EHA 2016
Multiple myeloma highlights from EHA 2016
Prof Marivi Mateos – University Hospital of Salamanca, Salamanca, Spain
Prof Meletios Dimopoulos – University of Athens, Athens, Greece
Prof Paul Richardson – Dana-Farber Cancer Institute, Boston, USA
Prof Philip McCarthy – Roswell Park Cancer Institute, New York, USA
MM: Good evening, my name is Maria Victoria Mateos and I am here in this meeting organised by ecancer.tv. We are attending the European Haematology Association meeting here in Copenhagen. It’s my pleasure to share this meeting with my colleagues, Dr Richardson from Dana-Farber in Boston, Dr McCarthy from Buffalo, also in the United States, and Dr Dimopoulos for Greece here in Europe. We are going to discuss the highlights of this European Haematology Association meeting. I would like to start congratulating Dr Dimopoulos for the excellent presentation he did at the plenary session today about a new combination that we will have very soon for our patients with multiple myeloma. I am talking about lenalidomide and dexamethasone plus daratumumab and I would like to ask you about this new combination and if you can summarise the results for the audience.
MD: Yes, thank you Dr Mateos. Indeed the POLLUX trial compared the combination of daratumumab with lenalidomide dexamethasone versus lenalidomide dexamethasone as a control in relapsed or refractory patients with myeloma who had received at least one prior line of therapy. So these patients could have received lenalidomide but they should not have been refractory to lenalidomide. The main finding of the study was an impressive prolongation of progression free survival in favour of DLD with a hazard ratio of 0.37 which corresponds to a 63% reduction in the risk of progression or death. Median PFS for the control arm actually was pretty good, it was 18 months, it has not been reached for the investigational arm. There is a nice early separation of the curves which continues and becomes even greater with time. Furthermore, the complete response rate was 43% and the overall response rate 93%, making this combination, at least, one of the most active if not the most active as far as response is concerned in the setting of one, two, prior therapies relapsing myeloma. There were also data regarding minimal residual disease and minimal residual disease negativity was increased by four times in the DRD arm versus RD. As far as the tolerability is concerned, the usual infusion reactions seen with single agent daratumumab, they were almost always grade 1 or 2 and they occurred in 92% of patients during the first infusion. So with appropriate pre-medication and when the reactions occurred with interruption of daratumumab and then supportive care almost all patients were able to continue daratumumab. Other toxicities seen are those typically seen with lenalidomide and dexamethasone, namely moderate to severe sometimes neutropenia, thrombocytopenia but very few episodes of neutropenic fever, no bleeding episodes, overall a well-tolerated combination which shows remarkable activity in relapsed refractory myeloma.
MM: Thank you. So I think that is an excellent combination and during this congress we will hear also results about another daratumumab-based combination, the CASTOR trial, in which bortezomib dexamethasone plus daratumumab is also significantly superior in comparison with the control arm bortezomib plus dexamethasone. So we can envision that in the near future or just today we have two new standards of care for the management of relapsed and refractory myeloma patients, bortezomib dexamethasone plus daratumumab, lenalidomide dexamethasone plus daratumumab. How do you envision these new combinations are going to impact in your clinical practice in the US, from the US perspective?
PR: Thank you Marivi. I think from our perspective it’s extremely exciting. Essentially from our first experience in the phase I setting with the 501 study we saw this powerful signal that was then validated in the SIRIUS trial. There was provocative pre-clinical information to suggest synergy not only with lenalidomide but also with bortezomib and now we have confirmatory studies beautifully executed and presented, both CASTOR and POLLUX, building on the important phase I work in the 503 trial which looked at lenalidomide, dexamethasone and daratumumab. So already in the US people have started combining these drugs pending, of course, the phase III data but at the same time based on the phase I and II information. I can tell you from practical experience of using, for example, the combination of daratumumab with pomalidomide, daratumumab already with lenalidomide in refractory patients, we’ve actually now started integrating proteasome inhibition and adding the three drugs all together, so, in other words, IMiD, proteasome inhibitor and antibody. The results are remarkable and I think prospective trials will validate this. My suspicion in the US anyway is that we shall move quickly to combinations upfront of, for example, RVD dara, KRD dara arguably, subject to the appropriate testing. Of course there is already data on VTD dara which is very promising.
MM: Dr McCarthy, will you use in your clinical practice len dex plus daratumumab, VD plus daratumumab?
PM: Absolutely. I think the biggest issue had been that the healthcare providers would often limit the use and we have been primarily restricted to single agent daratumumab. Now that we have this data in abstract form but still very exciting I can’t imagine that it won’t be long before we’ll be combining. Paul didn’t talk about… well he’s leading a study looking at RVD dara versus RVD with Peter Voorhees in the alliance. So we’re going to be very excited about having that up front data. But for relapsed refractory I think we’re going to be moving towards combinations with the antibodies for control of disease.
PR: Yes. I couldn’t agree more and I think in the US it’s very interesting because where Phil practices in up-state New York there are certain different limitations with providers. In Massachusetts we’re very lucky, we have real license and as long as there is phase I/II information to support what we do the insurers will typically allow us to do these combinations. I will say, though, a word of caution – we have patients in whom the combination has failed and whilst there’s tremendous hope here, and especially with the POLLUX and CASTOR data being early, what is clear in double refractory, quadruple refractory disease is unfortunately some patients do not benefit even to these powerful combinations. So very exciting but I think we would be remiss in saying it’s working for everyone because that has not been my experience.
MM: Dr Dimopoulos, in Europe the situation is different because you know that we don’t use commonly lenalidomide as part of the maintenance. So at the moment of relapse you know that we have the possibility of choosing between different lenalidomide dexamethasone based combinations or a carfilzomib dexamethasone or bortezomib dexamethasone based combination. How do you consider that physicians will choose one or other combination or do you consider that everybody will use RD plus dara because the results are the best?
MD: Yes, first of all we will have to wait for the approval of single agent daratumumab which occurred by EMA to be reimbursed which in Europe is another step that sometimes may take from several months to years. Then subsequently I believe that if one had the possibility to use all these regimens, right now if you go by hazard ratio, by safety and tolerability, I think daratumumab with lenalidomide dexamethasone is clearly taking the lead here. Until then I believe that we have to choose between a doublet, a triplet, we have to rely on prior exposure to different drugs, resistance on lenalidomide maybe is a signal that the patient may benefit from carfilzomib dexamethasone, prior resistance to bortezomib may favour a combination such as elotuzumab with lenalidomide dexamethasone. Of course, high risk cytogenetics, it appears that with elotuzumab lenalidomide dexamethasone there is a positive signal there, maybe with ixazomib lenalidomide dexamethasone. For older patients interestingly carfilzomib dexamethasone did quite well for those more than 75 years of age. Even here in the POLLUX trial about 10% of patients older than 75 years of age did very well. So we will never have comparative data from those trials so we’ll have to use our clinical judgement in order to decide the best treatment for the patient.
MM: One or other combination. Thank you, and in line with this lenalidomide and dexamethasone based combination data we have for the management of relapsed and refractory myeloma patients in Europe lenalidomide is not approved to be used as maintenance therapy after autologous stem cell transplantation. However, I think that Dr McCarthy presented at the last ASCO meeting and Dr Palumbo will present here at the EHA meeting an important meta-analysis coming from the most important randomised trial in which lenalidomide has been compared with placebo after autologous stem cell transplant. I think probably the results of this meta-analysis will change our standard of care here in Europe in which lenalidomide is not approved. Can you summarise the results of your meta-analysis?
PM: Thank you. Yes, there were three large trials that looked at lenalidomide versus placebo or no maintenance and in a prospective manner. The primary results had been reported and there was primary source data available from the patient documents. So 1,200 patients were looked at, about 605 on the lenalidomide arm and 604 on placebo. All patients had received some form of induction, there were differences between the three studies, the IFM 05-02, CALGB 100104 and the RV-209 from GIMEMA. After randomisation to len or placebo after transplant then there were differences in conduct of the trials so that it led to some differences in outcome. We had a crossover, the IFM did not; the IFM stopped lenalidomide after an SPM, second primary malignancy, signal and GIMEMA continued but with smaller numbers. So by pooling them together we were able to see that there is an overall survival benefit but the median overall survival in the placebo or no therapy arm was 80 months so it took a long time to find this. In addition the hazard ratio was 0.74, a 26% reduction in the risk of death, and that translated to approximately a 2.5 year difference between the len arm and the placebo arm. We were pleased to see this type of difference and we think now that len maintenance, even with the secondary primary malignancy signal, is now becoming a standard of care.
MM: I would like to ask you a provocative question because my only concern about the use of lenalidomide as continuous therapy after autologous stem cell transplantation is in the group of patients with high risk cytogenetic abnormalities.
PM: Yes, in both the IFM and the GIMEMA trials we’re able to see the [4;14] and deletion 17. In unpublished data it appears that deletion 17 may benefit from lenalidomide but it has to be looked at in more detail. But, you’re right, when we looked at the high risk cytogenetics there didn’t seem to be quite as much of a benefit but small numbers, there were 60 patients, 30 patients. So we need bigger numbers. But it also points out that we’re probably going to need to look at other things so we’re going to probably have to add things to lenalidomide but now we have a base as standard.
PR: I would agree with that, Marivi. I think the point is that lenalidomide is established as a backbone and you can then rationally add, be it with monoclonal antibodies, proteasome inhibitors or otherwise to high risk patients. One important point to emphasise, though, is the second primary malignancy signal is relatively well established that that’s an interaction with melphalan. Certainly speaking from preliminary data in our own prospective study looking at early versus later transplant with lenalidomide both up front and out back, there’s interaction with lenalidomide, we’re seeing a very low rate of any signal of any malignancy on the non-melphalan containing side of things and on the melphalan side of things we’re seeing, with less chemotherapy at least, even there a lower signal than we saw with the original CALGB 100104 experience. So this interaction with lenalidomide has to be in perspective and I think Phil should be congratulated on really his careful and appropriate approach to the second primary malignancy signal because your work, Phil, has been absolutely central in helping nail this down and understand that it’s real but it is small. That’s tremendously important as we think about this.
MM: Thank you very much. Do you want to add any comment to this about this meta-analysis?
MD: Yes, I’m a little bit sceptical regarding the role of lenalidomide in patients with high risk cytogenetics because from their meta-analysis I believe the hazard ratio was really…
MM: 1.18.
MD: So I believe that these patients, I fully agree with Paul that you need continuous therapy, especially in these particular patients, maybe a proteasome inhibitor based continuous therapy, a double autologous transplant for now, adding a monoclonal antibody, this type of approach.
PM: Yes, just to add, I think that we did see that the ISS1 patients were the ones who benefitted the most and I agree that we need to do more for the higher risk patients, ISS3s and high risk cytogenetics. Thus the idea of a consolidation and addition of new drugs is going to really be necessary for those higher risk patients who fortunately are the minority of patients. I think the majority of patients will benefit from lenalidomide.
MM: Thank you very much.
