The latest in multiple myeloma: a European and US perspective
Prof Paul Richardson – Harvard Medical School, Boston, USA
Prof Marivi Mateos – University Hospital of Salamanca, Salamanca, Spain
MM: Good afternoon, my name is Maria-Victoria Mateos and I work as a haematologist at the University Hospital of Salamanca in Spain. It’s my pleasure to be here attending the European Haematology Association meeting in Vienna and it’s my pleasure to welcome too Professor Richardson from the University of Harvard in Boston in the US. Good afternoon, Dr Richardson.
PR: Marivi, it’s my pleasure. Lovely to see you.
MM: I would like to discuss with you the latest news that we are attending during this congress for the management of our patients with multiple myeloma. What is your feedback?
PR: This meeting has really built so nicely on ASCO with I think the excitement around the monoclonal antibodies dominating the presentations in myeloma. And also, of course, the very positive results in the area of new proteasome inhibitors, importantly carfilzomib really showing the results of the ENDEAVOUR study and at the same time also some of the excitement around next generation proteasome inhibitors like ixazomib. So I think that has been very encouraging and then the other piece of this has been very positive data with pomalidomide continuing to show its activity in combination and its very reassuring safety profile. But really, for me, the most exciting aspect of this meeting has been the immunotherapeutics and in particular the monoclonal antibodies. We’ve got the ground-breaking data of elotuzumab which basically is the first randomised phase III trial in myeloma to show the clinical benefit of elotuzumab when partnered with immunomodulatory therapy. To see a substantial progression free survival benefit between the control group and the three drug platform which is, of course, elotuzumab, lenalidomide and dexamethasone, but to also see that in high risk patients with adverse cytogenetics that the effects are particularly impressive and to see that in high quality responses the durability of disease control is remarkable has been really exciting. The flip of that has been that the tolerability of the combination has been great, it’s been great to see the same efficacy in patients under the age of 65 and over the age of 65, that is emblematic. The final comment I would make is that the data surrounding daratumumab with the presentation of the results from the large phase II study in the United States is really encouraging for patients. It’s showing that as a single agent daratumumab in multiply resistant patients is able to overdrive all of those features and generate a robust response rate in about a third of patients. That provides, I think, the platform for an approval for daratumumab going forward. So I think we’ve got two great new antibodies and lots of data around that which I think are very encouraging.
MM: Yes, you know that also during this congress an abstract will be presented about the combination of daratumumab as backbone for relapsed and refractory myeloma patients in combination with pomalidomide and dexamethasone and also in newly diagnosed myeloma patients in combination with bortezomib dexamethasone and bortezomib melphalan and prednisone or bortezomib plus thalidomide plus dexamethasone. So, from my point of view, these results showed encouraging results because more than 50% of the patients responded to daratumumab plus pomalidomide and dexamethasone and all patients responded in newly diagnosed. So I think that daratumumab probably will represent a backbone for the therapy of all of our myeloma patients. However, I would like also to discuss with you the different approaches to therapy in the US and Europe because you know that here in Europe bortezomib based combinations remain the standard of care for newly diagnosed myeloma patients, lenalidomide and dexamethasone at the moment of first relapse because we don’t usually use lenalidomide in first line. We have recently approved pomalidomide as a rescue therapy after lenalidomide. How is your situation, how different is your standard of care in the US?
PR: I think it’s a great question and I think as these new antibodies arrive what we have to realise globally in our myeloma community is the value of these new combinations. We’ve got, as you so nicely point out, the IMiD backbone and the proteasome inhibitor backbone and we can add to that monoclonals that are transformative in terms of outcome. Obviously we have the very encouraging data from elotuzumab which is in a different class of antibody to the CD38 targeting molecules. Now we have CD38 targeting antibodies, not just one but several, where I think we’re going to see absolute changes in the treatment paradigm. As you know, we’re already looking at the issue of transplant, where does transplant belong? As you see these cellular therapies i.e. the manipulation of autologous immunity in a way that doesn’t necessarily require the stem cell platform, we’re going to see our treatment paradigms fundamentally change. From a regulatory point of view it’s a very dynamic landscape and from a cost point of view it’s equally dynamic. So I think the differences between the US and outside of the US centre on a number of things. On the one hand we are blessed with a very, very interactive and constructive relationship with our FDA, particularly the myeloma team, and we’ve seen approvals. For example, we’ve seen the HDAC inhibitor panobinostat approved in the US and now approved in Europe. That is a completely new mechanism of action and there is data on panobinostat at this meeting and also data on other HDACs, importantly the ricolinostat molecule which is showing promise because it’s not only more selective but it’s less toxic. So I think these are new drugs that are going to change the way we treat this disease. So putting that all together, my sense of it is that in the US we’re lucky because we have access; we have the ready approval of new drugs, not least of which is carfilzomib in addition to pomalidomide. I think in Europe carfilzomib is coming, isn’t it? I very much hope so.
PR: Yes, I think so. I think it’s a terrific new addition to the armamentarium. So I think the way to think of this is that in the US we’re fortunate to have access so we are able to use drugs earlier but what I think is very wise is to recognise the value of real evidence based approaches because if you use everything that you have early, what are you then left with? I personally think that the algorithm of bortezomib based therapy up front, the integration of lenalidomide early, the use of pomalidomide in relapse and the rational introduction of the antibodies in an orderly fashion is as applicable in the US as it is in Europe. So I think whilst there are differences there are very common themes that must underlie what we do. Again, we’re thinking about a disease that at the moment is not curable, therefore it behoves us to be very careful about long-term consequences of what we do. Whilst you and I are very familiar and comfortable with the use of bortezomib I think carfilzomib is an amazing drug but there is a signal there that it can have some side effects in a few patients that can be long-lasting. So do we move carfilzomib right up front? No we don’t because we need to figure out where it best belongs and randomised trials will guide us in that regard. I think the same applies to the antibodies but having said that, my sense of the antibodies is they will move earlier in the same way that carfilzomib will and also, arguably, the HDAC inhibitors. But I do think it has to be in a rational fashion.
MM: Finally I would like to ask about the checkpoint inhibitors - PD1 inhibitors, PDL1 inhibitors. What is your opinion about these new agents?
PR: Yes, I’m very glad you asked that I think that we touched on it at a presentation we gave yesterday. The point is that what I showed yesterday was the very promising pre-clinical rationale for their use. We’ve recognised from very elegant work from colleagues in the laboratory that PD1 and PDL1 is as important a target in myeloma as it is in other diseases. We’ve tested early some of the inhibitors, be it the Pembrol [?] compound or nivolumab. As single agents they’ve not shown very much. That’s actually exactly as you would expect, it’s very analogous to elotuzumab, actually. But when you add the over-driver or the supercharger of immunomodulation through an IMiD, and specifically lenalidomide, the picture completely changes. What I showed yesterday was that in the laboratory systems if you add immunomodulation to the checkpoint inhibitors it’s highly synergistic and we have tantalising clues from early trial data that remain unpresented. So one has to be a little bit careful but suffice to say the early reports of these trials from investigators is very favourable. So I would suggest to you that this will be a very important new frontier, just as the antibodies are so will be the checkpoint inhibitors. Arguably I would foresee us as clinical investigators together exploring elotuzumab, pomalidomide, nivolumab and starting to use these immunological strategies with CD38 inhibition as a construct. It was so interesting yesterday because as part of our panel in our symposium we were blessed with a phenomenal patient who was diagnosed about twenty years ago, he’s a lovely man from Texas. He’s never had a stem cell transplant and he had bad disease when it presented. [?? 9:56] disease was not indolent, it was very active and aggressive and he for twenty years has done very well with novel therapies. So I think this reflects that he is an example of the sea change in the way we manage this illness.
MM: Yes, absolutely. Do you think that we are going to go through a personalised medicine in myeloma?
PR: You’re absolutely right, I completely agree. I think that, as you and I know, myeloma is not one disease it is many and, sorry to sound terribly metaphorical, but one size really does not fit all, I think that’s very important. So I think that when you think of it in that context we realise that having therapeutic options allows us to be tailored and the parallel fashion, for us as clinicians, it’s wonderful that our laboratory and correlative science colleagues are bringing us tools through gene expression profiling and obviously all of the new, exciting technologies, MRD and so forth, that will give us the way to tailor people’s treatment even more.
MM: I absolutely agree and in fact we have had the opportunity to see new agents, as you mentioned, with no activity as single agent but we need investigational studies, additional research studies because sometimes these new agents with no activity as single agents in combination with other drugs are able even to overcome the refractiveness to the prior agents. This is relevant for the management of our patients with myeloma, that it’s clear that they are living longer and longer now at the present time and we need new options of therapy to be treated.
PR: I completely agree. I think it’s a very promising time. The subtext here is that whilst there’s great optimism we have to be very realistic that this remains an incurable illness. For you and I who work day in, day out in the clinic and take care of our patients continuously, we know that this remains a fundamentally very challenging and dangerous haematological malignancy. So I think you’re absolutely right, it’s not a zero sum game, we need all the options we can get. We’re blessed at the moment that there’s a steady throughput. I think what, particularly for me, is exciting is this whole immuno-oncological field has to it a flavour of durability that will further enhance where we already are. If you had told me five or six years ago that we would have antibodies of the quality we have and immunologic tools that we have, this promise, I would never have guessed that we would be in such a good position as we are now.
MM: So I think that summarising, I think that the message for this interview is optimistic for myeloma physicians and also especially for myeloma patients because there are many new agents that will be incorporated in the future for the treatment, probably before in the US, a little bit later in Europe, but all patients will obtain a benefit. Thank you very much, Paul, and it has been a pleasure for me to be here with you.
PR: Absolutely, thank you Marivi. The pleasure is all mine, thank you.