Landscape change with oral proteasome maintenance in multiple myeloma patients

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Published: 3 Dec 2018
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Prof Maria-Victoria Mateos, Prof Wee Joo Chng, Prof Meral Beksac and Dr Sagar Lonial

Prof Maria-Victoria Mateos, Prof Wee Joo Chng, Prof Meral Beksac and Dr Sagar Lonial meet in San Diego at the American Society of Hematology 2018 conference for an educational multiple myeloma panel discussion.

Their talk covers the results of the Tourmaline-MM3 study – maintenance therapy with the oral proteasome Inhibitor Ixazomib following autologous stem cell transplantation in patients with newly diagnosed multiple myeloma.

Prof Mateos chairs the discussion, opening the talk by asking Dr Lonial to describe the rationale for the study and why a new option of maintenance therapy is needed for the treatment of newly diagnosed multiple myeloma patients.

She then ask Prof Beksac to comment on her experience of Proteasome Inhibitor use in clinic. Beksac outlines the issue with tolerability that is often found with drugs used in the maintenance setting, and explains why it makes sense to use an oral therapy in this setting.

The discussion then turns to Prof Chng who comments on the trial’s efficacy results vs placebo, before Prof Mateos prompts Dr Lonial to outline Ixazomib’s safety profile based on the results from the trial.

The panel move on to discuss the rationale for setting the duration of maintenance to two years in the study and how this could have impacted the results, before outlining the specific patient subgroups that benefitted from the therapy.

Prof Mateos then directs the discussion to the future use of Ixazomib, where this could be used in the treatment pathway for patients with newly diagnosed multiple myeloma, and how its role compares to other drugs used to treat this patient group.

The discussion is finalised by summarising the key findings from the Tourmaline-MM3 study – that Ixazomib is found to be an effective maintenance therapy for the treatment of patients with newly diagnosed Multiple Myeloma following autologous stem cell transplantation, and has the potential to be used as a standard of care treatment.

Rationale for the Tourmaline-MM3 study
Use of bortezomib in the clinic
Efficacy of Ixazomib
Response of Ixazomib as a maintenance therapy
Safety profile of Ixazomib
Duration of maintenance therapy in the Tourmaline-MM3 study
Treatment options for specific patient sub-groups

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

Prof Maria-Victoria Mateos – University of Salamanca, Salamanca, Spain
Prof Wee Joo Chng – Nationa University Cancer Institute, Singapore
Prof Meral Beksac – University of Ankara, Ankara, Turkey
Dr Sagar Lonial – Winsip Cancer Institute, Atlanta, USA

MVM: Welcome to this ecancer meeting in which we are here in San Diego attending the 2018 American Society of Hematology meeting. My name is Maria-Victoria Mateos and I work as a haematologist at the University Hospital of Salamanca in Spain. We will discuss today about the changes in the landscape of maintenance therapy for newly diagnosed multiple myeloma patients, especially after autologous stem cell transplantation. I have the pleasure to be here today with my colleagues and if you want to you can do a brief introduction.

WJC: My name is Wee Joo Chng, I’m from the National University Cancer Institute in Singapore.

MB: My name is Meral Beksac, I’m working at the University of Ankara as a clinical haematologist, Turkey.

SL: I’m Sagar Lonial from the Winship Cancer Institute of Emory University in Atlanta, Georgia.

MVM: Welcome all of you. You know that during this congress the results of an important pivotal study were presented based on a new option to be used as maintenance therapy in newly diagnosed myeloma patients after autologous stem cell transplantation. It is the TOURMALINE-MM3 study. Sagar, maybe you can comment about the rationale for this study?

SL: Yes, the MM-003 trial was a randomised maintenance trial where patients could receive either ixazomib, the new oral proteasome inhibitor, or placebo after having received induction and transplant at their home institution. The principle behind it is really the idea that we know that proteasome inhibitors are very active; there is good data from the Dutch group looking at bortezomib in the maintenance setting but coming into the clinic frequently for sub-cu or IV infusions is a little bit more challenging. Ixazomib is clearly very active, we’ve seen that in the up front and in the relapse setting and so trying to apply the concept of proteasome inhibitor in maintenance therapy was really the principle behind the trial.

MVM: Did you have any experience about the use of bortezomib as maintenance in your clinic?

MB: Yes, we do since bortezomib has been approved for more than ten years. During the last couple of years it has been recognised as a drug which covers and is approved for high risk patients and for those, especially, we use long-term, such as every two weeks, bortezomib as a maintenance but the problem is with the tolerability.

MVM: Yes, the tolerability, as Sagar mentioned, the inconvenience because maintenance, from my point of view, has to be effective, safe and convenient for the patient. So the role of ixazomib as an oral proteasome inhibitor does make sense to be evaluated as part of maintenance. In this MM3 study the control arm is observation, it’s placebo, because when the trial was designed the standard of care after autologous stem cell transplantation was no maintenance. Do you want to comment about the efficacy results that were reported coming from the TOURMALINE-MM3 study?

WJC: Yes. What the results show is that it meets its primary endpoint which is a PFS advantage. So the use of ixazomib is associated with a significant improvement in PFS compared to placebo. What that shows is that ixazomib as a single agent is clearly active as a maintenance therapy for myeloma patients. So in that context ixazomib would be an option that physicians can consider for use in patients post-transplant for maintenance.

MVM: Meral, how do you see the improvements in response observed with ixazomib as maintenance? I think that is also a positive aspect to see how ixazomib oral proteasome inhibitor single agent and responses upgrade during maintenance.

MB: I think that’s an important issue because we know today that the treatment should be continued until a very deep and sustainable response is obtained for myeloma patients. It starts with transplant and it should be consolidated and it should be continued. In this trial we see a response upgrade, mainly in the treatment arm; there is a lower response upgrade in the control arm which is the long-term effect of the high dose melphalan but it continues throughout the study.

MVM: In fact there is a subgroup of patients in which the minimal residual disease positive converted to minimal residual disease negative and these patients had the greatest benefit from ixazomib as maintenance. Sagar, what about the safety profile?

SL: We know a fair amount about ixazomib from the induction therapy and the relapse therapy trials and what we know about it is the most common side effects that we can see are GI, nausea, occasionally some diarrhoea and then occasionally skin rashes as well. This appeared to be very well tolerated in the maintenance setting with a very low incidence of these side effects, probably because you’re getting away from many of the other drugs that ixazomib is often combined with. I can tell you, we have extensive experience with bortezomib and lenalidomide in the maintenance setting for high risk and we are now switching the bortezomib out for ixazomib because of its convenience and well-tolerated partnership with lenalidomide.

MVM: Wee Joo, do you want to comment something about the fact that in this TOURMALINE-MM3 study the maintenance was limited for up to two years? So, from the conventional point of view we understand the maintenance as continued therapy until disease progression.

WJC: Yes, it’s important to go back to when the trial was designed. At that stage the concept of continuous therapy was not quite there yet. Actual duration of maintenance was not very well established at that point. There was even signal from the French trial that because of concern of secondary malignancy on lenalidomide they have limited duration of maintenance or changed the duration of maintenance to two years. So there is some rationale behind the use of two years in this particular trial; it shows the efficacy of ixazomib. Moving forward, an important question would be that if we use ixazomib continuously whether it will lead to a bigger benefit. Certainly based on the toxicity profile ixazomib is a drug that would be well-tolerated for continuous use as well.

MB: But the study may give some light for the future when the treatment was stopped how long it will take for a relapse to occur. So this could be an advantage in a scientific point of view.

MVM: Yes, of course and in fact we don’t know what is the optimal duration for maintenance. So now we are starting to talk about the potential cure for newly diagnosed myeloma patients and I don’t know what are your thoughts but my personal view is that cure means disease free but also treatment free.

MB: Exactly.

MVM: So we don’t know but there are many trials currently ongoing trying to answer if all patients have to receive maintenance until disease progression or maybe we can stop at any time.

SL: One other point to bring up is that this short duration maintenance therapy, and I think two years is short because we typically tend to give longer, really has impact on one big patient population and that’s the high risk patients where we know one year of lenalidomide is probably not good enough. Short duration maintenance is probably not sufficient either so we may have lost a benefit in the high risk patients by stopping at two years. The second point to make is the issue around MRD assessment. MRD assessment means something in the context of most of the data that we have with limited duration maintenance therapy but, particularly in high risk, you may be able to control MRD positivity in either standard risk or high risk with continuous therapy. So we may have lost an opportunity there.

MB: But Sagar, do you think they would in this study. All the subgroups benefitted from the drug, including high risk and standard risk. So even within this two year treatment period the high risk gave the same amount of response.

SL: Right, but their duration could have been prolonged even further.

MVM: I agree with Sagar’s point, so we don’t know if the treatment has to be continued or not for all patients but especially for high risk. If we focus on high risk, Meral said that it’s true that the hazard ratio is exactly the same in the TOURMALINE-MM3 study for standard risk and high risk. I can imagine that right now in your different institutions lenalidomide is the standard of care to be used as maintenance after autologous stem cell transplantation because, in fact, it was approved some years ago. Is this correct in your different hospitals?

MB: I think in certain countries it’s approved and in some it’s not approved. But if our target is to achieve complete response, in that case we can continue treatment until that goal without an approval for maintenance. But for lenalidomide specifically we do not know if it works for all subgroups of myeloma and since we are talking about high risk I think that requires special attention.

MVM: Is there any other specific subgroup of patients in which you can potentially challenge lenalidomide to be used as maintenance?

SL: Yes, in the (4;14) subset we’re routinely using proteasome inhibitor based maintenance therapy and having an oral option has supplanted, in our practice, that approach. Then, as I mentioned earlier, for the truly high risk, the 17p, the (14;16), using IRD as maintenance and consolidation as opposed to just VRD has become our default as well.
MVM: Any other subgroup of patients in which you can’t potentially use lenalidomide? So patients with severe thrombotic events or renal impairment?

MB: Renal impairment, yes.

SL: And there are some patients who just have intolerance to lenalidomide even at the lower doses with either rash or just fatigue or other symptoms. It’s not a big number but certainly now there’s an option.

MVM: Yes, in our clinic we have all of us some patients in which we have finally to early discontinue lenalidomide due to poor tolerance. Based on this do you see any role for the use of ixazomib in some specific subgroups of patients in special or just in patients in which lenalidomide is not the best option? Or, as Sagar mentioned, maybe to combine lenalidomide plus ixazomib, maybe not in all patients but, as you mentioned, in patients with high risk cytogenetic abnormalities.

WJC: As mentioned, now even today, we do give proteasome inhibitor based maintenance therapy for some subgroups of patients. So now with the data from ixazomib it will be commonly used in practice to replace Velcade in those settings. In patients with renal impairment where the dosing of lenalidomide may be a bit more challenging may be another subpopulation that we can use. Then for those that are intolerant it’s always very useful to have an alternative which ixazomib will be as well. So those are probably going to be the main population but actually, moving forward, I suspect that increasingly more and more people will be using combinations of drugs even for maintenance. Not necessarily just for the high risk, although they will be the main target group, but I suspect in the future even for standard risk patients. Because with the improvement in the induction treatment that we’re getting, to truly benefit patients with the subsequent consolidation and maintenance we probably also need very potent combinations.

MB: On top of that we can consider that the neurotoxicity of ixazomib was not as potent as bortezomib. Within our experience in MM3 and MM1 we did not observe any discontinuation due to neurotoxicity so patients who have achieved neurotoxicity in the induction or earlier phases, those could be other potential candidates for ixazomib.

MVM: Yes. Sagar, I think that you have a lot of experience with the use of bortezomib, lenalidomide and dexamethasone as continuous therapy, many cycles, especially in patients with high risk. Can you comment on the results you have in your series of patients? How do you see the role of ixazomib instead of bortezomib in this population and if you would expect the same efficacy and safety results?

SL: That’s a great question and I think we’ve got now probably close to 80 or 100 patients with high risk that have been treated this way. Our original paper was somewhere in the 40-ish patients, something along those lines. What we showed was that the median PFS for the combination was somewhere around 36 months, 34-36 months, somewhere in that ballpark but the coming in for weekly sub-cu administration of bortezomib for three years is certainly challenging for patients. The other piece that we noted and we had a similar paradigm for (4;14)s where we would give three years of bortezomib maintenance and then stop. What we discovered was that many of the (4;14)s would relapse shortly thereafter stopping but were controlled. So having an oral option really makes it a lot easier for patients going forward.

MVM: Do you maintain dexamethasone?

SL: No. No, we usually taper that off around a year.

MVM: Do you see any role for dexamethasone added to…?

MB: I think that long-term dexamethasone is horrible for the patients. They have severe… Since these are patients who are also prone to having diabetes and other comorbidities which are affected by steroids, so cataracts and other issues, it’s wonderful for a patient to have a steroid free regimen.

MVM: Do you want to comment something?

WJC: No, I agree with that; long-term steroids are really not very good for patients. The other thing is the long-term tolerability of ixazomib is a big advantage and I think it will be a useful new drug that we have in our armamentarium.

MVM: OK, so thank you very much. I don’t know if you agree with that, about our discussion we can say that the TOURMALINE-MM3 study confirms the role of ixazomib oral proteasome inhibitor to be potentially used as maintenance therapy after autologous stem cell transplantation in newly diagnosed myeloma patients. Today ixazomib can be a potential standard of care, so we have had the opportunity to discuss how maybe the combination with lenalidomide, especially in patients with high risk cytogenetic abnormalities would be of great value. Definitely it represents a new option for therapy for our patients with multiple myeloma. Do you agree with this summary?

WJC: Yes, absolutely.

MB: Certainly.

MVM: So thank you very much for this ecancer education event and we’ll see you at the next ASH meeting in Orlando.