PM: So dear colleagues, welcome to this filming from ecancer.tv. I’m joined today by three colleagues, Dr Hillengass from Germany, Dr Dimopoulos from Greece and Dr McCarthy from the US. My name is Phillipe Moreau and I’m working in France. We are going to discuss some very important points for the treatment of patients that are not eligible for stem cell transplantation and we will also discuss some new data on the treatment for myeloma patients at the time of their relapse. So we have heard recently about the final overall survival analysis of the first study comparing len-dex during a fixed period of time versus len-dex until progression versus MPT and we have the clear demonstration that len-dex until progression is associated with a better overall survival as compared with MPT. So len-dex is becoming one of the standards of care. But Phil, your opinion regarding continuous treatment or a fixed duration with lenalidomide and dexamethasone?
PMc: Absolutely. We’re beginning to see now that continuous therapy for both transplant eligible and transplant ineligible is becoming a standard of care. Obviously in the first trial we saw that RD continuous is superior to MPT and we see this for prolonged effects. In other words, we think even after patients stop therapy there is a benefit, however we think that prolonged therapy, as opposed to a fixed duration, especially a short fixed duration, is probably going to result in a better overall outcome.
PM: But, Thanos, there is no difference in terms of overall survival when looking at the two arms with lenalidomide dexamethasone, fixed duration or lenalidomide dexamethasone until progression? So your choice, in fact, in the daily routine practice.
MD: Yes, I think for some patients who achieve a very good partial response or better it is worthwhile to continue lenalidomide dexamethasone until disease progression. For the remaining of the patients I think treatment for about two years may be sufficient.
PM: That’s a very important point, so lenalidomide and dexamethasone is one of the standards of care in the US, in Europe, in many countries all over the world. And we did also hear about important results of the SWOG study, a study performed in the US, comparing len-dex versus len-dex plus bortezomib. So, Jens, would you like to comment on this paper that was published at the end of last December by Dr Brian Durie?
JH: Yes, since VRd is becoming the standard of care for the transplant eligible patients it was just logical to try it in the transplant ineligible and it showed superiority again for triplet versus the doublet. So I think maybe it’s not the standard of care because in Europe it’s not approved for the transplant ineligible but in the US it’s getting used more and more as kind of a standard of care also in the transplant ineligible. It will be interesting to see further triplets in first line in the elderly patients, for example, with daratumumab and then len-dex. So there’s a lot to learn from that.
PM: What we can say about this important SWOG study is that the median age was less than 65, it was 63. So this study has included not only young patients but also obviously elderly patients and some patients are benefitting from the triplet combination. We have to mention that VRd was proposed during a fixed duration of time and then in the VRd arm of the study patients were receiving, following VRd, len-dex until progression as well. But there is a true overall survival benefit so it would be possible, probably in the US first but very soon in Europe, to use VRd as well in elderly patients. Another backbone, in fact, for elderly patients is VMP that was developed in Europe mostly; I think that in the US VMP is not widely used. We are going to hear about the results of the CLARION study, Thanos, could you comment on this comparison of VMP versus carfilzomib, melphalan and prednisone? Carfilzomib versus bortezomib associated with MP?
MD: Yes, this large prospective randomised study showed that there is no difference in the progression free survival between the two groups and also there is no essential difference in the overall survival. This is quite strange because in all other trials that have been performed so far it appears that carfilzomib is more active than bortezomib. There could be some explanations, for example maybe the dose of carfilzomib being 36mg/m2 on two consecutive days versus 56mg in the ENDEAVOR trial, or also maybe melphalan may not be the best alkylating agent to combine with carfilzomib.
PM: So yes, that’s probably the point in fact – melphalan is not the best partner in fact to be combined with carfilzomib. So currently our guidelines in Europe and in the US are going to change probably for the frontline treatment of elderly patients; we are going to propose len-dex until progression for those patients that are able to have a very good response and also a good tolerance to this combination. VRd - I think that you are using already VRd quite a lot in the US and VMP in Europe or in other countries will remain also a backbone. But patients are going to progress following VMP, for example, and in this setting we have quite a lot of new data with triplet combinations. So what could be your choice, Jens, in the patients progressing on VMP at the time of the first relapse? VMP is proposed during a fixed duration so what would be your proposal, in fact, in the near future?
JH: Since in the second line there are a lot of options available there’s a lot of discussion which one is the best. I think there’s not a straight algorithm to say, OK, every patient will get this triplet at second line and this at third line. You mentioned that the patients started with VMP, so it’s bortezomib or a proteasome inhibitor based induction, so it might be positive to use an IMiD based second line, so to change, to switch, yes. But then again you have a PI plus IMiD combination, two options for that with ixazomib and lenalidomide-dex and carfilzomib, lenalidomide, dexamethasone. So you will still have this proteasome inhibitor in it. Actually in the daily clinical practice it depends very much on the side effects the patient had, their response to the first line therapy. The risk stratification, what they had and where they live, if they accept to travel to the clinic for IV or for subcutaneous injections. So it depends very much on the individual patient so it’s not really personalised medicine but it’s very individualised because the patient, at least in Europe and in Germany, has a say in it. So if they want an oral combination it might be IRD; if they have maybe an aggressive relapse it might be better to use a very active or maybe even more active combination like KRD. With the CASTOR and POLLUX trials if those are approved in Europe they will be also very good to use because they have this very beneficial MRD signal. So there’s a lot to choose from and it depends very much on the patient and on the decision of the doctor and the patient together.
PM: Thanos, you are the PI of the POLLUX study looking at len-dex as a backbone versus len-dex plus daratumumab. So, as mentioned by Jens, we have at least if we want to use len-dex plus a third drug we have ASPIRE with carfilzomib, we have TOURMALINE with ixazomib, we have POLLUX with daratumumab and we also have ELOQUENT with len-dex plus elotuzumab. So can you comment on these possibilities – monoclonal antibodies or PIs in combination with len-dex?
MD: Yes, for the particular patient that you mentioned, if the patient progresses on bortezomib it is obvious that one could select a monoclonal antibody combined with lenalidomide and dexamethasone. And provided all options are available it appears that daratumumab with lenalidomide dexamethasone is the most effective combination. For patients who have a bortezomib free interval, so they’re not considered to be bortezomib refractory, they are potentially proteasome inhibitor sensitive, again you can go with bortezomib dexamethasone daratumumab or if the patient is older, has adverse cytogenetic features, one may want to try and use ixazomib with lenalidomide dexamethasone. If the patient has a long period between initial treatment and relapse maybe elotuzumab with lenalidomide dexamethasone. So there are many options.
PM: Many options for sure, yes. We discussed, Phil, the results of minimal residual disease, MRD, negativity into the POLLUX and into the CASTOR study, so len-dex plus daratumumab or bortezomib dexamethasone plus daratumumab. What do you think about these MRD data that are striking because for the first time we are reaching MRD negativity in the relapsed setting?
PMc: Absolutely. MRD had been, as you say, primarily been in the up-front setting and we’ve been using that, although we don’t have the final word on how to use it, as a surrogate for outcome. I think we’re going to need to incorporate cytogenetic risk because you could argue that somebody has deletion 17 would be somebody, even if they are MRD negative, that you would want to stop therapy. So we’re going to have to figure out how do we incorporate this; plus we also have the issue of long term because now that we’re generating outcomes with MRD negativity will this become a surrogate for overall survival? So if we can allow at one year to be able to predict what will happen at five years this would be quite a great option for our patients and also for clinical trials otherwise we’re going to have them open for a very long time while we try and figure out what to do.
PM: So it means that in your routine practice you are not using MRD yet? Because you mentioned that we don’t know exactly how to use it.
PMc: We are using it both in the transplant and non-transplant setting to help us guide treatment in the sense that we feel better if somebody is MRD negative, of course. But we still have some patients who are MRD positive who then we will continue therapy they will become negative. And then we still have some patients who have control of their disease so there are other things going on such as immune profiling, immune reconstitution. That’s where MRD was ten years ago and we now need to figure out how we incorporate that into our clinical practice. So we use it but we haven’t defined it as if you’re MRD negative you go down this pathway or another, that’s what we need to study.
PM: So in the relapsed setting we mentioned that we can use len-dex based combinations and we do have a lot of triplet combinations available now but we also discussed this len-dex frontline treatment for elderly patients that will become a backbone for sure. So those patients that are going to progress on len-dex at the time of the progression we are going to use proteasome inhibitor based combinations and we know that bortezomib dexamethasone is one of the standards of care but we have now better results with bortezomib and dexamethasone plus daratumumab, the CASTOR study. We have also a comparison, head to head comparison, of bortezomib versus carfilzomib into the ENDEAVOR study. So can you comment, Thanos, on this CASTOR and the other results?
MD: Yes. The results regarding progression free survival, they look quite similar and we now have also overall survival data in the ENDEAVOR trial which shows that there is a survival advantage in favour of patients receiving KD. So this may have an impact on the decision of the practising physicians to have another endpoint which is even more important than progression free survival. However, the CASTOR data are also very impressive, especially with the continuation of daratumumab as maintenance therapy, with deepening responses and prolongation of PFS, especially when given as second line.
PM: So that’s very important and this is one of the big news, in fact, that we’ve heard here in Delhi during the Myeloma Workshop meeting is this survival benefit achieved with carfil-dex versus bortezomib-dex. The follow-up is now immature so we do have this overall survival benefit that will impact on the routine daily clinical practice, as you are mentioning. Based on the hazard ratio that was achieved into the CASTOR study, a hazard ratio of less than 0.4, we can maybe expect or anticipate that we will have in the near future with a longer follow-up an overall survival benefit as well with bortezomib-dex plus daratumumab. So these two combinations will be very important ones for sure for the future. I would like to ask you, Jens, what about we discussed MRD briefly but that’s not routine yet for the assessment, the follow-up, of the patients. What about imaging technologies for the follow-up – is it important or not? Would you like to use MRI, would you like to use PET-CT, is it important? Can you tell us your…?
JH: Obviously I will say it is important and I actually believe that it is important because, as was mentioned several times, you do the MRD. We are not able at the moment to really have substantial MRD out of the peripheral blood so it’s not systemic information, it’s mostly local information of the pelvis where we acquire the bone marrow from. So, as you have shown and the IFM has shown very elegantly, it’s important to not only look into one single part of the bone marrow of the pelvis where we, of course, get the best or the easiest way to get the bone marrow out of but also to have a whole body image, maybe independent on the technique, but an image of the whole body to see if there are residual lesions or focal accumulations of plasma cells after therapy. Because even if the MRD is negative, and that was shown in your IFM trial, even if the bone marrow in the pelvis is negative it could be that there are residual lesions elsewhere in the body and the best technique at the moment, of course, is FDG PET-CT because you see if those lesions which are still there are really containing vital cells. MRI is very sensitive as well but you cannot distinguish between vital and maybe just necrotic lesions. So at the moment FDG PET is the best. There is an upcoming technique called diffusion weighted imaging and I know that you also use that and we started to use it and we will compare it with PET-CT because if you are going to do follow-up imaging it might be important, especially since our patients live longer and longer which is great. We have to really respect also radiation dose and maybe this MRI technique might be, at least a good addition to the PET-CT and to the PET information and maybe even the development of better PET traces because FDG is good but it’s not the best for myeloma, obviously. Maybe also there is potential to develop new tracers and to get more information and more specific information on myeloma patients.
PM: Thank you for this important comment. In fact, we will use in the future, for sure, new combinations at the time of the relapse, very effective triplet combinations or doublets such as KD, for example. And we need MRD assessment, we will need MRD assessment, not only within the bone marrow but also with imaging techniques and that’s right now PET-CT the best one and probably this will change in the near future. So I would like to thank you all for attending this meeting today and I would like to thank Jens, Thanos and Phillip for these great comments.
