SS: We’ve had a fascinating two days kindly hosted at Mayo Clinic, a fascinating workshop. Perhaps we can start with one of the underwriting themes was the complexity of treating myeloma, it seemed to come up in a number of the presentations. I wonder if you could perhaps comment on that?
GM: It’s a very interesting question because we naturally assume myeloma is one disease where, in fact, it’s probably a collection of diseases all of which look like plasma cells and have a similar clinical pattern. But if we’re going to improve the treatment one of the things we have to take note of are these different genetic subgroups and one of the clear messages in the meeting was that if we’re to improve outcomes we have to subgroup myeloma based on its genetics, treat those differently. But superimposed upon that, as well as this personalised medicine approach, there’s the approach of treating the biology of the disease because one thing’s for certain – they are all plasma cells and they will all have a plasma cell biology. So we’re looking at two approaches to treatment now, one is treating the genetics and the other is treating the biology.
KS: I think that’s a good summary, Gareth. One of the focusses of the early part of the meeting was on all the emerging genomic data that is coming out quickly in sequencing myeloma. That is some ways is concerning because it shows extreme complexity, diverging clones, competition between different myeloma clones, clones coming and going in tidal waves in response to drugs which makes you worried as a treating physician. On the other hand, as Gareth just said, there are some unifying themes, it seems, susceptible for all patients so one of the themes that came out was if we combine generic treatments which will target all plasma cells with individualised targeted therapies in a cocktail of therapies we’re going to make great progress very quickly, I think. So in some ways the genomic sequencing era, while revealing the complexity, has taken us back to our roots by understanding that perhaps that’s not going to be the answer to go after one gene in one patient but rather to try and target the roots of the tree, as Gareth alluded to in his talk, or to at least prune it low to the ground to get some…
GM: So the trunk and branch hypothesis of the way cancer develops has been very important and was well made in this meeting with your data and the stuff that I presented. But clearly the way forward is if you target something in the trunk of the tree you can prune all the branches directly. One good area that you could test that hypothesis with is by targeting MMSET in the (4;14) subgroup. So the fact that we now understand that MMSET modifies the structure of the DNA and it can be reversible based on switching off its histone methyltransferase activity is a very exciting hypothesis that we should test because it’s a truncal mutation, all the cells should have that variant and if you switch it off you should get responses.
KS: One of the key themes, of course, in myeloma is we’re making dramatic progress in treating the disease, and we’ll talk about that in a bit, about how patients are doing better. We just had another proteasome inhibitor drug approved in the United States, carfilzomib, to add to bortezomib and we have some oral inhibitors coming from some of our pharmaceutical colleagues. They are drugs which target the root cause of the myeloma and the plasma cell development and they’re very effective and powerful and if we can just now… One of the things that came up in the discussion a lot was what makes you resistant to those drugs, what makes you sensitive. We had some new themes and concepts emerge which were novel, one of which, for example, was that if the plasma cell does not fully differentiate they are resistant to those drugs and that may be part of the reason that we have relapses and we have to target that earlier population.
GM: So just developing on that theme, novel proteasome inhibitors that are more effective than prior generation drugs are an important step forward and we heard a lot about how you may enhance the activity of those drugs. So you could target upstream members of the pathway such as the D ubiquitin 18 enzymes as well as going downstream of them and targeting the unfolded proteins in the cell. We heard a number of strategies for that, including HSP90 inhibitors, and then targeting the master regulator of that pathway which is HSF1. There are drug development strategies now that try to develop targeted agents for HSF1 so I thought that was very exciting.
SS: There was quite a lot of discussion about biomarkers and targeted therapies, I wonder if you’d like to comment on that?
KS: We’ve talked a little bit already about the proteasome inhibitors and how you become sensitive or resistant to those class of drugs. The other class of drugs, of course, that we use in modern therapies is the so-called immune modulators and a big step forward in the past couple of years has been the discovery of a protein-binding target for those drugs called cereblon. When these drugs bind to cereblon essentially the myeloma cell dies. It may also predispose to birth defects, as we’ve seen with thalidomide in the past. The discovery of that lock to the door that we couldn’t open before really is going to result in great strides in understanding how these drugs work in myeloma, how we can modify them. We heard from company representatives that presented their own data that they have thousand-fold more potent versions of the drugs we currently use in the clinic that are already into phase I testing; very exciting stuff to make progress with. And perhaps to develop a diagnostic test that could be used to predict whether patients will respond to these therapies or not and both save time and money for the patients who won’t respond and the ability to use the drugs properly in the ones that will and to keep them on those drugs.
GM: The discussion of the biomarker was really interesting and people fell into two camps, in a way: there were the very pro-biomarker and then then very, ‘Well, we don’t need a biomarker.’ I think that just reflects when in the disease stage you were going to use it. Up front in combination almost 95% of people will respond makes a biomarker irrelevant but for relapsed refractory cases where you only have 30-40% who are actively responding, in that situation identifying those 30% or the 70% that don’t respond could be a really significant way forward. Measuring the level of cereblon is a very interesting approach to biomarker development.
SS: We also had a very interesting debate about whether myeloma is curable. So, for example, we had Bart Barlogie presenting that, we had Sagar Lonial perhaps debating whether myeloma is more of a chronic disease and then Antonio Palumbo debating whether myeloma is actually incurable. It was a very interesting discussion, I wonder if you’d just like to try and capture that if you can?
GM: It all boils down to the semantics of what do you mean by cure and what is incurable. The final definitive answer to these is said by some people to be the thoughts of Chairman Wikipedia. However, I think that probably ignores the relevance to patients and I actually think the winner in the discussion was myeloma is curable in a percentage of patients and in other patients we’re making them live for significantly longer periods of time. We have to control the disease but we see over the last decade that we’ve gone from people treated with melphalan and prednisone with a 2½ year survival to now people with slower growing myeloma who are well and alive beyond ten years. No matter which way you look at it, we’re making huge progress.
SS: And actually your Wikipedia comment was about the definition of...
GM: Definitions – what’s curable, what’s incurable. Yes, ignoring those definitions I think the reality is that people and patients are doing better.
SS: It was a very stimulating debate.
KS: Yes, we had a spirited debate on the subject and I think the good news for patients listening is that the conclusion of all the experts was that we are curing some myeloma patients which is a real shift in thinking over the past five years or so, that there are definitely patients alive 15-20 years after their initial therapy. Probably every year that goes by more and more people are being cured although it will take many years until we see that tail on the curve. It is important to note, however, that there are two major subgroups of myeloma, there are good risk patients who we know will do well and the debate there is whether you need to give them all the treatment and they’ll do even better or just back off a bit and we had lots of discussion about that. Then there’s the higher risk group who we still continue to, frankly, struggle a little bit with to get long-term control. We have good drugs that get them in remission quickly but keeping people in remission with high risk disease is challenging. Some of the good news was when we talked about new drugs there were two or three examples of new drugs coming that were really specifically looking at these higher risk patients to see if we can make another leap forward in their therapy.
GM: So just following on from that point, it is really important. One is can we develop approaches to readily identifying high risk and standard risk disease in the clinic and people talked about gene expression profiling to do this. There’s always a tendency, I think, because the high risk patients do worse to try and offer them novel treatments, more intensive treatment, whereas actually in some respects it’s the people with the standard risk disease that are benefitting from having these additional modes of treatment and even some of the more intensive treatments are working better in the standard risk group.
KS: We’ve talked with this at previous workshops and this isn’t going to be new to the audience to hear this but what was a little bit different today was the clarity of thought that these really need to be treated differently and that we have ideas in mind. Then why are they high risk? So there were some talks on genomic instability, even though that’s an initiating event by itself that isn’t why you’re higher risk. It’s because it sets the stage for genomic disruption, genomic damage over time. It seems like the high risk patients are more susceptible to DNA damage and that’s probably why they become high risk, more than the fact that they had a specific chromosome translocation.
SS: So the last couple of sessions on the second day really focussing on the emerging therapies. I wonder if you could try and summarise some of these emerging treatments?
GM: I think importantly for patients is that there are significant advances in the treatment and in a five to ten year period we will see new drugs coming to market that will be available for people when they’re in troubles. Some of the good ones and the ones we’ve heard about recently are carfilzomib, a next generation proteasome inhibitor that has recently been approved in America. We await for that to be fully introduced into Europe. The derivatives of Revlimid such as pomalidomide and the new IMiD drugs also look important. Then there’s a list of drugs and ones that you could put together with IMiDs such as anti-CD38, daratumumab, CS1, elotuzumab. We do make significant progress and we heard a lot about these drugs and their use in combination.
KS: What we’re really looking for, now we have two proteasome inhibitors on the market, more coming, we have two immune modulators on the market, thalidomide and lenalidomide, and another one coming, maybe more after that. So what I thought was most interesting at the meeting was what’s not in that class that we don’t have. So we had the monoclonal antibodies, daratumumab particularly, we heard about elotuzumab. We have the kinase inhibitors, MEK kinase, PI3 kinase, AKT, all of which are showing activity on their own and what we have to figure out now is who is going to respond to those drugs, at what time do you treat them, what combinations do you use them in. Let’s supply them along with the more broadly acting drugs as we discussed already. I do think we saw at this meeting two or three of these drugs that are working at least in some patients and we just have to figure out who those patients are and make sure we apply the therapies to the right person, whether it be by biomarkers, genomic sequencing or just knowledge from other trials that we’ve generated.
GM: My vision for the future is the targeted approach. We heard that the RAS pathway is deregulated in maybe 40% of all patients. You can target that with AKT and MEK inhibitors but the crucial challenge is to, one, identify patients with the mutated pathway then to sequentially introduce these inhibitors and prove that they actually inhibit that pathway and then kill the cells. That is such an appealing concept going forward and we have a study with a BRAF inhibitor. But 4% of the total of patients have a mutation of BRAF so finding those patients to put them into a study becomes a real challenge. Then you need these molecular genetic screening tests, you have to deliver those at a reasonable price because if you have to screen two hundred patients to find eight that’s two hundred times whatever the cost of the test is and that becomes prohibitive, in Europe at least.
SS: Perhaps just to finish off we had a couple of very interesting presentations at the end looking at the immune system, for example the role of T-cell and T-cell therapy. There was an analogy with the relative success in non-small cell lung cancer and how that might relate to potential treatment in myeloma. I wonder if you would perhaps pick up on that?
KS: I think there’s no doubt that if we can harness the immune system appropriately it’s going to be a very effective therapy, whether it’s a monoclonal antibody or one of the drugs which blocks the T-cell response, some of the drugs of which have shown early success in melanoma and lung cancer. We’re not quite there yet but I think we’re right at the brink. We heard about some really exciting new work on how we might harness that; we even heard about some drugs which only work when the immune system is very active. How we apply that to patients is going to be obviously the subject of future workshops.
GM: The other way you can use it are these bi-specific antibodies that are really very appealing in that by having an antibody with dual specificity, one that fixes the immune effector on the T-cell to the target cell with the other component of the antibody, is a way of using the immune system in a designer way. You actually force it to kill the cells that you’re interested in. If we can really get that to work I think that will be a very important way forward. Using that sort of treatment in states when patients are in a remission and their disease is stable, that’s going to be very important because long-term we need to control the disease in its minimal disease state and the optimum way of doing that is probably going to be with some sort of immune vehicle. We don’t know what that is, of course, as yet but I’m sure we’ll work it out.
SS: Fascinating. Keith, Gareth, thank you very much for your time.