Can you give us an overview of the myeloma treatment landscape?

We’ve come a long way with the treatment of myeloma in the last decade, I think, and so the landscape has been constantly changing and we’ve come up now with several backbone treatments, including proteasome inhibition, the IMiD drugs, transplantation and alkylating agents. There are single institution studies, including one from our own institution that has shown that over the last ten years we’ve improved the survival of patients with myeloma remarkably. We’re trying to fine tune some of these treatments these days and I think that’s one of the major roles of national trial bodies – do you have a proteasome inhibitor first, do you have an IMiD drug first? Is there a role for transplantation? What is the role of maintenance treatment? One of the big things that comes out in this meeting is the role for on-going treatment both with Revlimid and with Velcade. It seems to me that a lot of the benefit of these drugs comes from their prolonged administration which, I think, is very encouraging for controlling the biology of the residual myeloma clone.

It’s interesting, because I’m beginning to feel old and have been doing it for some time, that you can really see the changes in terms of patient outcome. So I remember when I first started doing this that patients, their bones would crumble, people could lose six to ten inches in height, their rib cage would set on their pelvis and their quality of life was really poor. At that stage we were just aiming for stable disease and of course that’s changed now. One of the paradigms of treatment is to use these new drugs, the proteasome inhibitors and the IMiDs, as combinations to increase the number of response rates, increase the depth of response so we’re getting complete responses. Another one of the things that we’re learning about is how flow cytometry can define stringent CR where there’s no detectable disease at all. So I think that is the major difference – we accepted lots of residual disease years ago and now we aim for complete responses where there’s none detectable. Of course this is improving quality of life, decreasing bone disease and our clinics these days have patients that are fully fit and well who have had myeloma for five and ten years and beyond.

Can you describe single agent drugs of combinations, twins, triplets and quadruplets?

I think this is one of the really important features for people out there to understand is do you use single agents, a combination of two, three or four drugs? I think the data is now really quite clear, certainly for younger patients. For younger patients I think we should use a combination of three drugs because they’re tolerable, the side effect profiles are good and you get really good complete responses. There’s a proviso to that data: if you’re frail and older it could be that on some occasions that doublets are indicated because you really don’t want to be losing patients because of toxicity; but for the majority I’d say triplets. There has been some data presented here about quadruplets of therapy and it does seem that they work, they increase responses, probably increase progression free survival. The trouble is, and the thing at the back of everybody’s mind is do you increase toxicity. So there’s still a big question, I think, in younger patients whether we use triplets or quadruplets of drugs. But this is all good news because we really are seeing these improved complete responses. At one stage we had two tools in our toolbox, as it were, melphalan and steroids, and now we’re starting to have a range of second generation anti-myeloma treatments that we can target the treatment to the individual patient. One of the things I’ve been interested in is how you use laboratory work and laboratory tests to slice myeloma up into biologically relevant subgroups then pick the appropriate treatment for that subgroup of patients. That’s one of the things we’ve really seen a step change in, I think, in this meeting. Going forward I think you’ll hear more and more about treating subtypes based on their laboratory features.

Can you describe the mutational landscape of myeloma?

I’ve had an interest in in using this massively parallel sequencing approach to characterise the mutational landscape of myeloma. At first glance that sounds terribly dry but one of the things we noticed was that not all the variants were present in all of the cells. So where we thought cancer, myeloma say, was a pure population of cancer cells and they would all response equally to a treatment, it’s now become obvious that within the cancer there is variability so some cancer cells will be sensitive to one treatment and other components of the tumour will be sensitive to another treatment. This has important implications for how we use treatment. It comes back to our discussion about do you use single agents or quadruplets because certainly in order to overcome that heterogeneity within the myeloma cells you need to combine drugs to be sure that you don’t really put a selective pressure on the cancer and let resistant cells grow out and that way impair patients’ outcomes. So I would really make a strong argument for using combinations of drugs of different classes, sequencing drugs so that when there are a few cells left you change the nature of the drug and then over time alternating treatment so you prevent the emergence of resistance. That way we’ll do better in the future.

One of the things that I think I’ve learned by thinking about this intraclonal variation is that as we go forward we’re going to have to be smarter about the assessment of patient relapse. So before it was all about clinical things – how long did the relapse take and was the disease coming back quickly or slowly? Now we need to know is it the same clone, is it a different clone, is it sensitive, is it resistant, are there mutations present that we could take a drug and target the treatment to that. It’s going to involve not just clinical assessment, which is important, but also the laboratory assessment. I’ve got a really interesting patient who was completely stable, nothing wrong with him and we’d started doing diffusion weighted MRI to look for small foci of disease. Randomly on his annual screening we found a lesion in his pelvis and before he’d progressed with totally stable disease, no symptoms, we were able to use localised radiotherapy with a gamma knife to oblate that focus of bad disease. That way we’re going to keep him free of symptoms, at home, skiing, having a good time. It’s simple clinical things like that that are really making a difference.