ASH 2015
ASH 2015: Novel combination approaches for multiple myeloma
Prof Marivi Mateos - University Hospital of Salamanca, Salamanca, Spain
Prof Sagar Lonial - Emory University School of Medicine, Atlanta, USA
Dr Torben Plesner - Vejle Hospital, University of Southern Denmark, Vejle, Denmark
Prof Meletios Dimopoulos - University of Athens, Athens, Greece
MM: Hello everybody, we are here in Orlando, Florida for discussion about the highlights on multiple myeloma from the American Society of Haematology 2015. This discussion takes part of ecancer’s educational programme. My name is Maria Vittoria Mateos and I am a haematologist at University Hospital of Salamanca in Spain. Joining me are Dr Dimopoulos from Athens, Greece, Dr Plesner from Copenhagen, Denmark and Dr Lonial from Atlanta in the US. So, thank you very much for joining me in this discussion about highlights from ASH. I don’t know if you agree with me but if I have to summarise the highlights from this ASH meeting as far as myeloma is concerned our first transplant is consolidated as standard of care for young, newly diagnosed myeloma patients. The second important thing that we have learned from this ASH meeting is new combinations and also the immunotherapy has arrived to the myeloma treatment. Starting by the new combinations I would like to start with Dr Dimopoulos about the second generation proteasome inhibitors, specifically carfilzomib. What are the new combinations that you consider exciting in this ASH meeting?
MD: Yes, we have heard the primary presentations of the ASPIRE trial which compared carfilzomib, lenalidomide and dexamethasone to lenalidomide and dexamethasone about a year ago and six months ago the ENDEAVOUR trial which compared carfilzomib dexamethasone with bortezomib and dexamethasone. In this meeting there are several secondary analyses regarding cytogenetics, prior therapies, impact of age for both trials. So it appears that combinations based on carfilzomib may overcome to a certain degree the adverse cytogenetic features which are associated in approximately 20-25% of patients with myeloma. KLD may be doing better in that aspect than carfilzomib and dexamethasone. Also these combinations are well tolerated, even in elderly patients and this is important because we know that myeloma patients are aging. Clearly carfilzomib is replacing bortezomib, at least in the relapsed setting, one to three prior lines of therapy.
MM: Thank you. Dr Lonial, what about other exciting combinations also based on lenalidomide and dexamethasone but now in combination with elotuzumab? Because an update has been also presented here at this ASH meeting.
SL: Yes, I think we saw an update of the ELOQUENT-2 trial with now three years follow-up that suggests that the difference in the progression free survival curves continues to be about 28-30%, similar to what we had seen before. This time for the first time we saw overall survival data presented as well and the two curves looked separate, similar to what we’ve seen from ASPIRE. Neither of those trials met the pre-specified boundary for the interim analysis so I think we need the final analysis to really see but it certainly looked like those curves were beginning to separate.
MM: And also Philippe Moreau from the French group will present tomorrow in the afternoon the results of another exciting combination also based on len-dex. Ixazomib, the oral proteasome inhibitor, in combination with len-dex and he will see superiority also in terms of progression free survival in comparison with lenalidomide and dexamethasone alone. So let me ask you a provocative question: how are we going to choose the best option for our patient in first, second or even third relapse when elo, ixazomib and carfilzomib in combination with len-dex are available?
MD: I think that it’s very unlikely that there will be any trials that will guide us towards that question so we have to use our judgement. For example, if I have a patient who needs rapid disease control due to renal impairment or to extensive bone disease I will favour a carfilzomib based combination. Whereas if I have, let’s say, an older lady who is concerned about frequent visits to the hospital, her disease is progressing with anaemia but not a lot of bone lesions, not very symptomatic, I may consider an ixazomib lenalidomide dexamethasone regimen.
SL: Yes, I think that’s a good way to think about it. It’s not going to be if this then that, I don’t think we’re at the lung cancer stage yet in terms of defining therapies. I suspect things like disease characteristics and rapidity of response are going to be important differentiators. I actually think ixazomib might be used better from a convenience perspective in the induction therapy setting and perhaps in the maintenance therapy setting as well.
MD: Absolutely.
SL: So while we have nice data in relapse I’m not sure that’s exactly where it’s going to fit 100%.
MM: Torben, do you agree?
TP: I agree, yes. I think maintenance will be a major role for ixazomib.
MM: So now let’s move on to evaluate the immunotherapy. So the monoclonal antibodies have arrived to the treatment of multiple myeloma and daratumumab anti-CD38 monoclonal antibody is the most widely developed. In fact, many abstracts are going to be presented during this ASH meeting. In fact, the results of the SIRIUS trial together with the GEN502 trial were presented yesterday showing that when more than a hundred relapsed and refractory myeloma patients received daratumumab as single agent responded to this combination in approximately one-third of them with durable responses resulting in a significant benefit, from my point of view, in terms of overall survival more than in terms of progression free survival because we are treating heavily pre-treated myeloma patients.
SL: I think what’s interesting about that data, and you may know this a little bit better, but it’s not just the response and the post-relapse response that looks really interesting, it’s actually this data that’s going to be presented at the meeting as well that speaks to the suppression of Tregs and the suppression of the myeloid dendritic suppressor cells as well, suggesting there may be this immune focussing or immune modulatory effect of anti-CD38. Whether it’s a consequence of response or the treatment I don’t know but it’s really interesting to think about.
MM: Yes, I think that it is a new mechanism of action for daratumumab more than the typical monoclonal antibody. In fact I think that this should be considered as a monoclonal antibody belonging to the immuno-oncotherapeutics.
TP: I agree.
MM: So I think that exciting data will be presented in combinations and I think that Dr Plesner will present data about the combination of daratumumab with lenalidomide and dexamethasone.
TP: Yes, we now have data from a phase II trial combining daratumumab, lenalidomide and dexamethasone. What we have seen confirms what we saw in the phase I part of it, that it’s safe to combine daratumumab with lenalidomide and dexamethasone. We see very impressive response rates and very high quality responses with 25% of the patients reaching stringent CR and an overall response rate of 81%. What’s also very important is that the responses are very durable so we have long term responses and it comes with, in my opinion, a very good quality of life with very few side effects, actually no side effects apart from the infusion related reactions added to what we know from lenalidomide and dexamethasone.
MM: In fact, this combination has been the rationale for the randomised trial comparing len-dex with len-dex plus daratumumab and we don’t know yet the results but they will be coming probably in the next year. Another exciting combination also based on daratumumab is pomalidomide plus dexamethasone plus daratumumab. I think that Dr Lonial can comment something about this abstract.
SL: Yes, I think it’s built on that same idea for your trial as well that the IMiDs may enhance the efficacy of monoclonal antibodies. This was a relapsed refractory trial combining pomalidomide based on the label in the US, which is lenalidomide refractory, exposed to a proteasome inhibitor. In a group the trial enrolled over a hundred patients, there were about 75 that were evaluable for the presentation. It looks like the response rate approaches 70%. I’ll tell you, certainly in our centre the people that went on this were 17p deleted high risk patients that had relapsed on three drug maintenance therapy. So that kind of a response and durability is coming as well, it certainly speaks to the power of the immune oncology piece.
MM: So I think that you are a key expert on the management of daratumumab and I would like to ask you about the side effects, especially about the infusion related reaction. Any specific recommendation for the audience about this?
TP: Well we see these actually in about half the patients, we see some reactions during the first infusion which are really trivial in nature like nasal congestion and so on, easily manageable by pausing the infusion for one hour, giving extra pre-medication and then you can resume again with the infusion and treat the patient, dismiss the patient at the end of the day. So these are really trivial reactions and they disappear from the second infusion onwards.
SL: In your group also you used singular as a potential way and we’ve adopted that as well but I think you had the first data set on that?
TP: We don’t really have…
Yes my group has. We don’t really have data on that, we’re trying to develop a dataset to support that but the idea is that it could prevent bronchospasm of the infusion, related to infusion.
MD: We have to say that, as you mentioned, most of the reactions are trivial but occasional patients may develop a reaction that may be…
TP: Less than trivial.
MD: Less than trivial, yes.
SL: Just like any monoclonal.
MD: Absolutely.
MM: Any other specific recommendation for the audience in the management of daratumumab?
TP: We know that Janssen now is developing a sub-cue formulation that will be tested in a clinical trial to perhaps ease the treatment.
MM: So this new route of administration would optimise the use of daratumumab?
TP: Yes.
MM: Let me ask you a question, to Sagar Lonial, because daratumumab has just been approved here in the US. In which specific patient population are you going to use daratumumab as single agent?
SL: I think right now the label in the US is greater than three prior lines of therapy, resistant to an IMiD and a proteasome inhibitor. So that’s where it’s going to get used and the first shipments of commercial drug have already reached the clinics and I know several patients have been dosed already. I suspect, though, with the data combining with pom as well as other drugs that’s going to really start to happen much more frequently because even if the IMiD, even if the tumour cells are resistant to the IMiD it’s possible the addition of the IMiD may enhance immune effector cells, making the antibody even better than it is by itself.
TP: Actually, in the early days I enrolled a patient in the Genmab trial 503 who was formerly refractory to lenalidomide because he had progressive disease within 60 days after finishing lenalidomide. He responded for almost two years to the combination of dara and dex.
MM: So I think that these are exciting data, especially for the management of our patients with myeloma. Before finishing this discussion I would like…
TP: Perhaps…
MM: Yes, of course.
TP: I have a comment about we need to educate our colleagues about using daratumumab and there are two important aspects to be aware of. One is that it’s important to have a blood typing done before you start treating patients because dara is bound to the red blood cells and will cause trouble in the blood typing after treatment. The other aspect to pay attention to is that dara will circulate in the plasma of the patient so you will see a small monoclonal event because dara is IgG kappa so you will see a small monoclonal component in the serum of patients. You should be aware of that because it can be tested and shown that it is indeed dara so you can confirm that the patient is in CR if you suspect it.
MD: The same applies with elotuzumab too, yes, IgG kappa.
MM: So you think that a general comment for the physicians who are going to treat these patients with monoclonal antibodies is please look at the serum protein to look at the m component of the patient and the m component corresponding to the monoclonal antibody to well evaluate the response.
MD: Yes, especially when you are reaching a VGPR state and you see that there is a very small residual…
TP: Yes, it will typically be an m component of 0.5g/l and less, at that level.
SL: It’s very interesting. Our lab is so used to seeing it now that they’re calling it. They’re seeing the band on the SPEP and saying this is daratumumab.
TP: The dara band.
SL: Yes.
MM: Directly they are able to identify the daratumumab.
MD: It has a different motility.
MM: Yes. Daratumumab is located at the end of the gamma region, elotuzumab is located at the beginning of the gamma region. So different monoclonal antibodies are located in different places.
MD: To prove it you need a special immunofixation, of course.
SL: You do, you do, but they can see where the old band was so they know it’s not where the old band was.
MM: OK, last question. Where do you envision daratumumab in five or ten years’ time?
MD: Well I think that daratumumab is very likely to become a backbone for the treatment of myeloma and for sure quadruple combinations will be used in the front line setting, especially for younger patients who may move to high dose therapy and then as consolidation. It is logical that, especially with the synergy that we see with lenalidomide, it will be used as maintenance therapy for at least several months.
SL: I’m glad as the European you said that because that’s exactly what I think as well; it will be a four drug induction regimen. I think one of the trade-offs if we do four drugs up front is that you don’t have indefinite maintenance after transplant, that you might be able to get low enough that you can stop therapy at some point.
MD: And hopefully with the MRD data and the trials that will have to be performed…
MM: We will be able to stratify the therapy according to the MRD status to individualise much more the treatment of our patients.
MD: Yes, of course we need the studies to be done first.
SL: Yes.
MM: Torben?
TP: The nice thing with daratumumab is there’s no overlapping toxicity to any of the other drugs we are using to treat myeloma and it has a separate mode of action so this comes in as a very important feature. So I think that dara will be the rituximab for myeloma in the future.
MM: Any additional comments, Sagar?
SL: No, I agree, I agree.
MM: Thank you very much for the discussion and we close here this roundtable discussion from Orlando in Florida about the highlights of myeloma from ASH 2015.
