Around the Practice: Improving Outcomes in Newly Diagnosed Multiple Myeloma - Episode 1
After reviewing the case of a patient with transplant-eligible newly-diagnosed multiple myeloma, experts consider optimal selection of first-line treatment.
Sagar Lonial, MD, FACP: Welcome to this CancerNetwork® presentation titled “Around the Practice: Improving Outcomes in Newly Diagnosed Multiple Myeloma.” I’m your host, Dr Sagar Lonial, a professor and the chair in the department of hematology and medical oncology at the Emory University School of Medicine and the chief medical officer for the Winship Cancer Institute of Emory University in Atlanta, Georgia.
I’m very fortunate to be joined by a great panel of experts, and I’d like to invite my esteemed fellow panelists to introduce themselves. Let’s start with Dr Gertz.
Morie A. Gertz, MD, MACP: Thank you, Professor Lonial. I’m Morie Gertz, and I’m junior faculty at the Mayo Clinic in Rochester, Minnesota.
Sagar Lonial, MD, FACP: Because everybody is equal, right? Dr Jakubowiak.
Andrzej Jakubowiak, MD, PhD: Hi, I’m Andrzej Jakubowiak. I’m a professor of medicine, not a junior, and I’m also the director [of the myeloma program] at the University of Chicago in Chicago, Illinois.
Sagar Lonial, MD, FACP: Thank you. Last but not least, Dr Hari.
Parameswaran Hari, MD, MRCP: Thanks, Dr Lonial. I’m Parameswaran Hari from the Medical College of Wisconsin [in Milwaukee, Wisconsin], and I’m a junior faculty as well.
Sagar Lonial, MD, FACP: There are a bunch of junior people here. This will be an eventful uninformed discussion then. Thank you for joining me. We’re going to discuss strategies in optimizing first-line therapy for patients with newly diagnosed multiple myeloma, including patients with high-risk disease. We’ll review 2 patient cases and involve our audience by using an interactive online platform to answer several polling questions that will be discussed by our panelists.
Let’s begin. We’ve got a few polling questions to start off. First, what is your specialty? General medical oncology, hematologic oncology, hematology, or other? Please take a moment to answer. I always think it’s interesting the way this works, because our European colleagues are very separate about hematology and medical oncology. In the United States, we tend to group a little more. It looks like we’ve got a good mix. There are a few folks who are only in hematology, but some in hematologic oncology and some general as well.
Approximately what percentage of your patients have a diagnosis of multiple myeloma? Less than 10%, 11% to 20%, 21% to 30%, 31% to 40%, or greater than 50%? It looks like we’ve got about 30% who see less than 10%, another third who are 11% to 20%. That’s a pretty active myeloma practice. We’ve got a few percentages or others who have a little more than that as well. That’s a good mix of different types of experience.
Let’s begin Module 1: Choosing an Optimal Induction Regimen in Transplant-Eligible Newly Diagnosed Multiple Myeloma. We’ve got a case, and we’re going to ask our experts to weigh in on some questions about it. Let’s start with that first slide describing the case.
Case 1 is a 47-year-old gentleman with a hemoglobin of 9 g/dL, calcium of 11.3 mg/dL, LDH [lactate dehydrogenase] of 200 U/L, albumin of 3.8 g/dL, and creatinine clearance of about 45 mL/min. Bone marrow showed about 17% clonal plasma cells, free kappa light chain was 20 mg/dL, serum M protein was 8 g/dL, cytogenetics were normal, and he had an ECOG performance status of 1. PET [positron emission tomography]-CT showed multiple bone lesions in the thorax and vertebra, which I’m going to presume were PET-positive. There was no extramedullary disease. He was diagnosed at that point with an IgG kappa multiple myeloma and was identified by the physician as being transplant eligible. This is a pretty straightforward case that all my colleagues have seen before, maybe even this week.
Let’s go on to the next question, which is choices and discussion on what the audience might use as their first-line treatment for this patient. The choices are: A) VRd [bortezomib, lenalidomide, dexamethasone]; B) daratumumab plus VRd [bortezomib, lenalidomide, dexamethasone]; C) KRd [carfilzomib, lenalidomide, dexamethasone]; D) daratumumab-KRd [carfilzomib, lenalidomide, dexamethasone]; E) bortezomib-cyclophosphamide-dexamethasone [VCd]; or F) other. If you’re going to say other, send us what your choices might be. We’ll wait a second while we’re waiting for this poll to go through. We’ve got some discussion questions. Please don’t forget to send your questions to us through the questions tab as well because we can get to those during our group discussion.
Let’s see what the survey says in terms of results. It looks like about 57% went with option A, which was VRd [bortezomib, lenalidomide, dexamethasone], and we had a few more equally divided among the daratumumab–VRd [bortezomib, lenalidomide, dexamethasone], KRd [carfilzomib, lenalidomide, dexamethasone], and daratumumab–KRd [carfilzomib, lenalidomide, dexamethasone]. Nobody said VCd [bortezomib, cyclophosphamide, dexamethasone], which I’m really excited about, because now I don’t have to attack VCd [bortezomib-cyclophosphamide-dexamethasone]. We had 1 person who said other. That’s a good mix of answers.
Let’s start with our panel. I’m going to start with Dr Gertz. How do you determine if a patient is eligible for autologous stem cell transplantation? What are the criteria you look at?
Morie A. Gertz, MD, MACP: The big thing with transplant is safety. At the end of the day, the transplant isn’t successful if we have therapy-related mortality or 2 months in the hospital. That’s not where we want to end up. So we’re looking for mortality rates of about 0.5%—certainly less than 1%—and that should be the major determinant: Is this patient’s therapy-related mortality going to be above 1%? That’s primarily done by fitness. You can use questionnaires, and there are scales, but the truth is that it’s not very practical for daily clinic function. Age is certainly not a criterion. We transplant up to 78 years of age with full-dose melphalan 200 mg/m2. And creatinine absolutely isn’t a criterion because, although we’ll adjust the dose in that case, we’ll transplant patients on chronic dialysis and a GFR [glomerular filtration rate] of 20 mL/min.
It boils down to the comorbidities. Do we have someone with profound COPD [chronic obstructive pulmonary disease], who is oxygen dependent or with poor diffusing capacity? Are there a lot of comorbidities associated with cardiac disease? The age group is 60 to 75. They have coronary artery disease, hypertrophic cardiomyopathy—all those things. I can’t give you a website where I fill out a number, but I look at their fitness and ask, “What’s the possibility that this patient won’t survive the transplant?” Of course, if you look at someone this age, the likelihood of transplant is 100%. Certainly, we’re transplanting patients who are 75 years old, but it would be only 15% of the 75-year-olds, because comorbidities increase with age. But your 2 key questions are, how fit are the patients? And what’s the likelihood of therapy-related mortality?
Sagar Lonial, MD, FACP: Thank you. Dr Hari and Dr Jakubowiak, do you want to add anything to that?
Parameswaran Hari, MD, MRCP: To add to what Dr Gertz just said, I want to point out that transplanters are very good at selecting patients for transplant. As Dr Gertz said, even in older patients who undergo transplant, the CIBMTR [Center for International Blood and Marrow Transplant Research] just published about a year ago that with 70-year-olds, the transplant-related mortality is very close to 0%, defined as the first 100 days of mortality. Essentially, the message is that most patients who you think are transplant eligible should have a meeting with a transplanter so that they can decide for themselves in conjunction with the discussion with the transplanter.
Andrzej Jakubowiak, MD, PhD: I could add 1 brief comment on our experience. For patients who are getting close to the edge—in our institution, that’s anybody over 65 years old—we have 2 layers of selecting patients for transplant where the safety, as Dr Gertz indicated, will be assured. There’s a multidisciplinary half-day clinic, which essentially looks through a variety of tests, and specialists eye whether a patient is in good shape and, maybe most important from our perspective, whether we need to optimize anything to make this as safe as possible. The optimization component is probably more important. It sounded very supported until we analyzed the data and found a dramatic difference in outcomes for the patients who were going to the clinic. It’s something we published. Maybe not in every institution, but it’s good to think about this from that perspective and have a different set of eyes to determine eligibility.
Sagar Lonial, MD, FACP: Yes. That’s an interesting point. The idea of age not being an independent criterion is really important. Dr Hari and his group have published a really important paper talking about using CIBMTR data, where age demonstrated that older patients could gain equal benefit. We’ve got that data institutionally as well, and that’s sometimes lost in the community where older patients can get through this safely whether or not you adjust the dose of melphalan. Let’s ask you to put your stake in the ground. I’ll start with Dr Jakubowiak this time. What induction would you have chosen, and why? What factors do you take into account when you make that decision?
Andrzej Jakubowiak, MD, PhD: I would have chosen daratumumab–KRd [carfilzomib, lenalidomide, dexamethasone], and I’ll explain why. There are some limitations for that choice, which I’ll also discuss. We don’t know all the details about his risks and other factors, but the important factor for me is that this patient is young. He’s 47 years old, so from my perspective—more for this than somebody who’s in their 70s—we need to pick a regimen that has the best chance of achieving as extended a remission as possible. From that perspective, we’ve recently seen very good results with quadruplets. As we know, backbone RVd [lenalidomide, bortezomib, dexamethasone] and KRd [carfilzomib, lenalidomide, dexamethasone] for this quadruplet would be a natural choice for this patient in the United States.
There’s maybe an edge, which isn’t supported by data from randomized trials but by independent comparison, for quadruplet with daratumumab and KRd [carfilzomib, lenalidomide, dexamethasone], with outstanding results published by Ola Landgren from the MANHATTAN study, showing that it’s equally good for patients who are transplant candidates from Dr [Luciano] Costa’s group and his MASTER trial results. We published smaller results from a smaller 20-something-year patient study, which also shows results in our hands with our experience. We have ongoing daratumumab–KRd [carfilzomib, lenalidomide, dexamethasone]. It’s very well tolerated, fairly safe, and an extremely active regimen. I’ve treated an 85-year-old with this regimen who was in good shape, but somebody in this age has been able to tolerate it. This would be my vote.
My concerns, and I’ll share how we sometimes handle these patients, include that he has pretty high total protein, or M protein. He has borderline renal insufficiency. It’s OK to go directly to daratumumab–KRd [carfilzomib, lenalidomide, dexamethasone] in my opinion, but with maybe higher risk of complications during the first cycle. We typically—especially if there’s already hypercalcemia—sometimes apply a short course of steroids, which I’m no longer using, or maybe 1 cycle of Velcade, a bortezomib-based regimen, and then convert to daratumumab–KRd [carfilzomib, lenalidomide, dexamethasone]. In short, I would have chosen daratumumab–KRd [carfilzomib, lenalidomide, dexamethasone] with maybe those additional comments.
Sagar Lonial, MD, FACP: All right. Dr Hari, what are your thoughts?
Parameswaran Hari, MD, MRCP: I generally agree with what Dr Jakubowiak said. Having said that, I’d probably choose to treat this patient based on age with the quadruplet because we know that based on the large randomized GRIFFIN trial, which compared with triplet VRd [bortezomib, lenalidomide, dexamethasone], the addition of daratumumab gives you a higher percentage of deep responses to complete response, which was the primary end point for that study, along with MRD [minimal residual disease] negativity and PFS [progression-free survival] advantage. Based on that, I’d probably choose to do daratumumab–VRd [bortezomib, lenalidomide, dexamethasone]. We don’t have the data on this patient’s cytogenetic risk or R-ISS [Revised Multiple Myeloma International Staging System] stage, etc. We know that the LDH is normal from the case that’s given. Based on that, I’d probably settle for daratumumab–VRd [bortezomib, lenalidomide, dexamethasone], which is very well tolerated. The patient seems to be transplant eligible and going for a transplant. So I’d tend to follow based on age and the need for him to get to a deep MRD-negative remission. That’s my choice.
Sagar Lonial, MD, FACP: Dr Gertz?
Morie A. Gertz, MD, MACP: We know from the joint ECOG and SWOG trial for patients where transplant isn’t intended and high-risk genetics aren’t known that VRd [bortezomib, lenalidomide, dexamethasone] and KRd [carfilzomib, lenalidomide, dexamethasone] are identical in terms of progression-free and overall survival. This patient has the best possible prognosis that you could see. For me, this would be daratumumab–VRd [bortezomib, lenalidomide, dexamethasone] and transplant for sure. I certainly would use a quadruplet. Unlike my colleagues, I have patients who still relapse with multiple myeloma, and I’m going to save carfilzomib as second-line therapy.
Sagar Lonial, MD, FACP: All right. If one were to take this microcosm and broaden it to the rest of the country, we might be a pretty narrow minority of folks who would start with a quadruplet. What do you think has driven that change? What are the data that have driven that change? I do the same thing, so I’m not going to put you guys in as if you’re early adopters. I use daratumumab–VRd [bortezomib, lenalidomide, dexamethasone] as well, but each of us has a different rationale for why we do what we do. Andrzej, you listed some small phase 2 studies, which don’t always pan out when they go head-to-head. What’s driving your decision? What’s the end point you’re using to make that decision?
Andrzej Jakubowiak, MD, PhD: As I started saying, this is a young patient. Whether there’s high risk or some risk, achieving MRD negativity is predicting the longer remission. We can buy this patient more time, and the difference in safety is very much great between those 2 regimens. Independent comparison from the smaller phase 2 studies, like our 2 KRd [carfilzomib, lenalidomide, dexamethasone] studies already published and the French study with transplant, seem to be mirroring one another. That was supported to some extent from trusting endurance results from ECOG by the randomized phase 3 Italian FORTE trial in which KRd [carfilzomib, lenalidomide, dexamethasone] arms without antibody performed similarly to our phase 2 study.
I’m extrapolating that to what I’m seeing with the MRD rates reported from Dr Costa’s group with the MASTER trial, as well as the MANHATTAN trial with Dr Landgren, where we’ve seen our highest reported. I understand that there’s no appropriate way of choosing, but 1 way or another, we choose. We always pick based on what we see. Daratumumab–KRd [carfilzomib, lenalidomide, dexamethasone] wasn’t compared in randomized trials, but there’s some reason to believe that this could be a good backbone with KRd [carfilzomib, lenalidomide, dexamethasone] and antibody.
A number of studies are conducting randomized trials with KRd [carfilzomib, lenalidomide, dexamethasone] and daratumumab or KRd [carfilzomib, lenalidomide, dexamethasone]–isatuximab, so that’s another quadruplet similar to this 1. Many of us believe this is a good regimen to potentially continue to explore. I agree with Dr Gertz that ultimately that needs to be proven in the randomized setting, especially having endurance results. I’m defending my choice based on this particular rationale: it’s a young patient, we’re getting him statistically better, and the probability of achieving MRD negativity and a good long-standing response is good.
Sagar Lonial, MD, FACP: I presume you’re using MRD at cycle 4 as your end point. Dr Hari and Dr Gertz, what end point are you looking at to make that decision for quadruplets over triplets?
Parameswaran Hari, MD, MRCP: For me, it’s a different end point, which is MRD at the end of about a year. Essentially, in a year’s time, you’ll catch up if you do a transplant.
Sagar Lonial, MD, FACP: Yes. OK.
Andrzej Jakubowiak, MD, PhD: I have to qualify that we wouldn’t use MRD results for decision-making at 4 cycles.
Sagar Lonial, MD, FACP: No, I understand. We’ll get to that in a minute.
Morie A. Gertz, MD, MACP: Not for decision-making. But in terms of why you would pick a quadruplet over a triplet, there are a bazillion studies that show that if you’re MRD negative, you’ll do better. It doesn’t matter how you get there. It doesn’t mean that it changes how you treat, but if you get there, then you’re going to do better. When you look at these quadruplet studies, the MRD-negative rates are higher than anyone else has reported. I’m not going to sit and wait for the progression-free survival 5 years from now, which would be after undertreating 400 patients.
Sagar Lonial, MD, FACP: I understand. You guys are all aligned that you’re looking at MRD negativity rates within the first 3 months of treatment that likely drive that decision. I get it. That’s perfect. Is there anybody now in 2021 who you’d treat with a triplet instead of a quadruplet?
Morie A. Gertz, MD, MACP: I’ll have to say no. Even with very frail patients, I’ll do modified quadruplets. I may reduce the dose and certainly scale the dexamethasone way back or not give them the full dose of bortezomib or whatever. I’m still going to expose them to 4 drugs.
Sagar Lonial, MD, FACP: OK.
Andrzej Jakubowiak, MD, PhD: I agree, and we probably should add to this discussion that not only do we see great MRD rates with quadruplets, but we have evidence from the CASSIOPEIA study where the quadruplet was shown to be superior to the triplet. It’s VTd [bortezomib, thalidomide, dexamethasone], but extrapolation is appropriate probably for RVd [lenalidomide, bortezomib, dexamethasone] backbone and KRd [carfilzomib, lenalidomide, dexamethasone] backbone. That’s why I’m thinking that this is well supported. I completely agree with Morie. Knowing all this, I’d carefully adjust the treatment plan but still consider quadruplet for even older patients, but maybe not those who are super frail.
Sagar Lonial, MD, FACP: Yes.
Parameswaran Hari, MD, MRCP: I’m pretty much the same, with quadruplet lite for older patients.
Sagar Lonial, MD, FACP: Got it. Let’s go to our next polling question then, because this has been a great discussion. Based on the response criteria used in clinical trials, which of the following do you consider an adequate or successful treatment response in your patients following induction? What response would lead you to say you’re not going to change to another regimen? MRD negativity, CR [complete response], VGPR [very good partial response], or other? We’ll take a second to see what the response looks like, and then we’ve got some questions for our panel around that. This is a moving target in many ways. There was another nice CIBMTR analysis a few years ago from Ravi Vij that spoke to the futility of a second induction if you didn’t get to where you wanted to be.
Most folks are saying MRD negativity or CR. How do you all view this in the current paradigm of very active treatments? What are you looking for before you move on to the collection of cells and transplant? We’ll start with you, Morie.
Morie A. Gertz, MD, MACP: It’s a loaded question. I would have picked other. If you’ve got someone who’s had an IgG kappa MGUS [monoclonal gammopathy of undetermined significance] for 8 years and then develops lytic bone lesions, and I got their M-spike [monoclonal protein] from 1.6 to 1.0 g/dL, which is less than a PR [partial response], I’d go ahead and transplant them and ride it out because they have proven indolent biology. If I have an 80-year-old who I’m not transplanting and I do a quadruplet and get an OK response, I’m not saying it’s inadequate based on a single snapshot in time that the M-spike didn’t hit 90%. I’m going to finish induction, start maintenance, and ride it out. Because this issue about what the end point is doesn’t take into account their underlying biology and whether they have high proliferative rates or adverse genetics.
If I get MRD negative, then I’m cheering them and waving flags. But if they don’t get a PR, I’m saying, “It’s OK. Let’s see.” They haven’t really failed the treatment. They’ve had cytoreduction. Before I say, “This isn’t working anymore, we’re going to abandon these drugs and use up the next regimen,” which I want to save for when they relapse. I’m very excited when they’re MRD negative, but I’m not making the treatment decisions and going to second-line therapy because I thought it wasn’t deep enough. It depends on their biology.
Sagar Lonial, MD, FACP: You’ve added 3 more degrees of complexity to this question by bringing that up, but we’ll turn to Dr Hari. What’s your answer?
Parameswaran Hari, MD, MRCP: I’m a big believer in response-adapted therapy, so I usually start with daratumumab–VRd [bortezomib, lenalidomide, dexamethasone]. Most of these patients are in a PR, sometimes a VGPR, by about 8 weeks. If that’s not happening, then I go Andrzej’s route and upgrade the treatment to daratumumab–KRd [carfilzomib, lenalidomide, dexamethasone] or something. I try to get the transplant-eligible patients close to VGPR before collection, because I believe that the closer you are to MRD negativity before—especially the younger patients—the better outcomes you get with transplant, and the more likely they’re going to be MRD-negative after. But I totally see Morie’s point that if you’re getting to a PR with a known biology, a transplant is the best thing to do instead of adding on the toxicity of reinduction and keeping them going.
Sagar Lonial, MD, FACP: Dr Jakubowiak, you get the last word on this question before our polling question.
Andrzej Jakubowiak, MD, PhD: I have 2 quick comments. First, I agree with the approach Dr Hari just presented. If we have patients who started on even RVd [lenalidomide, bortezomib, dexamethasone] with or without daratumumab and are slowly heading in the right direction quickly enough, then we modify treatment. Data to support that isn’t great, but we all try to get to VGPR or better. We collect almost everybody after 4 cycles unless they aren’t reduced enough. If they’re in PR, we probably extend it for 2 more cycles or make a change in therapy. But we would decide whether to transplant these patients or not based on the status of the patient. At that point, we aren’t necessarily anticipating the patient will be top of response. If they’re not in MRD-negative status, it doesn’t preclude whether they will get there later with or without transplant.
I want to add 1 more comment, which may come up maybe later in our discussion. Achieving MRD negativity 1 way or the other for the subgroup of patients who are considered by whatever criteria we use for high-risk myeloma appears to be extremely critical in the context of recent data. For these patients, not achieving MRD negativity makes their outcome clearly inferior compared with those who achieve MRD negativity, and it’s driven by their biology. For these patients, maybe driving to MRD would be even more recommended or supported by data than in other standard patients with whom we can be patient without necessarily being anxious about not getting there.
Sagar Lonial, MD, FACP: That’s a fair discussion. We’re going to talk about MRD in the post-transplant setting a little later. But looking at early end points, for us, I’m looking for a PR, particularly in patients with really big tumor burden at the time of presentation because I worry that A) if you don’t collect them, then you might not be able to collect them, and B) you want to get at least a PR. We haven’t made that switch to VGPR, although practically using a 4-drug regimen, almost everybody gets there. It’s a pretty small number of patients who don’t get there.
Andrzej Jakubowiak, MD, PhD: More than 90% of patients get there.
Sagar Lonial, MD, FACP: Let’s get to polling question 5. If a patient achieves what you consider to be an adequate treatment response following induction, what’s your next step? A) continue induction therapy until transplant, or B) discontinue induction therapy while the patient waits for transplant? I’m guessing that wait is probably a pretty short period of time. At least at our center, it’s 2 weeks unless they want to add in an extra few days here and there for family-related things. It looks like most are opting for continuing induction until transplantation. Let’s talk about a couple of things as a group again. What’s your strategy once a patient achieves an adequate response on induction? Continue the patient on induction or proceed straight to high-dose therapy and transplant? Let’s start with Andrzej.
Andrzej Jakubowiak, MD, PhD: In our practice, outside a clinical trial, if patient has adequate response—which I would consider VGPR or better—we’re believers in the role of transplant in initial setting. At this point, for most of our patients, we discontinue treatment, plan some additional therapy post-transplant, and then—some of these studies have been published already or presented—proceed to transplant. In general, I don’t plan a deferred transplant even in good responders in complete response. We consolidate with transplant and usually plan to extend the treatment with the initial regimen because it has been shown in all the studies: GRIFFIN, MASTER, and CASSIOPEIA. It seems to be the pattern we’ve seen, and it looks as though it’s working well. That’s our practice.
Sagar Lonial, MD, FACP: Dr Hari?
Parameswaran Hari, MD, MRCP: The polling question and this question probably relate to the handover between a patient who’s being treated in the community to a transplant center where they’re moving. If the patient is closely tied to the transplant center and the referral has been made at the second cycle, there’s usually very little gap between the finishing of induction and then going straight to transplant. But I’d be hesitant to discontinue all the induction therapy and wait for a transplant to be set up. If that wait is more than 2 or 3 weeks, it’s not good. Patients should be suppressed and the myeloma should be suppressed until we get to the biggest possible treatment. As Andrzej said, moving to transplant is the right thing to do, and that’s what I intend to do. Very few people in our center are collect and hold.
Sagar Lonial, MD, FACP: Morie, are you going to make it unanimous?
Morie A. Gertz, MD, MACP: Yes. Early transplant and discontinue chemotherapy 14 days before the first injection of GCSF.
Andrzej Jakubowiak, MD, PhD: I’d like to make a very brief comment as far as the break, which I didn’t address because of the way the question was phrased. A break is not advised, and it’s sometimes happening in this transfer of care from local oncologist to transplant center. It’s sometimes a matter of communication and understanding. For the most part, it probably doesn’t hurt outcome if you have a break longer than 2 or 3 weeks. But for high-risk patients, any break more than minimal is harmful. That’s why it would be important to stress that those breaks aren’t advised, because we might not know the risks.
Sagar Lonial, MD, FACP: Yes. Let’s talk then about consolidation and maintenance. What I mean by that is the post-transplant treatment. There are lots of randomized trials from Europe showing the benefit of consolidation. There are lots of trials from the United States showing that there’s no benefit of consolidation and going straight to maintenance. How do you all play that? Does your choice of induction impact what you choose for consolidation and maintenance? Morie, we’ll start with you.
Morie A. Gertz, MD, MACP: My practice fits the American trial better. The European trial was VTd [bortezomib, thalidomide, dexamethasone] and then transplant within 4 months, while the American trial was up to 2 regimens 1 year before transplant. I believe that trial didn’t demonstrate consolidation was beneficial. My practice is that on day 100, if they don’t go on a maintenance trial, they go on maintenance therapy off-study, day 100 without a consolidation.
Sagar Lonial, MD, FACP: Dr Hari?
Parameswaran Hari, MD, MRCP: I somewhat follow the standard-risk study which showed that there was no benefit to consolidation, and lenalidomide maintenance was just as good as VRd [bortezomib, lenalidomide, dexamethasone] consolidation. For my standard-risk patients, I just do lenalidomide maintenance. I was doing a GRIFFIN-type consolidation, but for the daratumumab-induced patients, I’m dropping daratumumab after the CASSIOPEIA data came out suggesting that if you did daratumumab up front, you might not benefit as much from daratumumab. As you know, there are problems with the schedule of daratumumab and other things, but I’m increasingly giving up on that. I’m just doing lenalidomide maintenance for the standard-risk patients. But for the higher-risk patients, I’m using the Emory University approach, which you have here, of giving 3-drug maintenance for at least a couple of years—2 to 3 years—and then going on to lenalidomide for another year or so.
Sagar Lonial, MD, FACP: Got it. Andrzej?
Andrzej Jakubowiak, MD, PhD: I echo what Morie said. We have best data for post-transplant maintenance—especially in the context of the STaMINA trial—that single-agent lenalidomide wasn’t worse than 2 other studies using consolidation. Based on that and some of the observations that extended treatment, not only consolidation but maybe more by going into 8, 10, and more cycles post-transplant may provide better outcome.
We ran and completed enrollment for the KRd [carfilzomib, lenalidomide, dexamethasone] vs R [lenalidomide] plus transplant trial, and I was very comfortable enrolling in this trial because the patient probably went into lenalidomide maintenance. It was 3 to 4 years ago. As I said, this is a dynamically evolving field. We have emerging data. In a year or 2, lenalidomide alone as a maintenance will become history, maybe with an exception in standard-risk patients. We have FORTE data, which clearly showed that extended KR [carfilzomib, lenalidomide] gives better outcomes, particularly for high-risk patients. That was clearly shown. Several other studies support that, including our KRd [carfilzomib, lenalidomide, dexamethasone] and transplant trial, which was 1 arm so it’s not as good. Consolidation short course probably isn’t the best option, but if there are going to be some data to support extended treatment post-transplant, we may be moving in this direction. We’re on the edge there.
Sagar Lonial, MD, FACP: Yes. It’s going to be interesting as the data pan out. All of you have mentioned the CASSIOPEIA trial. I’ve got a bit of struggle with the PFS end point in CASSIOPEIA, given that 1 arm didn’t get any maintenance at all, and interestingly enough, that’s when the curves began to separate. If you’re going to take all patients and prove that lenalidomide-daratumumab is better than lenalidomide, as the GRIFFIN trial is trying to show, your median PFS needs to be 65 months or longer. That’s a hard time frame to show, given our short attention span. As you all mentioned, this case was a standard-risk, young patient. In our RVd [lenalidomide, bortezomib, dexamethasone] series with 1000 [consecutive patients], 78 months is the median PFS with single-agent lenalidomide. You have to show pretty good PFS to be able to beat 78 months. I’m not sure that’s easy, given the trial designs we have so far, but we’ll see. I’m curious.
Andrzej Jakubowiak, MD, PhD: We may use MRD as a surrogate end point to guide us rather than PFS. It still isn’t established, but the FDA appears to be leaning in this direction once they have more data that this could be a good surrogate in these types of decisions.
Sagar Lonial, MD, FACP: Yes. Although I’ll put my skeptic’s hat on and say that we have to be cautious about early MRD end points predicting long-term outcomes. Many of those trials looked at patients who didn’t have continuous maintenance or high-risk patients who didn’t get triplet maintenance, which all 3 of us would agree is a more standard approach in the United States. We have to be careful. I have a clinic full of high-risk patients who aren’t MRD negative who are doing fine 3 years after transplant. We just have to be cautious.
Transcript edited for clarity.