Expert discussion on current experience with monoclonal antibodies in multiple myeloma

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Published: 6 Oct 2015
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Prof Antonio Palumbo and Prof Philippe Moreau

Prof Antonio Palumbo (University of Torina, Torina, Italy) and Prof Philippe Moreau (Centre Hospitalier Universitaire de Nantes, France) discuss clinical developments and experience with monoclonal antibodies in the treatment of multiple myeloma at the 15th International Myeloma Workshop.

In particular, they talk about the promising results being seen with monoclonal antibodies that target SLAM (signalling lymphocyte activation molecule) F7, a glycoprotein present on multiple myeloma and natural killer but not normal cells.

Results of the phase II ELOQUENT-2 trial of elotuzumab in patients with relapsed or refractory disease were presented at the meeting and suggest that this monoclonal antibody could improve upon progression-free survival when added to the standard of care, which is currently lenalidomide in combination with dexamethasone, versus the standard of care alone.

They also highlight the results of studies with CD38-targetting monoclonal antibodies, such as daratumumab. This investigational drug has been tested as monotherapy, with results from a Dutch trial recently being published in the New England Journal of Medicine. It is also showing promise in combination with other drugs in the relapsed/refractory setting.

Finally, Prof Moreau comments about what backbone regimens may be appropriate to use with these new agents and suggests that daratumumab could be used in a similar manner as rituximab in non-Hodgkin lymphoma, with studies also looking at its as a maintenance therapy.

This programme has been supported by an unrestricted educational grant from Janssen Pharmaceutica (A Johnson & Johnson Company).

15th International Myeloma Workshop

Expert discussion on current experience with monoclonal antibodies in multiple myeloma

Prof Antonio Palumbo – University of Torino, Torino, Italy
Prof Philippe Moreau – Centre Hospitalier Universitaire de Nantes, France

AP: Hi, we are here in Rome for the 15th International Myeloma Workshop. My name is Antonio Palumbo from Italy, Torino, and I am pleased to be here with Philippe Moreau from Nantes, France. We are just coming from a very interesting session on monoclonal antibodies and humanised monoclonal antibodies. So the first question I would like to raise to Philippe is what was the major interest, starting with SLAM F7, which the results have been presented?

PM: Yes, in fact we heard about the results of the ELOQUENT-2 study. It is a randomised prospective phase III trial comparing in the relapsed setting lenalidomide and dexamethasone, that is one of the standards of care, versus lenalidomide dexamethasone plus elotuzumab. As you mentioned, elotuzumab is a monoclonal antibody targeting SLAM F7 that is always expressed by the tumour cells. Preclinical data show that this agent could be effective, especially in mouse models; even though there is no single agent activity with elotuzumab there is a synergistic activity with lenalidomide. So the results are showing on a very large number of patients that the addition of elotuzumab, that is provided IV, is increasing the duration of response. The progression free survival that was the primary endpoint of the study is increased by almost 5 months. What is quite interesting is that the impact on the response is lasting, not only at one year but also at two years, and moreover this agent is not adding a lot of toxicity. Elo is very well tolerated without impacting, for example, the infection rate. So that’s very important. We have, of course, with all monoclonal antibodies some infusion related reactions but really few in fact and mostly at the time of the first infusion. So this agent will be the first in class available in a phase III randomised study.

AP: I completely agree that they show superiority over the standard of care, lenalidomide and dexamethasone and certainly there is a major advantage for patients who achieve GPR because they have a long lasting remission. Of course we have to probably wait for the three years follow-up to confirm it but at present there is an excellent progression free survival curve for this subgroup of patients.

PM: Yes. Maybe we can add as well that the survival data are not mature because the number of events is not reached but, as you mentioned, progression free survival is a very important surrogate endpoint, yes.

AP: You were one of the presenters for the daratumumab symposium, so which was your take home message from this symposium?

PM: Well I think that we also discussed SLAM F7, elotuzumab is a very important monoclonal antibody, but we also discussed on the results of daratumumab. Dara is another monoclonal antibody, fully  human, targeting CD38 that is also always expressed on the tumour cells. You have presented some data on the combination of dara plus other agents but we’ve also heard about dara as a single agent in very, very advanced patients. We do have two trials, one in Europe that was recently, very recently, published in The New England Journal of Medicine by the group from the Netherlands and we also have another study coming from the US, the SIRIUS study, in patients progressing and refractory to both IMiDs and proteasome inhibitors. Dara as a single agent at the optimal dose, 16mg/kg IV, is able to induce a 30% response rate, that is very, very important for sure for the patients without any other treatment possibilities. The duration of response is roughly 5, 4 months, but the overall survival is something like one year. So we are adding something for sure when dara is used as a single agent. And looking at the toxicity, very few toxicities as well with dara. So I think that very, very soon this drug will be available, not only in the US but also in Europe and we will have some early access to this drug for sure early next year. But you did present some data on dara in combination with other agents so can you tell us about your ideas?

AP: Yes. Certainly the evidence coming from daratumumab are much earlier on than elotuzumab because we are only right now at phase I and phase II studies. Besides the single agent there are some on-going combinations, especially with lenalidomide and dexamethasone. Daratumumab has been combined in newly relapsed refractory patients with lenalidomide and dexamethasone and also here the results are quite impressive: 100% response in all patients that did achieve at least a PR with around 40-50% of VGPR but probably this number will get better in the future because with a longer follow up and more cycles probably we will see an even better number. So certainly this is a major advantage and probably will change our treatment paradigm.

PM: And in addition with len-dex we are not increasing the toxicity of the combination?

AP: Certainly this is another very important issue - monoclonal antibodies do not have additive toxicity over the standard chemo. Daratumumab has a slight neutropenia but not that important. But the major issue is that monoclonals can be clearly added to current treatment without major increase in toxicities. The issue is usually related to an infusion reaction and some antibodies may have some more, someone else definitely less, but once again, as we were discussing, we are in the rituximab range in terms of infusion reaction.

PM: Yes.

AP: We saw also another antibody that is also the CD38 antibody, isatuximab. So how is your comment on this?

PM: The development of this antibody targeting CD38 as well is less advanced. I think that we have more data with dara. The development is only in phase I/II, we are hoping to have a phase III in the near future. The dose is also different, we’ve heard about the dose escalating study from 2 to 5 to 10mg/kg, 10mg/kg is the optimal dose with this drug, and it was immediately combined with lenalidomide and dexamethasone and Dr Martin reported twice some results at ASH and ASCO. This drug is going to add something to len-dex in patients refractory to len-dex when you are adding this monoclonal antibody you are going to overcome the resistance. So it is really something very fascinating although the response rate is not outstanding in the refractory population. I think that it will be probably difficult in the future to compare dara versus the SAR compound from Sanofi but I think that these two drugs are promising.

AP: And also we saw some early data of combination of daratumumab with different standard treatment, bortezomib, dex, VTD. Which is your impression when you may use lenalidomide from one side as a counterpart or bortezomib on the other side as a partner for daratumumab?

PM: I think that the idea that we do all have in mind is that daratumumab can become a sort of… not a must but a drug that should be added systematically to all the backbone regimens. We are using VMP in elderly patients and probably it will be possible to do the VMP plus dara in the future. We are using VTD, we are using Vel-dex and it is probably possible to add dara to these backbone regimens in order to increase the response rate, the duration of the response, like we did in fact almost twenty years ago in non-Hodgkin’s lymphoma when rituximab came on the market. We immediately added rituximab plus the CHOP regimen with the RCHOP, we did the same in the relapsed setting with the DAP with RDAP etc. So I think that probably dara will be used as we are using rituximab in the non-Hodgkin’s lymphoma setting. And in non-Hodgkin’s lymphoma we are using rituximab as a maintenance so there are some studies already ongoing dedicated to dara maintenance so that could be also a plus for our patients.

AP: Thank you very much, thank you for your presence here. As you can see what we are facing in myeloma is unbelievable, we already have ten years of major improvement, we are still here with some even more interesting drugs coming and I think this will be in the benefit of everybody and I hope this will translate into major clinical benefit, especially for our patients. Thank you very much.