EHA 17

Maintenance therapy in multiple myeloma; the way forward

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: Maintenance seems to be a very, very important way forward, so what do you think, Antonio, about the role of maintenance strategies for younger and older patients with myeloma?

AP: I think, as I usually say, that in the treatment of myeloma we have two major concepts. One is a combinational approach as induction that is increasing as much as possible the CR rate but the other must be the continuous treatment because we do need a continuous treatment in a disease such as myeloma when we always have residual disease. So from this point of view that’s why the maintenance has such an important role in terms of prolonging the progression free survival. So with all the concern, with all the discussions, maintenance will become a major change in the treatment of multiple myeloma.

GM: And so what’s your current practice in America then, Paul?

PR: We’re obviously very fortunate in that we have ready access to the novel agents and in that regard in our group it’s standard practice now to utilise lenalidomide both on and off protocol. The NCI Myeloma committee in the United States has required that future protocols all have a minimum of two years of lenalidomide as part of them and in the Alliance, which is now the new organisation that was the former CALGB, we’re advocating for lenalidomide-based strategies until progression, based upon the strength of not just our own studies but Antonio’s and indeed the support of information from the French study. So our approach therefore is now to be restratified – we use lenalidomide routinely as a backbone and then the question is in the higher risk patient what else can we offer? In that regard we’re impressed by the bortezomib data from the Dutch German study showing that bortezomib administered once every two weeks, which we’ve found extremely well-tolerated, can be easily added to the lenalidomide backbone and used.

GM: Yes, I guess part of the problem, their published study is with thalidomide but there was no maintenance randomisation so what you know from that study is that the thalidomide combination plus maintenance was not as good as the Velcade induction plus maintenance but we don’t know which one you should use.

AP: No, to some extent what this is showing is that with thalidomide, with a higher rate of discontinuation, shorter period on treatment, this is lowering the efficacy in comparison with bortezomib that in that study had a longer period of treatment and therefore showing that the maintenance and the continuous approach is quite essential. The slight difference between the two drugs and bortezomab.

GM: They really, really show that Velcade subcut every two weeks is tolerable and you can stay on it for a prolonged period of time, which has changed my approach, I have to say.

PR: Well I agree with you but I think the other thing is in the report they didn’t use subcut, they used IV.

GM: It was IV.

PR: So the important message to us was actually the effect on the 17p population in that trial. What Pieter showed so nicely was that there was a substantial reduction in the risk of progression for that particularly poor prognosis group with 17p positivity, recognising it wasn’t complete. And so, based on that, our strategy is if we have someone with high risk and supported by just the point Antonio made, we will integrate that into our strategies for patients. On protocol, of course, there are different considerations and there we’re looking really at more what’s the impact of consolidation and then what’s the impact of maintenance because consolidation now, particularly after the work of Michele Cavo and Antonio in their randomised study comparing bortezomib with thalidomide-dex to thalidomide-dex, we’re very impressed by that data and we think that the consolidation step is a very important aspect to explore in the post-transplant setting.

GM: I think these high risk strategies, there’s a real need for randomisation for these things because we simply do not know how the addition of bortezomib to anything in a proper randomised comparison in a pre-defined group really does. So I think there has to be a bit of caution about some of these things.

PR: Yes, I think that’s reasonable but, Gareth, it’s important to note the results of the Cavo trial, they’re quite striking. I mean the VTD combination clearly outperformed TD, recognising that TD obviously doesn’t necessarily compare to RD. Having said that, for high risk patients, certainly in our group, our view is that this is such an exquisitely vulnerable group with such bad biology typically, especially the 17p deletion positive patients, we tend to be as creative as we can for these folks.

GM: So this creativity and fact and I think it’s important to distinguish those two issues. One of the important things, I think a real important take home message, is that we really are making progress with the low risk disease.

PR: I agree with that, yes.

GM: And intensifying treatment in the low risk patients may really transform their outcomes and we need to be careful with the high risk and be creative in our trial design.

PR: I agree with that and if I may, one thing, Gareth, I think the term low risk is a bit of a misnomer.

GM: OK, standard risk. I’m with you on that.

PR: I agree. Because we have an incurable malignancy and I totally understand, your caution is well placed, but I do think it’s very important for us to be positive and creative because, at the end of the day, we’re not curing anybody. For all the progress we’ve made, I see too many patients in whom our treatments fail.

GM: There’s interesting stuff about the genetics and, as you know, we’ve done this really rather big study of the genetics and, as a single agent, 17p minus is not as bad prognosis as you suggest. The combination of 17p with another lesion, such as a (4;14) or a (14;20), that is a really ultra-high risk group and the sensitivity specificity of a test and the potential for over-treating is something that we shouldn’t discount as physicians.

PR: Yes, I accept that but again I want to be careful here because I think it’s very important, study after study has shown that therapeutic parsimony with non-toxic drugs, that’s the key point, is misplaced.

GM: That is the key, yes.

PR: The bottom line is that I take your point that we need to know more about cytogenetic abnormalities and understand their interaction with other features but the good news is that we have combinations of well-tolerated drugs. And I completely agree with you, Gareth, if we were talking, with the greatest of respect, to total therapy strategists, if we’re talking total therapy, three transplants, multiple drugs, long-term treatments, significant morbidity, I would absolutely agree with you. But to me the real bonus of where we sit today is that we have drugs like lenalidomide, extremely well tolerated; we now have bortezomib figured on a weekly schedule sub-cue, well tolerated; we now have second generation proteasome inhibitors with much less neurotoxicity and finally we have third generation immunomodulators. So I think we do need to be creative about this, Gareth, going forward.

GM: So I am, I’m not arguing for lack of creativity, it’s creativity with factual data and randomisation. I think the creativity going forward is about using innovative treatment strategies, combining these new drugs in different sequences that take advantage of their different biology and side-effect profile that can contain the malignant clone for a prolonged period of time. What I think we’ve learnt in this meeting is that there’s a reality to that fact and that maintenance and on-going treatment strategies really are transforming the outcome of this disease and we need to spend more time working out the exact way to do it. But I think everybody here should be really pleased that we’ve actually made such progress.

PR: I completely agree. I’ll just share with you one patient experience which, to me, just keeps me very humble. Using some novel strategies to try and characterise his disease we identified at least three different clones within his marrow and this is a patient who is now responsive to a four drug cocktail. It just exemplifies just what you’re alluding to that hopefully with the newer technologies that we have, plus the new drugs that we have, we’re able to deal with this extraordinary entity of disease heterogeneity, not just between patients but within a patient.

GM: Yes, just to make it clear that the new sequencing technologies highlight this intraclonal heterogeneity. When we’ve looked using single cell analysis you can really see cells that behave differently, have different features within the same tumour. So it really argues for combinations and sequential strategies, I think. So I think the way forward is not clear, not without problems, but that’s where we’re going to wind up.

PR: Right, I completely agree.

GM: So, gentlemen, thank you very much. Thank you for joining us for that lively debate. I’d like to thank my two colleagues and hopefully it was educational and worthwhile listening to. Thank you very much.