Upcoming trends in myeloma therapy

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Published: 15 May 2014
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Dr Kenneth Anderson; Prof Gareth Morgan; Prof Paul Richardson

Dr Anderson (Dana Farber Cancer Institute, Boston, USA) chairs a discussion with Prof Gareth Morgan (The Royal Marsden Hospital, London, UK) and Prof Paul Richardson (Harvard Medical School, Boston, USA) for ecancertv at Myeloma 2014 about the treatment of myeloma.

They discuss the trends in therapy they expect to see in the next decade and provide a response to the definitions workshop.

Myeloma 2014

Upcoming trends in myeloma therapy

Dr Kenneth Anderson - Dana Farber Cancer Institute, Boston, USA
Prof Gareth Morgan - The Royal Marsden Hospital, London, UK
Prof Paul Richardson - Harvard Medical School, Boston, USA

KA: I’m Ken Anderson, here at Myeloma 2014 in Boston, arguably the most exciting myeloma meeting we’ve ever had. We talked earlier of the exciting first morning session and we’re here now to talk about the sessions in the afternoon. I’m delighted to be joined by Professor Gareth Morgan and Professor Paul Richardson. We had very lively discussions here this afternoon, the first of which was to ask the question of how transplantation will be used now and in the future in the era of novel therapies. So, Paul, I know you were one of the featured speakers here, so maybe you can give us your perspective on where transplant will fit in in the next few years to managing myeloma?

PR: Well, thank you Ken. I think it was an incredibly lively and productive discussion. I think we all believe there’s a strong role for transplantation currently in myeloma in eligible younger patients, the question arose where will we be in a decade from now. Obviously building upon the progress made with the integration of first generation novel therapies such as proteasome inhibitors and immuno-modulators we’ve seen some real tangible differences in terms of improving transplant and improving outcome for non-transplant eligible patients. One of the key questions is will an increasing proportion of younger patients be able to be spared high dose therapy with autologous stem cell transplant with the success of next generation novel agents, be they monoclonal antibodies, vaccine-based strategies and some of the really incredible excitement around PD1 blockade. Obviously we don’t know yet but certainly there seems to be great promise for the fact that one size may not fit all and that in reality for a substantial proportion of patients transplant may remain an important option but for another proportion it may be something that can either be kept in reserve or, arguably, perhaps in some selected patients it may not be useful at all. That’s an open question as we go forward with current studies.

KA: So, Gareth, given that happy problem that we have now developed in myeloma, that is the novel therapies having been integrated into the transplant and giving us such positive outcomes, the question being actually where does the transplant now fit in? What’s your view on that?

GM: The clear aim of treatment has to be to achieve a stringent CR, by which we mean no detectable residual disease with very sensitive flow cytometry and molecular testing and a negative PET CT and some monitoring with whole body diffusion weighted MRI. So that’s what we need to achieve and I think if we can achieve that, based on what we heard yesterday about intraclonal heterogeneity, we should be able to reduce the number of clones to a minimum, reduce the minimal residual disease to very small amounts, then coming in with your immune therapies, we may then be able to achieve cures. I think we really do need to address this about not throwing treatments out but getting patients to the correct therapeutic endpoint so that we can truly get to that sort of cure stage for more patients.

KA: Yes, and that’s a wonderful link in to the second session that we had here this afternoon which had to do with how is the minimal residual disease best measured now. So we had wonderful discussions about multicolour flow cytometry, eight different colours, sensitivity, perhaps, 10-6, sequencing – similar sensitivity. We had a very nice talk from Dr Cavo about the imaging, PET CT and MRI for example. But the issue comes, how are we as a community going to actually come to some common ground here where we actually in real time we can’t have sequential studies that really don’t answer the questions. We really want to have, a year or two years from now, a good uniform definition. So Paul, I know you have a trial ongoing in collaboration with the French, are you trying to look at these issues in that trial?

PR: Absolutely, MRD is a key endpoint as part of our correlative studies done in the trial, recognising that, I completely agree with Gareth, the last thing we want to do is put aside an effective therapy in the patient if it’s going to help. The critical question is how much is enough? How much do you need to achieve the standards that Gareth alludes to? And recognising that there can be some unexpected and long-term toxicities to some of these approaches that we also need to minimise. So recognising all of that, in our trial on the US side there is a comprehensive effort at MRD assessment and on the French side there’s actually also built in a comprehensive imaging strategy, utilising MRI and PET CT. We hope by combining these two data sets we’ll be to drive exactly to the point that you allude to, Ken, that can we define an MRD state that then results in true evidence of clinical benefit longer term and so inform and tailor therapy accordingly.

GM: So the lessons from CML are that it’s really, really important to report not just positive or negative but you have to have a level. So we should be… it may not matter what technology we use as long as you know the sensitivity. So whenever a report of MRD or residual disease comes out it should be asterisked with ‘to a level of sensitivity of’ 10-1, 10-4, 10-6, because then you have some idea of the amount of disease left in the patient because there’s still quite a lot of disease left, even below a level of sensitivity of 10-5.

KA: So I could not agree more and I think that as we go forward as a community hopefully we can come to some uniform metrics here. It is a lot like chronic myelocytic leukaemia was fifteen years ago.

GM: Very much.

KA: You know, if we can establish some uniform criteria and we can actually have clinical data that is of clinical significance to the MRD status then we can use that information to inform future therapies. Do I need to be more aggressive? Can I continue maintenance? Can I stop maintenance? The same kinds of questions that were present in CML fifteen years ago are now relevant in myeloma.

PR: I completely agree, Ken, and I think it’s an extraordinarily good place to be. I think that it’s a point that was made very well, actually, by Antonio which is that we are more in CML and arguably even also some solid tumour territory biologically than we are in the setting of acute leukaemia or aggressive lymphoma. That key biological distinction really, to me anyway, emphasises the point that one size does not fit all. I think the good news is that we have multiple new treatments and multiple new combinations available that will help us best derive the best outcome for each individual patient.

KA: So I just want to summarise here from Myeloma 2014. We’ve had amazing progress in the last 10-15 years, survival of patients has at least tripled. But what came out of this meeting in the area of genomics, epigenetics, immune therapies entirely new classes of targeted agents used singly or in combination but coupled with new metrics for success, extent and frequency of response we simply have not seen before. All of these updates really say to me and should say to all of you that the future promise for myeloma being a chronic illness with curative potential has never been higher.