Challenges and importance of long-term treatment for newly diagnosed multiple myeloma patients; community-based trial data

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Published: 9 Dec 2019
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Prof Sagar Lonial, Prof Meral Beksaç, Dr Robert Rifkin

Prof Sagar Lonial (Emory University, Atlanta, USA), Prof Meral Beksaç (University of Ankara, Ankara, Turkey) and Dr Robert Rifkin (Rocky Mountain Cancer Centers, Denver, USA) discuss the results from the US MM-6 study, along with the challenges associated with the long-term treatment of patients with newly diagnosed multiple myeloma (NDMM). This study was conducted in community-based oncology settings, where real-world treatment patterns were observed.

Dr Rifkin gives an overview of the US MM-6 study and explains the unique design of the study, which evaluated the transition from bortezomib to ixazomib in these patients. He discusses the main results from this study, which assessed patient quality of life and mentions that this treatment was well-tolerated and achieved a compliance rate of more than 90 percent.

Prof Beksaç highlights the current treatment landscape of these patients in Europe and the panel discuss some of the treatment challenges – especially in the older and frail population.

The panel emphasise that the use of real-world data presents an accurate reflection of this patient population and similar studies in this area are needed. Dr Rifkin mentions that this study will be expanded in the future, with the addition of European centres.

This programme has been supported by an unrestricted educational grant from Takeda.

Background of the US MM-6 study
Results of the US MM-6 study
Tolerability and safety of the IRd regimen
Implications of the real-world study design
Current treatment landscape in Europe
Challenges of long-term treatment
Evaluating quality of life data
Challenges in the management of MM patients

 

This programme has been supported by an unrestricted educational grant from Takeda.

SL:         I’m Dr Sagar Lonial from Emory University and welcome to this multiple myeloma panel at ASH 2019. I’m joined by my colleagues, Dr Rob Rifkin from the Rocky Mountain Cancer Center and US Oncology Research Center and Dr Meral Beksaç at the University of Ankara in Turkey. We’re going to talk a little bit about the US MM6 trial which is a really interesting and innovative trial design. Do you mind telling us a little bit about it Dr Rifkin?

RR:         Well, thank you Sagar. This is a trial that has an unusual design in that we took newly diagnosed multiple myeloma patients and they could receive three cycles of a bortezomib based induction. Then all of them if they had stable disease or responding disease were switched over to an all-oral regimen utilising ixazomib, lenalidomide and dexamethasone. Then they were allowed to remain on this until disease progression, unacceptable toxicity or three years have elapsed. Additionally we’re looking at some different approaches to standard endpoints. As everybody knows, quality of life is extraordinarily important in myeloma patients and in addition to using traditional tools we’ve actually employed actigraphy where the patients are given the equivalent of a garment device and for half of every month we actually follow their activities and see how that correlates with their quality of life.

SL:         Yes, a really interesting trial design, trying to incorporate a patient-friendly all-oral regimen along with the quality of life indicator with the actigraphy, really, really neat. So the IRD regimen that you used was a pretty standard IRD that has been studied in phase III trials right?

RR:         Correct.

SL:         And were there any unique inclusion or exclusion criteria for the patients that were allowed in?

RR:         I think the unique thing about this is actually the very broad inclusion criteria. So oftentimes, as you know, VRD is frontline therapy but additionally there are often delays getting the Revlimid approved and you want to treat patients. So we took that into account and made the inclusion criteria very broad so we wouldn’t miss those people who had difficulty obtaining the [?? 2:15] drug.

SL:         And renal dysfunction, just to get a sense for inclusion/exclusion, how did that work?

RR:         We were as liberal as you’re allowed to go. So creatinine clearance in the 30s was acceptable because it’s a real world trial.

SL:         Yes, absolutely.

MB:        And about 36% of your patients had some renal or urological problems? That’s what’s shown in the table. So it’s quite common.

RR:         Right and, as we all know, neuropathy in myeloma is present in a significant number of patients at diagnosis and we intentionally made that quite liberal.

SL:         So talk me through some of the results because it was pretty amazing.

RR:         The results right now you have to realise are early. We’ve accrued in the mid-fifties of our goal of patients but what we’ve seen is the expected response rates to the induction therapy and very well tolerated IRD following that. Additionally the most surprising thing to me was with the actigraphy component which is somewhat unique. The patients really got engaged and involved and the compliance rates were well over 90%.

SL:         And did you notice that from when they entered the study to perhaps six or so months into treatment that activity increased? Because you can clearly measure that.

RR:         It’s fair to say it got better as their disease responded which that’s very exciting because now we’ve shown it in a slightly different way that is much more functional and much more realistic for the patients.

SL:         I’m curious because they were allowed to have up to three years of therapy with IRD, correct?

RR:         Correct.

SL:         Tell me about what happened with the dexamethasone because it would be really interesting to correlate activity with dexamethasone dose.

RR:         It’s probably fair to say right now we’re very early in analysing the data. I can’t speak specifically to dexamethasone and de-escalation but we all know that’s a significant problem. But this group of patients was actually feeling pretty well and having a nice response to treatment so it may have been less of an issue than usual. But we’re analysing all of that. Dexamethasone dosing in myeloma, as you know, is extraordinarily difficult to follow and we’re also looking at compliance too and adherence which is extraordinarily important as you enter treatment beyond induction in multiple myeloma.

MB:        There’s also a response upgrade which I think is very important. After three cycles of a bortezomib-based regimen of course you expect to have… because the inclusion criteria is responding patients. And when you switch to IRD your response upgrades so it’s even higher with CR and VGPR. I think that’s also a kind of confirmation that the PIs are working continuously and maybe due to the tolerability and sticking to the treatment you can get the best from the combination.

RR:         No, we’re very excited about that. In myeloma, as everybody knows, we’re really working on depth of response and duration as well.

SL:         No, I think it’s really interesting. The questions about continuous therapy have been asked in the maintenance setting, you’re really almost asking a three drug maintenance, if you will, because it is continuous therapy. Tell me about, just from your experience because I know it’s early in the trial, patients are doing fine with full doses of ixazomib and the lenalidomide or were there modifications?

RR:         No, I don’t think we’ve had to do a tremendous number of dose modifications. In our presentation you’ll see some of the treatment emergent adverse events. Nothing is out of the realm of what’s previously published for IRD so with this unique study design I don’t think we’re seeing anything new, different or unexpected in terms of a safety signal.

SL:         Yes, it’s interesting because you and your network have led several of these real world trial designs before. How does this experience compare, to you, to some of your previous trials?

RR:         I think this one was, if you will, more fun for the network because we had such easy inclusion criteria. The biggest issue, as everybody knows, in myeloma when you analyse registry data is that around 40% of patients are ineligible for clinical trials and we lose all that valuable resource. So that’s going to help us here. Since we are a community based network it needs to be something that’s easy to do but will eventually have an impact on quality of life. I don’t know that we’re going to change practice like a new drug, for example, but we’re going to make myeloma therapy tolerable for longer periods of time.

SL:         No, and I think that that’s a really important point. As patients are living longer and longer the ability to minimise their adverse events and toxicity early on in the treatment can have a huge impact downstream with subsequent therapies. So it’s a really interesting concept to try and really pay attention to that early on. So, Meral, how would this kind of approach fit in with some of the approaches you all take in your community?

MB:        Well, in general in Europe bortezomib based regimens are the most frequent ones and for transplant eligible VTD and VCD are the most common and VRD is increasing. In the transplant ineligible population group RD is becoming common but still bortezomib based regimens are still being used frequently. So this means that if you already have a neuropathy issue appearing there’s a need to move to a regimen which includes a PI but has less neurotoxic compounds and oral regimens are always preferable. So for this reason I think it has a real position. What’s even more important, in my opinion, is the durability of long-term treatment. We know that lenalidomide maintenance has about one-third of patients discontinuation problem but maybe that arises from the fact that it’s an insufficient treatment. So for this reason, not only due to the side effects, but because of the lack of complete deep response that patients drop out. With a more effective PI IMiD oral combination with a tolerable profile I think that will certainly have an impact on daily practice.

SL:         I think you both have nicely spoken to some of the challenges of trying to keep people on therapy for a long period of time. Obviously there are adverse events and inconvenience, so they have to come in to the office every week, every other week, to get injections versus being able to take a pill, that’s a clear advantage, particularly for an older patient. But what about some of the challenges, and you may have hit on some of them, Rob, challenges in the beginning to try and get patients adequate therapy from the front. What are some of the challenges you both notice, especially with this older, frailer population?

RR:         The interesting part about this study, actually, is that patients are getting their bortezomib based induction. When we get them consented we come to the end of cycle 3 and they’re responding and the commonest question we get asked is, ‘Why should I switch to an oral regimen? You could just keep going with what you have.’ Then you really have to address convenience, a variety of other things, and we’re all giving bisphosphonates to these people which allows us actually a nice way to follow them on study because we’re not really adding extra visits, they’re going to get something when they come to clinic. They’re going to get their myeloma markers followed. So it needs to be attractive and, as you well know from your other work, the most engaged patients and those that do well are actually playing an active role in the trial. They’re getting a return, if you will, which at the start is actigraphy but later on as we analyse the data. So I think it keeps them enthusiastic and engaged which sounds really crazy in a cancer trial. But the more the patients participate the better everything goes.

SL:         And, at least from what I know, this is the first trial to use actigraphy as part of the quality of life instrument. I know it’s being done in other diseases but were there any unique challenges or things that you learned from some of that data just on a first glance?

RR:         It’s a bit difficult to do because how do you validate your method when nobody has really done that before? So we did look at a lot of different vendors, a lot of different methods. We tried to find a device that was reliable. But you’re absolutely correct, they are unique challenges and when it evolves further and gets published I’m sure that will be one of the questions that are asked – why did you pick the garment over whatever?

MB:        But still it’s something objective compared to the older versions of quality of life assessment.

RR:         Right, and people quite honestly are tired of filling out forms.

MB:        Yes, that’s true.

SL:         Right. It’s interesting because I will often tell patients I want them to walk and the patient will say, ‘Yes, I’m walking every day,’ and the spouse will say, ‘They don’t walk at all.’ So some of them do have iPhones and I have them pull it out and click on the heart icon and you can see really whether or not they walk every day when you confront them with the data. Having that device not only measures it but it actually probably makes them do more than they would normally do.

MB:        Yes, there’s no escaping.

RR:         And it’s great real-time feedback because we know very quickly.

SL:         And Meral, what are some of the challenges that you know on the up-front management of patients as they present, particularly the older frailer patients.

MB:        Well the major problem is fatigue when they start on treatment. Even if they do not have anaemia fatigue is a major problem, especially when you combine an IMiD with a PI. For this reason maybe instead of bortezomib ixazomib is a better tolerable regimen. GI toxicity is not a major issue so it’s usually manageable but when it comes to VRD, VRD lite is something we are using more commonly. Still it changes the patient’s lifestyle in the beginning but it takes time for them to get adapted and in general steroids are really very problematic drugs. So with elderly people we need to modify regimens quickly, every 2-3 days we should be seeing them.

SL:         Good. So any final thoughts that you want to leave the audience with on this really innovative and interesting trial design as well as the correlates?

RR:         It’s exciting that we’re doing something that’s community based, maybe real world evidence, a more accurate reflection than some of the other trials which tend to be more selective. Hopefully it will pave the way for more actigraphy and novel ways to look at quality of life. But importantly the concept we’re doing will be spreading to Europe and we’ll be adding European centres to see how it works outside the United States. So we’re very excited with the early findings.

SL:         Yes, it’s very interesting. Meral, any final thoughts?

MB:        I think the best thing about this approach is the uniqueness of starting with one regimen and then switching to another one when the patient is responding and to compare the efficacy. Also to have a long-term treatment duration which is something very valid and accepted in society nowadays.

SL:         Great, well thank you guys for this great discussion and really interesting sharing of data. Thank you.

RR:         Thank you.

SL:         And thank you so much for joining us. We appreciate your attention.