Multiple Myeloma Podcast

Frontline Therapy for Multiple Myeloma

Joseph Mikhael, MD; Peter Voorhees, MD


May 03, 2022

This transcript has been edited for clarity.

Joseph Mikhael, MD: Hello. My name is Dr Joseph Mikhael, and welcome to Medscape InDiscussion Multiple Myeloma. Today we're talking about frontline therapy for multiple myeloma, and although sometimes we get very excited about so many of the things that are happening in relapsed myeloma with new immunotherapies and CAR-T cell therapy, I have to say there's a lot going on in frontline therapy. We've really had another tidal shift as we're using more and more agents and using them more effectively in the upfront setting.

Joining me today to have this discussion is a very close and dear friend of mine who's a professor of medicine and chief of the Plasma Cell Disorder Division at the Levine Cancer Institute, Dr Pete Voorhees. Welcome, Pete.

Peter Voorhees, MD: Very good to be here. Thank you, Joe.

Mikhael: It's always good to have you with me, my friend. I really appreciate the opportunity to have this discussion with you. This is really a hot topic.

As I said quickly in the introduction, we often get excited about relapse therapies, but there is a lot going on in frontline therapy. We know that a lot of the people listening today out in the community are trying to decide, how do I treat my patients frontline? Do we still do transplants in people? What is the best combination? How many drugs do I use?

I'm going to put you on the hot seat a little bit here today, because I have four big questions for you that relate to frontline therapy and I want to work through these with you. Before we dive into those, though, I want to tell you a little bit about a patient who I saw in clinic just last week, who kind of embodies a lot of the challenges and yet the gratifying features of what we can do when we treat people in frontline therapy.

This is a gentleman who's 71 years old and, I must say, quite fit. He's quite active, and he's recently been diagnosed with myeloma, and he has a lot of questions, which is great. I want to empower patients to be able to read about myeloma. He's been to, and he's been reading about it and trying to understand things that are going on. He had a whole series of questions for me before he started his treatment. He says, "Doc, you know what is the best treatment? Is it a triplet? Is it a doublet? Do I really need to go to transplant? I got a lot going on my life now. If I do well, can I delay the transplants or do I really have to have it right away?" And then he even asked me, "Should I think about trying to get CAR-T earlier rather than later?" He asked a lot of great questions that now I'm going to defer a little bit to you.

But let's start with the first of them, which is maybe the most relevant change in myeloma recently: We went from doublets to triplets. We had been giving bortezomib and dexamethasone (Vd) or sometimes lenalidomide and dexamethasone (Rd), and it was pretty clear the triplets did better, that we saw deeper and more durable responses and longer-term outcomes when we used primarily a lenalidomide, bortezomib, and dexamethasone (VRd) strategy (although I'll come back to that later). Sometimes we might use carfilzomib, lenalidomide, and dexamethasone (KRd), but have we now gone from triplets to quads? I know you've led a lot of really important work in this area.

If someone is planning to go to a transplant, have we really turned that corner? Are we absolutely giving quadruple therapy to everybody? Or are you still debating between doing triplets or quads?

Voorhees: I think that the evidence to support quadruple therapy for patients with newly diagnosed myeloma is strong, and I anticipate it's only going to get stronger going forward. The first study that lent support to the use of quadruplets in frontline therapy was the CASSIOPEIA trial, which looked at the backbone of bortezomib, thalidomide, and dexamethasone with or without daratumumab as part of induction and posttransplant consolidation for transplant-eligible patients with newly diagnosed myeloma. The study that for those who were assigned to the quadruplets by the end of posttransplant consolidation therapy, they were more likely to be in a stringent complete response had they received four drugs; they were more likely to be minimal residual disease (MRD) negative, and that translated into an improvement in progression-free survival that was statistically significant.

Now the one criticism that has been leveled in the study that's made a little harder to interpret — and we may talk about this more later — is that there was a second randomization at the time of maintenance therapy, where patients either received no maintenance therapy or they received once-every-8-week dosing of daratumumab for 2 years. So the question was, how did that influence progression-free survival in this trial? Thalidomide, while useful in many parts of the world, has been replaced with lenalidomide in the United States and other parts of the world as well.

So we embarked on the GRIFFIN trial, which is a randomized phase 2 study looking at the incorporation of daratumumab into the RVd, or lenalidomide bortezomib, and dexamethasone backbone for transplant-eligible patients with myeloma. It was constructed very similarly to CASSIOPEIA. Patients got induction therapy, they got frontline transplant. They got a couple of cycles of posttransplant consolidation, and then they went on to maintenance therapy with or without daratumumab incorporated into the entirety of the treatment.

One of the major differences is that there was no second randomization at the time of maintenance therapy. Everybody got maintenance therapy, so the standard-of-care arm got lenalidomide maintenance therapy and the experimental arm got lenalidomide and daratumumab for the first 2 years, and then patients were encouraged to remain on lenalidomide monotherapy thereafter.

What we showed in that study, just like with CASSIOPEIA, was that rates of stringent complete response were better at the end of consolidation therapy and rates of MRD negativity were also improved; we updated these data at the American Society of Hematology (ASH) meeting back in December. At that time, all the patients in this trial had completed a minimum of 2 years of maintenance therapy. By that point, the rates of complete response were approximately 80% in the quad arm vs 60% in the triplet arm. The rates of MRD negativity were 64% for the quad vs 30% for the triplet — so more than a doubling of MRD negativity, at a sensitivity of 10-5.

Mikhael: If I can jump in on that for just a second, because that's such an important area. The field is moving more and more, and this is going to be an important theme throughout all of our podcasts in that we see that depth of response — not in every single patient, but in general — is a predictor of duration of response. That's what's winning people over. You're right, there's the whole challenge of maintenance therapy, but it's an artificial situation. There was no maintenance therapy in one arm; they're giving it once every 8 weeks. I'm not sure it heavily influences [outcomes] right away. Obviously, we've got the big phase 3s ahead to really answer the question. But have the data you've just presented from GRIFFIN, where daratumumab-VRd (dVRd) was superior to VRd alone when incorporated in that strategy of induction and consolidation and maintenance, convinced you to now give dVRd to a patient tomorrow in clinic?

Voorhees: What I would say is that in the overwhelming majority of randomized studies that have been conducted in multiple myeloma, an improvement in MRD negativity has translated into more durable responses, speaking to your point. The only studies where that hasn't been shown to be the case is where there was a major toxicity signal that that shifted things. So, for example, in the BELLINI trial, for patients who were not selected for 11;14 translocations, the MRD negative rate was better with the inclusion of venetoclax. But that was offset by increased toxicity for those receiving the triplet vs the doublet of bortezomib and dexamethasone in the relapsed space. With CD38 antibody trials, over and over again, whether it's in the relapsed/refractory space or in the frontline space, the incorporation of CD38 antibodies has generally been safe, and uniformly that better MRD negative rate has translated into improved progression-free survival.

I will mention, too, that the GMMG performed a very similar study that looked at isatuximab with RVd in transplant-eligible patients with myeloma, and they presented the primary analysis of that trial at ASH in December. What they showed was that with six cycles of induction therapy, adding isatuximab to an VRd backbone increased the MRD negative rate. It was approximately 50% after six cycles of induction with the quad vs about 25% for those who got the triplet, so confirming what we saw in the GRIFFIN trial. You add that CD38 antibody into your immunomodulatory drugs (IMiD), proteasome inhibitor, dex triplet, you get a better MRD negative rate, and we are actually starting to see a signal toward improved progression-free survival in the GRIFFIN trial as well. Our hazard ratio was 0.46 in favor of the quadruplet, but the 95% CI was quite large and just crossed the magic 1.0, so we weren't quite to the level of statistical significance.

Mikhael: I think time will help us see that. I was particularly struck by that GMMG study in which even before patients received transplant, even before consolidation, we already saw 50% vs 35% — to me, quite a significant improvement in MRD negativity.

So you heard it here first, folks, that Pete Voorhees has gone on record saying that he thinks these quads are the way of the future. I think that's how the myeloma community is thinking about it.

Let's come to question two for a minute, which is maybe not as complex, but important nonetheless. You made reference to several studies — CASSIOPEIA, then the GRIFFIN study, then the GMMG-HD7 study, which used VRd. But as we know now, we're starting to see quadruplets using KRd, so carfilzomib instead of the bortezomib. Luciano Costa and colleagues' MASTER trial used dara-KRd, with quite impressive outcomes. We know that there was the ENDURANCE study that interestingly, in a completely different population, not high risk and not going to transplant, the regimens were equivalent with maybe more toxicity from a cardiac standpoint with carfilzomib, a little bit more toxicity from a neuro standpoint with bortezomib, but now thinking as a "quadrupalist," if there is such a word, what is your thinking going forward, Pete? Are we going to KRd? Or is it really whatever you think matches better your patient? A patient who has diabetes and preexisting neuropathy, you may focus toward KRd, or in other patients, you may focus towards VRd plus the CD38, be it daratumumab or isatuximab (ISA). What's your thinking there?

Voorhees: The data that have been presented and published thus far with dara-KRd quads are really quite impressive. So you've got the MANHATTAN trial from Ola Landgren and the Sloan Kettering Group, and then you've got the MASTER trial, from Luciano Costa and colleagues, using this quadruplet. What I think is amazing is the rates of MRD negativity that they've seen in these trials, and in particular in the MASTER trial. I was also struck, as these data were presented and then published, by the rates of MRD negativity, at 10-6. There's been no head-to-head comparisons with dara-RVd and dara-KRd, but certainly the depth of response and the quickness in which these patients are achieving MRD negativity is quite impressive. There's strong nonrandomized data right now to support the use of dara-KRd.

To your point, the ENDURANCE trial, which looked at KRd vs VRdin standard-risk patients with newly diagnosed disease that we're not going to transplant as part of frontline therapy. There was maybe a slight signal toward improved VGPR (very good partial response) and better with KRd over VRd, but progression-free survival was exactly the same. That was a bit of a surprise for a lot of us, because in the ENDEAVOR trial, Kd outperformed Vd in patients with early relapse in a very significant way. The difference here is that in the ENDURANCE trial, RVd and KRd were used for a defined duration of therapy, and then patients went on to maintenance treatment. Whereas in the ENDEAVOR trial in the relapsed setting, patients could stay on Kd or bortezomib/dexamethasone until disease progression. It's easier to stay on Kd longer because of the neuropathy signal. That's where the difference is.

So if we were to do a study comparing an RVd-based quad vs a KRd-based quad, I don't think that we would see major differences between them. We would see, to your point, differences in the toxicity profile. You would see more neuropathy with the RVd quad and you would see more vascular side effects — hypertension, renal signals, pulmonary hypertension, congestive heart failure (CHF) — with the KRd-based backbone. You have to take the patient characteristics and choose on the basis of side effects more than efficacy.

Mikhael: That's a really important point. You know what it's like as a myeloma doctor. What do we want? We want choice, right? We want to be able to tailor therapy to each patient. I do think that what you said is very true. There are differences in profiles. Head-to-head, if patients able to tolerate it, we probably have an advantage with carfilzomib, for sure. But I think in this era, especially when you're combining so many agents together, toxicity becomes a really important signal. And we have to look for that. It's kind of a stalemate. In some ways, you match it to the patient.

Here's a controversial question, number three — it's not that controversial, but perhaps becoming more controversial. Some of our colleagues are basically telling their patients, "Look, we don't need to transplant anymore." They say, "We have all these novel agents, sometimes we do more damage than good with giving people a big whopping dose of melphalan." This is at the same time as we see something like the FORTE trial that gave 12 months of KRd vs 8 months of KRd plus a transplant. And even though the response rates were similar, and MRD was close, it looks like the progression-free survival benefited from having had a transplant. So transplant ain't dead yet.

What is your approach in the clinic? Just pragmatically, do you still plan to take eligible patients to transplant? Do you have a system where you decide if you can delay it or go immediately to transplant? How is it that you approach it in clinic, Pete?

Voorhees: Well, I've always been impressed by the attrition data that we see with each myeloma relapse, and I'm actually quite surprised to see the numbers of people who fall out of treatment with first relapse, second relapse, et cetera. And the other thing that's important to recognize is that the field is changing so quickly, and the things that are happening in the relapsed/refractory space are so transformative. The longer you stay in remission the first time around, the more opportunities you're going to have at the time of your first relapse.

What I typically will tell patients is if you have transplant as part of frontline therapy, you are giving yourself the best odds of the longest remission that you can have. And by doing so, you have expanded your opportunities for the future at first relapse. And for the 71-year-old patient whom we're talking about, transplanting them as part of frontline therapy is probably even more important because 5 or 6 from now, getting them through a transplant would be a lot harder than it is at 71, when they're otherwise quite fit.

Mikhael: That window is really important. That's an excellent point. We do have the IFM data that looked at comparing — a bit like the FORTE study — eight cycles of VRd vs five cycles of VRd plus transplant. Now, some argue, because almost 80% of people in the nontransplant arm had one at first relapse, that's almost more of a sequential study. So it provides that opportunity. If you have a patient who really has a good, legitimate reason like, "This is just not the time I want to get transplanted, Doc," especially if they're standard risk and their disease under really good control. That patient, that's maybe higher risk and you're nervous about that early relapse, I agree with you. You're going to knock down more of those clones if you try and give them the transplant.

Now, if we did this program in a year or two from now, we might be talking about whether or not CAR-T replaces transplant, but we're not ready for that discussion. That's a little beyond us. My bottom line here typically is that you're the champ until someone knocks you out, as it were, and transplant is still the champ. Although it is reasonable in some people to maybe delay it, especially because you say we don't treat myeloma, we treat people. If they really feel that this is not the time for them to have transplant, then I don't think that delaying it is unreasonable.

Voorhees: I agree. The survival signal was the same in both IFM 2009 and in the EMN Hovon trial, and we haven't gotten survival data yet from FORTE. So longer remission with that frontline transplant, but with a lot of people getting transplanted as part of first relapse in those trials, and the survival is the same. So yes, you're right: There are patients who can appropriately defer transplant.

Mikhael: That brings us to the fourth and the final question, and we've been focusing so far on people that are that are going to transplant. With the aging of the population with greater diagnostic techniques, we're detecting more people with this disease, a lot of people are not going to be transplant-eligible. We will address this in a whole discussion with Dr Ashley Rosko around geriatric assessment and deciding it, but let's say that you've got your patient whom you have decided is not eligible for transplant; you're not going in that direction. We've seen that triplets are really significantly better than doublets; I don't think we're quite ready for quads in the field, but I know it's being tested. Let's keep it to the triplets for now. What is your preferred triplet? Because we have VRd, which has been a standard of care. But now recently we have great data on DRd vs Rd: daratumumab-lenalidomide-dexamethasone vs lenalidomide-dexamethasone. Do you have a preferred selection between VRd or DRd in your transplant-ineligible patient?

Voorhees: I do. I've generally gravitated towards daratumumab with lenalidomide and dexamethasone for transplant-ineligible patients with newly diagnosed myeloma. Largely, that has to do with the fact that the neuropathy signal is far lower with daratumumab-lenalidomide-dexamethasone vs bortezomib-lenalidomide-dexamethasone, and it's hard to ignore the progression-free and overall survival data that have been presented and published from the MAIA trial.

Mikhael: Over 5 years now, right?

Voorhees: Yes, it's going to be beyond 5 years. At that 5-year mark, about 52% or 53% of patients in the triplet arm have still not progressed, which is really quite remarkable. And now we're seeing a survival improvement. So at the 5-year mark, 66% vs 53% of people are alive with the triplet vs the doublet. These are progression-free and overall survival data that we've never seen before in a newly diagnosed, transplant-ineligible patient population.

The other thing that I'll point out is that VRd is a terrific regimen well, but a lot of the patients who were in the SWOG trial were transplant-deferring patients like we just talked about. They weren't necessarily the elderly patients. So 57% of the patients on the SWOG trial were less than 65 years of age. The overwhelming majority of those were probably transplant eligible, but they elected not to get transplanted as part of frontline therapy. Whereas in the MAIA trial, the overwhelming majority of people were 65 years of age or older; only 1% of the patients in that trial were less than 65 years of age.

Again, there are a lot of data pointing in favor of daratumumab-lenalidomide-dexamethasone. That said, they've never been compared head to head. I know that's something that the SWOG is very interested in doing going forward, and I think it'll be incredibly important to see how they perform head to head.

Mikhael: I agree with you. The average age in the SWOG study was 63. The average age in the MAIA trial was 73, so it's a 10-year difference. It really is apples and oranges.

I agree with you. In my view, perhaps the only situation where I may start thinking a little bit more about VRd would be in the high-risk patient or very high-risk patient who may want the proteasome inhibitor. I definitely wouldn't give it like SWOG, I'd try to give it in a way that produces less neuropathy — subcutaneously once a week, maybe for 6 months. And then even after 6 months, I might switch to every other week.

Well, Pete, thanks so much for your input today. This has been a great discussion. We've covered a lot of ground and a lot of studies in a short period of time, so I would try and summarize what we've said today is that in those patients who are going for transplant, we really do seem to be moving from triplets to quadruplets. The good news is we have choices of whether the CD38 is daratumumab or isatuximab, and even to some degree, whether or not the protease inhibitor is bortezomib or carfilzomib. Those are options that can be looked at. But in that transplant-eligible population, we're almost definitely moving toward quadruplets to get a deeper and a more durable response. Transplant still remains a preferred option, but in some patients, especially those who have had a deep response and are lower risk, it's reasonable to defer. And then lastly, in those patients who are not going to transplant, I think we are seeing a shift toward a daratumumab-lenalidomide-dexamethasone approach that is more tolerable and probably yields a deeper and more durable response, although there still may be a role for VRd.

Thanks again, Pete, for helping us put this together.

Voorhees: And thank you, Joe. Pleasure to be here.


International Myeloma Foundation

Lenalidomide, Bortezomib, and Dexamethasone (RVD) Regimen for Multiple Myeloma

Carfilzomib, Lenalidomide, and Dexamethasone Plus Transplant in Newly Diagnosed Multiple Myeloma

Maintenance With Daratumumab or Observation Following Treatment With Bortezomib, Thalidomide, and Dexamethasone With or Without Daratumumab and Autologous Stem-Cell Transplant in Patients With Newly Diagnosed Multiple Myeloma (CASSIOPEIA): An Open-Label, Randomised, Phase 3 Trial

Daratumumab, Lenalidomide, Bortezomib, and Dexamethasone for Transplant-Eligible Newly Diagnosed Multiple Myeloma: The GRIFFIN Trial

Daratumumab (DARA) Plus Lenalidomide, Bortezomib, and Dexamethasone (RVd) in Patients (Pts) with Transplant-Eligible Newly Diagnosed Multiple Myeloma (NDMM): Updated Analysis of GRIFFIN After 24 Months of Maintenance

Venetoclax or Placebo in Combination With Bortezomib and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma (BELLINI): A Randomised, Double-Blind, Multicentre, Phase 3 Trial

Addition of Isatuximab to Lenalidomide, Bortezomib and Dexamethasone As Induction Therapy for Newly-Diagnosed, Transplant-Eligible Multiple Myeloma Patients: The Phase III GMMG-HD7 Trial

Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone With Minimal Residual Disease Response-Adapted Therapy in Newly Diagnosed Multiple Myeloma

Carfilzomib or Bortezomib in Combination With Lenalidomide and Dexamethasone for Patients With Newly Diagnosed Multiple Myeloma Without Intention for Immediate Autologous Stem-Cell Transplantation (ENDURANCE): A Multicentre, Open-Label, Phase 3, Randomised, Controlled Trial

Safety and Effectiveness of Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Daratumumab Combination Therapy for Patients With Newly Diagnosed Multiple Myeloma The MANHATTAN Nonrandomized Clinical Trial

Carfilzomib or Bortezomib in Relapsed or Refractory Multiple Myeloma (ENDEAVOR): An Interim Overall Survival Analysis of an Open-Label, Randomised, Phase 3 Trial

Carfilzomib With Cyclophosphamide and Dexamethasone or Lenalidomide and Dexamethasone Plus Autologous Transplantation or Carfilzomib Plus Lenalidomide and Dexamethasone, Followed by Maintenance With Carfilzomib Plus Lenalidomide or Lenalidomide Alone for Patients With Newly Diagnosed Multiple Myeloma (FORTE): A Randomised, Open-Label, Phase 2 Trial

Lenalidomide, Bortezomib, and Dexamethasone With Transplantation for Myeloma

Phase III Study of Isatuximab-Carfilzomib-Lenalidomide-Dexamethasone (Isa-KRd) Versus Carfilzomib-Lenalidomide-Dexamethasone (KRd) in Newly Diagnosed Multiple Myeloma Patients Eligible for Autologous Stem Cell Transplantation (IsKia trial)

Daratumumab, Lenalidomide, and Dexamethasone Versus Lenalidomide and Dexamethasone Alone In Newly Diagnosed Multiple Myeloma (MAIA): Overall Survival Results From a Randomised, Open-Label, Phase 3 Trial

Longer Term Follow-up of the Randomized Phase III Trial SWOG S0777: Bortezomib, Lenalidomide and Dexamethasone vs. Lenalidomide and Dexamethasone in Patients (Pts) With Previously Untreated Multiple Myeloma Without an intent for Immediate Autologous Stem Cell Transplant (ASCT)

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