PR: Hello everybody and it’s my pleasure to welcome you to the International Myeloma Workshop here in New Delhi for the 2017 meeting. It’s my pleasure to be here today actually with my wonderful friend and colleague Professor Marivi Mateos who actually leads the programme at the University of Salamanca in Spain. Marivi, welcome and lovely to be with you.
MVM: Thank you very much.
PR: It’s been a wonderful meeting, hasn’t it, and it’s great to be here in New Delhi, quite a testimony to the extraordinarily international nature of the myeloma research community.
MVM: Yes, you are absolutely right. So it’s a pleasure also for me to be here in New Delhi enjoying this International Myeloma Workshop.
PR: Absolutely and we’ve had some very exciting data and if I may dive straight into that. We had a really interesting session yesterday on smouldering myeloma from biology to clinical translation. Obviously your pivotal work in this field with really your ground-breaking phase III trial published in The New England Journal a few years ago has really opened the door to exploration in this area. I wondered, Marivi, if you could share with me what are the takeaways that you took from the session yesterday and then perhaps I can give you some of my own thoughts.
MVM: Yes, you know that smouldering is a plasma cell disorder characterised by an M component higher than 3 and/or plasma cell bone marrow infiltration between 10 and 60 but with no myeloma defining event. Smouldering myeloma is a heterogeneous disease and this is one of the main problems because we call smouldering myeloma to patients with a very low risk of progression to myeloma but also we call smouldering to patients in which the risk of progression is high. Some years ago the International Myeloma Working Group did a great effort for the identification of ultra-high risk smouldering myeloma patients, those with a risk of approximately 80% of progression risk to myeloma at two years. These patients should not be called anymore smouldering, these patients are now myeloma and they have to start active treatment. The problem is what happens with the other smouldering myeloma patients, with those patients in which the risk of progression is approximately 50% at two years. We know how to identify them and the question mark is if we should treat or not to these patients. You mentioned the Spanish Myeloma Group conducted a phase III randomised trial showing a significant benefit treating these patients with lenalidomide and dexamethasone in terms of time to progression because it was significantly delayed in comparison with no treatment. Also we observed a benefit in terms of overall survival. It’s true that this is the unique phase III randomised trial with consolidated results at the present time. Probably we have to wait to know the results of the other trials that are being conducted at the present time but if I have to envision I think that in the future I would say that probably high risk smouldering myeloma patients should be incorporated into the definition of myeloma and myeloma will be treated as you treat your patients with newly diagnosed myeloma. This would be the optimal way.
PR: I completely agree with you and the takeaway I had from yesterday when we listened to the science from Dr Bergsagel and Dr Mitsiades was essentially the same degree of heterogeneity and evolutionary thrust that we see with active myeloma. So I wasn’t left with anything scientifically at the preclinical or biological level that distinguished where we might be other than, perhaps, some features of gene expression profiling. But my impression clinically was exactly as you say, that we’ll ultimately be left with active myeloma and MGUS and this smouldering space will evolve accordingly. You’re to be congratulated, Marivi, at so many levels for really breaking the ground here. I was impressed from the studies presented that on the one hand active myeloma needs to be treated very proactively with the goal of durable remission and sustained and deep remission but at the same time that in that grey area toxicity really matters, doesn’t it? That was the impression I had from the discussions held. Also the other thing is the whole area of how do you define endpoints in this group of patients. Dr Voorhees presented on the challenges there and I was left with as many questions as there seem to be answers. So I wonder, from what you heard yesterday, what direction do you think studies will go? Because what I saw was a very intensive approach on the one hand and then a much more immunologically based approach on the other and I wondered what you thought of that.
MVM: I think that both approaches are fine and are acceptable. So if we consider that from the biological point of view smouldering is different to myeloma because some new events are necessary to move from even high risk smouldering to myeloma. Probably the immunotherapies approach are very attractive because you know that the immune system is much more preserved in these patients and the stimulation and the harassment of the immune system probably is enough to control the disease. However, on the other side our proposal, our new proposal coming from the Spanish Myeloma Group and also from the International Myeloma Foundation, is to move forward and to try to cure these patients. This is the reason why we have decided to approach with a much more intensive optional therapy including induction, transplant, consolidation and maintenance. So we have to wait to have more consolidated results. Concerning the safety profile, I have to say that in our experience smouldering myeloma are asymptomatic myeloma patients, that they are doing their daily living activities without any problem. Toxicity profile is much better than symptomatic myeloma and, in fact in the QuiRedex trial when we compared len-dex versus observation tolerability was perfect – few grade 3/4 adverse events so-called. The same we are seeing now in our new study including carfilzomib as part of the induction and also transplant.
PR: How very interesting because I completely agree with you; I think the ability to look at both is very, very important. The flipside of that is that the immunological aspects, to me certainly anyway, I’m very pleased with our own experience with monotherapy using elotuzumab, very well tolerated, long, long disease control we’ve seen in our single arm trials so that’s the caveat. However, what I have noticed is that in my asymptomatic patients, whilst I completely agree with you their tolerability because they are stable is good, from a symptom point of view from a patient perspective they are far more sensitive to any side effects in the sense that they are not symptomatic to start with and they’re not anticipating anything necessarily. So it’s very exciting; on the one hand we’ve got the intensive approach, on the other hand we have the more immunological based approach and we will see which translates into the better outcomes for these different groups of patients. But I do agree, the heterogeneity will remain a challenge. Were you left with any particular… or do you have any messages for our audience, I should say, as to any particular aspects of biology that may help to start to discriminate these two? Because I must say from the session yesterday it wasn’t clear to me that we really understand that but I wondered, Marivi, if you had any insights?
MVM: So from the biological point of view you know that if you do gene expression profiling there is some specific signal for the identification of smouldering and even high risk smouldering myeloma that is completely different from symptomatic myeloma. The problem is that, at least for us in Europe, so we are not going to be able to use this technology in our routine. We have to do, of course, all these investigations in research to try really to identify and to know how the biology of the disease is different.
PR: What do you see in those? For example, just to drill down on that, in the gene expression signature that there is could you share with our audience a little bit about that? Because, again, to me from the presentations yesterday I was clear that there are some features from Dr Bergsagel but then in Dr Mitsiades’ presentation there seemed to be greater complexity. I just wondered what was your takeaway?
MVM: Yes, also at the last ASCO meeting an abstract was presented by the group of Ola Landgren in which the mutations present in myeloma and present in smouldering were the same. The problem is that the number of patients with a mutational burden was significantly lower in smouldering than in myeloma and that only two out of twenty patients had this mutational profile whilst patients with symptomatic myeloma most of them have this mutation. So there are clear proofs showing that the biology is different.
PR: Excellent, so in that context, just to frame this for our audience again, would you think, Marivi, that in the future in this high risk group… I fully agree with you, the ultra-high risk group are active disease and need to be treated as such. This high risk group, which is the target population, do you think we’ll be left with a gene expression profile that will help us guide whether or not these patients either receive an immunological based strategy that’s less intensive versus a more intensive full course
MVM: For sure, I think that it will be the future.
PR: Excellent. If you could speculate, what would you see as the distinguishing features between those two groups in terms of mutational profile?
MVM: Really I don’t know how are we going to proceed in the near future so I think that probably it’s also possible to evaluate the immune profiling and patients with one specific immune profiling can benefit most from an immunotherapy strategy based on IMiDs plus a monoclonal antibody…
PR: … vaccine or something.
MVM: Whilst another patient can benefit from a much more intensive option of therapy.
PR: Interesting. So I would agree with you so I think it won’t be just necessarily gene expression profiling, it will be whether or not there’s an immunological repertoire that can be exploited to maximise the advantage of that. My sense from the conversations yesterday was that there will be specific oncogenes such as c-Myc that tell us whether or not in a particular patient it is justified to move forward with a particular approach. So in a funny sort of way we might be rather like our breast cancer counterparts in whom early breast cancer can be distinguished by gene expression profiling as to exactly what you add in terms of adjuvant therapy. We may be in that very exciting spot of a precursor illness in myeloma where we can, as you say, strive for a cure.