giving out a lot of handbooks about how the drugs were approved and dosing. We have very important organizations such as the Multiple Myeloma Research Foundation (IMF), the International Myeloma Foundation, HealthTree, and of course Oncology Data Advisor, all these platforms to disseminate the information. Over the weekend, I actually gave a talk at a patient/family seminar in Boca Raton that was held by the IMF, where we disseminated this information. There are a lot of concerted efforts to get this information in the patients' hands.

Then even on YouTube, sometimes when I do patient education on CAR T-cell therapy or therapies, I spend my 20 or 30 minutes in the clinic with them and then I say, "You know what? I need you to mull over this. Go to YouTube, type in this organization and CAR T and myeloma." You're not getting information from Dr. Google; you're getting information in those videos, such as this one which is going to be available online, where the specialists who are informing you and giving you the knowledge are people who are actually treating the disease on a daily basis. There are actually a lot of good and practical resources out there, this being one of them.

Dr. Banerjee: I completely agree. I'll echo that entirely. International Myeloma Foundation has been helpful. In Seattle, for example, we have the Multiple Myeloma Fighters, it's MMFighters.com. I tell my patients, it's not MMA Fighters, that's mixed martial arts, but MMFighters.com. They're great, and we're actually faculty and give them talks by Zoom once a month, talking about updates from ASH, updates in MRD, et cetera. I think I've actually learned a lot. I gave a talk at the conference in San Diego, and I learned some tips from patients in that area about how they manage dexamethasone and side effects, and that's helpful.

Pivoting to the next question, "Is there any paper you can point to with any information on retrying daratumumab or on patients not becoming refractory daratumumab?" It's tricky, because a lot of the clinical trials haven't done this. Many of the trials of daratumumab prohibited prior exposure to the drug in real life. We do it all the time. I have my own style and Gurbakhash probably has her own too, because it depends. Even within our group, it depends. Typically, six to 12 months is what I would say is a pause that's sufficient to retrial it. The idea is that protein that the daratumumab targets, called CD38, is kind of a core protein to myeloma cell growth. If you give it enough time off the therapy, the myeloma cells that express that start to be the ones that start to grow again and then thereby become susceptible to being targeted again. Typically, I would try to do it combined with something different. I wouldn't combine the exact same drugs again, perhaps keeping the daratumumab or using isatuximab. There's not huge evidence for that if there's a pause in between, but I think it's reasonable with something else.

As all you know, daratumumab typically becomes once a month over the long haul, and isatuximab becomes once every two weeks. There have been some posters at previous ASH meetings talking about reloading the patient—giving them back the once-a-week daratumumab combined with something else, and that's often enough to put the myeloma back temporarily on the path towards remission. That's not a durable solution by itself, but it's something, and it proves that the dosing matters and time matters. Some centers—and I don't do this, I'd love to hear if any of your centers do this—will look at a bone marrow biopsy and look at CD38 expression on the cells by flow cytometry. Flow cytometry is a particular test that looks at the outside of cells and what they express. Most centers are able to stain or look for CD38 as one of the gates on that test, which is the marker that daratumumab uses. It's not that simple. In the initial studies of daratumumab, it actually didn't matter how much CD38 was on the cells or not. I don't typically tend to use that as a barometer, meaning that if it's been a year, for example, since their last exposure to that particular drug, I would be very inclined to reuse it again with or without a different partner agent. Doing a bone marrow biopsy might be curious. I don't know if any of you look at CD38 by flow to tell you whether someone should get the drug again or not?

Dr. Taneja: I've actually just heard this for the first time. It sounds very interesting, but I guess what the understanding has been over the years is that it's not just the CD38 expression at that time, but eventually there's clonal tiding that can happen. As Rahul just mentioned, CD38 is really important for the cells to proliferate, and eventually the cells that have CD38 are going to outgrow the ones that do not have it. The receptors on the original cells could also regulate with time. I have not really heard of the flow cytometry for this but would love to learn about it for theoretical purposes and to see the scientific excitement. I would like to see what the results would show with that.

Dr. Banerjee: I'll just add, the other test that we don't have now but might be available in the future—and patients have asked for this—is ex vivo drug sensitivity testing, which is a mouthful. I'm sure that could take up a whole row of a Scrabble board there. The idea of ex vivo drug sensitivity testing is actually testing whether a drug works against the myeloma cells by doing the experiment ex vivo, outside of the patient, using their myeloma cells and then going from there. This research was done by the University of Colorado. Dr. Sherbenou was the lead author. That assay is not commercially available; we don't know enough about it. So, I'm not saying that we should use that for everything we do in life, but I hope that in the future, as they've practiced using it more and as they make it available at more centers, that style of testing would be really interesting. At the end of the day, saying, "Oh, we should wait six months or wait 12 months" is a little bit arbitrary. Everyone's pace of disease is different, and everyone's myeloma is different. Potentially, there may be a time where we can say, "Look, based on the bone marrow biopsy, I can tell you this drug, this drug, this drug, this drug, and this drug will work. We're done." That would be wonderful. We are not there yet, but hopefully some day we will be.

Dr. Kaur: I wanted to add to that, that also requires one to get a routine bone marrow. Not everybody who relapses is able to get a bone marrow, and there are logistical patient preferences, because those are painful. Then flow often underestimates the population of plasma cells as well depending on how sensitive everything is. I think that is to be kept in mind. At UT, we have one of my colleagues who is a basic researcher, his name is Dr. Kareem Azab. He has a 3D bone marrow model. Actually, we've submitted grants where we're trying to combine three or four of the same drugs that we're doing in clinical practice. We want to take a patient's bone marrow, put it into this bone marrow model, and then add the drug to it and see what the response ends up being and how the disease ends up being eradicated. Oftentimes there's a big gap in that you can do these clinical trials in the lab, and they look so exciting, but there's a big stretch in how it gets translated into practice. But these are all cool and novel ways to see how we can make medicine very personalized, especially myeloma care, because a lot of treatments already have become very personalized. We're going towards that. It looks like another question from Kathy came up?

Dr. Taneja: I think this is a great opportunity to talk about transplant and how we assess eligibility. I know Rahul talked about dynamic frailty and how by giving people more of these frontline treatments, more of them are actually eligible for transplant with their treatment even if they were not at the time they first presented. The question is, "Is transplant still the best treatment for multiple myeloma?" I think we'd love to hear all your opinions, because I think it's who you ask about it these days.

Dr. Kaur: Are you talking to a transplanter, not transplanter? I think that's a prerequisite to start this conversation. I do transplant, I do CAR T, I do start-to-finish myeloma therapy. At the present, I still do transplant. We have seen over time that transplant utilization has become less, and there are so many factors that go into it, right? Patient's age and dynamic frailty are definitely an aspect of it. What is the quality of life? What are the patient's preferences? What kind of support system? These are markers that are independent of disease and sort of tell us whether we should do transplant or not, putting the patient first.

In my book, someone who has high-risk disease, which are those genetic mutations that the bone marrow has in the myeloma cells that tell you your risk status—and if doctor doesn't disclose them to you, you should always ask them about it. There's high-risk status and then we have this phrase called functional high risk. Rahul, you and I have talked about this very often—the patients who don't have these high-risk genetic features of their myeloma but are relapsing very quickly or not exhibiting a deep response to the four drugs or the three drugs that we're giving. For those high-risk patients, there's no doubt. If they are physically capable, if they have good heart function, good kidney function—well, irrespective of kidney function because we even take dialysis patients to transplant—I very much advocate for stem cell transplant. If someone is younger, the disease is standard-risk, and the patient wants to defer, then I leave it up to the patient, and we discuss the data. Ultimately, it's a patient-centered discussion that happens.

We discuss the data about the DETERMINATION trial, which is a trial where patients in one group got lenalidomide/bortezomib/dex and the other group got lenalidomide/bortezomib/dex. But then one group got stem cell transplant right after, and the second group got more RVd followed by lenalidomide maintenance. What it showed was that the patients who had upfront transplant had a longer remission time by almost 20 months, but in the end, the survival was the same. That information really helps patients make a decision about whether or not they want to do transplant.

Now, some patients may want to do it, but they may not want to do it now. You have to remember that if you want to do it, 20% of patients end up having some sort of complication or toxicity from their myeloma or from their disease treatments that they get, and they end up not becoming transplant-eligible later on. That's a key point to take home. But the DETERMINATION trial sort of helps us guide our patients when it comes to the transplant discussion. I very much still do it. There's a second part of that question, which is cardiac amyloidosis. For cardiac amyloidosis, it's a very complex discussion. I think beyond the scope of our talk, we can even briefly go into it, but that's a very nuanced discussion because individual cardiac biomarkers, what their response was to their prior therapy, and so many other factors drive the discussion. Maybe we can dedicate another patient webinar to talking about amyloidosis, but for now just focus on this if that's okay with y'all.

Dr. Thakur: I think another thing we often overlook with transplant is what patients have to go through to even get to transplant. In general, with treatment for myeloma, there's induction and consolidation, and while you're planning consolidation, you're getting everything ready for transplant. Most myeloma patients have to see two different oncologists, one that's a transplant specialist and one that's their oncologist that's been giving chemotherapy for the myeloma. At the same time when getting ready for transplant, these patients often are hospitalized for up to two to four weeks depending on how aggressive a center is. Then even after that, because they get such high intensity-chemotherapy based on the type of transplant, they get three to six months where they're really isolated. Often, patients aren't able to work unless they're working from home because they can't go outside and require frequent weekly visits with their centers.

So, transplant often has a ton of great benefits for patients in terms of improved survival in some populations and keeping the disease under better control in most populations. But when you're also thinking about whether your patient can physically get to a transplant center, unfortunately not every patient in this country lives that close to be able to do that. They often have to uproot their lives and move for three to six months, and if there are any complications, even longer.

Dr. Banerjee: Agreed. The last thing I'll say, because I know we should probably pivot to the relapsed/refractory setting shortly, is that I always tell patients that I hope every time I give a talk like this, a year from now, it's out of date. Part of this stuff will already be out of date next year. Everyone's talking about CAR T, and we're about to start talking about CAR T for this webinar. There is a study that was just activated in Europe and is already starting to accrue—Gurbakhash is nodding you might have it at your center too, eventually—called CARTITUDE-6. It's looking at CAR T versus transplant in patients who got a quadruplet induction. In 2035, ask us again when that study's fully read out, hopefully maybe 2030 for MRD or some of the preliminary end points, but we'll know then. I think that'll be a really interesting study to see, in the modern era, where transplant truly fits with a quadruplet induction and with CAR T being the competitor, so to speak. We'll see. Until then, I would still offer transplant to everybody, and it's a values discussion for all the reasons that everyone just talked about.

Dr. Taneja: Sounds great. I think just a couple more points that we can briefly talk about—apart from this specific regimen that we were talking about, dara/RVd as per the PERSEUS trial—are the other quadruplet regimens such as the one studied in the IsKia trial with isatuximab/carfilzomib. Which patients would you consider for one or either of these?

Dr. Banerjee: What I tell community doctors is I don't care which quadruplet it is, as long as it's a quadruplet. That's the short answer to it. I think a lot of patients agonize over, "should I get dara/RVd or dara/KRd (carfilzomib/lenalidomide/dex)? Or Kaiser is offering isatuximab/VRd, should I do that? Or isa/KRd? "I will say that starting with four drugs doesn't mean you're legally obligated to finish with four drugs. Most of my patients end up on two or three or dose reductions. In general, I tend to use or consider carfilzomib—so dara/KRd or isa/KRd—for patients who have one or two high-risk features, typically two or more high-risk features. Isatuximab is not yet routinely used or approved for frontline therapy in the US. Some insurance companies like Kaiser can do it. In terms of dara versus isa, I wouldn't sweat that in the frontline setting. In terms of bortezomib versus carfilzomib, for boards, we teach the medical students that bortezomib causes neuropathy, and carfilzomib causes heart issues. In real life, it's much more complicated than that. It depends on the dosing that we talked about—once weekly, twice weekly—it depends on the dosing of the carfilzomib. Is it the full dose or is it a partial dose? Are they given lots of fluids? Do they have a cardiologist, do they not? I tend to talk about both. However, this is going to be topic for another day. I think I know centers in New York, for example, like Memorial Sloan Kettering has moved dara/KRd for almost everyone regardless of such genetic risk. I'm doing it more for the two-plus high-risk patients based on a study called the MASTER study, which may be beyond the scope of this, because I know we need to pivot. Gurbakhash, any thoughts on that?

Dr. Kaur: No, I think you guys have mentioned all the appropriate points. The only thing is to keep in mind is that different centers, whether an oncology practice or cancer center, have something called formularies, and there are Pharmacy & Therapeutics (P&T) committees that go through the financial aspect of which drug is more feasible. That's just a reality of what we have to deal with. Many may want to do isatuximab, but their formulary only carries daratumumab and vice versa. That also plays a role in the backend of how this ends up being chosen. But we can pivot to the next topic.

Dr. Taneja: A lot of patients, as per the PERSEUS trial, were actually getting dara and lenalidomide maintenance after transplant and consolidation, and 64% of them were able to come off the daratumumab based on MRD negativity. I think that is something new and exciting in terms of maintenance therapies for myeloma patients. Historically, they've always been on treatment with maintenance. With the MRD testing, we are at least able to deescalate some of these in trials. What is your practice regarding the use of MRD testing or maintenance therapies?

Dr. Kaur: I can go first. I only reserve doublet maintenance, which means two-drug combinations, for high-risk patients. Generally, even if I do a quadruplet, which is the four-drug regimen for induction, I will mostly do lenalidomide for maintenance. If somebody has a deletion 17p or those genetic markers that we talked about, then I would do a doublet, a two-drug combination, whether it's dara/lenalidomide or a proteasome inhibitor, bortezomib/lenalidomide. The factors that help decide which one you end up choosing include history of cardiac disease or neuropathy and what their exposure was. Generally, it's one drug for standard-risk patients.

Dr. Banerjee: I would agree. I think for the topic of MRD-guided discontinuation, to be fair, they would go from dara/len to just len maintenance for the long haul. I think that is still the US standard of care—lenalidomide until progressive disease or intolerable toxicity. But again, ask us again in a year. Studies like MASTER and MASTER-2, and there's another study called DRAMMATIC—a Cooperative Group study, SWOG s1803—are looking at this. Every year, we'll get more and more information about patients for whom we can stop based on MRD, what threshold to use, how long to wait, and so forth. There's more to come on this

Dr. Thakur: So far, we've talked about when a patient is newly diagnosed with multiple myeloma, but unfortunately, myeloma does have multiple episodes of relapse. While we have different drugs to treat each of the relapses, there have been some new drugs that are FDA-approved, and in the past, they've been used much further down the line. But just because they've been blowing everything out of the water, we've been bringing them more upfront. Two of them are CAR T cells; one is idecabtagene vicleucel (ide-cel) and the other is ciltacabtagene autoleucel (cilta-cel). Then we also now have a ton of BiTEs and bispecifics, so I think maybe we can start talking about those therapies too for myeloma. With the KarMMA and the CARTITUDE trials, how have you guys started incorporating those treatments into your practice for patients?

Dr. Kaur: Before we go into that, let's what talk about, what is CAR T-cell therapy and bispecific therapy? We should spend a few minutes on that, so I can do that. CAR T-cell therapy is basically the patient's T cells are taken out, you get hooked up to a machine, they get collected, and then they're sent to a lab. In the lab, the cells are basically retrained to think of myeloma as a foreign entity, to say, "This is foreign, you've got to go back in the body and kill it. If you see cancer myeloma cells, you've got to do your job." And that's exactly what happens. That retraining or re-engineering time takes about four to six weeks at minimum. It could be longer based on the current products we have. Then those CAR T cells are reinfused into the patient, and that requires a seven-to-14–day hospitalization or outpatient period where patients are very closely monitored for toxicity. It's a big gun, one-and-done kind of an approach where you're harnessing the power of the immune system through bispecific therapy. I

Then T-cell engager therapy is where the T-cell is kind of shy, hiding out in the backend, and then the BiTE comes in and says, "Hey, I'm going to play matchmaker. I'm going to hook onto the T-cell and I'm going to hook onto the myeloma cell and bring them close together." And when they come, what happens? The T-cell is recognizing, "Oops, this is a foreign entity, I've got to do something about it." Then the T cell goes and targets the myeloma cell. The BiTE therapy has to be given weekly or every other week, and there are even some clinical trials where it's being given on a monthly basis.

CAR T-cell therapy and BiTE therapy are both very effective therapies in an era where, if you take a single myeloma drug, such as belantamab, the response rates as a single agent were usually about 20% to 30%. Now we have CAR T-cell therapy and BiTE therapy. The responses when patients are given these therapies are about 70% to 90%, and these are very deep and durable remission. Patients get into remission, and they stay into remission. That has revolutionized, as Richa was saying, what we as myeloma specialists do to. With this background, I'll turn it over to Rahul to talk about how he incorporates these agents.

Dr. Banerjee: That was an excellent introduction, thank you, Gurbakhash. I agree, and I think the tricky part is, as Richa had mentioned earlier, that historically, a lot of times all of our newer treatments get saved for later lines of therapy. That's just how clinical trials are designed, and now they're slowly being moved up into earlier lines. As of right now, March 18, 2024, in the US, CAR T and bispecifics are only approved for patients who've had four or more prior lines of therapy.

A line of therapy is sort of a dated term referring to a treatment not working because myeloma starts to relapse, or patients have toxicities from it. That may change. Just last Friday, for example, even newer than ASH, the FDA's Oncology Drugs Advisory Committee (ODA) met to discuss two trials that are moving CAR T into earlier lines. In one of the studies, it's after two prior lines of therapy, with a drug called ide-cel or Abecma®. And in the other study, it's after just one prior line, even at first relapse, with a drug called cilta-cel or Carvykti®. In both cases, the advisory committee recommended moving these drugs into the earlier settings. It still needs to be approved by the FDA and then employed, into as Gurbakhash alluded to, through insurance, formulators, and so forth. But it's coming, and I think it's very likely that by this time next year, CAR T will routinely be available in earlier lines of therapy.

As of right now, I'm going by the book, as we have to, because insurance won't pay for it otherwise. We have to say, "Look, get to four prior lines of therapy, and only then are you a candidate for CAR T or bispecifics." It's tricky because in real life, for most patients, once three lines of therapy have stopped working for the patient, that fourth line is not really doing much. It's just checking off a box, in my mind.

I'm actually very grateful that if CAR T moves up, it'll put the decision making back into my hands with my patients in front of me and not the insurance company dictating who's able to get what. They'll still certainly try, no doubt about that. But what I would say is as of now, as soon as someone's had their first relapse, I start thinking about how might CAR T fit into their future.

One could argue that for someone who may get CAR T in the future, a drug like bendamustine or certain chemotherapy drugs might actually make CAR T not work as well. Dr Kaur alluded to the fact that as of now, our approved CAR T-cell therapies require that patients' own immune cells to be collected, and certain chemotherapy drugs like bendamustine tend to interfere with that. There's a theoretical risk that if someone is on a bispecific antibody like teclistamab, talquetamab, and elranatamab for a long time and then you try to collect your T cells for CAR T, those T cells might get exhausted from the continued redirection that the bispecific antibody has led to them. So, if someone has CAR T in their future, I might try to avoid that and try to sequence the therapies. Real life is not so simple, and some patients cannot get CAR T or it's not safe for them to get CAR T. In those cases, bispecifics are an excellent option.

I think my bottom line as of now is I tend to try to get patients to CAR T if I can—clinically, logistically, and safely for the patient—rather than bispecifics. However, bispecifics are super important. If CAR T is not an option or doesn't work, or patients can't get to CAR T right now, as soon as someone's had their first relapse, I start thinking about it as soon as they've had three prior lines. I definitely start planning for CAR T by default. The fourth line is not going to work no matter what it is. Hopefully a year, if not six months from now, CAR T will be approved in earlier lines. Then probably my sweet spot would be that third or fourth line of therapy probably should be CAR T. Second line is controversial because I think there are a lot of good second-line treatments out there. A lot of my patients for CAR T, which Richa alluded to, have to move and relocate to get here. If my patient has to choose between CAR T and six months of their life being uprooted and moving to the big city, versus dara/KRd or isa/KRd where they are with their primary oncologist, and they'll get equal amounts of mileage, I would say, "Don't come here, keep doing what you're doing, and come find me afterwards."

Dr. Thakur: I think those are all really good points, and it's so interesting to see how insurance really plays a big role in what we're able to give to our patients. Typically, when patients have relapsed after CAR T, do you still consider switching the different agents, or do you think that you need to go back to other more traditional chemotherapy agents?

Dr. Kaur: That is an excellent question. First of all, no insurance company is going to pay us to do another CAR T, especially if it's the same target, and right now the only target we have is BCMA. You are right. A lot of our life revolves around insurance companies and begging them to give up therapies for our patients. We end up not utilizing that just because of the financial and insurance issues. The second thing is if you do relapse after CAR T, there's this idea that maybe the CAR T cells are exhausted, and you want to reinvigorate them. There are actually clinical trials that are in development for giving some sort of immune awakening kind of medication to do that.

One of those medications is actually what patients are already taking, such as immunomodulatory agent (IMIDs). I believe one of my colleagues at City of Hope is going to have a trial where patients get ide-cel, and post–idel, they may continue on mezigdomide, which is one of the CELMoDs. It's not a drug that's approved yet, but it's in clinical trials to keep the T-cell activated so they don't lose their response. Another trial that's in development already—and we're actually going to participate as a center—is an investigator-initiated trial to give something called a programmed cell death protein 1 (PD-1) inhibitor such as nivolumab after you achieve a partial response. There are strategies that are in development right now. They're looking at how to keep those T-cell reinvigorated; that's one.

The other thing is how to sequence, because once you've gotten CAR T in the fifth line, what's beyond that? How do you sequence immunotherapies? We have the bispecifics and CAR T cells, and like Rahul said earlier, maybe you don't want to do the BiTEs before the CAR T-cell. In our clinical practice, when we don't have options, I've given both teclistamab and talquetamab post–CAR T failure—particularly teclistamab, even though it targets the same thing, which is BCMA on the myeloma cells, we're still able to have deep and durable responses. There's a lot of research going on in that space as well, because we don't have the exact answer. I think we'll get more information as time goes on. Then obviously I recommend clinical trial participation to all patients, as that's what helps us get these therapies approved for all patients. So, I try different approaches in this space in order to capture the responses. I don't know what Rahul thinks, and he can add on.

Dr. Banerjee: Not much to add there, that was excellently stated. Again, we're coming back to the same principal that every year, this talk will be a little bit irrelevant, bit by bit. Alankrita, I think you alluded to this earlier in terms of sequencing—there may very well come a time when we use CAR T second-line for almost everybody 20 years from now, and some of these older drugs are coming out after CAR T failure. So, the whole cart gets put before the horse—I guess that's a pun—CAR T gets put before the horse and everything else beforehand. Time will tell, and I think that will be really interesting.

The other part that we haven't really talked about is precision diagnostics. Gurbakhash briefly alluded to the idea of functional high-risk, and I know Alankrita put that note in the chat, that unfortunately we can't always tell who those patients are who need more aggressive therapy or need two-drug maintenance and not one. We kind of wing it. For patients who have high-risk cytogenetics, we typically use two if not three drugs for maintenance versus not. Many of these patients with functional high-risk who have an early relapse have standard-risk cytogenetics. I've had patients, as I'm sure Gurbakhash has as well, who have deletion 17p, but they are in remission for years and years. So, those diagnostic criteria are not destiny. We need better tools to understand who needs that extra layer of support versus for whom we can deescalate therapy and how can we catch relapses earlier.

We talked about imaging, and one of my takeaways from these last couple of ASH meetings has been whole-body MRIs. MRIs focused on the bone marrow often can pick very subtle lesions within the bone marrow before the myeloma cells start chewing into the bones around them. There's actually an ongoing study by Dr. Mohyuddin at the University of Utah, looking at smoldering myeloma using MRIs, not treating those patients, and seeing what happens. It may be that if we are able to find a smarter—I don't want to say more intensive monitoring, because for a lot of patients, there's a lot of time toxicity that comes from MRI, an extra lab work, and soluble BCMA—there may be a way in the future for us to tailor our intensity of monitoring to catch the relapses like that when they happen and give therapies when they're needed and not when they're not needed.

We have about three minutes left, so maybe we can just go around and say one cool abstract or parting words of advice from ASH for patients, or just share some guidance for patients with myeloma. I will let Gurbakhash go first, and then we can go back around, and I can go last.

Dr. Kaur: I think everything that's coming out is quite exciting. Sometimes we're overdoing it, sometimes we're underdoing it. But the point is that we're very fortunate to be in this era where there's so much remarkable discovery happening. As a patient, just keep on advocating for yourself, because you are your best advocate. Seeking a second opinion or seeking extra information from colleagues or other people is the best way to go about it. And hopefully, we'll have better therapies with less toxicity in the future.

Dr. Banerjee: Richa, do you want to go next in reverse order and then I can round it out?

Dr. Thakur: My parting advice for patients would be, so many of the abstracts at ASH this year were really focused on side effects and toxicity profile for patients. Oftentimes, patients aren't very vocal with what side effects they're having. There are so many different ways we can help manage these. Especially as a palliative specialist, I love treating these side effects all the time. So, please bring these up with your oncologist, because you can always do dose reductions for your chemotherapy. You can always add a secondary medicine to address pain. The thing is, patients with uncontrolled symptoms do worse than if your symptoms are better controlled, and it also helps us as oncologists to take care of you better, so please don't ever hide your side effects.

Dr. Banerjee: Excellent. Alankrita?

Dr. Taneja: I actually want to talk about lifestyle medicine and how it's also being integrated in the care of our myeloma patients. Particularly, a lot of my mentors are working in the fields of exercise and plant-based diets, which can improve T-cell exhaustion. T-cell exhaustion is the big problem with CAR Ts. I know it's basic information and something our grandmothers tell us, to just eat good food and exercise and stay healthy, but we should not undermine the benefits of those as well.

Dr. Banerjee: These are all excellent points. I would add something that Gurbakhash mentioned earlier is that—and I think it might not be a problem for anyone listening to this, because you're clearly very empowered patients—but also, I think seeking guidance from other patients and patient support groups, I cannot understate enough how important that's been for many of my patients. Many of them are pretty reluctant. Some of you listening to this may be reluctant and say, "Oh, I don't want to zoom with other patients, because everyone's case is different." I agree with that, but I also have found that it's very helpful for patients to learn stuff from each other that I couldn't tell them. It is one thing for me to talk about CAR T and bispecifics, but for the details of lenalidomide funding mechanisms and which grants to use and how to pay for this and which resources to use, things like that, patients are excellent.

I will say that the IMF has groups that they can organize in person, or virtual support groups or Facebook groups. Obviously, there's a lot of misinformation on the internet, but I think having that community important, because multiple myeloma is not a rare cancer by any means. It's getting more and more common as people are getting older and more detection is happening. There's a lot of work left to be done, but I think having patients as advocates is really nice.

With that in mind, maybe I can close things out then. I will say thank you all, Dr. Thakur, Dr. Taneja, and Dr. Kaur, for speaking here. Thank you, Keira, for organizing this, and thank you all for listening. I think March historically been called Multiple Myeloma Awareness Month. The IMF has tried to change that to Myeloma Action Month, and I love that. I think hopefully all of you have learned or heard about different tools that we've talked about and ways to take action with your own health—whether it be lifestyle interventions, better talking about your toxicities, getting a second opinion in an academic center, or having a patient support group, or any combination thereof. I think these are all great ways to help people live with myeloma for better and for longer. So with that, thank you all for your time. Have a good afternoon.

Keira Smith: Amazing, thank you all so much. Thank you again to the audience for watching and for submitting such thoughtful questions. I'm glad our panelists were able to answer these and provide such insightful answers to them. Thank you again to everybody for watching, and I hope you have a great rest of the night.

About the Speakers

Rahul Banerjee, MD, FACP, Editor in Chief, is an Assistant Professor in the Division of Medical Oncology at the University of Washington (Seattle, WA); he also holds a faculty appointment at the Fred Hutchinson Cancer Center. He previously completed his Hematology/Oncology Fellowship and Advanced BMT/CAR-T Fellowship at the University of California, San Francisco. His clinical interests are in multiple myeloma, AL amyloidosis, and CAR-T therapy. His research interests are in toxicity management, digital health, and the patient experience.

Alankrita Taneja, MD, is a Hematology/Oncology Fellow at Roswell Park Comprehensive Cancer Center. She is interested in multiple myeloma and cellular therapies and is passionate about humanism and equitable care.

Richa Thakur, MD, is both a Palliative Care Physician and Hematology/Oncology Fellow at Zucker School of Medicine at Hofstra/Northwell Health. She graduated from Washington University in St. Louis with a bachelor's in chemistry, medical school at Texas A&M, residency in Internal Medicine, and a fellowship Palliative Care at Zucker School of Medicine. Her research interests include improving quality of life in patients diagnosed with hematologic malignancies.

Gurbakhash Kaur, MD, is an Assistant Professor of Medicine in the Department of Internal Medicine at the University of Texas Southwestern Medical Center and Harold C. Simmons Comprehensive Cancer Center. She specializes in the treatment of patients with multiple myeloma, AL amyloidosis, andother plasma cell disorders, including the use of CAR T-cell therapy, immunotherapy, and stem cell transplantation. She actively participates in clinical trials investigating novel therapeutic options and quality-of-life improvements for patients with multiple myeloma.

Transcript edited for clarity. Any views expressed above are the speakers' own and do not necessarily reflect those of Oncology Data Advisor. 


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