ASH 2012

Advances in multiple myeloma from ASH 2012

Professor Thierry Facon – Centre Hospitalier Universitaire, France

What is the standard treatment for multiple myeloma?

For transplant eligible patients the standard of care is usually a three part regimen for induction which may be different across countries. So, for example, Velcade-cyclophosphamide-dexamethasone is used as induction in many European countries; we have the Velcade thalidomide and dexamethasone induction in France and Italy, so you may have different induction regimens basically with three part combination regimens and usually based on Velcade. So after induction usually you have stem cell transplantation, usually a single stem cell transplant, a double stem cell transplant in some patients but not a lot. After stem cell transplant we have now more and more frequently consolidation, in fact.

So consolidation is still investigational so it has not been implemented into routine practice in all countries. But, for example, in France, in Italy we have implemented VTD consolidation after stem cell transplantation and that’s part of many clinical trials, many small phase II trials have investigated consolidation regimens after stem cell transplantation.

The next part is maintenance; lenalidomide maintenance has not been approved in Europe yet, it is used in some US centres but not in Europe because it has not been approved yet. Some investigators have used Velcade maintenance as well but probably not a lot in Europe. So usually we may say that at the present time maintenance has not been implemented into routine practice because it has not been approved. But, as you know, things are going very fast in myeloma so we may have lenalidomide maintenance approved next year, for example, and so that will change again.

What about the proteasome inhibitor bortezomib?

Bortezomib is a very well… I would say the vast majority of younger transplant eligible patients receive a bortezomib based induction regimen and some of them receive a bortezomib based consolidation regimen after stem cell transplantation. If you look at transplant ineligible patients, so the two standards of care we have in Europe are still MP Thalidomide and VMP, so bortezomib is also a very well accepted standard of care for transplant ineligible patients. Looking at transplant ineligible patients lenalidomide has not been approved yet but that may be the case in 2014. So we have very important on-going trials investigating lenalidomide front line in the elderly patients.

Can you tell us about some of the phase III trials that are under way?

Next year will be very important for large phase III trials designed for approval. We will have several trials in fact. Probably one of the most important will be the MM-020 study which is a Celgene study with IFM; this is MPT versus len-low dose dex frontline in the elderly patients. So that’s a huge study, that’s 1,600 patients over the age of 65. The study has been designed for global approval of lenalidomide frontline so that will be reported at ASH next year. At ASH next year we will have also probably the final analysis of the IFM lenalidomide maintenance study in the transplant setting and we hope to show… we still consider that we may see a survival benefit at the end. We will have the report of the phase III study with panobinostat in relapsed myeloma patients so we will have some very interesting results coming from large phase III studies.

What interesting data is there for multiple myeloma from ASH 2012?

We have seen basically that probably one of the most interesting studies is the daratumumab phase I/II study. Daratumumab is a monoclonal antibody which targets the CD38 molecule and so the phase I/II was designed for safety. Safety was fine but importantly they got some response with daratumumab as a single agent, which is unexpected, in fact, for a monoclonal antibody. So that’s very promising. They got approximately 50% response with daratumumab as a single agent in relapsed myeloma patients in advanced disease. So that’s extremely promising, that was not expected from a phase I/II study. So there is a lot of enthusiasm about daratumumab; for sure many trials will be planned for next year and after, not only in the relapsed setting but I think the drug will be investigated in the unmet medical needs so patients refractory to Velcade and Revlimid the drug will be investigated as part of induction, before transplant, for consolidation, for maintenance, potentially for asymptomatic myeloma as well, in relapsed patients who have received one to three lines of therapy, so the programme will be extremely large. So that’s very good news because looking at monoclonal antibodies, usually monoclonal antibodies do not provide response as a single agent and the first time daratumumab was able to do that so that’s very important.

We have interesting results with carfilzomib, with pomalidomide, with MLN9708, which is a novel proteasome inhibitor. So, for example, the pomalidomide study, the 003 study in relapsed myeloma, the phase III randomised study in relapsed myeloma has been reported as a late breaking abstract, so the study is positive. The study was len-pom-low dose dex versus high dose dex and the study is positive for PFS and survival. That study will be extremely important for European approval of pomalidomide in relapsed patients and based on that study, and based on the very promising results achieved in the phase II studies with pomalidomide, for sure the pomalidomide will be approved both in the US and in Europe early next year or at some time point next year. So that’s good news for patients.

MLN9708 seems to be extremely promising as well. We have heard results with MLN RD in the front line setting with some transplant ineligible patients and some patients who proceed to stem cell transplantation as well. This is a three part oral combination with a proteasome inhibitor and an IMiD and that will be the first one. The results seem to be extremely interesting as well.

Looking at something different, we got early signs of activity of other agents because basically we have proteasome inhibitors we have IMiDs and we may have monoclonal antibodies but it’s always good to look at something different, in fact. That’s only early signs so you may say that needs confirmation and a longer follow up, etc. but, for example, we have heard about a KSP inhibitor, the molecule is called ARRY-520, from a very small company and apparently the drug is able to achieve response in very refractory patients, very advanced myeloma patients refractory to Velcade, Revlimid and pomalidomide as well. So that’s something different. The toxicity was manageable and so the drug may be combined with other agents; that’s basically interesting. We have other small molecules, we have heard results with an inhibitor of CDK5, for example. That’s potentially good news for patients because basically we will need, outside of proteasome inhibitors and IMiDs and maybe monoclonal antibodies, we will need additional drugs which will be very different, in fact, without any cross-resistance with IMiDs or proteasome inhibitors, with a different safety profile. If these drugs have an acceptable safety profile and can be combined with other very effective agents, that’s very good news for patients.

So it’s an exciting period for myeloma.

That’s an exciting period for myeloma for some years but that’s still a very exciting period for myeloma. That’s a debate among experts but, to me, we are currently curing some myeloma patients and we will cure more and more myeloma patients in the next few years.