New emerging treatments in multiple myeloma

Prof Pieter Sonneveld - University Hospital Rotterdam, Rotterdam, Netherlands
Prof Antonio Palumbo - University of Torino, Torino, Italy
Prof Heinz Ludwig - Wilhelminenspital, Center for Oncology and Hematology, Vienna, Austria
Prof Philippe Moreau - Centre Hospitalier Universitaire de Nantes, France
Prof Mario Boccadoro - San Giovanni Hospital, Turin, Italy

PS: Good afternoon. We are here in Amsterdam at the Clinical Practice Meeting and we had extensive discussion today on the diagnosis and treatment of multiple myeloma with a group of experts. I am here with Dr Antonio Palumbo from Torino, Italy, Dr Heinz Ludwig from Vienna in Austria, Dr Philippe Moreau from Nantes in France and Dr Mario Boccadoro, also from Torino, Italy. This occasion can be used to review some of the new data that we have presented at ASCO in the United States and the recent EHA meeting in Vienna. So I would like to start; we’ll discuss three important trials that have been presented at these meetings. The first one is about the use of proteasome inhibitors, the so-called ENDEAVOR trial. Dr Palumbo, can you explain what this trial was and what the outcome is?

AP: Well this has been an important trial that did show the superiority of carfilzomib over bortezomib. This was a study evaluating relapsed refractory patients in a randomised fashion, comparing the combination of bortezomib and dexamethasone versus carfilzomib and dexamethasone at the dose of 56mg. What the trial is showing is that the progression free survival is moving from 9 months to 18 months, almost a doubling in the remission duration that has been achieved by bortezomib. To some extent it’s showing the superiority of a second generation proteasome inhibitor over the first generation bortezomib.

PS: So, just from my understanding, were these refractory patients or relapsed patients?
AP: They were early relapse, 1-3 prior lines of therapy and inside this population there was both refractory and relapsed patients.

PS: So will this have an impact on the clinical practice now or in the near future?

AP: Certainly, yes, because we can certainly see that, at least at the dose of 56mg, there is a superiority of a second generation proteasome inhibitor over a first generation proteasome inhibitor.

PS: Thank you. Two other trials were about the use of monoclonal antibodies in multiple myeloma. One was ELOQUENT-2, a trial with elotuzumab. Dr Boccadoro, would you like to comment on that trial?
MB: This is a very important trial because it’s a phase III trial showing the efficacy of a monoclonal antibody in patients that were in relapse or refractory. This is an early treatment because again, like in the other trial, the patients were from first to third relapse. The response rate was really not so different in the two arms because of the monoclonal antibody administration that probably is hindering a little bit the response rate. But the progression free survival was longer using the antibody. The author pointed out especially the morphology of these curves because the curves diverge from the beginning and they stay away, one from the other also in the last part of the curve. The author pointed out the different action of this immunotherapy that is able not to give a strong response rate but is able to maintain as an immunotherapy this response rate for a long period of time.

PS: So there are lots of types of immunotherapy, you’ll have to explain a bit – what is elotuzumab in fact doing?

MB: Elotuzumab, it’s a monoclonal antibody with a dual action. It’s stimulating the NK cells and is acting directly on the plasma cells stimulating the apoptosis of the plasma cells through the immune system. So it’s really a different mechanism of action in comparison to the other immunotherapies, not an active immunotherapy like rituximab that is quite common in haematology.

PS: So it’s effective by itself only or does it need a partner?

MB: No, no. By itself only it’s not active at all but it’s active in combination, like in this trial in combination with lenalidomide in the two arms.

PS: The third important trial that was presented is dealing with daratumumab, another antibody. Dr Moreau, can you inform us what were the results and the background of this trial?

PM: We have heard at ASCO but also at EHA about the results of the SIRIUS study. It’s a phase II study studying the monoclonal antibody daratumumab. Daratumumab is an IGG fully humanised monoclonal antibody targeting CD38 that is almost constantly expressed by the plasma cells. Elotuzumab is targeting SLAMF7 so that’s another target on the surface of the plasma cells. Dara has a single agent activity and that’s also different from what we’ve heard about elotuzumab. So this population of patients were really advanced ones. The study was performed in the US only and patients were refractory to lenalidomide in almost all cases, refractory to bortezomib in almost all cases but many of them were also refractory to pomalidomide, the second in class IMiD, and also refractory to carfilzomib for many of them, the second in class proteasome inhibitor. So we have a population of patients very advanced and 87% of them are also refractory to alkylators. So in this situation of unmet medical need and we’ve heard that on more than one hundred patients, 106 patients, treated at a dose of 16mg/kg that dara was able to induce a 30% response rate and for patients responding the duration of response is 8 months. Overall the progression free survival, the duration of response, something… the progression free survival is 4 months and the overall survival of the whole group is superior to one year. It means that dara is probably a new class of agent, new monoclonal antibody, with a single agent activity and this study probably will lead to the approval of this drug, at least in the US. We will see if the European authorities are also accepting dara as a single agent. But, nevertheless, we are here opening a new door and we are currently testing dara in combination with many other drugs earlier in the course of the disease, in combination with lenalidomide, in combination with bortezomib for relapsed patients.

PS: So when do you think daratumumab will become available in general practice?

PM: We don’t know if the European authorities are going to approve dara based on this phase II SIRIUS study. I’m not sure because in Europe very often the authorities are asking for a phase III trial in addition with phase II data but we have, for example, completed for enrolment two important trials: bortezomib dex plus or minus daratumumab phase III and also lenalidomide dexamethasone plus or minus daratumumab. When these trials will be reported and published I think that dara will be available. To my opinion maybe the end of 2016 or early 2017, so that’s not tomorrow but it will come soon.

PS: So, Dr Ludwig, one of the new developments that we discussed is how to define the criteria for multiple myeloma. We have a lot of new techniques to assess the patient; what’s your idea about the recent proposal to change the definition of multiple myeloma?

HL: That is a major step forward because nowadays it is recommended to use whole body CT for evaluating skeletal disease. If that is not is possible, if you have still conventional radiography and you have a smouldering myeloma patient you should look with MRI at the spine and at the pelvis because that’s where the lesions are most frequently situated. So if you have defined bone lesions, lytic lesions and more than one lytic lesion, this is probably a case for early therapy because when you follow those patients for two years you see that after two years 70-80% will progress to active disease. Another high risk group is the patient group with high free light chain ratio of higher than 100. Again, after two years 70-80% will progress to active myeloma. In order to prevent untoward complications of the disease an early start of treatment is recommended by these guidelines. The third group, which is a very clear group where early treatment is immediately recommended, is a group with more than 60% bone marrow plasma cell infiltration, either seen in the aspirate or in the bone marrow biopsy. These patients have an even higher risk to transform and they should be started on therapy after diagnosis as soon as possible.

PS: OK, so this includes a new group within the diagnosis of multiple myeloma.

HL: This is a new group of early myelomas and this is one of the achievements of the ESA recommendation. Also I personally, of course, recommend to discuss this situation with the patient and to hear his preferences and to show him the data and then to start treatment if the patient agrees.

PS: The importance is that we recognise that some smouldering myeloma patients have early advance to myeloma and that we can improve their prognosis by recognising them.

HL: There was some discussion because if you have a risk of 53% to transform into a myeloma, as was shown by Waxman, after two years then you can take different standpoints whether you want to treat those patients immediately.

PS: Dr Boccadoro, you don’t agree?

MB: No, no, I totally agree but this new classification is a step forward because it’s including all the new imaging techniques like MRI, PET-CT, that were not included in the previous one. So it’s not written in stone and will be changed again in two years. But certainly it’s different than the previous one and there are several small details that we have still to define but it is a step forward that will be really useful for all the myeloma doctors around the world.

PS: Thank you. So, if I move to the other important topic that we discussed, how can we assess the response in patients? What’s the best way to do that and how should we use modern techniques like MRD analysis and so on? Dr Palumbo.

AP: Well there is, I believe, a major change in the definition of a response and specifically we are currently introducing the concept of minimal response disease, MRD, in the evaluation of response after treatment. This is a more sophisticated and more sensitive way to define residual disease in myeloma. We have basically two techniques, one is the next generation flow, based on antibodies reacting against plasma cell antigen. The other one is the next generation sequence based on the definition of a specific sequence related to immunoglobulin genes. Those two techniques today seem fairly equivalent; we still need to better standardise this technique to make it available in different labs in different time points. The next generation sequencing is probably more precise time to time; the flow is probably more feasible in several labs. So there are plus and minus in the two techniques but certainly it’s true that we are moving from a definition of CR that is 10-2 to a definition of CR with MRD that is 10-5 , even 10-6. The other major issue, as mentioned, is that we are moving and we are recognising that the bone marrow has from one side a patch invasion and therefore we might have a negative bone marrow with a positive localisation of myeloma as well. So it’s very important also to introduce the imaging in the definition of response.  From this point of view we have basically three techniques: one is the low dose CT scan, probably the best to use at diagnosis. The other one is the whole body MRI, probably the most sensitive, and the other one is the CT-PET scan, probably the best to evaluate residual disease after treatment. So in the future we will see the introduction of those techniques in the evaluation of response after treatment.

PS: So this is very nice, so we can use more precise response assessments. Does it also lead to treatment decisions?

AP: Not yet, I would say. Today the definition of MRD negativity is one, probably, of the best prognostic factors. We are not yet that ready, we need some future studies to really use this technique and a major standardisation of those techniques to really use those techniques to change therapy.

PS: With all these new drugs we, as doctors, have to make choices for therapy, we cannot give everything at the same time. So we also have to know if our patients are at risk for not responding to a treatment or having early relapse. So in this days, Dr Moreau, what would you define as a group of high risk patients?

PM: We have a number of factors that can predict for the outcome of the patients. At the time of diagnosis, of course, we know perfectly that international staging system, ISS3 for example is high risk prognostic factor. We know as well that high LDH is another one, cytogenetics, obviously, for 14 17p and we also can combine these factors in several scores, in fact, to predict if a patient, for example, has high ISS – ISS3 plus high LDH plus or cytogenetics. We know that the risk of dying from progressive disease is very high so we are able to segregate and to define some subgroups of patients that will do well or patients that will have a very poor outcome but we cannot anticipate a very important prognostic factor that is the response of the disease and that’s a sort of dynamic prognostic factor that we are not incorporating into our treatment algorithm right now. And we are on the way to also defining new tools such as genomics, probably, to define patients at very high risk of progressive disease. So right now we are not systematically implementing this definition of high risk versus non-high risk or, let’s say, standard risk patients into our treatment strategy. Some colleagues are doing it in the US, we are not doing it systematically in Europe but the goal, in fact, for the future is to try to have specific trials or specific treatment options according to the risk. We have to work on that because we are not ready yet to do like our colleagues in acute leukaemia, for example, are doing. They are looking at the prognostic factor, they are finding a mutation, for example, and they are treating according to some initial parameters.

PS: OK, well I would like to thank you all for your comments and also the audience. Thank you very much again.