Let’s move to the transplant-ineligible. We don’t want to shortchange this population, which is a huge percentage of the patients being treated, especially in the community. Historically, in the United States, we’ve used Rd [lenalidomide, dexamethasone]-based backbones, and some use bortezomib. [There are] interesting data about [daratumumab], some data about ixazomib, and of course, across the Atlantic, there’s a lot of VMP [bortezomib, melphalan, prednisone] being used out there with or without the [daratumumab] added. With that, Rafael, maybe you could start us with the MAIA study [NCT02252172] and why that’s important to you.

 The MAIA study, as our audience knows, is a combination of 3 drugs—daratumumab, Rd vs Rd randomized—a phase 3 study with 737 patients, and the results are nothing short of remarkable. We see a prolongation of progression-free survival [PFS] and clear evidence of an improvement in overall survival. We’ve [also] seen updates—I think Sharif Aicon has published this already in 

 and is going to be presented again in a few days at ICA, but we’re seeing overall survival that gets into the 66% plus at 5 years, which, for this patient population, is something we had not seen. As you stated, the 2 preferred regimens supported by the [National Comprehensive Cancer Network] are VRd [bortezomib, lenalidomide, dexamethasone], which was essentially based on the SWOG-S0777 study [NCT00644228], and the MAIA. They both come with category 1 evidence because they both are with PFS with overall survival. Those are the 2 regimens to consider in the United States. There might even be room for a doublet still, but even within MAIA, there [are] some data that those patients that are frail. If you can get the 3 drugs, they do better than if they’re treated with a doublet. There are a lot of things being challenged right now. One of the things that dawned on me yesterday is [that] we can’t conclude but we always compare. But if you look at the PFS of MAIA’s experimental arm, it’s not that different from the DETERMINATION trial [NCT01208662].

 I agree. [That is] what I was saying, adding the antibody—I didn’t know we were going to make a difference.

This is a perfect segue…. Omar, we’re not supposed to do cross-study, but please compare MAIA [with] SWOG-S0777.

 As Rafael pointed out, 2 of our most commonly used regimens. There are some important differences, though, between the studies. You clearly see what seems to be much longer PFS with the antibody lenalidomide combination with daratumumab compared [with] the SWOG-S0777 trial, which was [approximately] 43 months in terms of PFS. The difference is that the bortezomib was fixed duration. So the question remains: If you’re doing fixed-duration therapy with bortezomib for 8 cycles and going on [lenalidomide] maintenance, is that enough? We’ve talked a lot about combination maintenance strategies already in the transplant-eligible population. So in this case, it really is a fixed duration. Part of the problem there is that it was given twice weekly in the traditional schedule. So in this older population, you had a higher incidence of peripheral neuropathy. That is its limitations in the real world. How can we get bortezomib? That’s why the RVD-lite [

lenalidomide, bortezomib, and dexamethasone

] platform came out in the transplant-ineligible population, showing you can give it weekly and still get the same responses and durability. In practice, that’s become the comparator. I think it’s a little unfair to bortezomib to compare it head-to-head [with] MAIA because it wasn’t really given until progression. But I will say, in practice, the Dara-Len-dex regimen is amazing. You see absolutely amazing tolerability, it’s so convenient, you give it monthly in maintenance, and not subcutaneous. So advantages seem to be trending in that direction.

 You alluded to the neuropathy, the tolerability, which is important, even within these older patients. There’s obviously heterogeneity. The frailty index is becoming increasingly important and recognized across all of oncology; it’s not your age but your geriatric fitness. There was a subgroup analysis presented by Dr Hugh Falco and published in 

 that showed even frail patients in the MAIA have the same benefit. This was done retrospectively using Charlson comorbidity performance status, but even the frail patients have the same benefit. This is nice to see because that’s something we can talk more about with the SWOG-S0777 [trial]. But I’m curious—we’ve talked about frailty, but the other concern would be high-risk. How are you treating high-risk older patients?

 There’s this belief that we really need PIs for high-risk patients. We have lots of smaller subsets of patients, [in which] we’ve all come to that [realization]. I tried to do GRIFFIN [NCT02874742]. I tried to do [quadruplet therapy] in my frail patients that have high-risk disease, because I think [daratumumab] adds a lot. But my true high-risk patients with 17p deletion, or my ultra–highrisk older patients—if I can get away with weekly bortezomib and the [daratumumab] and [lenalidomide] at a lower dose, 10 to 15mg, and even a lower dose of steroids—I tend to feel like that’s going to help them get better responses and hopefully deeper responses.

I think you hit the nail on the head, which is an important point. It’s not always the number of drugs; it’s the dose intensity of what you’re giving. One could argue that [

 at full dose in a petite elderly [woman] might be much more poorly tolerated than an added CD38 or even bortezomib, right?

Your advice about dose attenuating is essential. I’m curious, Christina, what about you? How do you pick between these choices?

 I try to individualize, as well. And I agree with Krina, the problem is that if you look at the overall survival projected of the younger patients, it is much longer compared [with] the older population and not because there is anything different in the biology of the disease. It’s just because we are unable to deliver the same therapy. I also try to treat [those who are] high risk a little more aggressively. Of course, you have to make dose adjustments or dose modifications, but the CD38 antibody has changed the treatment algorithm because they are well tolerated. In fact, in MAIA, several patients end up discontinuing 

, but they continue the single-agent [daratumumab]. That is also one of the reasons why the PFS—and probably the overall survival—were superior because they were able to stay on therapy longer.

 That’s a great segue for Omar. You heard about discontinuation, so how long do you have to continue these drugs? What’s your end point? Does everybody need everything forever?

It’s a little different in the transplant-ineligible population. We talked about transplant-eligible patients trying to get the deepest response as quickly as possible and get them through all the steps of transplant, etc. With the older patient population, it’s more about the continuation of therapy and trying to limit toxicity to have good quality of life. So dose attenuations and continuation of therapy until progression—MAIA is a perfect example of that, [which] makes such a huge difference for these patients. It gives us a lot more flexibility. If you’re not so dependent on 1 particular agent in a combination, then these patients are able to tolerate it. We have patients on 2.5 mg of lenalidomide, sometimes in combinations with daratumumab, and that’s OK [if] they’re in a response. It could be many years into their therapy, and that’s good enough. Then we have so many salvage strategies now that are tolerated in the older patient population. It’s more about maximizing the benefit and therapy is continuing until a progression, but I don’t necessarily make too many changes to the therapy to try to get a deeper response.

Both of your points about the dose attenuation are shown in a well-done prospective study by Larocca, which was published, that a planned dose attenuation of [daratumumab] and elimination of [dexamethasone] led to less [adverse] events, [which is] a reminder that we need to think about our patients.

Videos

An overview of the frontline treatment armamentarium for patients with transplant-ineligible multiple myeloma and review of the MAIA and SWOG-S0777 trials. 

Transplant-Ineligible NDMM: MAIA Study and SWOG-S0777 Studies

We’ve spent a little time [discussing this, and] it sounds like everybody’s doing 4 to 6 cycles and like we’ve all drank the transplant Kool-Aid. But there was an interesting study about what to do post transplant. This also gets to your point about the ATLAS study [NCT02659293], which [is a] randomized study of carfilzomib [lenalidomide] vs [lenalidomide]. It was 8 cycles of KRd [carfilzomib, lenalidomide, dexamethasone] or KR [carfilzomib, lenalidomide] vs [lenalidomide] alone. This was presented by the Polish Chicago Group and it showed a significant benefit to KR maintenance. [It was] similar to the FORTE study [NCT02203643], which we had heard about from [the American Society of Hematology]. I’m curious what [you] think about dual maintenance therapy. Were you impressed by the data?

 The data [are] impressive. I think it’s agnostic to the drug. I’m thinking it builds on the MRD [minimal residual disease]. If you have residual disease, now I say more of good treatment is good until we can eradicate whatever’s left behind. We see this through FORTE and through an [electrophoretic mobility of cell nuclei] study. I know there’s the exception of stamina, but in general, we’re seeing more of good treatment—whether that’s [daratumumab], carfilzomib, etc—[which] results in better outcomes. Now people are going to say that’s a foregone conclusion, [which is] true, but that’s why we [must] continue to measure the depth of these responses. Because part of the reason is once your MRD is 10-6, there are 2 possibilities: you’re less than 10-6, but there is disease left behind, or there’s a real possibility in some patients [that] there are no cells left behind. And we will never be able to prove that. You can’t prove a negative. That is the biggest question we have.

Anybody else on posttransplant? Are you changing your practice with more monotherapy maintenance?

Cristina Gasparetto, MD: I’ve always used double therapy for high-risk [patients] for ages. With standard risk, I’m content with single agents. I always felt uncomfortable, so I’m not surprised to see some of these data with double PI [proliferative index].I wish when we designed studies in maintenance, the maintenance could also differentiate between high risk and standard risk. We need to have more genomic differentiation and choices, because we can’t treat all our patients the same way.

Another point to make with these double maintenance therapies is, again, moving from clinical trial to the real world.

It’s one thing to do twice-weekly carfilzomib in a clinical trial, but is that happening in the real world in the era of COVID-19?

 We need these studies. To conclude this exciting discussion, what are our take-home messages? I think this slide tries to summarize some of the messages. One important question is the role of transplant. [With] this slide—for the interest of simplicity—we’ll focus on the PFS [progression-free survival], which is shown in the bar graphs, and then the studies or titles are there. IFMO-9, FORTE, and DETERMINATION [NCT01208662] are on the very right and share the question of whether to transplant and what the role [is]. They’re all showing the transplant has a value add of [approximately] 40% improvement in PFS, [which is] shown at the hazard ratio on the top.

Then the other studies are asking the question of 4 vs 3 drugs, so you can either do DVTd [daratumumab, bortezomib, thalidomide, dexamethasone], DVRd [daratumumab, bortezomib, lenalidomide, dexamethasone], DKRd [daratumumab carfilzomib, lenalidomide, dexamethasone], or ISA-VRd [isatuximab, bortezomib, lenalidomide, dexamethasone]. Again, we’re seeing a consistent message for those that have a more mature follow-up with PFS benefit. Interestingly, CASSIOPEIA [NCT02541383] is also trending toward [overall survival] benefit, [and the] GRIFFIN trial [NCT02874742] is a randomized phase 2, so we’ll have to stay tuned.

This is all exciting, and there’s just a wealth of evidence-based medicine [that is] fortunately helping us guide. It seems like the panel agreed on the role of transplant. It seems like everybody’s doing [quadruplet therapy]. There may be slight nuances in which PI or which CD38, but [quadruplet therapy], transplant, [lenalidomide] maintenance, [and] perhaps double maintenance for high risk. So at least we agreed on something, which is an accomplishment.

Before closing out their discussion on transplant-eligible NDMM, expert panelists consider the role of maintenance therapy following transplant.

Role of Maintenance Therapy and Key Takeaways in Transplant-Eligible NDMM

Another important thing to think about: name a study in which people who do better don’t do better, right? MRD [minimal residual disease] negativity in some ways is just another tool in our arsenal. Is somebody who has a VGPR [very good partial response] going to do better than a PR [partial response] or a CR [complete response]? This is our next tool.The MASTER study is a very important 1. We should take a moment to commend the study.

Does everybody need treatment forever? We need to start asking this question. Many of us feel that we’re curing maybe 10% of patients with myeloma. And if we’re treating everybody forever, we’re potentially overtreating a not-so-insignificant number. We need to start asking about discontinuation. They should be commended for the first predictive.

Until now, as Rafael mentioned, in meta-analysis after meta-analysis, it’s a prognostically very clean test. In the clinical trials, this ivory tower, where all those other tests and imaging had been done, it’s clear. But in the community we’ve all seen patients who aren’t even getting IFEs [immunofixation electrophoreses]. Maybe they get immunoglobulins and not even M [monoclonal] spike. We need to make sure we’re going to that stringency, but I want to explore more about what MASTER might be telling us because it speaks to the limitations of MRD negativity, especially at 1 time point. Even though they use 2 consecutive time points, they’re relatively close together.

What do you think about the use of MRD? We already heard that MASTER showed high-risk patients when relapsed earlier. What do you think is going to happen with the standard risk?

 I agree with a fixed duration for our standard-risk patients. We lose patients to infections and secondary malignancies and all these other things, and we need to know who those are. Hopefully, MRD is the biomarker that proves it, because that will make it a lot easier than trying to guess clinically. But if I were a patient, and I was going to get the same amount of years, I’d also like to not be on medication.

Are others are doing fixed duration firsthand?

 The perfect oncologic treatment is short and highly effective. I always think of MRD as defining the 2 boundaries: on the y-axis is the depth of the response, and on the x-axis is the duration of therapy. We can think of it as a tool that’s going to limit the duration of therapy. If MASTER pans out, it’s a major step forward. As much as we say maintenance is just a pill, that’s a big burden on patients. Even if it was just simple, oral maintenance, it can be a big burden, and the quality of life is affected. I’m excited about how MRD can change that.

 I worry that these MRD-negative patients do so much better. That’s been proven over and over. If we’re de-escalating therapy on those patients, are we going to change that narrative? That’s what gives me a little pause because the standard patients are supposed to do well for a long time. Survival is well over a decade for these patients in the frontline setting. Do we alter that without knowing that first? That’s my hesitation for those patients. If you look at the duration of maintenance therapy across all these big phase 3 trials and clinical determination, it’s usually about 3 years on maintenance.

So even though the intent isn’t to see a progression, we don’t always see that. We don’t see that in clinical practice. You also saw dosing of lenalidomide was a lot lower for post-transplant patients, particularly because of their counts. So there are a lot of questions. Right now, for a standard-risk patient, MRD negative, I’d feel good about their prognosis. I still recommend maintenance until progression and would not necessarily stop it based on that.

I completely agree with you. I really disagree with the fixed-duration standard risk. Keep in mind, MASTER is a single-arm study; there’s no control arm. That’s problem No. 1. Problem No. 2, we’ve had several other studies that initially looked 1 way but then follow-up is another way. FORTE was an example. At 1 year, it looked like only high-risk patient needed a transplant. With additional follow-up, everybody needed transplant. The same thing is coming out with DETERMINATION. The French study MRD negativity of transplant and nontransplant was separate. If it’s such a good test, why does it matter how you got there? Before we start, and this is the problem with using MRD at the bedside, moving from prognostic to predictive, we need prospective risk–adapted studies and not just post hoc analyses.

Expert perspectives on the optimal duration of treatment in patients with transplant-eligible newly diagnosed multiple myeloma.

Transplant-Eligible NDMM: Optimal Duration of Treatment

Let’s move to Omar. You heard about MASTER alluding to this as MRD [minimal residual disease] negativity. How do you change your treatment? What’s your end point? How do you make decisions about this induction?

It’s great that we have so many choices and combinations. The good news is that most patients are having amazing responses to induction therapy, and in the triplet and quadruplet [therapy] era. That’s only getting better as time goes on. In our practice, we’re using mostly quadruplets for transplant-eligible patients, and most patients respond and tend to get deeper responses. The challenging part is making treatment decisions based on MRD. If they haven’t achieved MRD negativity at a certain point, that doesn’t mean they won’t eventually become MRD negative. If they’re following a good path, they’re achieving the benchmarks, getting to a PR [partial response], then a VGPR [very good partial response], then heading to transplant, I don’t feel the need to modify therapy because they haven’t gotten to a particular response at that given time. So many patients convert to MRD negativity well into maintenance if they’re following that path. As long as they’re responding and deepening the response, I don’t usually modify therapy just because they haven’t reached a certain benchmark at that point.

You don’t use MRD to make a decision about transplant?

After transplant, are you using it to make consolidation decisions?

You’re consistent throughout the whole thing.

 Right now we’re seeing from the MASTER trial some MRD adaptive therapy designs. As Cristina mentioned, high-risk patients still had early relapses. We know that’s not enough despite having repeated cycles of consolidation and probably the most intensive frontline therapy they can get. However, from DETERMINATION we see amazing results: 67 months of PFS [progression-free survival] when assigned triplet and single-agent maintenance. We’re starting to see durable responses in that area. With getting the quad [quadruplet therapy] and having multiagent maintenance, we’re seeing benefits in numerous trials. The story isn’t just in that initial short window, in my opinion.

I want to come back to that because that’s an interesting study that we heard about, but MRD is an amazing Pandora’s box that we’ve got to open. How are you using MRD in clinic?

 I’m a little different from Omar. I actually base my post-transplant therapy on MRD.

 The reason for that is we’ve seen that attainment of MRD as very important. We have 3 meta-analyses that show that it correlates with OS [overall survival] and PFS. We know that better treatments result in higher percentages of MRD negativity, and we know that attainment of MRD negativity can overcome the prognostic effect of the genetic markers. When I see a patient post-transplant, if they have standard risk and are MRD positive, then I acknowledge that some of them will convert to MRD negative with maintenance alone, but I discuss and offer consolidation with the daratumumab-based combination. If they’re high risk, I insist on additional treatment. I don’t want to leave cells behind. I know all this needs to be tested empirically, and we’re going through clinical trials, but if I was a patient in that spot, I’d want to get more treatment.

 Absolutely, I totally agree. I think that way with high-risk patients. I’m not joking. Some of the data on the quadruplet therapy rate of MRD after 4 cycles of consolidation was phenomenal, at 50%. With the daratumumab–RVd [lenalidomide, bortezomib, dexamethasone], it’s at the same level after transplant, after consolidation, so with the high-risk patient, I’m more aggressive. I want to achieve that because I don’t want that clone to proliferate when I’m thinking about and going to clone evolution, so I push it. With the standard risk, sometimes I balance because it takes a little longer to achieve MRD negativity, so sometimes I push the envelope. It depends on the frailty and the age, but I’m chasing MRD. I do sequential MRD. Do you know why? Because if I had myeloma, I’d like that to be done for me. I’d want the MRD negativity, the sustainability.

You gave a beautiful presentation about the love equation.

It’s better to have loved and lost or to never have at all, right?

Your point is important. Having MRD at 1 point in time but not sustaining it isn’t good enough, right?

But especially for community folks, it’s important we clarify how MRD is being done in these studies. It’s SPEP [serum protein electrophoresis] negative, IFE [serum immunofixation electrophoresis] negative, UPEP [urine protein electrophoresis] negative, urine immunofixation negative, and imaging negative. That’s when we’re looking at MRD for most of these studies. Sometimes in some hematologic malignancies, you use blood-based PCR [polymerase chain reaction] assays to do your MRD. This is very different. We have to keep in mind that the sampling of the marrow is indeed that, and it may not be representative. Krina, what about you? How are you using MRD?

I’m more like Omar. My high-risk patients, MRD negative or not, get consolidation and doublet or triplet maintenance for a few years. For my standard-risk patients, I use MRD for those who are worried about going to transplant. I have a lot of patients who just don’t want to do it. Sometimes it helps me show them that maybe this is still the right thing to do. Very few of my patients are MRD negative before transplant. We use it in that sense. I try not to use it to say whether we’re going to transplant. But I use any tool that can help them look at it.

For maintenance, we have a couple of trials. If you’re MRD positive, you can go on the SWOG trial…. I try to put them on those trials to get the answer if that’s the right thing to do for standard risk. But with a lot of my patients, especially during COVID-19, we were trying to get them off therapy to give their immune systems time to come back. I’m still on the fence a little about treating some patients.

Ajai, it’s important for the audience to know there’s significant subjectivity. The DETERMINATION trial, which was in the Plenary Series [at ASCO], is the sister trial of IFM 2009, which is in France. It was started in 2009, so as we learn, we have to decide what we do for today’s patients. I wouldn’t say what we’re saying is in any way written in stone. There’s maybe a preponderance of evidence, but it’s not beyond a reasonable doubt that you can put patients on maintenance.

 Absolutely. That trial, of course, doesn’t have the antibody, the daratumumab. I’m always pro transplant, and I’ve always been pro transplant. However, I’m amazed by the data of the MAIA, the long-term follow-up. I’m trying to reconsider and say the addition of the antibody may push us in a different direction.

Comprehensive discussion on the assessment of response to frontline therapy for transplant-eligible multiple myeloma and the role of MRD negativity in assessing response.

Transplant-Eligible NDMM: Assessing Response to Therapy and Role of MRD Negativity

Let’s start with Rafael, because he did bring up something in quads [quadruplet therapy] already. Can you tell us a little about GRIFFIN and what your take was?

That was a perfect segue. We saw an update at ASH [American Society of Hematology Annual Meeting] and ASCO [American Society of Clinical Oncology Annual Meeting] regarding the GRIFFIN study. GRIFFIN is a randomized phase 2 study of daratumumab–RVd [lenalidomide, bortezomib, dexamethasone] vs RVd [lenalidomide, bortezomib, dexamethasone] as a backbone for induction therapy in patients who get a transplant and subsequent therapy. I said this was a perfect segue because we’re seeing a dramatic difference in the ability to induce deep responses as measured by MRD [minimal residual disease].

I like to remove this aura of a mystique or a very special test. It’s just 1 more test. It’s just more sensitive. That’s what MRD is. If you look at the difference in absolute percentage points, there are 30 absolute percentage points in the difference of attainment of MRD with a quad vs the 3-drug combination. At this ASCO meeting, Cesar Rodriguez made a great update on what happens over time. We saw a little of that at ASH. In reality, first, if you take all comers and you look at patients who get the quad we’re looking at PFS [progression-free survival] that is close to 90% at 4 years. But if you look at ones that are MRD negative and are sustaining MRD negative, there’s still a small fraction of patients, and if you take the stringency of 10-6, you see a flat curve. The writing is on the wall.

Once you start therapy on myeloma, you have to do the best possible and you have to try to put these patients in this MRD-negative status. We’ll talk more about that as we talk about the other abstracts. I don’t know why we’re dancing around the topic, because as long as you do it safely, we get it. You have to do it safely, but if you can do that with quads, this will translate better downstream for patients. As we often say, the first treatment is probably the most important phase of the treatment of myeloma.

Your quad and MRD could not be a better segue for Cristina to discuss the MASTER study. To be fair and balanced, there’s more than D-VRd [daratumumab, bortezomib, lenalidomide, dexamethasone].

 Absolutely. The MASTER trial was very interesting because with daratumumab–KRd [carfilzomib, lenalidomide, dexamethasone] we see a different proteasome inhibitor. What was interesting in the MASTER trial was that the carfilzomib was given only once a week, which I liked because it’s so difficult to bring the clinical trial design to the real world. I always say that. I repeat myself, but it’s the truth, and we love KRd [carfilzomib, lenalidomide, dexamethasone]. We have the FORTE trial with the longer follow-up and the transplant. Another important point in the MASTER trial was that the MRD was guiding treatment, so the patient received induction therapy, transplant, and then based on the MRD status they received additional therapy: 0, 4, or 8 cycles. We want to achieve MRD, but we can’t treat everybody the same way. That’s a very interesting concept.

What I’d like to see in the future—[I wonder if] you guys agree or disagree—is a little differentiation between the standard and the high-risk. The high-risk patients tend to achieve MRD faster, but they also progress faster. We need to push the envelope on these patients. We can’t stop therapy, but with the standard therapy or standard risk, we can do that. We can follow the MRD sequential and eventually stop therapy. I’d like the new design to also think about that because we need to pay attention. We can’t stop therapy completely in patients with high-risk disease because of MRD, the durability of MRD, the sequential MRD, and the sustainability.

With those great summaries, let’s go to Krina. Triplet or quad? Which triplet, which quad?

 It probably changes every 2 weeks. With the quads, before I would be scared about infections or other comorbidities, but we’ve seen patients do well with our quads. For most of my patients, I do the standard of care, which is now daratumumab–VRd [bortezomib, lenalidomide, dexamethasone]. I have patients who are a little more frail or have horrible neuropathy. For them, I might adjust the V [bortezomib]. Or I go to the MAYA data instead and do DRd [daratumumab, lenalidomide, dexamethasone]. For my high-risk patients, sometimes I throw the K [carfilzomib] in there instead of the V [bortezomib]. It used to be KRd [carfilzomib, lenalidomide, dexamethasone] because I couldn’t get insurance to approve. But with all these data, I’m hopefully going to be able to do more daratumumab-KRd for my high-risk patients. That’s what I want to do.

Just to follow up a little, because Cristina alluded to this, the bortezomib in GRIFFIN was twice weekly and a lot of the K [carfilzomib] regimens are twice weekly. What are you doing in clinic?

 With my standard-risk patients without any issues, we go with daratumumab–VRd [bortezomib, lenalidomide, dexamethasone]. The V [bortezomib] is twice weekly, but for my patients who are frail or who have baseline neuropathy, we change it to a D-VRd [daratumumab, lenalidomide, bortezomib, dexamethasone] lite. We’re doing it weekly, so we do 4-week cycles with Velcade weekly. With K [carfilzomib], I’m doing it once weekly.

 It depends on the patient. For K [carfilzomib], I try to get to at least 56 mg/m². If they have a high risk, I try to get to 70 mg/m², but that’s a little harder in terms of cytopenias for some.

 If we could go down the line, I’m curious if everybody could just say weekly or twice weekly for V [bortezomib] and K [carfilzomib].

 I’ll make it simple: weekly carfilzomib is my go-to regimen. My main limitation is getting coverage from the insurance companies. But Dr Patel and I are hoping that with all these data, things will be better.

 I do that too: once a week and in combination. I’m always reluctant to go up to 70 mg/m², so I keep it at 56 mg/m².

 Exactly the same. Weekly 56 mg/m² is the max in most combinations and weekly for bortezomib.

The reason I wanted to go through that is because many people, especially in the community, are historically doing weekly. That’s 1 benefit of adding that CD38 up front.

 Historically we were doing twice weekly PIs [proteasome inhibitors] in these studies and once weekly in the real world, but now maybe that synergy comes. The other point that everybody on the panel alluded to but that was never clearly stated is that if you’re giving carfilzomib 70 mg/m² weekly, you can run into more cardiopulmonary issues with giving an IMiD [immunomodulatory imide drug]. We all agree, which is rare. We’ve got 5 myeloma doctors.

 It’s absolutely true. You want to balance the toxicity.

The other part is considering NOACs [novel oral anticoagulants] instead of aspirin because it’s a concurrent.

 Yes, even in the MASTER trial, there was an increased incidence.

It’s always in the footnotes, right? No one talks about it, but we think the initial VTE [venous thromboembolism] risk is higher.

Shared insight on clinical trial results from both the GRIFFIN and MASTER trials, and the key role of frontline quadruplet regimens in transplant-eligible NDMM.

Quadruplet Therapy in Transplant-Eligible NDMM: Implications of GRIFFIN and MASTER Studies

® titled “A New Wave of Progress in the Treatment of Multiple Myeloma: Translating Evidence to Clinical Practice.” My name is Ajai Chari. I’m a professor of medicine and the director of clinical research at the Icahn School of Medicine at Mount Sinai in New York [New York]. It’s my pleasure to have a distinguished panel of experts in multiple myeloma. I’ll let them introduce themselves.

 Hi, I’m Krina Patel. I’m an associate professor at [The University of Texas] MD Anderson Cancer Center in Houston, Texas.

 Hi, I’m Rafael Fonseca. I’m a professor of medicine at the Mayo Clinic in Phoenix, Arizona.

 Hi, I’m Cristina Gasparetto. I’m a professor of medicine at Duke University [School of Medicine in Durham, North Carolina].

 Hi, I’m Omar Nadeem. I’m the director of the immune effector cell therapy at Dana-Faber Cancer Institute in Boston [Massachusetts].

Welcome, everyone. Thank you for joining me. Let’s get started on our first topic. If we’re true to form, there’s that joke that if you ask 5 myeloma doctors, you’ll get 6 opinions. Let’s see what we come up with. We’re going to start with the newly diagnosed setting, the evolving treatment landscape of newly diagnosed myeloma. Let’s set the stage with what we’re talking about: the choices of regimens for this transplant-eligible population. Historically, we’ve done VRd [bortezomib, lenalidomide, dexamethasone] in the United States. Some have done KRd [carfilzomib, lenalidomide, dexamethasone]. In Europe, we see VTd [bortezomib, thalidomide, dexamethasone], and there’s a question of whether to transplant early vs delayed. The newer questions are quads [quadruplet therapy]: can you add a CD38 up front with VRd [bortezomib, lenalidomide, dexamethasone] or KRd [carfilzomib, lenalidomide, dexamethasone]?

We’re going to go through some of those regimens together, but let me get things started with the exciting update at this year’s ASH [American Society of Hematology Annual Meeting], which was long awaited…. This is the DETERMINATION study. This is the American response, and things take longer here because of slower clinical trial accrual. But there’s also an important difference in the French design. The IFM study, which has been published in the 

, was VRd [bortezomib, lenalidomide, dexamethasone] followed by transplant or continuing VRd [bortezomib, lenalidomide, dexamethasone] and then lenalidomide maintenance for 1 year. The American difference is that the lenalidomide was given till progression. A lot of people felt that the criticism of the French study was that you’re going to stack the odds in favor of transplant because the control arm isn’t getting treatment beyond 1 year. What did that show? We see that with the randomized study of about 360 patients, and the follow-up is quite impressive, at 76 months. We see that the primary end point, which is important because people are often going to talk about other end points, was PFS [progression-free survival].

After there was a median follow-up of 76 months, the PFS of the control arm was 46.2 months, and the transplant was 67.6 months. That by itself was very impressive. It translated into a hazard ratio of 1.53, which was statistically significant. There were deeper responses and more MRD [minimal residual disease] negativity. Overall survival at this follow-up wasn’t statistically significantly different. I’m curious to hear people’s takes on that.

Safety is the other question. There was more hematologic toxicity. Quality of life, which is going to be increasingly important when you have so many choices, diminished transiently after transplant. But other than that, it was comparable. We’re always concerned about secondary malignancy, especially with lenalidomide post-transplant, but there was no difference in all SPMs [second primary malignancies]. There was an increase in hematologic malignancies, however: with AML [acute myeloid leukemia] and MDS [myelodysplastic syndrome], 0 patients in the nontransplant. That was statistically significant. We’re waiting on additional data about whole-genome sequencing, more quality of life, and correlative analyses. I’m curious about your thoughts are on this. Is this practice changing for you? Are you surprised? Krina, do you want to start?

 The question is always transplant or not. My patients are asking about it, but this actually showed us that transplant still gives you a 21-month PFS benefit. It hasn’t changed my practice in that sense because I recommend transplant for the majority of my patients. But I do have serious discussions with them about secondary malignancies and things like that. Some of my patients don’t necessarily want to go because of that, but we try to explain the myeloma is what we’re trying to treat. That’s what this trial has proven: that you’ll have a better response with better myeloma control for longer, which is always what we’re looking for.

So you’re impressed by the PFS benefit. We all see that, but does anybody have a different take from that? For the lack of overall survival [OS], does that change your practice? Does that dissuade you from doing a transplant?

 I don’t think so. There are a lot of questions that are still out there. The lack of overall survival always has to be taken with a grain of salt because, as I always say, the absence of evidence is not evidence of absence. We have to wait for a long time with these clinical trials, and there are exceptions. We get it, but for the most part, PFS anticipates what’s going to happen later, and for the most part, adaptive response anticipates what we’re going to see with PFS.

The interesting question is what’s going to happen with the quads. That’s important. The benefit of transplant seems to be there. In fact, I have it in my disclosure slides. I’m biased totally toward transplant, and I’m scratching my head because I might be changing that, particularly if we start measuring things like MRD before transplant. There’s a lot to unpack on the study.

One thing that should be said, though, is what you mentioned with the secondary malignancies. There was nothing in the transplant arm, so the contribution of the lenalidomide to the myeloid secondary malignancies is questioned because we’ve assumed it was the lenalidomide. There’s good biology behind this—there’s ALL [acute lymphoblastic leukemia], which we can talk about—but not a lot on the myeloid side. This trial in many ways opens more questions than it ends up closing.

Does anybody want to comment further on the primary vs secondary end point? That’s a really important distinction. Go ahead, Cristina.

 First, I agree with the importance of PFS and the longer follow-up for some of these patients. The projected survival is the same, but how can we keep them alive with the continuation of therapy? I was surprised by the MRD of patients after transplant. When you showed the slides—that if you achieve MRD after transplant or with the continuation of therapy, there was a similarity—that surprised me. I always thought that the MRD we can achieve after high-dose chemotherapy, after transplant, was deeper. My concern is when I recommend transplant vs continuation of therapy. In a clinical trial, we’re capable of pushing a patient to remain on therapy, particularly in this regimen. We have Velcade [bortezomib] twice a week with cumulative toxicity and peripheral neuropathy. In the real world, we’re not [capable], so patients tend to discontinue therapy too prematurely. We’re not achieving the goal with MRD, and then we’re stuck with the patient progressing very rapidly, so we have to be very careful. The transplant allows us to control the disease faster, allows the patient to go off therapy and remain off therapy for a prolonged period of time. Also, every time we start a new therapy, there’s a clock ticking. If we start 5 or 6 years later, probably better. We have new therapies available vs continuation of therapy.

You bring up some important points regarding MRD negativity and how that translates. But here we have MRD negativity, which translates into PFS already. The key thing I want people to pay attention to is, from a statistical point of view, why is a primary end point- what it is? That’s where all your power is. Once people progress, you lose all statistical control. The ability of PFS to translate into OS is based on not only the efficacy and toxicity of the randomized intervention but also what happens at progression. We know that 22% of patients got transplants. Based on global variations and practice patterns here—this is a US study—you’re not controlling for all those downstream events, and you have relatively limited follow-up. Maybe MRD negativity with a transplant will translate differently relative to nontransplant, but not with current follow up.

Expert hematologist-oncologists open their discussion on NDMM management by reviewing frontline data from the recent DETERMINATION trial.

Evaluating Frontline Treatment Strategies in NDMM: The DETERMINATION Trial

Krina K. Patel, MD, MSc, associate professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses mitigating CAR T-cell therapy–related cytokine release syndrome (CRS) in multiple myeloma.

Toxicity can be a limiting factor with CAR T-cell therapy in hematologic malignancies, Patel says. In lymphoma, key toxicities associated with CAR T-cell therapy include CRS and neurotoxicity; however, in multiple myeloma, CRS is the main toxicity to be aware of, Patel explains.

CRS often presents as grade 1 fever that responds to acetaminophen. Moreover, fevers are a good sign that the CAR T-cell therapy is working rather than indicative of a serious toxicity, such as sepsis, Patel explains. 

However, in cases of higher-grade fevers that are accompanied by hypoxia or hypotension, tocilizumab (Actemra) can be considered, Patel says. Many patients with COVID-19 were treated with tocilizumab, which led to a shortage of the agent for patients with multiple myeloma receiving CAR T-cell therapy. As such, other options to treat CRS were utilized, including dexamethasone and IL-6 inhibitors like siltuximab (Sylvant), which elicited rapid responses, Patel concludes.

Krina K. Patel, MD, MSc, discusses mitigating CAR T-cell therapy–related cytokine release syndrome in multiple myeloma.  



Dr. Patel on Mitigating CAR T-Cell Therapy­–Related CRS in Multiple Myeloma 

Krina K. Patel, MD, MSc, associate professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the integration of CAR T-cell therapy into the treatment paradigm of relapsed/refractory multiple myeloma.

Having an FDA-approved CAR T-cell therapy with idecabtagene vicleucel (ide-cel; Abecma) has been a significant advancement in the treatment of patients with heavily pretreated, relapsed/refractory multiple myeloma, Patel says. The demand for ide-cel currently outweighs the supply. However, many patients receiving ide-cel are unfit for clinical trials because of kidney function impairment or non-secretory disease, so having any FDA-approved options in this setting is significant. In addition to ide-cel, a second CAR T-cell therapy, ciltacabtagene autoleucel, may also be approved, further expanding treatment options for this patient population, Patel says. 

Although these therapies are not curative, patients are able to derive substantial responses with a single dose of therapy, Patel says. The response rates with CAR T-cell therapies are in the range of 80% to 100% compared with about 30% for other approved agents for this patient population. Moreover, the progression-free survival can surpass 1 year with some products. Ultimately, offering a potential treatment-free interval to patients with heavily pretreated disease is a significant achievement, Patel concludes.

Krina K. Patel, MD, MSc, discusses the integration of CAR T-cell therapy into the treatment paradigm of relapsed/refractory multiple myeloma.  



Dr. Patel on the Integration of CAR T-Cell Therapy in Multiple Myeloma 

Krina K. Patel, MD, MSc, associate professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses future research directions with CAR T-cell therapy in patients with multiple myeloma.

For most patients receiving BCMA-targeted approaches, sequencing decisions may present a challenge, Patel explains. More information is needed to better understand resistance mechanisms with these agents so that they are not administered to patients who no longer have BCMA expression, Patel adds. However, this only occurs in a small number of patients rather than the majority, especially with the advent of CAR T-cell therapy, Patel notes.

Ideally, CAR T-cell therapy should be an option for every patient if eligible, according to Patel. Eventually, the goal is to use these products in those who previously received them and have relapsed, Patel says. Some anecdotal cases of this have been reported in clinical trials, Patel adds.

Additionally, the emergence of new antigens beyond BCMA are generating excitement in the paradigm, Patel adds. Future efforts will likely explore CAR T-cell therapies that target these antigens and explore novel combinations with these products. Looking forward, data on head-to-head comparisons between CAR-T cell therapy and stem cell transplant are highly anticipated, Patel concludes.

Krina K. Patel, MD, MSc, discusses future research directions with CAR T-cell therapy in patients with multiple myeloma.


Dr. Patel on Future Research Directions With CAR T-Cell Therapy in Myeloma

Krina K. Patel, MD, MSc, associate professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the potential utility of elranatamab (PF-06863135) in multiple myeloma.

Elranatamab is a bispecific antibody that targets BCMA and CD3, Patel says. Rather than replacing T cells with a new receptor, which is the case with CAR T-cell therapy, bispecific antibodies harness a patient’s own T cells to effectively kill myeloma cells, Patel explains. In the case of elranatamab, CD3 and BCMA push the activated T cells and myeloma cells close together so that the T cells can kill the myeloma cells, Patel says.

Findings from the phase 1 MagnetisMM-1 trial (NCT03269136) demonstrated a 70% overall response rate with elranatamab, dosed at 215 or more µg/kg, in patients with relapsed/refractory multiple myeloma. Although these are early data, they suggest that bispecific antibodies could play a significant role in the treatment of heavily pretreated patients with multiple myeloma, Patel says. Moreover, the agents alone or in combination with other therapies could offer an effective option for patients who have progressed on CAR T-cell therapy or those who are ineligible for CAR T-cell therapy, Patel concludes.

Krina K. Patel, MD, MSc, discusses the potential utility of elranatamab in multiple myeloma.  



Krina K. Patel, MD, MSc, University of Texas MD Anderson Cancer Center

Articles

Transplant-Ineligible NDMM: MAIA Study and SWOG-S0777 Studies

Role of Maintenance Therapy and Key Takeaways in Transplant-Eligible NDMM

Transplant-Eligible NDMM: Optimal Duration of Treatment

Transplant-Eligible NDMM: Assessing Response to Therapy and Role of MRD Negativity

Quadruplet Therapy in Transplant-Eligible NDMM: Implications of GRIFFIN and MASTER Studies

Evaluating Frontline Treatment Strategies in NDMM: The DETERMINATION Trial

Dr. Patel on Mitigating CAR T-Cell Therapy–Related CRS in Multiple Myeloma

Dr. Patel on the Integration of CAR T-Cell Therapy in Multiple Myeloma

Dr. Patel on Future Research Directions With CAR T-Cell Therapy in Myeloma

Dr. Patel on the Potential Utility of Elranatamab in Multiple Myeloma

Krina K. Patel, MD, MSc, University of Texas MD Anderson Cancer Center

Articles

Transplant-Ineligible NDMM: MAIA Study and SWOG-S0777 Studies

Role of Maintenance Therapy and Key Takeaways in Transplant-Eligible NDMM

Transplant-Eligible NDMM: Optimal Duration of Treatment

Transplant-Eligible NDMM: Assessing Response to Therapy and Role of MRD Negativity

Quadruplet Therapy in Transplant-Eligible NDMM: Implications of GRIFFIN and MASTER Studies

Evaluating Frontline Treatment Strategies in NDMM: The DETERMINATION Trial

Dr. Patel on Mitigating CAR T-Cell Therapy­–Related CRS in Multiple Myeloma

Dr. Patel on the Integration of CAR T-Cell Therapy in Multiple Myeloma

Dr. Patel on Future Research Directions With CAR T-Cell Therapy in Myeloma

Dr. Patel on the Potential Utility of Elranatamab in Multiple Myeloma

Dr. Patel on Mitigating CAR T-Cell Therapy–Related CRS in Multiple Myeloma