A new treatment paradigm in multiple myeloma
Professor Gareth Morgan – The Royal Marsden Hospital, London
Professor Antonio Palumbo – University Hospital of Torino, Italy
Dr Paul Richardson – Dana-Farber Cancer Institute, USA
GM: Hello, my name is Gareth Morgan, I’m Professor of Haematology at the Royal Marsden Hospital in London in the UK. I’m here today in Amsterdam at the EHA Congress 2012. I’m with two esteemed colleagues again, perhaps you’d like to introduce yourselves gentlemen?
AP: I’m Antonio Palumbo, I’m the chief of the Myeloma Unit at the University of Torino, Italy.
PR: My name is Paul Richardson, I’m the Clinical Director of the Jerome Lipper Myeloma Centre at Dana-Farber Cancer Institute in Boston.
GM: Thank you for coming today. We’ve had some great advances here and we’ve learnt a lot. One of the important studies was the MMO15 study, perhaps you could just comment on that for me?
PR: Well, obviously sitting next to the mastermind to my left here, I would say that, to me anyway, it’s an extremely important trial and reflective of that fact it was published as one of three key papers in the New England Journal just last month. But I think Antonio’s work is, to me, impressive because it shows clearly that adding a novel agent to the melphalan-prednisone platform, and particularly the use of lenalidomide in the context of maintenance, has resulted in a substantial progression free survival advantage. The quality of the information from it is very strong, it’s a large trial, three armed, and it shows to me that the lenalidomide is the key aspect of the treatment combination because in fact for one of the arms, which involved just melphalan-prednisone and lenalidomide but for a short period, just during the induction phase, the difference between MPR and MP per se was not particularly pronounced whereas in contrast lenalidomide maintenance made all the difference. That, I think, is a very important observation.
GM: So how do you think, Antonio, we should be using lenalidomide as induction and maintenance? As both, as one or the other?
AP: Certainly I believe that these studies make a major change for the future in the treatment paradigm of myeloma because if you want to make a few comparisons the MP plus thalidomide, when it was compared with melphalan, the advantage was six months. Melphalan-prednisone plus bortezomib when it was compared to melphalan, the advantage was eight months. In these studies with MP plus lenalidomide, but especially followed by lenalidomide maintenance, the advantage over MP alone was seventeen months. So from those numbers you can imagine which is the change in the treatment of those patients.
GM: I think the magnitude of the effect is outstanding really. The study, I think, was designed for people over the age of 65 but there were some pre-planned analyses or subgroup analyses for 65-75 year olds compared to the over-75s. So what do you think that comparison has taught us?
PR: I think that the one caution I have is that I’m really not sure how great a part the melphalan-prednisone is for lenalidomide myself. Certainly in the US we’re fortunate enough where we can utilise other drugs in the up-front setting and I’m very struck that with the biggest challenge being myelo-suppression from melphalan and prednisone that, as I understand it from Antonio’s work, for younger patients this was a well-tolerated, effective regimen but for the patients over 75 it was more challenging. In the US we’re fortunate that we can integrate non-cytotoxic combination strategies up front and, for example, in our own centre we’re exploring the value of adding proteasome inhibition to lenalidomide but using it in a weekly fashion less intensively, so improving tolerability.
GM: I guess what you mean by non-cytotoxic is non-DNA damaging?
PR: Exactly, that’s exactly what I mean. The point is not a conventional therapeutic with myelo-suppression as a major issue.
GM: Absolutely. So Antonio, you’ve become increasingly an expert on management of myeloma in the older patient so why do you think the patients older than 75 were unable to stay on the drug and how should we manage that going forward?
AP: I think this is another very important point because generally speaking we should start to divide the so-called elderly population, those over the age of 65, into two groups. One are the fit, usually between 65 and 75, and the other which we might call the unfit or the frail, over the age of 75. So every physician should start thinking about two groups of patients, one is the fit without comorbidities, the other one unfit with maybe comorbidities, and treat those patients differently with a lower dose intensity for the unfit.
GM: So you answered the second part of the question perfectly, part of this. Do you think MPL is intolerable for 75 years and older or should we just dose reduce? Should we use RD, RP?
AP: As the study is concerned, len maintenance has been equally well tolerated both in patients over the age of 75, the new patient age 65-75. As Paul was saying before, the combination of melphalan-prednisone and lenalidomide was very nicely tolerated and effective in patients 65-75 while it was not and was too toxic in patients over the age of 75. Again, if you want a summary of the study, the induction has been a good induction for fit patients, maintenance has been a good maintenance for both the fit and unfit patients.
GM: So we’ve explored the combination of Revlimid with cyclophosphamide in the so-called CRD regimen. How do you think those melphalan combination versus the cyclo combination is going to play out in the next years?
PR: I think it’s very important to recognise, certainly in my experience, cyclophosphamide is a very well tolerated conventional chemotherapeutic and it’s significantly less mutagenic than melphalan and one shouldn’t forget the small but important incidence of second primaries that was seen with a melphalan based platform. Whilst I don’t in any way want to overstate that risk, I think it’s important to recognise that we need to have strategies that reduce that because if our patients are living, thank goodness, much longer then we need to put together combinations that minimise long-term side effects. So I think cyclophosphamide is a particularly well-tolerated drug in the older population, appropriately dosed and appropriately monitored, and again we’ve also had good luck with other novel therapies combined, particularly if they’re appropriately dosed, say, on a weekly schedule, the obvious example being bortezomib. Right now in our own centre we’re exploring what we call RVD light, which is lenalidomide, bortezomib and dexamethasone with bortezomib administered subcutaneously and weekly. Certainly off protocol our experience with that combination has been excellent.
GM: So how have things developed with these second primary malignancies? I think you’ve done some really rather large analysis of some of your trial data sets, what has that shown us?
AP: What is coming up is certainly that melphalan is a major concern and secondary primary malignancy is related because probably the signal that is coming from this trial in terms of second cancer is mainly related to the use of melphalan. In the group of patients who didn’t receive melphalan the risk of a second cancer was dramatically lower. So what seems to be a concern is mainly the combination of melphalan with lenalidomide although we should always consider that if we are looking at the risk of progressing from myeloma versus the risk of a second cancer we are talking about 10-15 higher probability of progressing from myeloma versus the risk of secondaries. Besides this, anyway, I would also mention that as a solid tumour there is not a major difference. The difference might be for hematologic tumours and from this point of view certainly the suggestion is to avoid a combination including melphalan.
GM: We have this experience with cyclophosphamide Revlimid and dex and while the follow-up is not good at this point in time there are 1300 patients recruited into it of which half of them have had that combination and half will go on to get maintenance. But to this point we’ve only seen one second primary malignancy and that was in the thalidomide arm. So used appropriately it looks like a safe medicine and, like Antonio says, the disease control benefits so far outweigh the second primary malignancies.
PR: I completely agree and the same goes for our experience with RBD, with bortezomib in combination with lenalidomide, we simply haven’t seen secondary primaries yet and, as you say, we have to be careful because it’s only follow-up but we have exactly the same experience. We really do need to recognise, in my view, especially from what we saw in the French trial, the association with genotoxic chemotherapy, not just the melphalan but in the French experience the association with DCEP chemotherapy which, in that setting anyway, didn’t convey any clinical benefit. They also saw an association with anthracyclines, Adriamycin, and interestingly we saw the same thing with the CLGB trial, Gareth, where it was the interaction with the conventional chemotherapeutics that appeared to drive the risk.
GM: Yes, they can, no doubt about that. In the subsequent analysis I’m not sure if those kind sof features still have statistical significance.
PR: I know and I didn’t understand that, to be honest, in the French study. I didn’t understand it because in the paper Michele describes the seven cases of Hodgkin’s disease and ALL all being associated with DCEP so why that still didn’t retain significance I am unclear and I need to ask him, especially as it was significant on multi-variant previously. The data set I can speak to, which is the CLGB one, we clearly see the association with the genotoxic therapy.
GM: Interestingly in the French data set part of the second haem cancers were after people had had allotransplants, which was another interesting observation.
AP: MPV might play a role in that.
PR: Yes, that’s an extremely good point.
GM: Yes, that’s a very good point. One of the interesting things is the improvement in quality of life for the people treated with lenalidomide, how do you think that plays out?
AP: This was another important finding because clearly there was a signal in a significant improvement in terms of quality of life and it was even more interesting to see that the improvement of quality of life was even more pronounced after twelve or eighteen months of treatment, therefore showing that the use of maintenance is even more, increasing more and more, the quality of life after the induction. So Dr Dimopoulos made an analysis showing that there was a significant improvement during induction and this improvement in quality of life was further increasing with the maintenance.
GM: Yes, it’s really compelling data because in the elderly group especially quality of life is important and in the control arm, from the time of maintenance it was only 5-6 months until that control arm needed to be considered for treatment again whereas in the experimental arm those people are at home with their families for two years on average which is a remarkable difference. What do you think of that?
PR: I think it’s huge and I think the important point is also that we don’t just see that measure of clinical benefit just in the older population alone. We had essentially the same experience in the CLGB trial that the maintenance was well tolerated and, of course, in the CLGB trial we were able to demonstrate a survival advantage to lenalidomide use as well as a substantial PFS advantage. I’m just reminded that we’re looking at median progression free survivals of 48 months or so, or that order of magnitude, that’s four years, it’s just dramatic compared to what we were dealing with in the past. When the control arms are half that, 24 months, I think the magnitude of that benefit is unprecedented and bodes very well for the future.
GM: One of the interesting things is in the time that we’ve all been working together that the control M and P arms for up-front patients have continued to improve trial after trial, all of the major trials, this study and the others. This current one, the control arm is the best performing of all of them, which must be because when they’re relapsing the patients are being exposed to these novel agents that are rescuing them. So for patients I think this is dramatic news.
PR: I rather hope, though, that now we’re not going to have too many control arms of just MP any more. I think M and P is truly…
PR: Exactly, of historic interest.
GM: As you say to quote Vince Raj.
PR: Yes, well exactly; to paraphrase VAD. But I do think it’s time to move on because for our patients we know from the VISTA study, for example, that therapeutic parsimony early didn’t translate and the bottom line was you did far better if you got your novel therapy first.
GM: Yes, absolutely.
PR: So I think we need to move on now and I think the big question is going to be what do we do beyond M and P as a platform with novel agents?