PM: Welcome everyone to this ecancer.tv programme. We are in San Francisco for the annual meeting of the ASH 2014. My name is Philippe Moreau, I’m based in Nantes in France and I’m happy to share this talk with you today with Marivi Mateos, you know her, she’s working in Salamanca in Spain; with my very famous colleague, Keith Stewart from Scottsdale, Arizona and Thanos Dimopoulos who is working in Greece, Athens. So welcome everyone and my first question is for you, Keith. You are one of the stars of ASH 2014; you have presented a very important study in the relapsed setting so can you briefly summarise your results and your study?
KS: I’d be happy to, Philippe. Our study was called the ASPIRE clinical trial; it was a large phase III clinical trial, 790 patients. We tried to see if we could improve on the reference treatment of Revlimid and low dose dexamethasone at relapse in myeloma. We tried to do that by adding the drug carfilzomib to the combination. The bottom line of the trial, I think there were three or four take home points, the triplet combination of KRD, carfilzomib, Kyprolis, Revlimid and dexamethasone, prolonged progression free survival by almost nine months and had a 26 month progression free survival which really is somewhat unprecedented. Secondly, people went into complete remission three times more frequently than the control arm. Third, quality of life was better for patients taking three drugs rather than two, which is somewhat astonishing, and then finally this trial was very reassuring with respect to the safety profile of this combination which really didn’t send out any strong signals that we should be concerned about.
PM: So that’s a very, very important study. I know that Kyprolis is widely used in the US, carfilzomib, but you know that in Europe probably this study would be the pivotal one for the approval of carfilzomib. So from the European point of view that’s a very, very important study. Can you tell us about risk - the standard risk patients versus high risk patients? This combination is also effective for patients with high risk versus lenalidomide and dex?
KS: Thank you for asking. We had high risk cytogenetic data on a number of patients. KRD, the combination, maintained its superiority in the high risk patients almost as long as with the overall sub-population. In standard risk patients it was even better, it was almost a ten month progression free survival which is really amazing when you think about it.
PM: That’s huge.
KS: Unfortunately, in neither arm of the trial did the high risk group perform as well as the standard. It remained higher risk by about six months but overall high risk patients still benefitted from the combination.
PM: Thank you very much for this outstanding presentation. Many, many people in the audience were amazed by your data. And Thanos, you have also presented a very important study on pomalidomide and low dose dexamethasone. This regimen is widely used now in very advanced patients so can you comment on your data?
MP: Yes, Philippe, this was a phase IIIb trial which included 700 patients and the primary endpoint was to show that the safety of the combination of pomalidomide with low dose dexamethasone was similar to that reported previously from the pivotal trials. This endpoint was met so the primary toxicities were neutropenia with low rate of neutropenic fever and low rate of discontinuation due to adverse events at about 5%. As far as response rate is concerned, it was confirmed that one in three patients achieved at least a partial response. The median duration of response for responding patients was eight months and responses occurred in patients who were refractory to bortezomib, to lenalidomide or to both agents. Median PFS was four months and the median overall survival was 12 months. Thus it is reassuring that the pomalidomide low dose dexamethasone can help significantly approximately one third of the patients with myeloma. Moreover, as we saw from other trials, it can be a backbone on which other regimens can be added. We know that there is experience with cyclophosphamide, with carfilzomib, with Biaxin and also with monoclonal antibodies. So pomalidomide low dose dexamethasone is an effective salvage regimen for patients with unmet need myeloma.
PM: That’s very important. Once again, thank you for this very interesting presentation; you were both speaking in the same session. So, Marivi, you are one of the most important specialists, let’s say, about the treatment of elderly patients. We can move now to the front line setting. So you have presented the very interesting data on the sequencing of lenalidomide and VMP and I would like you to tell us about these results and what you are calling the total therapy for elderly patients, that’s quite provocative. Maybe you can also comment on another presentation that was presented by Cyrille Hulin regarding very elderly patients above the age of 75 years treated by lenalidomide and dex or MPT.
MM: OK, Philippe, the first trial that you mentioned has been conducted by the Spanish Myeloma Group and what we decided to do is to optimise the treatment of elderly patients with multiple myeloma. As you know, VMP is one standard of care commonly used in Europe and lenalidomide plus low dose dex is the new standard of care for this patient population. So we planned to put both standards of care in this patient population but not all together but in sequential or alternating schemes. So nine cycles of VMP followed by nine cycles of len-dex or the same, one cycle of VMP, one cycle of len-dex and so on. Our hypothesis was that the alternating scheme would be superior to the sequential one due to early exposition to drugs with different mechanisms of action. But the first conclusion of our study is that our hypothesis was not confirmed because the alternating scheme was not superior to the sequential one. In fact, both arms were almost identical. But what is much more important of our trial is that this combination, including a fixed duration of therapy, eighteen cycles, including both VMP and RD in a sequential or an alternating arm resulted in a complete remission rate of 40%. 50% of these complete remission patients were in immunophenotypic complete remission. The median progression free survival is about three years with survival superior to 80% at three years. I consider that these results are in favour, as compared with the standards of care used for the rationale of this trial, the VISTA trial and FIRST trial.
PM: And what was the feasibility in very elderly patients above the age of 75? Can you compare this with the data presented by Dr Hulin?
MM: This is clearly relevant because, in fact, in our study 50% of the patients were older than 75 years and toxicity was higher in this patient population. Probably this is not very optimal for this very elderly patient population and in line with this Dr Cyrille Hulin presented this morning the results of the FIRST trial, continuous treatment with lenalidomide plus dexamethasone versus RD18 versus MPT in really this patient population, very elderly patient population. His results supported that probably this combination, continuous treatment with RD, is much more feasible for this very elderly patient population.
PM: That’s very interesting. So len low dose dex can become, maybe in the near future in Europe, at least, the standard of care. We know perfectly that it is widely used in the US already.
MM: Yes. Of course, at the moment that len-dex is approved in Europe people would move to use this combination more and more because it includes just two drugs and, in fact, it’s of oral administration and it’s specifically useful in this very elderly patient population.
PM: So let’s move now, again, to the relapsed setting and, Thanos, we’ve heard this morning a very interesting result with two monoclonal antibodies, two different ones in fact, targeting both CD38. What are you thinking about the results with SAR, the compound that was presented, the phase Ib, in combination with lenalidomide and dex in very advanced patient?
MD: Correct. This was a phase I/II trial where patients previously treated with multiple regimens, several of those were refractory to pomalidomide, to carfilzomib, all of them have been exposed to lenalidomide, to bortezomib, were treated with a combination of lenalidomide dexamethasone and increasing doses of SAR from 3mg/kg up to 10mg/kg. The overall response rate was approximately 60% which clearly shows that there is a synergism between this monoclonal antibody and lenalidomide with dexamethasone. We envision that there will be other trials in that setting combining SAR with pomalidomide and low dose dexamethasone and also studies evaluating the role of SAR with lenalidomide dexamethasone in earlier phases of myeloma in the relapsing setting.
PM: So that’s a very, very promising drug. And during the same session we heard, Keith, about the other monoclonal antibody targeting CD38, daratumumab, also in combination with lenalidomide and dex in less advanced patients. So what are your thoughts regarding this interesting combination?
KS: I was very impressed by it. We have worked with the SAR antibody but not yet with daratumumab and first the combination was very well tolerated so that is not going to be an issue. Secondly the response rate was very, very promising and it shows that these drugs are going to be, as Dr Ola Landgren told me yesterday, these are going to be blockbusters in myeloma; they’re going to be used throughout treatment. It’s too early to tell which of the two might have an advantage over the other, they both seem to be very good agents. The one thing that I was a little bit struck with was the infusional related reactions with both drugs but a little bit more with daratumumab perhaps, it seemed. I suspect those are very manageable in clinical practice. I don’t know what experience others have?
PM: Marivi, you have tested daratumumab front line. We have heard about very advanced patients last year at ASCO, for example, in refractory patients, single agent. We are hearing now about len-dex plus dara or SAR in the relapsed setting. But Marivi, you have the experience of dara front line, especially in combination with VMP so what do you think of this combination? We are going to have this R-CHOP for myeloma in the future and what about the toxicity?
MM: Probably although it’s too early to confirm this point but you know that there is a phase Ib trial in which daratumumab has been combined with different backbone treatments in first line therapy, including bortezomib plus dexamethasone; bortezomib, melphalan and prednisone and bortezomib, thalidomide and dexamethasone. From my personal point of view, the first important point is tolerability is perfect because, concerning the safety profile just to know few infusion reactions but most of them occur during the first infusions.
KS: And mostly grade 1.
MM: So no haematological toxicity, no non-haematological toxicity, and I think that is important, so tolerability is perfect. Of course in terms of efficacy in that we have to wait because now we can advance 100% of overall response rate but very few patients have been included in the trials. But the point of starting phase III randomised trials in which daratumumab will be added to these backbones but in randomised trials and we have to wait to obtain consolidated results. But, of course, in the near future the monoclonal antibodies can be the backbone of the therapy.
PM: So if I can summarise, I think that we have very interesting data in pomalidomide in very advanced patients, confirmatory trials in fact, and, Keith, you presented outstanding results, to my opinion, with carfilzomib in the relapsed setting in combination with len-dex. We are improving, as well, with novel agents such as monoclonal antibodies targeting CD38, SAR and dara, and as part of front line treatment we have, for sure, the confirmation of the feasibility of len low dose dex in very elderly patients and maybe for a sub-group of patients, younger, the addition of len-dex plus VMP could be a very interesting option with a very good progression free survival, as you mentioned and as you described today, Marivi. So thank you everyone for this very interesting presentation and see you soon in another meeting.
