SL: Hello, I’m Dr Sagar Lonial and I’m here for an ecancer expert to expert discussion. I’m joined by my colleague, Dr Wee-Joo Chng, Wee-Joo, do you want to introduce yourself?
WJC: Sure. Hi Sagar, it’s very nice to be on the same platform discussing this topic with you today. My name is Wee-Joo Chng, I’m from the National University Cancer Institute in Singapore.
SL: Great, thank you. And I’m Sagar Lonial from the Winship Cancer Institute of Emory University in Atlanta. I think we want to talk a little bit about some of the new maintenance approaches based on some data that came out at ASCO and ASH this year. Let’s start off just addressing the use of proteasome inhibitors in maintenance therapy. We’ve seen some data with bortezomib from the Dutch group, there have been some small, smattering amounts of data with ixazomib, tell me how you’re thinking about the use of PIs in the maintenance setting.
WJC: As you mentioned, in recent years we have some really quite important randomised studies looking at proteasome inhibitors as maintenance. As you know, for the longest time most of the data for maintenance therapy were with IMiDs in the randomised setting but in the last one or two years we have two very important randomised studies where it’s proteasome inhibitor compared to a placebo which, in my mind, are the proper kind of randomised study showing whether proteasome inhibitor is truly effective as a maintenance agent. In both these studies ixazomib was used, in earlier studies it was in the transplant eligible setting and then in this EHA conference the data from the randomised study in non-transplant eligible patients was presented by Thanos Dimopoulos. The data from these two studies are both positive in terms of improvement in the primary endpoint of progression free survival. In this particular meeting the data presented was particularly clinically meaningful as well because the improvement in PFS was quite substantial in terms of the absolute amount of time. So these are very promising data showing quite clearly that proteasome inhibitors have a role as a maintenance therapy. But this is only good for myeloma because it’s always good to have a choice. We all know that lenalidomide may have some disadvantages in terms of its long-term use in patients with renal impairment and other things so it’s always good to have a different agent which can potentially fill the gaps that we currently have in myeloma. So I’m excited about these results.
SL: I think one of the pieces that is really important, especially now in the context of COVID-19, is trying to minimise visits to the office or to the clinic or to the infusion centre. So the ability to have an oral proteasome inhibitor, its profile has really changed in the last 3-6 months because of this. So having this kind of data that demonstrates and I’ll give just a little bit of background on the MM4 trial – it was a large 706 patient randomised phase III trial, as you suggested, 425 were randomised to ixazomib with 281 randomised to placebo. The difference in PFS for this older non-transplant eligible patient population was 17.4 months for ixazomib compared to only 9.4 months for placebo. I think that this certainly is in the ballpark of many other treatments that we see out there and, again, the oral option is particularly important for an elderly patient population and in the context of the COVID-19 pandemic. So let’s talk a little bit about who you think about maintenance therapy for in the older patient population and how do you make that decision on IMiD versus PI, what’s your thought process?
WJC: For the elderly population the challenge is always tolerability for the treatment. In truth, actually based on all these data we should try to maintain patients on treatment for as long as we can so this continuous therapy approach is important. But currently the most popular regime would be with len-dex continuous but we all know that there is an issue with long-term use of dexamethasone, for example, and also potentially sometimes long-term tolerability of lenalidomide. So what is particularly impressive with this set of results is that the toxicity profile is very, very good. I certainly have a good number of patients that were enrolled in this study that were able to take the treatment until the end of the study period, which is two years on maintenance, with hardly any side effects. So in terms of choice between the two I would say that patients who particularly have renal impairment I would favour the use of ixazomib. Patients who have high risk cytogenetics, particularly the [4;14] I would prefer to use a PI because, again, PI has been known to be more effective in that subgroup of patients. Then for patients who, say, become intolerant to lenalidomide I would be quite willing to switch them over to ixazomib to continue the continuous treatment in that sense. So these are probably the kinds of settings that I would look at for the use of ixazomib in the maintenance setting for elderly patients.
SL: I think that’s exactly right and, certainly for me, the high risk group of patients are, to me, the easiest ones to think about a PI in the maintenance setting. As easy as it is to give lenalidomide because it’s oral, it can be a challenging drug to give in a number of different settings, particularly in the chronic administration setting. You raised a really important point that is worth further discussion here and that is in this trial therapy was limited for two years in duration. I think that that represents a move by our community to think about limited duration therapy when appropriate. Certainly I’m not sure that a blanket approach of limited duration therapy really makes sense given the mantra of continuous therapy that is so important. Certainly potentially using sustained MRD status as a way to say, ‘Maybe I should think about stopping or maybe I shouldn’t.’ In my practice we say three years is the minimum for ixazomib maintenance for patients and at three years they say, ‘Can I stop or not?’ and I’m very hesitant to make that stop in those patients. Typically I won’t – if they are tolerating therapy I will continue on beyond that. Tell me, how does that apply in your practice or in your thinking?
WJC: Yes, I would completely agree with you. One point to make was probably that at the point where the trials were designed it wasn’t common practice for continuous treatment. I think the results of the first trial with len-dex continuous hasn’t read out yet. So that’s why it was designed that way but I completely agree with you that in today’s landscape we will continue for as long as we can. This drug lends itself to that because of the very good safety profile as well. It’s exactly as you said, it’s very hard actually to maintain patients on very long-term treatment because they will ask you, ‘Can I stop the treatment?’ In some of the cases where the patients have been particularly insistent I have, like you said, used MRD. There is no data that we could use that as a guide but I would at least go back and tell the patient, ‘Look, you still actually have disease left. It’s better for us to continue.’ But if there is absolutely nothing then at least I can counsel them that, ‘Okay, if you really want to stop this may be reasonable but we don’t know actually whether this will short-change your outcome or not.’ But I agree with what you have said, actually.
SL: And I think that’s a subtle point that often is lost and that is just because patients don’t achieve MRD negativity doesn’t mean they can’t have sustained disease stability with the use of continuous maintenance. So that’s one of the concerns I have with many of the European trials that use MRD to change therapy. I’m not sure you always need to do that, I think you can continue patients and maintain that. Having an oral tolerated drug like ixazomib allows you to do that with a fair amount of flexibility. So I’m certainly very encouraged by some of this data and the quote that sticks with me from Thanos, who presented this data, is, ‘We couldn’t tell which patients were getting drug versus placebo.’ I’m sure you had that experience as well, perhaps?
WJC: Yes, absolutely. Yes, it’s often difficult, that’s why I said that this drug is really well tolerated which is one very impressive aspect of this trial actually.
SL: No, I think that this is certainly a big step forward for patients and we’re really excited to see this data. We planned this trial in 2013, if I remember right, so it took a long time to get where we are but certainly very, very exciting and a new option for patients. So let’s talk a little bit about that transition from induction to maintenance in the non-transplant eligible patient. That’s a bit of a grey area, I think. What’s the minimum number of cycles you think about for induction before you start to think about maintenance?
WJC: For myself it will be minimally six. Usually I will talk to the patients and a lot depends on how they tolerate the treatment and how fast the treatment works as well. For the patients who respond rather quickly and they have some toxicity issues with continuing on with the standard induction regime then I may allow a transition earlier. Conversely if their response is somewhat slower I may actually want to induce them for a longer period of time. So the ballpark is between six to nine cycles but six would be on average when I switch over. Is that true in your practice too?
SL: Yes, I completely agree. I think it really does have to do with speed and depth of response. Slow responses don’t necessarily portend for poor outcomes. We know, for instance that some of the [11;14] patients actually do tend to respond somewhat slower but they can do quite well, again with prolonged therapy and continuous maintenance. So I try to get six to eight cycles in before I make that switch. For me the first drug that often drops down is dexamethasone but our goal is to get to that well-tolerated maintenance once we think we’re close to or have exceeded maximum response for a cycle or two. That’s how I think about it. So thank you very much for your really insightful comments and input, Dr Chng. This has been an exciting discussion. Please stay tuned to ecancer for other expert to expert discussions. With the wealth of data that came out of ASCO and EHA there’s a lot to catch up on. Thank you very much for your attention.
WJC: Thank you.