ASCO 2015: Latest developments in multiple myeloma

Prof Philippe Moreau - Centre Hospitalier Universitaire de Nantes, Nantes, France
Prof Sagar Lonial - Emory University, Atlanta, USA
Prof Meletios Dimopoulos - University of Athens, Athens, Greece

PM: Welcome to ecancer.tv. My name is Philippe Moreau, I’m a haematologist working in Nantes in France. Today I’m with Dr Dimopoulos, he’s working in Athens, Greece, and Dr Lonial, he’s working in Atlanta, US. We are going to highlight some very important data from ASCO 2015. We’ve heard about, Thanos, very important results on a phase III trial comparing in patients with myeloma in the relapsed setting bortezomib dexamethasone versus carfilzomib and dexamethasone, so that’s a head to head comparison. So can you tell us about some important data in your opinion?

MD: Yes, thank you Philippe. This is the first head to head comparison of two proteasome inhibitors. The primary finding of the study was a significant improvement in the progression free survival in favour of Kd versus Vd. The hazard ratio was 0.53 and the actual numbers were 18.4 months for Kd versus 9.3 months for bortezomib and dexamethasone. Furthermore, there was an improvement in the overall response rate and a doubling of the very good partial response or better in favour with Kd. Survival data not yet mature and toxicity in both arms was essentially comparable with some side effects being more common with bortezomib, others with carfilzomib. Overall, a very positive trial and I think that this will help the approval of carfilzomib in Europe whereas our patients do not have yet access to this drug.

PM: These results, in my opinion are really, really important and we were not expecting such a difference when comparing Kd versus Vd and this 18 month PFS duration is something… not outstanding but very, very positive, as you mentioned. But one caveat, maybe, in this study was that patients could be previously treated with bortezomib up front and receive bortezomib or carfilzomib following randomisation. So don’t you think that’s something that should be discussed because that could be a part of a sort of retreatment with bortezomib versus carfilzomib at the time of the relapse. What do you think about this?

MD: Yes, you’re correct. Almost one half of the patients were pre-treated with bortezomib; by inclusion criteria they have to have responded to bortezomib and to have a bortezomib free interval of at least six months. We performed a subgroup analysis according to prior exposure to bortezomib or not and we were able to show that the benefit was there for either group. So even patients pre-treated with bortezomib benefitted from Kd and also bortezomib naïve patients.

PM: That’s very important. And in the population of elderly or very elderly patients there was also a benefit in favour of carfilzomib?

MD: Yes, approximately 15% of the patients were older than the age of 75 and even in this group of patients there was a benefit in favour of Kd.

PM: I think that these data are really, really important. As you mentioned, I think that this phase III study will probably lead to the new approval, in fact, of carfilzomib in the relapsed setting so that’s very, very important. And Sagar, you presented important data on the role of elotuzumab in a phase III randomised prospective study, international study, comparing lenalidomide and dex, that is one of the standards of care in the relapsed setting, versus lenalidomide, dexamethasone plus elotuzumab. So could you tell us your results?

SL: Yes. This was an important phase III trial to follow up on earlier phase I and phase II data that suggested the combination of elotuzumab with len-dex was not just additive as somewhat synergistic. The response rates and duration of response that we saw in the early trials was certainly good enough that we thought moving to phase III made sense. What I showed was an improvement in progression free survival, of about a 30% improvement in progression free survival, almost 5 months difference. But what I also think is really quite striking is that the overall response rate was higher and the toxicity associated with the use of a monoclonal antibody was really pretty nominal – occasional infusion reactions in about 10-15% of patients that did not recur with subsequent doses of therapy. So I think it’s an effective treatment, it’s using an immune-based approach which we know our patients certainly in the US love the concept of immunotherapy or immune based approaches. So using an antibody that targets SLAMF7, which is present on both plasma cells and NK cells, was really quite exciting.

PM: We used to give oral drugs in this relapsed setting with lenalidomide and dex, don’t you think that’s not too heavy for the patients, let’s say, to receive an IV drug in addition to lenalidomide and dexamethasone?

SL: I think you have to think about it in terms of what’s the benefit. So, yes, there are… perhaps by taking an IV once a week for two months and then every other week beyond that, so two doses a month, there certainly are inconveniences for the patient but what’s the benefit? Well, if you look at the progression free survival curves, the magnitude of benefit actually increased with longer follow-up. So, while it was a percentage difference in PFS at one year, that percentage was actually bigger at two years, again speaking to the immune effects of the combination. The other piece that I think is really important was the benefit for patients with high risk disease. If you look at patients with 17p deletion and (4;14) translocations specifically, the benefit of adding in this immune based approach seems pretty clear there

PM: That’s also very important to see this good response rate and PFS in patients with a high risk disease. Can you tell us about the future of elo? It will be probably… well, we are expecting or hoping that it will be approved, in fact, in combination with len-dex in the relapsed setting. But what do you think about the frontline use of elo in the future?

SL: Yes, so there’s another companion trial with ELOQUENT-2 called ELOQUENT-1 which Dr Dimopoulos has been leading looking at elo-len-dex versus len-dex in a newly diagnosed myeloma patient population, similar to the first trial in terms of eligibility. We hope to have some results on that, I think, in the next year or so. That will give us guidance on looking at elotuzumab up front. It’s also being looked at in combinations such as RVD, a commonly used regimen in the US, that trial is ongoing now as well.
PM: This is a phase II or a phase III study?

SL: It’s a phase II.

PM: Phase II, that’s RVD plus elo?

SL: Correct, yes.

MD: So, Philippe, how about the other class of monoclonal antibodies, the anti-CD38?

PM: In fact that’s very interesting also to speak about daratumumab. In fact, elotuzumab will be probably the first monoclonal antibody in a phase III randomised study leading to the approval of this new class of drugs. But, of course, we are really interested in looking at the results of daratumumab single agent, the MMY2002 study. So dara targeting CD38 was provided as a single agent in very, very advanced patients, patients progressing on carfilzomib, progressing on pomalidomide, progressing on alkylators and dexamethasone. So for this population of patients there is no treatment available, we are in this, what we are calling, unmet medical need. In this situation dara single agent was able to induce a 30% response rate and in this population of patients, very heavily pre-treated, the duration of response is something like 7-8 months. So I think that these results are really important based on what we know from the authorities, the FDA in the US, probably dara will be approved in very advanced patients. So that’s the first step, so we have here a new class of agent, elotuzumab and daratumumab and your study, Thanos, showing that carfilzomib also is very important in the relapsed setting. So, to my opinion, ASCO this year was a very important meeting for the results of very new, new and positive, data. So I think that we’ve tried to cover the most important findings here reported in Chicago. Thank you for being with us today.