Advances in myeloma at ASH 2012 (2/2)

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Published: 18 Dec 2012
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Prof Gareth Morgan - The Royal Marsden Hospital, London

Professor Gareth Morgan from The Royal Marsden, UK, talks to ecancerTV about how far treatment in myeloma has come over the past decade.  Also where it is likely to go in the coming years as the use of newer agents are fine-tuned to further improve outcomes.  He focuses on new data from ASH 2012 such as maintenance treatment with lenalidomide and bortezomib, and notes how newer agents have considerably improved patients’ quality of life.


Professor Morgan touches on the issue of second malignancy and the new follow-up data from lenalidomide-treated maintenance cohort showing a higher risk of developing myelodysplasia and AML.  He also summarises promising new pomalidomide data in lenalidomide- andbortezomib-refractory patients, and notes the hope for carfilzomibanddaratumumab.  Professor Morgan notes the importance of changing drug schedules to improve outcomes with the newer generation agents.


Finally, Professor Morgan outlines the importance of epigenetic changes in cells that mean that drugs could be designed to counteract these, such as the identification of the 414 translocation, that could target MMSET. Also, the relevance of BTK signalling in myeloma.


This programme has been supported by an unrestricted educational grant from Janssen Pharmaceutica (A Johnson & Johnson Company).


ASH 2012

Advances in myeloma at ASH 2012 (2/2)

Professor Gareth Morgan – The Royal Marsden Hospital, London


Can you tell us about some of the issues around secondary malignancies?

The second malignancy issue has been important and was initially very worrying. The bottom line, I think, is that while it remains a clear signal that we understand more about it and the issue is not with cancer in general, it’s more to do with myelodysplasia and acute leukaemia. If we come back to the second cancer issue, the follow-up data from the Revlimid treated maintenance cohort is that there doesn’t seem to be a huge increase in second cancers in general but there is a real increase in the risk of getting myelodysplasia and acute myeloid leukaemia. The group from Little Rock presented their data with the total therapy programme and they seemed to have a significant rate of transient cytogenetic abnormalities consistent with myelodysplasia and AML. So I think we really do need to collect more data bout that as a signal. But from our own study, which is one of the largest ones to date, we’re really not seeing a huge signal and perhaps the take home message is that melphalan combined with IMiD drugs can be dangerous in terms of second cancers but if you use drugs like cyclophosphamide, there really doesn’t seem to be a particularly high signal.

What is interesting about pomalidomide?

When IMiD drugs were first discovered there were always two, one turned out to be called lenalidomide, or Revlimid, and the other is now what is called pomalidomide. Pomalidomide is more active in the laboratory and it turns out it’s more active in the clinic. So when you compare pomalidomide and dexamethasone to dexamethasone alone in a group of patients that have been proven to be refractory to lenalidomide and refractory to bortezomib, we see responses, improved progression free and improved overall survival. So that’s one of the important studies that has been broken here in ASH 2012.

It’s tolerable, it works and I think it’s another step change forward, I think that’s very important. The other new drug that has been important is carfilzomib which is one of the second generation proteasome inhibitors. I think these are developing on the steps forward that were made with Velcade and they seem to be slightly more potent, they lack some of the side effect profiles of the first generation drugs; some are being given orally and others intravenously. I guess, though, the confounding factor in all of this is that since we started using Velcade in a different schedule, we’ve started to see much less in the way of side effects. So subcutaneous Velcade given at a weekly schedule seems to be very well tolerated and you can keep people on it on a weekly schedule for many, many months. So it’s going to be interesting to see how the next years see the unfolding of the role of the first generation proteasome inhibitor with these newer generation drugs that have slightly different side effect and efficacy profiles.

Can you tell us about epigenetics?

While DNA change has been something that we’ve started to understand since the unravelling of the DNA code, it’s become obvious that there is a more deeper complexity and that’s this epigenetic change where the way the DNA is packed is changed. The importance of this is that if you have a mutation you can’t reverse it; if you have an epigenetic change it is possible to design drugs that will change the structure of the DNA and if a gene is switched on switch it off, if it’s switched on then switch it off. One of the key genes mediating this kind of epigenetic phenomena, in myeloma at least, is called MMSET and about 15% of all myelomas have a translocation called the (4;14). The consequence of the translocation is that MMSET is over-expressed. While this may seem a little dry, in the context of that group of patients, because the translocation switches on MMSET, if you can switch it off you can revert the myeloma to a normal state and hopefully control the tumour. So we’re starting to see more and more information about the way MMSET can be targeted. It’s a histone methyltransferase and molecules that have these ‘ase’ things on the end means they’re enzymes and so they’re relatively easy to target. So what I think we’re seeing is, in this meeting at least, the first recognition that MMSET can be a credible target in myeloma and a series of companies starting to develop drugs which target it specifically. I’m very hopeful for this type of treatment where you really define that subset of disease and treat it specifically. It’s not just myeloma, a significant proportion of solid cancers also express MMSET and would be candidates with treatment for an anti-MMSET drug.

Can you tell us about ibrutinib and why everyone is talking about it?

It’s one of these good examples of where understandings from the laboratory have translated into the clinic. It was realised that signalling, or constitutive signalling via the B-cell receptor pathway, was a crucial pathogenic mechanism in lymphomas. So if you could switch off that signalling then you could put people into remission. So BTK is a critical member of that signalling pathway and ibrutinib switches it off. So you would predict that if you could switch off that signalling you would get responses. So in chronic lymphocytic leukaemia that is exactly what is seen: there’s an interesting rise in the white cell count initially but then it falls and patients are controlled long-term. It’s a relatively non-toxic drug and has widespread applicability in B-cell tumours. For my sins I would say I wasn’t truly expecting BTK inhibition to work in myeloma because the B-cell signalling pathway is switched off but what I think is the explanation for why these things may have a significant role in myeloma is that you need to consider their interaction with their stromal environment and the number of positive signals that are delivered by these interactions. It turns out that ibrutinib is able to switch off many of these pathways and actually we are seeing responses in myeloma and we can expect it to be useful in the clinic.

Can you tell us about daratumumab?

I’ve always wanted to see an antibody regimen analogous to rituximab for lymphoma that was applicable in myeloma. To date we don’t have one that is regularly used in the clinic. The one that is furthest in development is elotuzumab and elotuzumab is directed against an antigen called CS1. As a single agent the antibody didn’t work but when combined with Revlimid there’s a very good signal and there’s quite a lot of data about Revlimid and elotuzumab in this meeting. At the same time as that antibody there’s another marker on the myeloma cell surface called CD38; so daratumumab is an antibody that recognises and binds to CD38 on the surface of the myeloma cell. When it’s there it fixes the immune system which then kills the cell. In contrast to elotuzumab, as a single agent we’re seeing responses with daratumumab which is really very exciting. So I think the next year or two will see further understanding of how to use daratumumab clinically and the design of effective combinations and hopefully we’ll see in the clinic a molecule or an antibody that really is myeloma specific that gives us the same impact that rituximab had in non-Hodgkin’s lymphoma.