Use of maintenance therapy following ASCT and real world treatment patterns in multiple myeloma

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Published: 15 Jun 2019
Views: 2961
Dr Evangelos Terpos, Prof Michele Cavo, Dr Eloísa Riva, Dr Fredrik Schjesvold

Dr Evangelos Terpos (University of Athens, Athens, Greece), Prof Michele Cavo (University of Bologna, Bologna, Italy), Dr Eloísa Riva (Hospital de Clínicas, Montevideo, Uruguay) and Dr Fredrik Schjesvold (Oslo University Hospital, Oslo, Norway) discuss the deepening response seen with the use of ixazomib as a maintenance therapy following autologous stem cell transplantation - as demonstrated in the TOURMALINE-MM3 study in patients with multiple myeloma.

The panel also highlight the main considerations for the use of this type of therapy and how quality of life may be impacted - as explained by Dr Schjesvold.

The session concludes with the discussion of evolving treatment patterns in the real world from a global perspective; with a mention of unfit and elderly patients.

Ixazomib maintenance therapy post-autologous stem cell transplantation
Discussion of impact on everyday clinical practice
Quality of life outcomes of ixazomib
Recommendations for lenalidomide maintenance
Management of high risk disease
Double autologous stem cell transplantation
Real world data vs clinical trials
Practice changing data from EHA 2019

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



DT: Hello, I am Evangelos Terpos, I’m a Professor of Haematology from the University of Athens School of Medicine and I’m here in Amsterdam from the European Haematology Association annual conference in order to discuss very important data for the myeloma treatment, mainly maintenance data but also data on quality of life and real world data. For this discussion I have with me Professor Michele Cavo from the University of Bologna, we have Dr Eloisa Riva from the University of Uruguay in Montevideo and we have Fredrik Schjesvold from the University of Oslo, it is, to be honest, an Oslo myeloma centre from Norway, in order to discuss this data. So in this meeting we had novel data about ixazomib maintenance therapy after autologous transplantation and these data were presented by Michele Cavo in a poster session in order to see the deeper response of ixazomib after maintenance therapy. We do have lenalidomide maintenance approved in multiple myeloma, for patients who are eligible for transplant, after transplant, now it seems that we are going to have a second drug, ixazomib. So Michele, as you are the first author of the abstract can you tell us a little bit about the findings of this paper and what do you believe is going to be the role of ixazomib in this setting?

MC: Data about ixazomib maintenance are coming from the TOURMALINE-MM3 trial. The comparison between ixazomib versus placebo showed a 5 month improvement in median PFS and, importantly, the rate of discontinuation with ixazomib was very low – approximately 7%. I think that this should be kept in mind in order to try to balance the pros and the cons. Obviously, the follow-up is still not enough mature for an overall survival analysis and the analysis will be performed with a longer follow-up. At this meeting data presented were related to the improvement in the quality of response for patients who were kept on therapy and continued to stay on therapy and for those patients who had an improvement in the quality of response there was obviously an improvement also in the overall outcome. So this data still needs to be confirmed with a longer follow-up but I think that at this time ixazomib may be considered as an alternative option in addition to lenalidomide that at this time is the only EMA approved novel agent for maintenance in myeloma patients.

DT: I want to ask Eloisa and Fredrik, do you have lenalidomide maintenance in your countries? Do you use it in your clinical practice and, if yes, what do you believe is going to be the impact of this study to your everyday clinical practice.

ER: In Uruguay we have lenalidomide as a maintenance choice for transplant eligible patients after transplant for two years. This is a recent incorporation of this drug in the maintenance setting. However, this is not the case in many other countries in Latin America, particularly in the public setting where thalidomide and dexamethasone are still the only options the physicians have for maintenance. Lenalidomide is also approved in the transplant ineligible setting for long-term treatment.

DT: Do you see a role of ixazomib in your country or in other Latin American countries for the maintenance setting and, if yes, in which setting do you see it?

ER: I think ixazomib is a great choice since it’s an oral formulation and, as results have shown, it has improved progression free survival compared to placebo with a low rate of discontinuation, low rate of side effects and also quality of life was maintained.

DT: Fredrik, how do you see this data? There are a lot of physicians from the Nordic countries who say that the duration of PFS, for example, with lenalidomide seems to be more important than that reported with ixazomib. We do know that it’s almost double, or around double, of what the placebo has performed in the studies of lenalidomide versus placebo maintenance. So I’ve seen that they are reluctant to use ixazomib when it’s going to be approved for this indication. What is your opinion? Is there a role of ixazomib in the maintenance and, if yes, according to your opinion in which patients?

FS: So far the data for the Revlimid maintenance is much more mature. You have survival data, you have several studies, so it’s a quite unfair competition with this quite early data from one study. The Revlimid data are good, they are standard of care. We can’t actually, not like Uruguay, use it, it’s not reimbursed in Norway so we still have that sort of problem because it’s too expensive. But it’s the standard of care before this study comes along. As long as you don’t go head to head and the data seem not to be at least not better it’s difficult to replace lenalidomide in any case. But the difference is mainly that lenalidomide has a much higher rate of discontinuation, the tolerance is worse in more patients. So the alternative, to have this as an alternative, for me it’s what I see it as today. A patient that cannot receive lenalidomide because of comorbidities or that doesn’t tolerate the drug, which is a not an insignificant number of patients, in a clinic that has to stop this treatment, then ixazomib is the alternative option. I think it’s very good to have an alternative option in these patients.

DT: You are the first author in a similar abstract, I think it is a sub-analysis of this study which is related to the quality of life. Do you want to comment on that?

FS: I’ll just refer to it briefly. It’s the first placebo-controlled study in this setting with a quality of life analysis. To be very simple, it’s completely the same, the quality of life is not different in any aspect. There are two major scales and subscales analysed and in no sense does it reach the point of minimal clinically important difference. That’s also the experience from the study. We had quite a lot of patients there and it was impossible for us to know if a patient received placebo or if they received ixazomib, it was impossible to tell, at least without looking at the response rates. And that’s different from lenalidomide where you see more subjective problems, in my opinion.

DT: I think there are important considerations for the maintenance therapy. One is that with lenalidomide maintenance possible patients at high risk disease or ISS-3 seem not to have, at least in the meta-analysis, the best outcome. On the other hand also in some patients lenalidomide has some side effects like fatigue and also it is the secondary primary malignancy issue that focuses on in many countries, Uruguay probably included, they give lenalidomide for two years and not until progression. Do you want to comment on that? How do you see ixazomib being in this setting?

MC: I think that when we are discussing about the potential advantage of ixazomib one has been already raised, that it is an option for those patients who become intolerant to lenalidomide and for whom there is the possibility to switch to a more safe and tolerable agent. The second is related to the lack of an overall survival benefit in particular subgroups of patients included in the lenalidomide meta-analysis and in particular the patients with ISS-3 and patients with a high risk cytogenetic profile.  Although at this time data are quite controversial since there are signals from the Myeloma-XI trial supporting a potential advantage of lenalidomide also for patients with 17p and/or t(4;14) translocation. However, ixazomib is a proteasome inhibitor, many of us think that proteasome inhibitors do work very well in patients with high risk cytogenetic abnormalities and studies aimed at combining lenalidomide with ixazomib in the overall patient population and in particular subgroups of patients are still running and we need to wait for these data in combination.

DT: Eloisa, what is your experience with lenalidomide maintenance? Do you believe that it is an extremely safe drug? Do you see secondary malignancies? Have you had anything in the Uruguay Myeloma Study Group? And do you believe that ixazomib can give an alternative for these problems?

ER: With lenalidomide we observe fatigue as the main side effect. We also have lenalidomide available for the relapsed setting, that’s why patients do tolerate worse the drug also. For high risk patients and ISS-3 and also high LDH, as said, lenalidomide has not been a very effective drug or as effective as in other subgroups. That’s why, and taking into account results, we provide bortezomib for two years for patients with high risk in Uruguay. Considering this, bortezomib implies every two weeks we have to take the patient into the hospital and this creates sometimes problems. Maybe an alternative, oral alternative, would be feasible if this shows that it’s beneficial.

DT: I think, Fredrik, that ixazomib in this study versus placebo showed also very good effects in the high risk population. Do you believe that possibly, based also on the observation that lenalidomide may not be the ideal drug for this setting, ixazomib can substitute lenalidomide or can be given together with it like they are doing in some centres in the US?

FS: I think that the Myeloma-XI has changed what we thought a little bit about lenalidomide in the high risk patients. Proteasome inhibitors are important in the high risk patients but I don’t think it can substitute because I don’t know if it’s better and even if it’s better it’s still not enough. So what’s so good about ixazomib is the combination of oral formulation and well tolerance makes it an ideal partner as a doublet maintenance regimen. So I would really like to see a study where that is randomised so we can actually get that indication. Because most studies I know about with a doublet in maintenance are only giving that regimen to the high risk patients to see what happens but not randomising towards the standard of care which would be Revlimid as of today. So I would like to see such a trial that makes it possible to have an approval of the doublet maintenance because I don’t think neither ixazomib nor lenalidomide alone in the maintenance phase in high risk patients is good enough.

MC: Probably one of the first available data will come from the Spanish trial randomising patients to receive len/dex versus len/dex/ixazomib and then based on MRD assessment a different treatment continuation. So it is important to have another option, it is important to have another oral drug with a very good safety profile. I personally think that probably the future will be for a combination of two different classes of agents, at least in particular subgroups of patients.

DT: I believe that in the high risk mainly where we know that the MRD negativity achievement seems to be crucial for their survival I also believe that your study which showed that with ixazomib during the time we see a deepening of the response. I think that possibly this is important in combination with lenalidomide to have a higher population that may achieve MRD negativity.

FS: If I could just have one more comment on that topic.

DT: Of course.

FS: I’m not sure that the maintenance approach is what the high risk patients need. Maybe they just need the continuous treatment in full dose, actually, especially if we can pick out the really high risk that will relapse anyway quite soon. So to maintain that is not the best option, I think we need to just keep the pressure up as long as they can tolerate it. That’s what I think, anyway.

DT: As we talk for the transplant patients maintenance or consolidation strategies, Michele, in your EMN02 study you have shown that the double autologous transplantation seems to be beneficial for the whole population and not only for the high risk that we have seen that is the standard in many European countries to give two autologous transplants, two tandem, for this population. Do you want to comment on that and also how do you see ixazomib in this setting?

MC: Yes, the data from the EMN02 trial, at least the data from the second interim analysis, showed a better outcome in terms of prolonged progression free survival and overall survival for the double transplant versus the single transplant group. The data at the time were particularly relevant for patients with high risk cytogenetics and these patients had an approximately 50-60% reduction of the risk of progression or death. So I think that, again, double transplant may be an option at this time for patients with high risk although the data were also in favour of a positive effect in the intention to treat population. For patients at standard risk we still need to wait for a longer follow-up.

DT: In the EHA meeting this year in Amsterdam we had also a lot of studies with real world data. Eloisa, do you believe that we need this real world data? We have randomised phase III studies, high levels of evidence. We’ve seen a lot of posters this year with real world data. Do you treat our patients or do you have any treatment decision based on real world data or do you base your decision only on phase III studies?

ER: In Uruguay we have a particular way of funding for high cost procedures and drugs. For the whole population, particularly in the high risk setting, we are now treating patients with VRD, four cycles, double autologous stem cell transplant and bortezomib maintenance. This is for the whole population but this is not the standard of care in the rest of Latin America. As part of the [??] group from Latin America we are more than twenty countries represented in that group and although many drugs are available patients do not have access. I mean they are commercially available but they have no access and, as shown in some of the posters in this congress, there is a big discrepancy between guidelines and evidence and what’s done in real life. One of the posters showed that there is no standard of care in newly diagnosed patients, even transplant eligible or transplant ineligible.

DT: Fredrik, are you interested in real world data? I mean that many physicians say that real world data are important because patients, elderly, frail or those with renal impairment, other subgroups of patients, cannot participate in clinical trials because of the inclusion and exclusion criteria of these studies. So approximately a population, depending, between 20-40% of myeloma patients cannot participate in clinical trials and the clinical trials cannot correspond, the results of these trials cannot correspond, to these patients. What is your opinion? Do you need the real world data mainly for this population?

FS: I think we need real world data for the whole population. I think we also need it for that because they are lacking in the phase III trials or the clinical trials. But there are several reasons for the registry and, yes, I am more and more interested in that kind of data. We’re working on that in Oslo in Norway. One thing is if you look at real world data it can be a sobering experience. Sometimes you have to see what really happens and it’s good to know that because if you’re talking to patients also and all they see is the clinical trial. So at Mayo Clinic everybody lives until they’re twenty and to see what actually happens in Norway, that’s one thing. Another thing is real world data to see, to compare hospitals, regions, because we are not doing the same thing. If everybody says that we’re doing the right thing you need some sort of level you can meet and discuss that one thing might be better. After that you can see what are we not doing so good and you can use registry data for that. The final thing now is that more and more we have in the Nordics and in Britain this cost-benefit analysis we need to have drugs reimbursed. More and more they want to base that and compare it to real world evidence and preferably from our own country because that’s the most relevant. So without that data it’s more difficult to have this cost-benefit analysis done. Then it’s only maybe one trial they have to do with no comparative solution. So we need those data for several reasons I think.

DT: Michele, in this conference there is a big real world registry, the name is INSIGHT, that includes data of the real world from different countries, from Asia, from Latin America, Europe, the US and Canada. From this study there was a subgroup of patients who received in the indication the combination of ixazomib, lenalidomide and dexamethasone, I mean for relapsed, refractory patients with 1-3 prior lines of therapy. There were approximately 160-170 patients who received this combination and the result was almost identical to what the TOURMALINE-001 study showed, the registrational study, with a median PFS in both studies around 21 months, 20.6, 20.9 in the two different studies. So the confirmation of the results of the TOURMALINE-001 in a real world population, how important is it for you?

MC: I think that they are important since all clinical trials have a bias which is represented by the selection criteria. So having data which are confirmed in the real life are very important.

DT: Do you want to comment on any other issue that was presented in this EHA meeting? Was there something that will change your treatment decisions in the near future?

MC: I think that the data were already presented two weeks ago at ASCO that results from the CASSIOPEIA trial will confirm that we are progressively moving from a three to a four drug induction and consolidation regimen. The data are still preliminary, are related to the part 1 of the study, however they are impressive in terms of progression free survival benefit and also increased MRD negativity.

DT: Eloisa, do you see any data that will change your practice in your country or in Latin America in general? Or do you believe that the lack of drugs in the other Latin American countries is a very important issue?

ER: There is always a big gap between what I hear in the congresses and what we can do. In Uruguay we are trying to shorten this gap and we have changed our guidelines, however, we have no real access for other options but for lenalidomide, bortezomib or transplant. Other novel drugs are exciting, just the CASSIOPEIA results are very exciting, but honestly this is not something that we can have available for all patients in Latin America. I would say that Latin America is a big and heterogeneous region, we represent 10% of the population of the world, but we have no clinical trials in most countries. So there is a need for this in our countries.

MC: However, you previously mentioned that you are able to offer to transplant eligible patients VRD as induction followed by transplant and bortezomib maintenance?

ER: Yes, but…

MC: This is not possible in Europe.

ER: Well, this is in Uruguay only because we have a particular funding for this that comes from the government. So we all pay taxes for this to have access.

DT: Fredrik, may I have also your comment on the IRD real world data which showed similar efficacy and safety with the one reported in the MM-01 study?

FS: I thought I was going to comment on what the change of practice will be after this last week, can I do that first?

DT: Of course.

FS: Because I find the main thing that can immediately, actually, have an effect when it’s matured a little bit is the new data for smouldering myeloma, the high risk population, and the data with the lenalidomide treatment with a very long PFS benefit. That is something that we have to consider to change immediately and that’s the main answer. It’s actually from ASCO two weeks ago but it has been also discussed here at EHA. Regarding the IRD, what I see is that some drugs are able to recapitulate, at least more closely, to the clinical trial data in the real world evidence. That’s more often the well-tolerated drugs, I think that’s the general picture. If you are able to do that that means that your drug is well tolerated because in the real world practice usually you use it on patients that would not be included in a trial. The thing that mostly makes them perform worse is that they don’t tolerate the drugs that were in the trial. But when you actually can get the same benefit in the real world as you did in a clinical trial, that’s a signal of a well-tolerated regime which fits with ixazomib.

DT: At this point I would like to thank Michele Cavo, Eloisa Riva and Fredrik Schjesvold for the very lively discussion that we had and to summarise that ixazomib maintenance after transplant in newly diagnosed myeloma patients seems to be a new standard of care. I believe that in patients with high risk features, possibly in combination with lenalidomide, it will give us a lot of solutions. Also in patients who do not tolerate lenalidomide it’s going to be a very good alternative. It does not affect quality of life, we’ve seen very good quality of life data from Fredrik in this conference and also it seems to be a very safe drug. On the other hand, the real world data with the IRD suggesting that the results of the TOURMALINE-001 study are confirmed in the real world suggest that it is also a very efficacious but safe population that reproduced the results of the phase III study and can be easily used in the approved settings. Thank you so much for being with us today.