 Yeah. This is 1 of the greatest areas that we’ve learned more about in the last few months. With further updates in the GRIFFIN study, which initially was D-VRd [daratumumab, bortezomib, lenalidomide, dexamethasone] vs VRd [bortezomib, lenalidomide, dexamethasone]. We all talked about the induction part, but we didn’t talk much about the maintenance part—which patients who had D-VRd [daratumumab, bortezomib, lenalidomide, dexamethasone] stayed on DR [daratumumab, lenalidomide] for up to 2 years, then the D daratumumab was dropped. If they remained in remission, then they continued lenalidomide vs lenalidomide alone.

The FORTE study that Sagar and others have mentioned, was a little different from KRd [carfilzomib, lenalidomide, dexamethasone] plus or minus transplant, and then a second randomization comparing KR [carfilzomib, lenalidomide] vs R [lenalidomide]. That was updated recently at ASCO [American Society of Clinical Oncology Annual Meeting]. What we’re seeing, Keith, is that we can do better than lenalidomide maintenance alone, in the higher-risk patients in particular. The evidence for KR [carfilzomib, lenalidomide], in the highest-risk patients, seems to be the strongest. In the other study I mentioned—in which the daratumumab maintenance maybe wasn’t necessary—if you had daratumumab in induction, then there still needs to be a bit of maturity. But the bottom line, at the end of it, is that we’re going to be doing more than lenalidomide alone. We’ve already been doing this for high-risk patients—adding something else, such as bortezomib. Now we have 2 more options: carfilzomib and daratumumab. Maybe, even in standard risk, we’ll be doing more than lenalidomide alone to keep that remission longer. Sagar’s comment about sustained MRD [minimal residual disease] negativity is critical.

We’re going to come to that. I want to focus in on this first issue. Of these medications, if I’m a community oncologist watching this—which is the majority of our audience—I’m thinking that nothing is FDA approved, except lenalidomide. That’s correct, right? Nina, what are you doing as maintenance in your post-transplant patients and standard high-risk patients?

 For standard risk, as it was called forever, the patient is taking the Revlimid [lenalidomide] because we know that the longer the patient gets lenalidomide, they do better. Multiple different analyses have shown this, and the higher dose that they get is better—but it’s sometimes difficult to tolerate more than 10 mg. For the high-risk patients, we also use proteasome inhibitor [PI] combination therapy because what we’re doing isn’t enough with standard lenalidomide therapy. I agree with you, Keith, that we haven’t had anything else come on board telling us that we should do anything different—as far as standard risk goes—aside from lenalidomide maintenance therapy. It is, as I call it, the Tom Brady of maintenance. It always wins.

When you say you’re using a proteasome inhibitor for high-risk patients, which 1 are you using? For how long?

 It depends. A lot of patients will come to us from a community oncologist who has already started therapy. If they already got VRd [bortezomib, lenalidomide, dexamethasone] up front, then I emulate it—with what the Emory University School of Medicine group has done—and give extended VRd [bortezomib, lenalidomide, dexamethasone] after transplant. But if they’ve gotten KRd [carfilzomib, lenalidomide, dexamethasone] up front, then I emulate what The University of Chicago Pritzker School of Medicine group does—a modification for another 4, and then 10 cycles. It depends on where the patient started before he or she came to me.

Is anybody using ixazomib [Ninlaro] or carfilzomib [Kyprolis] in the maintenance setting at this point? You’re nodding. Yes, Sagar?

 Not as a single agent. We may use ixazomib or carfilzomib in the 414 subset, where we tend to go with a PI in the maintenance setting. But with our switch to KRd for high-risk induction, we’ve switched our maintenance to KRd [carfilzomib, lenalidomide, dexamethasone] for 3 years, and then go to single-agent lenalidomide after that. We’ve made the switch from bortezomib maintenance and consolidation to carfilzomib in that situation.

Three years of carfilzomib. Wow, that’s brave.

 But you’re the 1 who loves carfilzomib. I thought you’d be excited about it.

 We give it once a week: 3 weeks on, 1 week off. Just like what we did with our VRd [bortezomib, lenalidomide, dexamethasone]: once a week, 3 weeks on, 1 week off.

Would you consider replacing carfilzomib with daratumumab and moving forward? It’s easier to take, and probably as effective.

 It is. If you’re talking about the high-risk cohort, then I’m going to need to see some convincing data. For the standard risk—you mentioned the RVd [lenalidomide, bortezomib, dexamethasone] 1000 series earlier—the median PFS [progression-free survival] for lenalidomide alone, after RVd [lenalidomide, bortezomib, dexamethasone] induction and transplant, is 77 months. So you’ve got to be pretty good, or say that we’re going to shorten the duration of maintenance by giving a doublet as consolidation and maintenance to the standard-risk patients.

Videos

Multiple myeloma experts share their thoughts on improving on currently available maintenance therapy, particularly for high-risk patients, and review their personal approaches to maintenance therapy for standard- and high-risk disease.

Improving Maintenance Therapy for Myeloma

Sagar, you’re a bortezomib lover. I think it’s dreadful stuff, it gives everyone neuropathy. Have you maintained use of botezomib in your older patients?

: We’ll use VRd [bortezomib, lenalidomide, and dexamethasone] in the high-risk group only. There hasn’t been a dara [daratumumab] upfront trial where the initial analysis showed a benefit for high-risk patients. If you put all the patients together and wait long enough, when all the high risk drops off, you’ll start to see, well, maybe it’s not so bad, but that’s a late effect. So, we’re using RVd [lenalidomide, bortezomib, dexamethasone] only in the high-risk patients.

One of you mentioned the ENDURANCE trial, I think you did, Nina. There wasn’t a PFS [progression-free survival] or overall survival [OS] advantage to carfilzomib compared to bortezomib in standard-risk transplant ineligible populations. We had a previous trial with the melphalan, prednisone, carfilzomib vs melphalan, prednisone, Velcade, which also showed no PFS. However, there was significantly less neuropathy in the carfilzomib arm of the trial. Are you using carfilzomib or bortezomib up front?

: I have to admit, based on the outcome of the ENDURANCE trial, for younger patients I like to use carfilzomib up front because the patients, for example, many of them don’t have cardiac abnormalities. I’d rather not risk the chance of neuropathy. If you’re going to dose it like the ENDURANCE trial did, there is still a significant amount of neuropathy that happens with bortezomib use. That’s a long-term adverse effect that’s difficult for the quality of life. I often choose KRd [carfilzomib, lenalidomide, dexamethasone] for my younger patients for that reason.

We get all of our medical knowledge from Twitter these days, but I see people on Twitter pushing back on this, saying, “Why on earth would you use carfilzomib when the trial was negative?” Cristina, do you use carfilzomib?

: I prefer bortezomib a bit more in the upfront setting. I like the dara-RVd [daratumumab plus lenalidomide, bortezomib, dexamethasone] a lot because of the rapidity of response and the depth of response. I’m chasing that a lot these days, particularly after transplant, for standard-risk and high-risk patients. I like the depth of the response that we see with the dara-RVd [daratumumab plus lenalidomide, bortezomib, dexamethasone]. However, as mentioned earlier, the FORTE trial, which was presented at ASCO [

American Society of Clinical Oncology Annual Meeting

] from the Italian group, KRd [carfilzomib, lenalidomide, dexamethasone] continued for 12 cycles vs KRd [carfilzomib, lenalidomide, dexamethasone], transplant, 2 cycles of consolidation. Then the patients were randomized to carfilzomib in the maintenance setting, it was carfilzomib, lenalidomide, versus lenalidomide. When Francesca Gay, MD, dissected all the different genetics, the different patient populations, it was impressive how the carfilzomib was performing in this population of patients. I’m rethinking a bit, except for the 1q amplification, the numbers were low. She didn’t see a lot of benefit. But the deletion 17p and all the translocations, they performed well. So I’m changing a little. I know you guys are working on using carfilzomib for high-risk disease, but I’m comfortable with the dara-RVd [daratumumab plus lenalidomide, bortezomib, dexamethasone] because the data were quite impressive with the depth of responses.

Sagar, have you added daratumumab to your standard regimen for all of your patients?

: Yes. For standard risk, we do RVD-dara [daratumumab plus lenalidomide, bortezomib, dexamethasone], up front. We haven’t added it to the high-risk patients, but that’s the only subgroup we switched to KRd [carfilzomib, lenalidomide, dexamethasone] up front.

So, you’re doing dara-RVD [daratumumab plus lenalidomide, bortezomib, dexamethasone] in a standard-risk younger patient, and KRd [carfilzomib, lenalidomide, dexamethasone] without daratumumab in high risk?

Why wouldn’t you use daratumumab? It didn’t make it worse.

: It’s not clear that it makes it better.

Are there any patients, Sagar, you wouldn’t take to transplant? We’ve got these 4-drug regimens with just 60% molecular CR [complete response] type of results. I don’t know the exact number, but it is in that range. Would you still transplant a patient in molecular CR, after 4 cycles of dara-RVd [daratumumab plus lenalidomide, bortezomib, dexamethasone] or KRd [carfilzomib, lenalidomide, dexamethasone]?

: Yes, I think that’s a really important question because there are a lot of mixed messages out there about the role of MRD [minimal residual disease] negativity, particularly at early time points. To me, the sustained MRD question is a much more important one. From the FORTE trial, that you heard about from Cristina, where patients got KRd [carfilzomib, lenalidomide, dexamethasone] with or without transplant, while the early data on depth of response looked the same whether or not you had a transplant, the long-term data suggested that using transplant improved PFS and sustained MRD negativity. The same is the case in the IFM trial, which randomized people to RVd [lenalidomide, bortezomib, dexamethasone] induction, transplant, or no transplant. Early on, it looked like if you got MRD at 10 to the minus 6, it didn’t matter. But with longer follow-up, PFS was better in the group that was 10 to the minus 6 and had a transplant. I think there’s still value.

In that trial, the transplant doesn’t matter whether it was done early or late, right?

: Well, they didn’t have a planned late transplant. So that’s off study. Not everybody who had the delayed option continued to a second transplant.

I think I’m hearing from the group that there’s a mix of 3-, or sometimes 4-drug therapies up front now, more daratumumab use, and transplant is still generally recommended for most people for the time being.

Sagar Lonial, MD, FACP, leads the discussion on selecting the optimal proteasome inhibitor, bortezomib or carfilzomib, for patients with high-risk multiple myeloma.

High-Risk Multiple Myeloma: Selecting Initial Therapy

 What is the standard of induction for a patient with newly diagnosed symptomatic multiple myeloma? Joe, I’m going to start with you, and ask what are you using as your standard backbone in both transplant eligible and ineligible patients?

 That’s a great question, Keith. I’ll keep it simple. In the transplant eligible, VRd [bortezomib, lenalidomide, dexamethasone] has remained the general standard of care. But now we’re starting to see that we can have 2 modifications for that. I agree with Sagar’s thinking that we have mounting evidence for the use of KRd [carfilzomib, lenalidomide, dexamethasone] in the high-risk patient. I think we know when not to use KRd [carfilzomib, lenalidomide, dexamethasone], in transplant ineligible and standard-risk patients. But KRd [carfilzomib, lenalidomide, dexamethasone] is an option, and evidence is mounting for a quadruplet with DVRd [daratumumab, bortezomib, lenalidomide, dexamethasone]. The question with time will be, when do you use KRd [carfilzomib, lenalidomide, dexamethasone] and when do you use DVRd [daratumumab, bortezomib, lenalidomide, dexamethasone]? Are we just going to blanket everybody with DVRd [daratumumab, bortezomib, lenalidomide, dexamethasone]? Furthermore, as I’m sure we’ll discuss, how much D [daratumumab] should someone get? The recent CASSIOPEIA study made us question, in patients who didn’t have dara [daratumumab] in their induction therapy but had it in maintenance therapy did well, but those who had daratumumab in their frontline therapy didn’t need daratumumab in maintenance therapy.

Let me put you on the spot. If you saw a 60-year-old patient tomorrow, what would you start them on? A patient with standard risk.

 Standard risk? I would still plan to use VRd [bortezomib, lenalidomide, dexamethasone]. But if there’s anything that makes me more concerned about this patient, I would like to try to add DVRd [daratumumab, bortezomib, lenalidomide, dexamethasone]. Insurance-wise, we can’t always get it. There are still some challenges with that. But at the minimum, VRd [bortezomib, lenalidomide, dexamethasone] and likely, DVRd [daratumumab, bortezomib, lenalidomide, dexamethasone].

Nina, in San Francisco what are you doing for younger patients?

 It’s a moving target. VRd [bortezomib, lenalidomide, dexamethasone] is still the standard. I will say, I was bummed about the ENDURANCE trial. I thought it was going to be positive and I would have an excuse to use KRd [carfilzomib, lenalidomide, dexamethasone].

When you mention the ENDURANCE trial, what was that?

 That was the upfront trial looking at KRd [carfilzomib, lenalidomide, dexamethasone] vs VRd [bortezomib, lenalidomide, dexamethasone] in nonplanned transplant patients with newly diagnosed multiple myeloma. It didn’t show a PFS [progression-free survival] difference for patients who got KRd [carfilzomib, lenalidomide, dexamethasone] vs VRd [bortezomib, lenalidomide, dexamethasone]. Basically, the major differences were toxicities. So if you have a patient who has known heart disease, you wouldn’t want to give them KRd [carfilzomib, lenalidomide, dexamethasone]. And with known peripheral neuropathy, you wouldn’t want to give them VRd [bortezomib, lenalidomide, dexamethasone]. The answer that I’ll give you is that we’re still doing VRd [bortezomib, lenalidomide, dexamethasone].

 As I always say, I’m a PFS girl, as Joe knows, and we don’t have the PFS data from the GRIFFIN study yet. It’s a randomized phase 2 trial with stringent complete response, sCR, as its end point after consolidation. But if the PERSEUS trial is positive, then I would consider doing that.

Again, people won’t know what PERSEUS is.

 Oh, yes. The trial is dara-RVd [daratumumab plus lenalidomide, bortezomib, dexamethasone] vs RVd [lenalidomide, bortezomib, dexamethasone] in patients who are going to transplant, and it’s a randomized phase 3 design instead of a randomized phase 2 trial. So that gives us a better understanding of what the outcomes are and how to apply those outcomes to our patients.

Cristina, what about older patients? What’s your frontline regimen for an older patient?

 There aren’t many choices. I think the MAIA study, of course, is my first choice.

 MAIA was the randomized study comparing the dara-RVd [daratumumab plus lenalidomide, bortezomib, dexamethasone], in the front line, for nontransplant eligible patients vs the doublet, lenalidomide plus dexamethasone. Even the longer follow-up is amazing, the durability of response, PFS, etc. However, it was a little inferior for high-risk disease. Thinking about the addition of a proteasome inhibitor, when I have a patient with high-risk disease and nontransplant eligible, I always think about adding the proteasome inhibitor. Of course, here you are stuck in a situation where you have to make adjustments based on comorbidity, such as age, like you mentioned, and frailty. I always think about the possibility that there may be nothing different in the biology of myeloma between younger and older patients. But we don’t treat the older patient as aggressively. We treat them sometimes suboptimally and get an inferior outcome. It’s a balance, right? I like to have the proteasome inhibitor, or bortezomib, weekly if I can, and then go from there.

If I recall correctly, at EHA [European Hematology Association Annual Meeting] dara-Rd [daratumumab plus lenalidomide, dexamethasone] had a PFS of more than 5 years of therapy, 63 months or something.

That’s pretty impressive. Do you think you need a proteasome inhibitor when you can get lots of neuropathy in an elderly patient?

 I thought about that when I saw the longer follow-up, thinking about what I gain. But I still think some of the high-risk genetics perform better with a proteasome inhibitor. I learned a lot from the update of the FORTE trial from Francesca Gay, MD, with all the dissection of the different cytogenetics.

 I would agree with Cristina. I’m pretty much using DRd [daratumumab, lenalidomide, dexamethasone] for all standard-risk patients who aren’t eligible for transplant, but I consider using VRd [bortezomib, lenalidomide, dexamethasone] in high-risk patients. Both the SWOG S0777 study, which was VRd [bortezomib, lenalidomide, dexamethasone] versus Rd [lenalidomide, dexamethasone], and the MAIA study, as Cristina said, which is DRd [daratumumab, lenalidomide, dexamethasone] versus Rd [lenalidomide, dexamethasone], now have survival advantage of the triplet. I think we can push Rd [lenalidomide, dexamethasone] behind us. But I think that in the evaluation of the DRd [daratumumab, lenalidomide, dexamethasone], the only kink in that armor was in high-risk patients. So I tend to favor using VRd [bortezomib, lenalidomide, dexamethasone]. The last thing I’ll say, Keith, is pragmatically for the community oncologists. I try to use VRd [bortezomib, lenalidomide, dexamethasone] a little differently than they did in SWOG, the original study. They started it IV [intravenously] at twice weekly. I plan to use it weekly for 6 months, if there’s no neuropathy, then I’ll back it down and give it every other week for the next 6 months. I think we have justification for a year based on other studies. Hopefully that strikes the balance, as Cristina said, of not giving a lot of neuropathy but holding high-risk disease down for longer.

Experts in multiple myeloma comment on standard induction therapy for patients with newly diagnosed symptomatic myeloma and consider recommended triplet regimens.

Standard Induction for Newly Diagnosed Symptomatic Myeloma

, “Evolving Practice Patterns for Multiple Myeloma.” I’m Dr Keith Stewart. Joining me today in this discussion are my colleagues who are all experts in the field of myeloma clinical research: Dr Sagar Lonial from the Winship Cancer Institute in Atlanta, Georgia; Dr Joseph Mikhael from the Translational Genomics Research Institute in Phoenix, Arizona; Dr Cristina Gasparetto from the Duke Cancer Institute in Durham, North Carolina; and Dr Nina Shah from UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, California. Today, we will be discussing modern management approaches to multiple myeloma, and we’ll reflect on the latest data from the recent ASH [American Society of Hematology] meeting and from ASCO [American Society of Clinical Oncology], which just finished its 2021 virtual meeting in June. Let’s get started on our first topic. I’m going to turn to Dr Shah to start us off. Dr Shah, or Nina, today, when you work up a patient with newly diagnosed multiple myeloma, what is your thinking with respect to whether that will influence what treatment you give? How is that relevant to younger and older patients?

: Thank you for having me. I think this is a really important question because we want to be as specific as possible to treat our patients with myeloma, but sometimes we don’t have all the information we need. I think it’s important to get, of course, standard patient cytogenetics, and I would say that’s probably the most pertinent information, and also the most available information you’ll get. But I also like to get things like a PET [positron emission tomography] scan, etc, to understand the true burden of disease. This helps us to understand not only what’s going on with the patient physiologically, but we also have to think about what’s going on functionally with the patient, understanding frailty calculators, etc, so that we can decide where we may start their treatment, thinking about transplant eligibility vs not.

There’s a lot packaged in what you just said. Let’s start with a frailty score. Do you use that in your assessment of your patients?

: I probably should use it more than I do. It’s pretty helpful because it incorporates some of the morbidities that a lot of patients with multiple myeloma have. You can think about that with whether there’s going to be a transplant in the future or not. And if not, that will help you decide on the induction therapy. But I have to say that I would like to apply it more rigorously than I actually do.

Cristina, what about you? Do you use frailty scores when you’re looking at patients?

: No, not necessarily. When I encounter the patient, trying to figure out the different comorbidities, I don’t necessarily follow it rigorously, like Nina mentioned. Of course, you have your own idea at the end of the day if a patient is robust vs being incapable of tolerating the aggressiveness of treatment.

Cristina, at your center, the Duke Cancer Institute, are you using an age cutoff for transplant eligibility? Or is it a frailty and comorbidity assessment?

: We do some transplants for patients older than 70, 75, 76 years old, robust patients, as I mentioned, with a good performance status. But the younger patients, we tend to push toward transplant even if they don’t have the best performance status, and sometimes, I question that decision. But we don’t have a real age cutoff. I have to admit, 76 years old is probably my higher age.

How about you, Joe? Dr…used to say you could transplant anyone, age was irrelevant. Are you an advocate of an upper age limit?

: I’m not an advocate of an exact limit. Even when we wrote the ASCO guidelines recently, we said that age shouldn’t be the only factor, but it is a factor. The way I look at it, Keith, is that we look for the benefit of transplant these days. I shudder to say this in the presence of individuals like Professor Shah, but for transplant, the best evidence we have is in people under 65. So when someone’s 65 to 75 years old, in my mind, it’s more of a gray area. That’s where I’m more rigorous in a frailty evaluation, especially now that we have long-term data from MAIA and other studies showing that we can do well with a transplant-less route. I have to say, I used to think 70 years old was the cutoff for sure. But now, for patients between 65 and 70 years old, I have to convince myself why to do a transplant, Keith.

Sagar, do you do a PET scan for every patient?

: I think we do PET scans on every patient at the time of diagnosis. I think skeletal surveys have fallen by the wayside. I want to add, if I can, to the last discussion because I think there have been multiple retrospective analyses that show that the benefit of transplant in patients over the age of 65 is the same magnitude as the benefit for younger patients. I think it does continue to offer significant benefit. When we get to the MRD [minimal residual disease] section, I’ll tell you why I think an age cutoff has taken us down the wrong path.

Sagar, your center, the Winship Cancer Institute, published some phenomenal single-center results with triplet therapy, transplant, and more triplet therapy. The median survival was more than 10 years for standard-risk patients, which was very impressive. Do you change your therapy based on the FISH [fluorescence in situ hybridization testing]? If you’re giving everybody that treatment and you’re not changing anything, why bother doing it?

: What we change is in the maintenance phase. The answer is, certainly in that series, our approach was to give everybody the same induction and change the maintenance phase. Our current guidelines are that the high-risk patients will receive KRd [carfilzomib, lenalidomide, dexamethasone] up front, whereas the standard-risk patients will get RVd-dara [lenalidomide, bortezomib, dexamethasone plus daratumumab]. Again, we can talk about that more as a group later.

Keith Stewart, MD, ChB, MBA; Sagar Lonial, MD, FACP; Cristina Gasparetto, MD; Joseph Mikhael, MD; and Nina Shah, MD, discuss the diagnostic work-up for a patient with newly diagnosed multiple myeloma and the impact of age and frailty scores on transplant eligibility.

Joseph Mikhael, MD, Translational Genomics Research Institute

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Improving Maintenance Therapy for Myeloma

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Standard Induction for Newly Diagnosed Symptomatic Myeloma

Overview of Newly Diagnosed Multiple Myeloma