Activity Transcript

S. Vincent Rajkumar, MD: Hi, I'm Vincent Rajkumar. I'm really happy to host this program, "Updates on Treating Newly Diagnosed Multiple Myeloma." I'm a professor of medicine at the Mayo Clinic. I'm really happy to be joined today by Dr Pete Voorhees, who's a professor of medicine and the chief of the Plasma Cells Disorder Program at the Atrium Health Levine Cancer Institute in Charlotte, North Carolina. Welcome, Pete. How are you today?

Peter M. Voorhees, MD: I'm doing very well, Vincent. Thanks for having me today.

Dr Rajkumar: Look forward to having a good discussion back and forth with you about approach to the treatment of multiple myeloma (MM) and also, recent updates. As you quite well know, we have a number of treatment choices for the frontline therapy in patients with newly diagnosed (ND) MM, a variety of options for patients who are transplant candidates, and a number of different options for patients who are not transplant candidates. Important options being bortezomib / lenalidomide / dexamethasone (VRd), which we commonly use, [and] daratumumab / lenalidomide / dexamethasone (DRd), which has come forth in the last few years as an alternative. Other regimens commonly used include carfilzomib-Rd and the one that you have pioneered, which is daratumumab plus VRd (dara-VRd), which may be the future.

Of course, when we think about what treatment options to use for a newly diagnosed patient, we are looking at a variety of factors. One is the host factors: who is the patient,  their performance status, their frailty, their comorbidities, presence or absence of renal function, their own preferences in terms of how intensely they would like to be treated. What is their access to care, what is their home situation like? And people who can help them take care of themselves -- caregiver support.

Then, we have the disease burden. How much myeloma are we talking about? How many lytic lesions or how significant the tumor burden is. The third factor that I usually think of is the aggressiveness of the disease, biologic aggressiveness, like presence or absence of high-risk abnormalities like 4;14, 14;16, del(17p), 1q gain, double- or triple-hit when they have more than 1 high risk factor. In my own mind, when I see a brand-new patient with MM, the first steps for me, too, is to look at the host factors, the tumor burden, the aggressiveness, and also transplant eligibility. Is the patient a candidate for transplant or not?

So, my first question to you would be that there are so many of these variables, how do you approach a new patient? And firstly, when should patients be referred to a transplant specialist? How do you really decide these factors, Pete?

Dr Voorhees: I think, Vincent, that's a very important question. I think, as we'll talk about later, what we find is a lot of these advances in frontline therapy have shown benefit, particularly for standard-risk patients, and a signal in high-risk patients as well. Always a little harder to see in the high-risk patients because the numbers of patients in these individual randomized trials oftentimes is fairly low. So, it's not unusual for me to be applying similar therapy to the standard and high-risk patients. Comorbidities, frailty, patient preference, and what the available data supports are probably the factors that I use most when making a decision about appropriate frontline therapy for a patient.

As far as referral to a transplant center, I think that the important thing to recognize is that this is something that should not be factored on simply by age or, for example, renal dysfunction. I think that there's very nice retrospective data from the Center for International Blood and Marrow Transplant Research (CIBMTR) that carefully selected older patients and carefully selected patients with renal dysfunction can benefit from high-dose melphalan supported by autologous stem cell transplantation. So, I think for patients who are fit, intermediate fit, those are patients that probably should be referred to hear about the advantages and disadvantages of frontline transplant. For frailer patients, perhaps that's not the best approach for them.

Dr Rajkumar: Would you prefer that we recommend referring patients after 1 or 2 cycles of therapy so that there's time then for the transplant team to decide when to collect stem cells?

Dr Voorhees: I think that's absolutely critical, and oftentimes, patients are referred a bit late. All of our centers have apheresis units that are very busy, and with the emergence of CAR T-cell therapy, it's evermore the case. So, the earlier you can get them in the better. And with the increasing use of CD38 antibodies with lenalidomide in the frontline space, there is an impact on stem cell mobilization with those 2 agents together. So, the sooner you can collect those stem cells, the better the yield you'll have.

Dr Rajkumar: That's fantastic. So, in summary, we have a number of factors we take into account when deciding the initial therapy. We'll get into what treatments to do, but whenever somebody starts a patient with newly diagnosed myeloma on therapy, they should keep in mind that age alone doesn't determine transplant eligibility. When in doubt, actually refer to a transplant center and then they can make the decision. And preferably refer after 1 or 2 cycles of therapy and not wait too long, so that we don't have an adverse effect on stem cell mobilization.

When you come to treatment selection, let's start with transplant-eligible patients. If we think somebody potentially is transplant eligible, the main regimen I have used for a long time is VRd, and that's because VRd has been around for 10, 15 years. We have data from the SWOG trial that VRd is better than Rd even though it's a non-transplant. We got a sense for how well it works and what to expect from the side effects. And then we have the DETERMINATION trial and the IFM trial, both of which use VRd as frontline.

So, we know kind of what to expect. We also know that bortezomib is now generic, so it's an easier regimen in terms of cost. In many countries, lenalidomide is also cheaper, so this is a good backbone to build on. Given that the Emory group has actually got a really good data set of 1000 patients where they treated with VRd transplant and then maintenance. In the standard risk patients, they gave just lenalidomide maintenance, and in the high-risk patients, they gave both lenalidomide and bortezomib. Their outcomes are outstanding: median overall survival (OS) of 13 years or so for the standard risk and about 8 years for the high risk.

I thought this was so unique only Emory could get it, but actually the Canadian group presented data at the American Society of Hematology (ASH) -- very similar results. So, we have made progress for both standard and high risk with this approach. How do we build on this and what data do you think we have to support the addition of a fourth drug, on top of the VRd regimen? Or some immunomodulatory drug (IMiD) / proteasome inhibitor (PI) backbone? What do we have data-wise to support the addition of, say, a fourth drug, particularly a monoclonal CD38 antibody?

Dr Voorhees: The bar is set very high, as you very well pointed out. VRd is an absolutely terrific backbone for patients with NDMM who are eligible for upfront stem cell transplant. So, what you add to this backbone has got to show improvement not just in depth of response but in longitudinal outcomes; and it's got to be safe to do so, as well. Now, as we all know, the addition of CD38 antibodies into standard-of-care (SOC) myeloma regimens has generally led to those outcomes. So, in the relapse space, when you add either isatuximab or daratumumab, the SOC backbones in the context of phase 3 studies, invariably we see an improvement in depth of response. Whether you measure that by complete response (CR) rates or minimal residual disease (MRD) negativity rates, typically translating into an improvement in progression-free survival (PFS). And, with longer follow-up, you start to see improvements in OS trickle through as well.

In the frontline space, CASSIOPEIA was a very important phase 3 study that took the bortezomib / thalidomide / dexamethasone (VTd) backbone for transplant-eligible patients and added daratumumab to it. So, patients in the control arm got 4 cycles of VTd induction, a transplant, 2 cycles of post-transplant VTd consolidation. And the experimental arm got the very same treatment with daratumumab incorporated into the induction and in the consolidation therapy.

Now, interestingly, they had a second randomization in the study after patients had recovered from post-transplant consolidation where patients were randomized to either no maintenance therapy or daratumumab maintenance therapy. And what they showed is that depth of response was improved: stringent CR (sCR) rates of 29% in the experimental arm vs 20% in the triplet arm. MRD-negative rates were better with the quad, 64% vs 44%, and PFS was improved as well with a hazard ratio (HR) of 0.47 and a trend, although early, of improvement in OS as well.

And now, you know, Vincent, that in the United States we've moved away from thalidomide in the backbone for frontline, gravitating towards VRd with the idea that lenalidomide is a bit more potent than thalidomide as far as the immunomodulatory activity and also has less neuropathy associated with it, so it pairs better with bortezomib, as a result. In the Alliance Myeloma Group we took the VRd backbone for transplant-eligible patients and added daratumumab to it. We took 4 cycles of VRd followed by a transplant, 2 cycles of post-transplant VRd, and we gave patients lenalidomide maintenance. The experimental arm got the very same thing, but they got the daratumumab in the induction, they got it in consolidation, and they got it in the first 2 years of maintenance therapy.

Very similarly to the CASSIOPEIA trial, we showed a similar magnitude of improvement in sCR with the quad vs the triplet. We also showed that MRD-negative rates were improved with the addition of daratumumab to the VRd backbone. And, with longer follow-up, we're starting to see a PFS difference emerge, with the curves really not spreading apart from one another until after 2 years of follow-up. So, the 4-year PFS was 87% with the quad vs 70% with the triplet. And that translated into a PFS HR of 0.45.

The German Multiple Myeloma Group (GMMG) has shown very similar data using isatuximab with the VRd backbone for transplant-eligible patients. They used VRd for 6 induction cycles with or without isatuximab prior to transplant. And what they showed is that MRD-negative rates in the lead-up to transplant were 50% vs 36% for the triplet arm prior to transplant. I think it's clear that the addition of the CD38 antibody improves depth of response, and we're starting to see benefits with regards to PFS.

Dr Rajkumar: That's really impressive -- particularly, your study -- because I used to say, if you see a newly diagnosed transplant-eligible patient and you start with VRd / transplant / lenalidomide maintenance, it'll be 4 years until they relapse, on average, which is, like,

 50/50. But, one, you found that even in the VRd arm, 70% are progression-free at 4 years, which is beyond the 50%. And it's more in line with DETERMINATION, too, what Dr Richardson reported. So the median PFS would be 5 years or so. But, importantly, with dara-VRd, you are showing almost all patients are progression-free at 4 years; you are getting 87% PFS at 4 years, which is really encouraging. The key question is, number 1, should all patients get quad induction now?

Dr Voorhees: I think that's a great question. I think GRIFFIN was a very important practice-informing randomized study for the United States. It was a phase 2 trial, and one of the criticisms that has been leveled against the GRIFFIN trial is the fact that there was a higher rate of patients dropping out of the control arm because of suboptimal response. Or perhaps the investigator felt that the patient was progressing prior to strict International Myeloma Working Group (IMWG) criteria being met for progression.

It's going to be important to verify these results. I think we probably got it right. We did a sensitivity analysis where we actually looked at those patients that dropped off to pursue alternate therapy, and we used their PFS2 data as an endpoint and we saw that the HR for PFS actually improved for the experimental arm, suggesting that those that pulled out to receive alternate therapy were higher-risk patients rather than better-risk patients. But nonetheless, I think it's important to make this a universal SOC. We need verification in randomized phase 3 studies, and that's exactly what the PERSEUS trial is setting out to do, which is being pursued in Europe and designed very similarly to what we did.

Dr Rajkumar: Sure. At Mayo, the way we are looking at it is we think this is really promising, and the question is, should all patients get it? One thing we are doing is with the current EQUATE trial (this is what Dr [Shaji] Kumar is leading in ECOG, and it's available throughout the United States) we are asking the question whether the fourth drug may be more necessary for patients who are still MRD positive after the initial triplet or do even MRD-negative patients need it? And that would help us decide. You know, when you add a fourth drug, you are adding cost and toxicity. And if we can show who really benefits, then we can trim down both of those signals.

The second thing is we are very impressed with your data and that's why we are willing to, even without phase 3, move on to the quads in the high-risk group -- not because it works better in high risk, but we think that those patients, we can give them the benefit of the doubt. I think you are right; I think you probably got it right and most likely we will see a switch toward a 4-drug regimen. Previously, I was opposed totally to 4 drugs for all. But now, if somebody says, "I want to use a quadruplet," I'm not going to stand in their way, because I feel like you probably got it right. Would you say that either daratumumab or isatuximab can be used depending on access and availability or do you think your results apply only with daratumumab?

Dr Voorhees: I think that the data with isatuximab and daratumumab, when they've been combined with the same backbone regimen, are nearly superimposable. They have the same target. The preclinical data, the antibodies have more similarities than differences. So, I feel very strongly that they're both going to perform equally well in the frontline space with quadruplets.

Dr Rajkumar: If somebody uses a quadruplet, any particular precautions they should take in terms of prophylaxis or preventing infections, or anything else of concern to you, like mobilization? What concerns do you have specifically when you add the fourth drug, and how do you mitigate that?

Dr Voorhees: So, the 3 most important things are: 1, adding the CD38 antibody to lenalidomide increases the rate of neutropenia. So, you have to monitor that closely and make potential adjustments to the lenalidomide, and potentially even introduce granulocyte colony-stimulating factor (G-CSF) in some cases to ensure that they're not experiencing high-grade neutropenia for any sustained period of time. There is an increased risk of infection when you add a CD38 antibody to a VRd backbone. At least in the GRIFFIN trial, while the overall rate of infection was higher with the quadruplet compared to the triplet, the rates of high-grade -- grade 3 and higher -- infections was very similar between the 2. Nonetheless, it's important to ensure that patients are up to date with vaccinations, whether it's COVID, influenza, pneumococcal vaccination, etc., and everybody should get zoster reactivation prophylaxis for sure. Then, as we alluded to before, the longer you're on a CD38 lenalidomide-based induction therapy, the more difficult it does become to mobilize those stem cells. So, I typically suggest that mobilization start either after 12 to 16 weeks of induction therapy.

Dr Rajkumar: Sounds good. Some really quick responses from you on questions that people get. The fact that we use daratumumab up front, does that limit your options at relapse?

Dr Voorhees: I think if you use daratumumab in the way that CASSIOPEIA and GRIFFIN used it, they'll get daratumumab for 2 years and then they'll stop. In the GRIFFIN trial, we did allow continued use of lenalidomide beyond that period of time, but I think most people in first relapse will still be CD38-sensitive. They may not be CD38-naive, but they'll be CD38-sensitive. But there is this emerging group of patients who are going to progress on lenalidomide and daratumumab, and it's going to be important that we develop randomized studies to address best therapies for that group of patients.

Dr Rajkumar: In CASSIOPEIA, you had that second randomization where patients who got the 6 months of dara-VTd did not really benefit from the extra daratumumab at maintenance. So, would it be reasonable for those of us who are still waiting for good phase 3 that, if we were to use a quad, use the dara-VRd for induction for 6 cycles, collect stem cells, transplant, and then for maintenance, rather than using daratumumab, just do what the Emory group has done with lenalidomide maintenance for standard risk and bortezomib / lenalidomide for the high risk?

Dr Voorhees: I think it's a great question. It's the million-dollar question, literally the million-dollar question. Unfortunately, there's not a second randomization in GRIFFIN to tease out the value of the daratumumab in the induction and consolidation vs the maintenance, nor is there in the PERSEUS trial as well. I do think that the GMMG study with isatuximab-VRd will answer that question, because after the patients gets transplanted, there is a second randomization in that trial to either lenalidomide monotherapy or isatuximab / lenalidomide maintenance therapy. And that'll really tell us the right answer. I think if you have a standard-risk patient who's had an excellent response to their induction therapy and transplant, using lenalidomide monotherapy is not a wrong thing to do.

Dr Rajkumar: Awesome. So helpful for clinical practice for people to hear from you. Again, we've talked a lot about bortezomib, again, there are a lot of advantages we know about it. VRd is a very easy regimen to use and we can minimize the neuropathy by using it once a week subcutaneous. Are there situations [for which] you would use carfilzomib for induction, like dara-carfilzomib / Rd (KRd) instead of, say, dara-VRd or dara-carfilzomib /cyclophosphamide / dexamethasone (KCd), or something else like that?

Dr Voorhees: I think that the obvious group are those patients who have pre-existing neuropathy, whether that's due to the underlying MM itself or perhaps they've had poorly controlled diabetes for a number of years in the lead-up to their diagnosis of myeloma. We sometimes have patients who've experienced significant spine injury related to their MM and have bad neuropathic pain related to that. Those are the patients who probably are not going to tolerate bortezomib terribly well from a neuropathy perspective. And there, I would be looking for utilization of carfilzomib in its place. One thing that I still struggle with a lot is whether or not I should be using KRd preferentially over VRd in the high-risk patients. And Vince, what do you guys do at the Mayo Clinic in that regard?

Dr Rajkumar: My own feeling is even though the ENDURANCE trial compared VRd and KRd only in the standard-risk patients, in general, most of the treatments we have in myeloma work better in standard risk than in high risk. So, I find it hard to believe that somehow carfilzomib will be able to do in the high risk what it didn't do in the standard risk. But, having said that, if patients have significant pre-existing neuropathy, like you said, or develop neuropathy while on dara-VRd, I'm okay with changing to carfilzomib-based induction. But, by and large, we are very happy with the dara-VRd quad or isa-VRd quad and then use carfilzomib more selectively.

Dr Voorhees: Yes.

Dr Rajkumar: The questions that come -- is the MASTER trial MRD-based adjustment of the consolidation or maintenance. What do you think about that approach? Again, it's a single-arm study, so hard to say.

Dr Voorhees: I think that their initial results for patients who have no high-risk cytogenetic abnormalities or 1 high-risk cytogenetic abnormality are very interesting. The PFS curves thus far look very good. I think it's going to be important that we re-evaluate that data set with longer follow-up, because it's conceivable that you could see a precipitous drop in the PFS curves in the absence of ongoing, continuous pressure in the form of maintenance therapy. I think for those that have ultra-high-risk MM with 2 or more high-risk cytogenic abnormalities, that approach is not appropriate. I think as far as de-escalating therapy based on MRD results, we really do need the randomized data to support that approach. So, I'm not doing that routinely in clinical practice.

I think the DRAMMATIC trial by SWOG, which is looking at lenalidomide vs daratumumab and lenalidomide in maintenance therapy, will address the question, because they've got the second randomization for those with MRD negativity at 10^-6 level sensitivity, where those that achieve that depth of response are randomized to continuing their therapy or stopping it at the 2-year-into-maintenance mark. And I think that that's going to really help address the issue of de-escalation.

Dr Rajkumar: I think de-escalation you are a little bit more wary of than escalation. When I look at MRD, the prognostic use of that measurement is clear. If you are negative, you do better than if you're positive, and the negative at 10^-6 does better than negative at 10^-5. But, in terms of surrogacy -- as you know, we are still doing the FDA correlation studies -- but, in terms of changing therapy, what you're saying is that we still need to wait for randomized trial. We see the benefit of MRD regardless of risk status. Would you adjust therapy, at least in the high-risk group, if they didn't go MRD? Let's say you did dara-VRd, transplant, bortezomib / lenalidomide maintenance, and a year later they're still MRD positive. For the high-risk group at least, would you adjust therapy, or would you say even that we need randomized trials?

Dr Voorhees: I think the devil's in the details, and there may be some select instances where persistent MRD positivity may bother me. But, for a high-risk patient that's 1 year into maintenance and they're MRD positive -- but they're in a CR and I'm using lenalidomide / PI maintenance, for example -- I mean, I have absolutely no data that switching to salvage therapy with dara-Kd or something like that, for example, is going to improve their long-term outcome. So, in most instances, I have not been escalating therapy solely based on MRD positivity. Again, I think randomized studies are going to be very important in that regard. And the MIDAS trial that's being conducted by the IFM, I think, will be very helpful in that regard.

Dr Rajkumar: Awesome. Because again, we are giving clear direction and I do the same. I'm very much wary of using an MRD result to change the therapy, to either de-escalate or escalate when patients are doing well. There must be some other factor that is there that worries us to do that. Otherwise, the patients are doing well, and they are responding, and they are tolerating therapy well, and if there's no evidence of any rise in protein . . .  I don't even know what to escalate with. And so, I'm just continuing the PI and lenalidomide, even for the high-risk patients.

Now, there are various ways of measuring MRD and various terms that we use for people to recognize. When we say "MRD negative", currently, the way the IMWG defines it is you should be in CR -- and the bone marrow, you either do sequencing or flow, next-generation sequencing or next-generation flow -- and they're negative at 10^-5. That's the way the IMWG defines MRD negative.

If the same measurements are confirmed 1 year apart, it's called sustained MRD negative. And, in addition, if the MR imaging test, like a positron emission tomography (PET) / computed tomography (CT), is also negative, then you call it imaging MRD negative. Now, we are then splitting hairs when we say if it's negative at -6 compared to -5, what does that mean? Maybe better for prognosis, but for people to know that either flow or sequencing is OK, but there are various techniques to measure. Would you have a preference, Pete? Or what do you guys do if you're assessing MRD clinically? Flow, sequencing, or is either OK?

Dr Voorhees: I think that the assays that have 10^-6 level of sensitivity are the most useful.  One of the things that I do like about the flow approach is that you get an assessment of sample quality, so you know if the sample is hemodilute or not, which can potentially lead to a false negative result. I think that can be actually quite helpful. And then the other thing is you don't need that baseline sequence from initial diagnosis to run the test. You can still get a result. I like the next-generation flow, but I think that they're both terrific assays.

Dr Rajkumar: Great. Same here. I think either one is OK with me. Clearly, the sequencing is more sensitive, if that's important for you to know. One question that comes up often in the community setting is, should they even routinely check for MRD status? Like, a patient had induction transplant maintenance and let's say they are in a CR, doing well. Do I put them through a marrow just to tell them that they're MRD negative?

Dr Voorhees: I think in the absence--

Dr Rajkumar: Oh, it's a hard one.

Dr Voorhees: No, it is. And I think, ultimately, we're all guilty of having done this, but I think that the challenge that we have is we don't really know what to do with the information. For example, with GRIFFIN, at the end of post-transplant consolidation, 50% were MRD negative. That means 50% were not. Did they do poorly? No. We've got 4-year PFS data that look absolutely terrific. So, you've got this half of the patients that you've treated who are terrified because they're MRD positive and they're just waiting for the shoe to drop. And then you've got us, who are not really sure what to do with the data. Do we escalate? Do we just stay the course? So, I don't know. I think in routine practice, until we've got clinical trials that really tell us how to use the information, I'm not sure that it's the best thing to do.

Dr Rajkumar: Again, really valuable for clinical practice, and I am in agreement with you as well. I get this question often from patients and I tell them, if you had to have bone marrow for some other reason, part of a clinical trial or something, fine. But if patients are in CR and doing well, I don't do a marrow just to document that they're MRD negative. That goes to the next question, because patients ask, "should I get it done serially, like every year or every 6 months?" And I think, in a trial, if it's required and you have signed informed consent, and they know the pros and cons, it's okay, but I don't do it in routine practice.

Dr Voorhees: You have these patients who are MRD negative and then they get a marrow 2 years into maintenance and they're now MRD positive at 10^-6, but they're negative at 10^-5. What do you do with that information? And I think that the time to which those patients go on to develop biochemical progression and clinical progression is quite variable. Again, I'm not sure what to do with the information. I think that the PERSEUS trial is doing something kind of cool where the patients that are treated with daratumumab-lenalidomide maintenance in the experimental arm, if they've had at least 2 years of maintenance and they're in a sustained MRD-negative status, they drop the daratumumab and they continue the lenalidomide. But if they flip back to MRD positivity, they add the daratumumab back into the regimen. And it'll be interesting to see what the rates of MRD conversion are after they stop the daratumumab and whether you can recapture MRD negativity with reintroduction of the drug.

Dr Rajkumar: Now, moving on to stem cell transplant, as you know, we've really had outstanding results with stem cell transplant. It's 1 of the real important tools we have in myeloma. It's one that is dependent on time -- you want to do it when the patients are eligible and fit. From the IFM trial, the DETERMINATION trial, we are really seeing 8-year survival rates that are outstanding. The 5-year OS rate in the DETERMINATION trial was, like, 80%. And we now know with Emory and the Canadian real-world data that is really seen in clinical practice as well. Same thing with CASSIOPEIA and your own GRIFFIN trial. And we've talked about the importance of referring patients early for transplant. Do you still recommend an early transplant whenever possible for patients? Are there situations when you are OK with a delayed transplant approach?

Dr Voorhees: There are clear data from DETERMINATION that PFS is better with upfront transplant for the high-risk patients defined by high-risk cytogenetics, although the numbers were not large enough that there was a clear signal for survival advantage in the high-risk patients as well. So, I think for that group of patients, I advocate fairly strongly for pursuing an upfront transplant. I do still think that there's a role for upfront transplant for standard risk patients as well. For those that are kind of getting into their late sixties, early seventies, if you're deciding to delay at that point, you're probably deciding not to do it at all, because you're going to have a very long PFS with that first round of therapy, like you said before. And by the time they relapse, they may have incurred additional comorbidities or frailty that would make transplant not possible.

So, I think for that group of patients, it's an important discussion to have, but I do lean towards upfront transplant there. For the standard-risk patient, particularly those who're younger, it's not unreasonable to collect and store. I don't think you can use MRD data based off of 4 cycles of therapy to kind of guide you. There's going to be a very small percentage of patients who are MRD negative after just 4 cycles of therapy, maybe about 20% of patients or so. So, you do 4 cycles, roughly. You collect stem cells, you continue them on their initial induction therapy after you've collected the stem cells, and if they achieve a deep response -- so here, I am using MRD. They achieve a deep response; I think putting them on maintenance thereafter and saving transplant to relapse is very appropriate.

Dr Rajkumar: Moving on to transplant-ineligible patients -- I mean, the real SOC for a long time has been VRd, again, similar to the transplant-eligible patients. Without a transplant, the SWOG trial established really good results. Median survival, I think, in the long-term follow-up, more than 5 years. The MAIA trial used dara-Rd instead of VRd. Again, the control arm in both trials was Rd and is showing really outstanding results with the PFS just about now reaching median and OS is still, the median is not reached at more than 5, 6 years of follow-up. How do you choose between VRd and DRd for transplant-ineligible patients? Or is either one OK?

Dr Voorhees: I do think that both approaches are highly reasonable. What I would say is that, in the SWOG study, there are a fair number of younger patients, those 65 years of age and younger. And when you look at the PFS and OS data, for those that were over the age of 65, the advantage with the addition of bortezomib was a bit less clear. There was a vanishingly small number of patients in MAIA that were younger than 65 years of age. So, I think a lot of the patients in SWOG may have been transplant deferred rather than truly transplant ineligible. I think, based off of that and just based off of the really remarkable progression free and now OS data with the dara-Rd triplet, that's become my SOC for really everybody. There are going to be those patients who are more susceptible to high-grade neutropenia with dara-Rd where a VRd or VRd-lite-based approach may be better tolerated. But, for the majority of patients, I've moved to dara-Rd.

The other thing to point out is that, for the MAIA trial, the 3 drugs were continued until disease progression. Whereas, in the SWOG study, patients received a defined course of 3-drug therapy followed by Rd thereafter. The question is, what would've happened if they had continued the bortezomib in the therapy? And I think SWOG is doing a nice randomized trial in newly diagnosed patients to kind of dissect this out. They're going to compare a defined course of dara-Rd followed by lenalidomide vs VRd followed by lenalidomide in frailer patients who are truly transplant ineligible. And I think that that'll answer the question definitively, but I think an VRd-based approach is very effective.

Dr Rajkumar: Sounds good. So again, for patients, as we discussed, you prefer dara-Rd and I think dara-Rd is a reasonable choice, VRd is a reasonable alternative. It has the advantage of a shorter duration of the triplet, so people have to take cost and that factor into consideration. Are there situations where you use something for frontline besides dara-Rd or VRd in elderly patients who are transplant ineligible?

Dr Voorhees: For patients who have severe renal dysfunction, when they're initially diagnosed, we will oftentimes use cyclophosphamide with a PI and dexamethasone -- usually bortezomib and dexamethasone -- just given some small but real risk of renal vascular issues with carfilzomib. So yes, we do use cyclophosphamide / bortezomib / dexamethasone in those patients, but what we've done more and more, as the body of literature supporting IMiD / PI triplets grows, once we have a good sense as to what their renal function is going to stabilize at, we will convert them over to renally dosed lenalidomide / PI deck. We'll start with, like, cyclophosphamide / bortezomib / dexamethasone, for example, but then we'll change that. You still have to be really careful with lenalidomide with renal dysfunction, because even when you adjust the dose to account for their renal dysfunction, they do have a higher rate of infection in high-grade hematologic toxicity as well.

What are your thoughts about the use of ixazomib in the place of, say, bortezomib or carfilzomib in the frontline, Vincent? Would you ever use ixazomib with Rd for a newly diagnosed myeloma patient?

Dr Rajkumar: Well, the problem is that ixazomib hasn't shown the promise that initially we thought it had. It's hard to take sometimes in the right dose. In the frontline trial, it hasn't shown the extent of benefit that we thought we would get. So again, it's a minority of patients, the patients who are frail, who we need to give a triplet, but they are not able to come to the clinic to get daratumumab or bortezomib. Particularly if they have high-risk features, they may benefit from ixazomib-Rd rather than just giving them Rd. And that's an oral regimen that you can take.

What about maintenance, though? It's well established as we talk for transplant-eligible patients, it prolongs OS. Now, in MAIA, they just gave daratumumab indefinitely, the dara-Rd is just continued -- and continuous therapy for transplant-ineligible patients, would you, using the SWOG and the MAIA trials, say that patients, whichever regimen they use, they do continue therapy in some form till the first relapse?

Dr Voorhees: What I've typically advised is that when you make a choice of what regimen to use, you should try and stick with how it was done in the clinical trial that proved its benefit. If I'm using VRd or VRd-lite in a newly diagnosed transplant-ineligible patient, I will use it like it was done in the trials. I think we all know that twice-weekly bortezomib is very challenging from a neurotoxicity perspective and neuropathy. I think a lot of us gravitate towards once-weekly bortezomib dosing. So, we do make some modifications to the SWOG VRd regimen, but I do use those 3 drugs for a defined period of time, typically 24 weeks of therapy, roughly. And then I move on to maintenance therapy with either lenalidomide alone for a standard-risk patient or the addition of a PI with the lenalidomide for a high-risk patient.

Dr Rajkumar: Great. I think we've covered a lot of points and just coming back to the summary of the session.

The many decision points in approaching newly diagnosed patients, you have to first know who the patient is: host factors, tumor burden, biology, how aggressive, high risk, standard risk. Then, we need to determine transplant eligibility. And when in doubt, refer for transplant, and when referring for transplant, refer early. For the transplant-eligible patients, as you've heard from both of us, we have VRd or dara-VRd as 2 good regimens that we use for induction, and we then prefer early transplant for most patients.

Then we go on to maintenance with either lenalidomide alone for standard-risk or lenalidomide-bortezomib for high-risk patients. In the non-transplant-eligible patients, we have both VRd and dara-Rd. Dr Voorhees pointed out why dara-Rd might be the better of the 2 in terms of long-term results and the data. And we also discussed that whichever regimen you use, we are still going to continue with some form of maintenance -- and preferably a doublet maintenance for the high-risk patients.

Any other closing thoughts you have, Pete, to add on to the summary? Otherwise, we've had a really good discussion.

Dr Voorhees: No, I mean, I think we've made a lot of progress, and with that progress come even more questions. So, I'm sure we will have to completely revise what we've just said a year from now.

Dr Rajkumar: Yes, thank you so much.

Dr Voorhees: That's a good problem to have.

Dr Rajkumar: It is a good problem to have, at least. But I think starting off with the 10, 20 regimens that are there, we have narrowed the choices for most people, too, in terms of giving them an outline. And I think, really, the OS of myeloma that we get now is far better than what we used to. In the future, we'll get randomized trials that inform us about MRD duration of therapy, MRD-guided therapy, and the like.

I thank you for all your comments, Pete, very valuable.  And I thank the audience for your attention and look forward to a different session in the near future. Thank you so much.

This transcript has not been copyedited.