ASH 2015

ASH 2015: Monoclonal antibodies for multiple myeloma

Dr Saad Usmani - Carolinas Healthcare System, Charlotte, USA
Prof Thierry Facon - Hospitalière et Universitaire, Lille, France

TF: Hello, we are here for ecancer.tv at ASH 2015 in Orlando. My name is Thierry Facon, I am a haematologist coming from France. I am here with Dr Saad Usmani from Charlotte in the US, he is a great myeloma expert and he presented today on daratumumab. So he presented a very important study on daratumumab in very advanced myeloma patients. This is basically a combined study combining two studies which have been presented before but you provide very useful information on the use of daratumumab for myeloma patients. So, Saad, could you comment on your study results?

SU: Sure, thanks Professor Facon. So daratumumab is the first biologic monoclonal antibody that just got FDA approved about a week ago. This current analysis is a combined analysis of 148 patients who participated in both the GEN501 and the SIRIUS trials, the data that actually led to the FDA approval of this drug. Daratumumab was given as a single agent in heavily pre-treated relapsed refractory myeloma patients. About half of the patients were exposed and refractory to carfilzomib and almost a third to pomalidomide as well. Five prior median lines of therapy; by the time they were enrolled on the trial they had been about five years from the time of diagnosis. So they were going through these lines of therapy fairly quickly. The key element that I find striking is despite the relapsed refractory nature of this patient population there was significant clinical activity. The overall response rate was about 31% and some very deep responses, VGPRs, CRs and stringent CRs were also seen. It wasn’t simply about the survival benefit conferred to patients who were responding, patients who had MR and stable disease. It appears that even though their PFS was about 3.5 months, so much shorter than the responders, but their overall survival was over 17 months which, if we look at historic data from Dr Shaji Kumar’s study published three years ago, it’s quite striking. So I find that these results are very encouraging and we appear to have a new platform as these monoclonal antibodies are coming out with anti-CD38s as being very effective medicines. And looking forward to future data with up front treatments.

TF: But you mention the PFS was about 4 months but in responders the duration of response was quite good. If I remember well it was between 7 and 8 months so some patients responded for a long time.

SU: That’s correct, absolutely. I think one of the things that we are trying to understand is the mechanism of action. We do feel that daratumumab works through the classical pathways that we understand monoclonal antibodies through ADCC, ADPC and CDC, but what we’ve learned from looking at the blood samples from the patients on these studies is that some patients, especially the responders, appear to have a very high level of CD8 T-cell expansion. What we are understanding is that it’s the action of daratumumab on the CD38 positive Treg cells, Breg cells and MDSCs that perhaps leads to an expansion of the CD8 positive cells.

TF: So these are immunomodulatory drugs in fact, which was not totally expected, but that’s the…

SU: Yes.

TF: And could you comment on the tolerance? We noted a few months ago that the toxicity profile was quite good, is that still valid in the combined analysis with a longer follow-up?

SU: Yes, yes it is. So we find that a little less than half of the patients develop an infusion related reaction and the vast majority of those infusion related reactions occur the first time the patients are getting it. I think this phenomenon is not unique just to daratumumab, we experienced this with rituximab in the past as well. The going hypothesis may be CD38 is expressed ubiquitously so it might as well cause some sort of hypersensitivity in the respiratory tract. Once the CD38 is under-expressed then patients don’t develop the infusion reaction again. So that’s quite possible. But outside of that we did not see any significant safety signals beyond what’s already been reported.

TF: Daratumumab is now combined with other immunomodulatory drugs such as pomalidomide, lenalidomide and also bortezomib, we have bortezomib studies as well. So I think everybody is quite enthusiastic about that. So you mentioned daratumumab itself has an immunomodulatory effect so you may expect that lenalidomide based studies, lenalidomide and daratumumab or pomalidomide and daratumumab, will provide a very good clinical outcome for patients.

SU: Yes, certainly. It would make intuitive sense that they would work well together. The other piece of the safety profile is that adding daratumumab to an available platform for medicines will not increase the safety signal hopefully.

TF: So you are lucky doctors in the US because you got approval for several myeloma drugs this year. So this is the case for daratumumab but almost at the same time elotuzumab got approval as well. So that’s amazing. And others, ixazomib got approval as well so that’s good news for patients, in fact. So this morning we got some additional elotuzumab results. I think these results were interesting; so these are the results of the ELOQUENT-2 study, len-dex versus len-dex elotuzumab. We already had one year PFS, two year PFS, so the elo arm had a PFS benefit which was quite clinically significant and statistically significant as well. But many people said, OK, we have to wait to three year PFS because if you have to manage an immuno-oncology drug you need to see a strong long-term benefit. So people were quite interested in looking at the three year PFS. You may say this is quite a detail, so that’s only an expert discussion, but I do believe this is something important. Basically, they saw that the PFS benefit was still there at three years and they got some… OK, it’s not the final survival but anyway they got some survival benefit as well. So that’s really good news for patients. So looking at antibodies and, as you know, there is a lot of interesting activity for myeloma patients. So we got some very impressive daratumumab results and also for elotuzumab and we may get other results with other CD38 antibodies as well.