Updates in the Treatment of Transplant-Ineligible NDMM


Shared insight on the evolving treatment landscape of transplant-ineligible newly diagnosed multiple myeloma.


Sagar Lonial, MD, FACP: Let’s go to polling question 6. Which of the following induction regimens would you most likely use as first-line therapy for a patient with newly diagnosed myeloma who’s transplant ineligible? VRd [bortezomib, lenalidomide, dexamethasone], DRd [daratumumab, lenalidomide, dexamethasone], D-VRd [daratumumab, bortezomib, lenalidomide, dexamethasone], KRd [carfilzomib, lenalidomide, dexamethasone], or other? This is a different patient, not the 47-year-old. Maybe it’s Morie’s 81-year-old who’s not as fit as many others. Which of these regimens are we thinking about? How do we think about choices between these regimens overall? About 50% are saying VRd [bortezomib, lenalidomide, dexamethasone], 16% say DRd [daratumumab, lenalidomide, dexamethasone], 16% say D-VRd [daratumumab, bortezomib, lenalidomide, dexamethasone], and about 9% say KRd [carfilzomib, lenalidomide, dexamethasone]. There’s some mix. VRd [bortezomib, lenalidomide, dexamethasone] is continuing to rule the day. How do you guys think through this? We’ll start with Andrzej.

Andrzej Jakubowiak, MD, PhD: I’m going to be a little repetitive, but we made the point earlier that quadruplets are emerging as the superior compared with triplets. In patients who aren’t necessarily transplant eligible, we can apply the same concept. In this particular situation, I’d favor quadruplet. We have some data coming from Dr Landgren’s MANHATTAN trial. It was 1 arm, so we don’t have perfect data in this regard. But in this context, I’d favor daratumumab–VRd [daratumumab, bortezomib, lenalidomide, dexamethasone]. In a European setting, we have evidence of quadruplet with daratumumab–VMP [bortezomib, melphalan, prednisone], which is more popular and clearly superior. To some extent, it’s not exactly the same, especially the daratumumab–VMP [bortezomib, melphalan, prednisone], which isn’t very different from DRd [daratumumab, lenalidomide, dexamethasone], which is a triplet. But with all understanding that we don’t have the ultimate answer, if I have a choice and would like to recommend to the patient who’s fit enough, I’d go ahead with daratumumab–VRd [bortezomib, lenalidomide, dexamethasone] from these choices.

Sagar Lonial, MD, FACP: Andrzej, I’m going to push you a little. Maybe Morie and Dr Hari can respond as well. I don’t think there are any data in the transplant-ineligible patient population that have a PFS [progression-free survival] of 60 months. Not even any of the phase 2 trials you described has a PFS of 60 months. That’s hard to beat, and it’s pretty easy to give. Anything beyond that is a bit of an extrapolation. But I’ll give you guys a chance to argue back.

Andrzej Jakubowiak, MD, PhD: I agree with that, but I’ll always use the argument that I was extrapolating to use lenalidomide as a maintenance when it wasn’t a standard. We’re evaluating the data and potentially applying it to our practice. That’s what we’re discussing.

Sagar Lonial, MD, FACP: I got you. Dr Hari?

Parameswaran Hari, MD, MRCP: The polling question referred to a standard-risk patient. For a standard-risk patient, as you mentioned, it’s a 60-month PFS median. VRd [bortezomib, lenalidomide, dexamethasone] showed 60 months with 52% still not progressing, and it’s very difficult to beat. When we’re coming from VRd [bortezomib, lenalidomide, dexamethasone] lite or Rd [lenalidomide, dexamethasone], it’s in the 30- to 40-month range. We’re adding 2 years to the first PFS for this patient, so I’m very comfortable using VRd [bortezomib, lenalidomide, dexamethasone] for a standard-risk patient.

For a higher-risk patient with the high-risk translocation, I go to D-VRd [daratumumab, bortezomib, lenalidomide, dexamethasone] lite. Basically, I’d use a backbone of VRd [bortezomib, lenalidomide, dexamethasone] lite, which serves the AR [androgen receptor]. I’d argue that a proteasome inhibitor [PI] is probably essential for some of these high-risk patients, especially the translocation patients, and then I’d add daratumumab based on the VRd [bortezomib, lenalidomide, dexamethasone] data. There’s no randomized situation that guides us here, but that’s what I would do for that small group of 15% or 20% of patients with high-risk disease who are transplant ineligible. But for the majority, I’m going to do VRd [bortezomib, lenalidomide, dexamethasone].

Sagar Lonial, MD, FACP: Dr Gertz?

Morie A. Gertz, MD, MACP: I’d go with quadruplet therapy in this situation as well. It adds almost no toxicity or morbidity to give 1800 mg of subcutaneous daratumumab eventually once every 4 weeks. And then serious attention to adjust down bortezomib-lenalidomide and especially dexamethasone for the transplant-ineligible patients, which I translate as a less fit population. But I’m still giving this group 4 drugs.

Sagar Lonial, MD, FACP: Morie, you’re usually more conservative than this. You’re surprising me a little.

Morie A. Gertz, MD, MACP: My apologies.

Parameswaran Hari, MD, MRCP: His patients relapse, unlike our patients. When they relapse, you’ve got to do more.

Sagar Lonial, MD, FACP: Interesting.

Morie A. Gertz, MD, MACP: That’s another seminar. By that time, we’ll have 5 BiTEs [bispecific T-cell engagers] to choose from.

Parameswaran Hari, MD, MRCP: That’s true.

Sagar Lonial, MD, FACP: That’s a good question. Let me ask you guys. Before, the question was, is there anybody you’d use a triplet on? And the answer was probably not. It sounds like no matter what, you guys are going to push for a quadruplet. I’m more in line with what Dr Hari is saying. With standard risk, a truly frail patient, I’m going to go with DRd [daratumumab, lenalidomide, dexamethasone]. It’s pretty straightforward. Is there anybody in whom you’d give a doublet, just lenalidomide-dexamethasone?

Parameswaran Hari, MD, MRCP: Nope.

Morie A. Gertz, MD, MACP: No.

Andrzej Jakubowiak, MD, PhD: No.

Sagar Lonial, MD, FACP: Universal no. OK.

Andrzej Jakubowiak, MD, PhD: I would maybe push you back. Why would you choose VRd [bortezomib, lenalidomide, dexamethasone] vs DRd [daratumumab, lenalidomide, dexamethasone]? We were part of the same initial RVd [lenalidomide, bortezomib, dexamethasone] trial. It was my standard of care for a long period of time. I’m very impressed, as you are, with daratumumab–Rd [lenalidomide, dexamethasone], in both the relapse and frontline settings. I agree that this is very impressive. If not quadruplet, I’d probably go with daratumumab-Rd [lenalidomide, dexamethasone] as my next choice and wouldn’t risk neuropathy in these patients. The argument about high risk is a separate issue, but it’s long discussion if you want to start it.

Sagar Lonial, MD, FACP: I’m with you. I’d use DRd [daratumumab, lenalidomide, dexamethasone] as well. The only people I wouldn’t give DRd [daratumumab, lenalidomide, dexamethasone] to are those in the high-risk group. That’s where I’d go to VRd [bortezomib, lenalidomide, dexamethasone] or modified VRd [bortezomib, lenalidomide, dexamethasone]. I’m with you guys. The clues on the efficacy in the MAIA study were in the tea leaves in the POLLUX trial, where we saw 48-plus months of PFS, and that was a clue that we were going to see really long PFS, although there were arguments on both sides. But let me ask you this. Let’s say you use DRd [daratumumab, lenalidomide, dexamethasone] for your patient up front. Morie, if you go to a triplet and not a quad, what would you then think about doing in the relapsed setting? How would you approach that patient?

Morie A. Gertz, MD, MACP: I’d probably do bortezomib-pomalidomide as my backbone.He hasn’t seen a proteasome inhibitor.

Sagar Lonial, MD, FACP: Right.

Morie A. Gertz, MD, MACP: Frankly, I like bortezomib better than ixazomib. I’m still saving carfilzomib as second-line PI.

Sagar Lonial, MD, FACP: I got you. Do you guys want to disagree with that very briefly? Or just say yes if you agree.

Andrzej Jakubowiak, MD, PhD: Yes.

Parameswaran Hari, MD, MRCP: Yes.

Sagar Lonial, MD, FACP: OK. Let me ask you this. We talked a lot about MRD [minimal residual disease] testing, depth of response, and adequacy of response to induction. How do you look at that in the frail-patient population? Do you look at it exactly the same, that if patients don’t achieve a CR [complete response], VGPR [very good partial response], or MRD negativity, you’re going to switch to a different regimen? Or are you a little more patient with this patient population? Andrzej?

Andrzej Jakubowiak, MD, PhD: I’m more patient with this patient population. We have to be respectful of how much we can push. And the comments from Dr Hari and Morie about how important it is to not create delays in treatment because of unnecessary or unneeded toxicity is probably on the risk-benefit ratio quite surpassing the efficacy. So I’d be careful and patient.

Sagar Lonial, MD, FACP: OK. Dr Hari?

Parameswaran Hari, MD, MRCP: It’s the same for me, and I’d generally be patient. As you know, there’s a small percentage—maybe 10% or 15%—of patients who surprise you when they’re showing signs of nonresponse or progressing. I might even change my mind and say, “You’re transplant-ineligible, but let’s try to do a lower-dose melphalan transplant,” or move them on to a CAR [chimeric antigen receptor] T-cell trial or something. Because if you’re failing DRd [daratumumab, lenalidomide, dexamethasone] or D-VRd [daratumumab, bortezomib, lenalidomide, dexamethasone], you’re in bad shape and you might have to. I don’t try to push hard with the induction. And when the biology declares itself, I try to move them off then and quickly go to something else.

Sagar Lonial, MD, FACP: OK. Morie?

Morie A. Gertz, MD, MACP: Briefly, these people are awfully easy to beat up. If you push too hard, they’re going to come back in a month and say, “I’m done with therapy. I don’t want to take any more treatment. I’m going home.” Then you’ve really lost the ballgame. I agree with both of my colleagues. It’s too easy to push too hard. Take it light.

Sagar Lonial, MD, FACP: OK. Then the whole question about the utility of MRD testing, whether it’s blood or marrow based, sounds as though it’s not as big an issue for you guys, given that you’re more of a slow-go in this situation anyway. Is that a fair summary?

Morie A. Gertz, MD, MACP: The only trial that exists is a duration of maintenance therapy for MRD-negative patients. Otherwise, there are no decision-making trials to suggest what to do. If you get it, it’s good, but if you don’t get it, as Andrzej said, you don’t make a therapeutic decision based on it.

Andrzej Jakubowiak, MD, PhD: I’d like to briefly add to that. We’re entering into the phase where we’ll be making decisions based on MRD. I don’t think it should be done in practice, but there are ongoing studies in which patients in long-standing remission with sustained MRD negativity are considered for discontinuation. We have an ongoing study based on 10−6 MRD negativity sustained and even deeper in 10-7. It’s important, because even in the context of Morie’s comment, if you have older patients—especially frail—in good response, you want to limit toxicity by not treating them too long if you don’t need to. Achieving MRD negativity may be important, and knowing whether they’re MRD negative may help you down the road—not necessarily now—with decision.

Sagar Lonial, MD, FACP: All right. That’s a great segue into polling question No. 7. What’s your approach to determining duration of treatment for the patient with transplant-ineligible myeloma? 1) Treat to progression, 2) Treat until a prespecified response criterion, 3) Treat until patient requests a drug holiday, 4) Treat for a predetermined fixed duration, or 5) Treat until tolerability issues arise? While they’re voting on that, there are some questions that have come in through the chat. I’m going to turn this 1 to Dr Hari. Is there any concern regarding mobilization and collection of cells in postquadruplet therapy?

Parameswaran Hari, MD, MRCP: We know from the GRIFFIN and MASTER studies for D-VRd [daratumumab, bortezomib, lenalidomide, dexamethasone] and D-KRd [daratumumab, carfilzomib, lenalidomide, dexamethasone] that there’s a slight decrement in the number of cells collected and increased use of plerixafor. There was also the CASSIOPEIA group that did the D-VTd [daratumumab, bortezomib, thalidomide, dexamethasone] study in France. They all reported that. However, almost everyone gets collected successfully. Moving forward, we may not need to collect as many stem cells as we did in the older era, because the choice of tandem transplants is going away—second salvage transplants are going away. We have better cellular therapies coming, so we should be OK with the quadruplet collection.

Sagar Lonial, MD, FACP: I got you. If we look at the responses, the most common response is to treat until progression. There are a few who say to treat until tolerability issues arise, and fewer who say to treat until a prespecified response duration. I want to get all your responses to that. Are there any guidelines or data to determine or support which of these we’d do? In the MAIA study, it was treatment until progression or toxicity for the triplet of daratumumab-lenalidomide-dexamethasone. This time we’ll start with Dr Jakubowiak.

Andrzej Jakubowiak, MD, PhD: We have limited data to answer this question, but our colleagues who are responding to this call are right on the money. The data support treatment until progression. It was clearly and elegantly documented in the FIRST trial, which was 18 months of lenalidomide-dexamethasone vs until progression, and then a lot of data showing that extended treatment provides better outcome vs other strategies with shorter treatment. If there’s toxicity, which is unacceptable, we may have to give a break from therapy if modifications wouldn’t work. In general, treat until progression, and at some point maybe we’ll be discontinuing in great responders in sustained MRD negativity, but that needs to be awaiting the data that we can do it.

Sagar Lonial, MD, FACP: Dr Hari?

Parameswaran Hari, MD, MRCP: I agree with Dr Jakubowiak that treatment until progression is the intent. In the real world, we know from maintenance studies that mandated treatment until progression—and from the MAIA study itself—that although the median PFS was not reached at 60 months for DRd [daratumumab, lenalidomide, dexamethasone], half the patients had stopped therapy by about 48 months. People stop therapy, and we need to accept that. I’d approach that by going with the intent of treatment for a long time or indefinitely, but then being responsive to a patient’s situation.

Sagar Lonial, MD, FACP: Morie, do you have anything to add?

Morie A. Gertz, MD, MACP: Yes. Treat to progression. After a long time, a lot of people end up on lenalidomide 5 mg every other day.

Sagar Lonial, MD, FACP: Right. And discontinuing dexamethasone pretty early on I would presume, right? I think we all do that now.

Morie A. Gertz, MD, MACP: Oh, very early.

Andrzej Jakubowiak, MD, PhD: Agreed.

Parameswaran Hari, MD, MRCP: Yes.

Transcript edited for clarity.

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