Myeloma 2014
Novel targets and immune based therapy in myeloma
Dr Kenneth Anderson - Dana Farber Cancer Institute, Boston, USA
Prof Antonio Palumbo - University of Torino, Torino, Italy
Prof Gareth Morgan - The Royal Marsden Hospital, London, UK
Prof Jesús San Miguel - University Hospital, Salamanca, Spain
KA: Hi, this is Ken Anderson, I’m here at day two of Myeloma 2014. It’s an extraordinarily exciting meeting in multiple myeloma; pre-clinical and clinical advances are making extraordinary progress and it’s clearly a landmark meeting in our field. I’m privileged to be joined by Dr Antonio Palumbo, Dr Gareth Morgan and Dr Jesús San Miguel here on day two. We’re going to talk about right now what some of the highlights from the morning session at this very exciting meeting. The first session had to do with novel targets in myeloma for treatment of, primarily, high risk disease. We’ve had great progress with the immunomodulatory drugs and proteasome inhibitors but this session had to do with entirely new classes of agents that could be used singly or together to address an unmet medical need. So perhaps I could just ask Antonio, in this session there were multiple different targets that were mentioned, CXCR4, the CRM1 inhibitor, selected HDAC inhibitors and IAP inhibitors, for example, but what’s your impression? Are these new agents going to allow us to really make further progress?
AP: Certainly yes, as you mentioned before, these novel agents that are still in the preclinical, some of them are already in the clinical, are certainly able to address the issue of the high risk myeloma that is still an open issue for our treatment. And especially the HDAC inhibitors that are already in the clinic have shown the ability to overcome resistance to the standard treatment and especially some more specific HDAC inhibitors such as the HDAC6 inhibitors. They are showing a very good safety profile and we look forward to seeing the results of the clinical trial.
KA: I would ask you, Gareth, which of these do you think represents potentially a novel mechanism but a novel mechanism that you can actually combine with some of the agents we have.
GM: I’ve kind of always been impressed by the idea that we’re getting people into remissions but the crucial problem is keeping people in remission. So to do that modulating the immune system in some way seems to be a good idea. So the talk about macrophages in the bone marrow that can be switched from a cytotoxic to a non-cytotoxic mode of action was really fascinating because then you really do have the potential for very little toxicity to keep people in remission for longer.
KA: And Jesús, were any of these in particular looking most promising to you?
JSM: I think the HDAC inhibitors are really promising in the way that they are already in the clinic. We had been facing those that were not so specific in targeting the HDACs that showed quite a lot of toxicity but apparently with the more specific HDAC inhibitors the toxicity is reduced and they are clearly synergistic in combination with proteasome inhibitors because you are targeting both the … and the proteasome. I think this is the science going into the clinic.
KA: Yes. I think one more time we are seeing this year that there are entirely new agents that are working in different mechanisms and so we’re all agreeing that the progress is likely to continue. Then the second session that we had here on day two at our meeting was about immune therapies. The promise of immune therapies has been long awaited for many decades but huge excitement here with monoclonal antibodies and checkpoint inhibitors, vaccines. So, Antonio, where do you think immune therapies are going to fit into our myeloma paradigm for treatment in the future?
AP: Certainly today, monoclonals do represent the major expectation for the treatment of myeloma. We have been using drugs, targeting drugs, until now. Now we finally have monoclonals able to bind a specific antigen on plasma cells. So our expectation is certainly from having a complete novel class of drugs to really have something that may completely change the outcome in the myeloma environment.
KA: Yes. And Gareth, we have monoclonal antibodies now, not just one but several that are coming, and we were updated today, exciting data, single agents and combinations. Do you think they are going to be effective even in high risk myeloma?
GM: So I think the challenge in using them is going to be understanding fully how they work. We have a selection of different ones, they’re all going to have a slightly different mode of action, and I think the point that came out was as well as targeting the tumour cell they may impact on the immune system in a variety of different ways. So there’s going to have to be an attempt to hit the sweet spot, as somebody said, about getting the dose right. But once all of those things are worked out I think they will be good for high risk disease and should be perfect increased responses, duration of responses, with low toxicity. So it looks good.
KA: Fantastic. And Jesús, do you think this is an opportunity to combine immune therapies just as we have combined novel targeted therapy?
JSM: Probably. Remember, Ken, a meeting that we had many, many years ago that was in Sweden, mainly focussing on immunotherapy and vaccination. Everybody was thinking of vaccination, probably it was the most novel treatment for myeloma. Unfortunately most of the trial failed but probably the mistake is we used it very late in the disease when the immune system of the patient. Now we have realised, and there is data already, that if you use vaccination early on in the disease you may exploit the immune activity of the patient. This together with the PDL1 antibodies plus the anti-CD38, the immunomodulatory drugs, I think the immune system, or all these immune vaccinations, are going to be really a revolution in the treatment of myeloma. Because there are so many things together; you are going to use vaccination, you are going to use anti-PDL1, you can use also immunomodulatory drugs and you can use monoclonal antibodies that will use the immune system. We need to learn a lot. We are going to work very hard.
KA: We are going to work very hard but, you know what, what I would just add is given the complexity that has been apparent at this meeting in terms of clones and sub-clones and the genomic heterogeneity which continually evolves, to me the immune system is honestly the main hope in terms of dealing with this ongoing genetic evolution that underlies the disease. So, anyway, it’s been very fascinating. Then our last session this morning had to do with new mechanisms of how drugs work or how cells become resistant. We heard about the cell, the precursor to the myeloma cells, that may be the proteasome inhibitor resistant cell. We heard from Dr Bergsagel a wonderful talk about the role of c-myc and how it plays a role in pathogenesis and how it might be targeted with treatments. And we heard about another entirely new class of agents, the deubiquitinating agent inhibitors, and then finally from Dr Mitsiades a new model of how tumour cells from patients might be able to be modelled and in a predictive way inform therapy someday. But in this regard, I guess, do you think we can really learn from resistance how to identify new targets and then go forward with the next generation of inhibitors?
JSM: No doubt. I think the presentation showing that if you go above the proteasome inhibitors it’s really another fascinating avenue for research.
KA: Yes, and the idea that we might be able to use the same pathways that we know are important therapeutically but maybe at a different level. And then different cells, so Dr Teitelman is telling us that maybe we should be thinking about a particular cell that might be causing MRD or might be the resistant .
GM: I thought Constantine Mitsiades’ model was really interesting. We’ve known about that model for a while, it’s clearly functional. But when you think about intraclonal heterogeneity and resistant tumour maintaining stem cell populations it’s perfect for understanding that, understanding metastasis and how you may target those different activities therapeutically.
KA: Right.
AP: I completely agree, I think for years we have been lacking a model that was copying the human system in the mouse. Now we do have the ability to have a model that could be very, very important for preclinical reasons to predict resistance. That’s a major issue that has been awaiting since many years, the ability to have a microenvironment model in the mouse. I would also comment on the inhibitors of MYC, that will be a very interesting new class of targets and that might represent a major class in the future because certainly the MYC gene has a major role in the proliferation of tumour and the ability to target the MYC will probably give some interesting results in the future.
GM: The thing I’d really like to do speculatively is that we develop that test that will identify maybe 20% of hyperdiploid patients at presentation that have a MYC translocation, they have a worse prognosis. Wouldn’t it be good to give those patients a bromodomain inhibitor to switch off MYC and try and improve their outcome?
AP: Yes.
JSM: Yes
KA: Yes. No, I totally agree. I think that MYC is an example of playing a more insignificant role in pathogenesis than we ever appreciated on the one hand. Secondly, it has been said for years that we can’t target c-myc and the more we work…
GM: It seems we can!
KA: The more we work about new drugs but also drugs that we already are using we actually are in different ways, either transcriptionally or otherwise, it turns out, targeting c-myc. So anyway, what I would say is from the morning sessions here at Myeloma 2014 huge excitement, new genetic targets, new epigenetic strategies, new immune strategies, and learning from drug resistance. So the future has never been brighter in myeloma.
