ASCO 2016: Expert discussion on the latest on multiple myeloma

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Published: 3 Jun 2016
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Dr Sagar Lonial and Dr Paul Richardson

Prof Sagar Lonial (Emory University, Atlanta, USA) and Dr Paul Richardson (Dana-Farber Cancer Institute, Boston, USA) discuss the highlights in multiple myeloma treatment arising from day one of ASCO 2016.

They discuss the results and implications of data coming from upfront autologous stem cell transplantation (ASCT) versus novel agent-based therapy.

This is a randomised phase III study of the European myeloma network with results showing that PFS is significantly prolonged in pts randomised to HDM (OS not yet mature).

One of the key highlights from day one looked at a meta-analysis of three studies (IFM 2005-02, CALGB 100104 [Alliance], GIMEMA RV-209) that had previously demonstrated PFS in patients with multiple myeloma, but were not originally powered for OS.

This meta-analysis now demonstrates that lenalidomide maintenance after high-dose melphalan and ASCT significantly prolonged OS versus placebo/no maintenance.

Some early phase trials were also discussed including a phase I/II trial of ixazomib, an oral proteasome inhibitor, cyclophosphamide, and dexamethasone for newly diagnosed multiple myeloma (NDMM).

A phase I study of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma and a phase I/II study of carfilzomib, pomalidomide, and dexamethasone (KPd) in patients with relapsed/refractory multiple myeloma (RRMM).

This programme has been supported by an unrestricted educational grant from Celgene


ASCO 2016

ASCO 2016: Expert discussion on the latest on multiple myeloma

Dr Sagar Lonial – Emory University, Atlanta, USA
Dr Paul Richardson – Dana-Farber Cancer Institute, Boston, USA

SL: Hello, and welcome to I’m Dr Sagar Lonial from the Winship Cancer Institute of Emory University and we’re here on the first day of the ASCO annual meeting and we’re going to talk a little bit about myeloma updates that were presented today. I’m joined by my colleague, Dr Paul Richardson from Dana-Farber in Boston. Paul, let’s get started. There was a lot of really interesting data presented in the oral sessions today. The role of transplant – it comes, it goes, it comes, it goes, it’s like tides, where are we after today?

PR: Thank you very much, Sagar, and thank you very much for inviting me here to this evening. It’s been an incredible day, a great myeloma session and in terms of the data that was presented this afternoon I was very struck, it was presented by Michele Cavo on behalf of the EMN. This was a randomised trial, a large number of patients, and basically it assigned patients to either essentially early transplantation after CyBorD induction, or bortezomib and cyclophosphamide based induction therapy, with a transplant relatively early and then lenalidomide maintenance until progression. The non-transplant arm received VMP. To be honest, that was the challenge in the study, that VMP would not be considered a standard approach for us in the US as a consolidation or intensification regimen. That being said, the response rates were very high in both arms. Interestingly enough, the rates of CR and near-CR were the same, what was striking though was that if you looked at partial response and greater transplant did help. What was impressive was that it was a statistically significant benefit in terms of progression free survival but overall survival was the same. So some early data there, very much reflecting or resonating with IFM data that’s showing early transplant results and a progression free benefit but no overall survival benefit. So where that leaves us is that studies like DETERMINATION, which we’re both part of, really for US practice are essential because there RVD obviously is a standard in the US now and the whole concept of a proteasome inhibitor, IMiD, dexamethasone platform, be it with other new next generation agents or otherwise, has become what US practitioners would offer patients. So the US study will be incredibly important in answering this question.  What I did like about the EMN study was the lenalidomide until progression but obviously the data are too early to comment on that. So that piece will remain to be seen. That  brings us to the next point, Sagar, which is what was the data from lenalidomide maintenance? That was from Dr Phil McCarthy.

SL: Let me make a quick comment about that because it’s a question that gets asked a lot, certainly in the US in the community, should I refer for transplant? Should patients have an early transplant? I’m actually debating Sergio Giralt on this next week and my take home message from this is going to be if you get sub-optimal induction and sub-optimal consolidation then, yes, you have to have a transplant.

PR: Sub-optimal response to induction?

SL: I don’t know, I think the use of alkylators up front has been shown now in a randomised trial to be inferior to an IMiD PI combination. So if you got VCD up front and you got an alkylator as consolidation, meaning MPV, then you need the transplant, you need the transplant. So I think as we get to IMiD PI combinations with or without monoclonals the benefit may be continuing to narrow a little bit so I think it’s an open question and one worth thinking about.

PR: I completely agree. That’s what I was left with, Bill Bensinger was the discussant for Michele’s data and essentially what Bill said was there’s survival benefit but the question that came from the audience, and from no less than Richard Little from the NCI, was wait a second, there is no survival benefit in those studies that are most applicable to US practice. They may be relevant to some of the limitations outside of the US, in Europe for example, but they’re not relevant to what you and I do and what we offer our patients. So I think you’re absolutely on target there, Sagar, what really matters now is this next wave and the next wave is going to be a proteasome inhibitor, an IMiD and an antibody.

SL: And an antibody, right.

PR: And in fact Bill did allude to this but I think the point is that does it mean that whatever we use as cellular therapy becomes now even more important because my own take on it is that high dose melphalan, great tool, great treatment but, as Bart has been famously quoted now as saying, it’s a Kalashnikov, it’s a relatively older gun in our armamentarium. So as we look to other platforms of cellular therapy, be they immunomodulatory based, immunologically based in the form of checkpoint inhibitors, CAR-T based, do we still need melphalan with its attendant late toxicities, that’s the question.

SL: As we think about making induction better, and hopefully we can look to that in the coming years or even at ASH this year, the second big study that was presented today talked about lenalidomide maintenance. There has been a lot of controversy even within the US about duration of lenalidomide maintenance and about whether lenalidomide maintenance really carries with it a survival benefit. The US trials showed it clearly did, the French trial initially did not. Today we saw data on an amalgamated meta-analysis between those two trials, what did we see?

PR: It was impressive. Essentially the meta-analysis was very well conducted, it was a proper approach to this with multiple studies pulled together and then actually the three major trials selected were 10104, which is the CALGB Alliance study, the IFM study and then the Italian group. What basically happened with those three, and this was the most interesting thing, is now with longer follow-up the French trial is positive for survival. The other thing that’s important is the magnitude of survival benefit is biggest with Alliance, then comes the Italian study and then comes the French. In that context Phil McCarthy did a magnificent job of presenting this data and showing that there is a clear survival benefit. It was actually a median of 2.5 years in favour of lenalidomide maintenance which is remarkable. So now we have a PFS difference of 2.5 years and a median overall survival benefit on meta-analysis of 2.5 years. To me anyway, this was the most impressive presentation of the whole session because it validated continuous therapy, it validated what you and I have felt for a long time, that this immunomodulatory platform is key, and that continuous maintenance until progression or intolerance is really a standard of care. Phil’s presentation was very convincing.

SL: Yes, there’s a lot of talk about using MRD as one way to potentially define duration of therapy and the problem with that is that even in the MRD negative group patients continue to relapse. So saying ‘I’m going to get to this other endpoint and be happy and call it good,’ I don’t think really speaks to how the drug may be working, which is not, perhaps, cytotoxic as opposed to cytostatic. Second, it may be missing the point.

PR: I couldn’t agree more. I think the immunomodulatory piece is everything. So if you’ve got an immuno-oncologic that’s an oral therapy that’s well tolerated, the impression I got from Phil’s presentation, irrespective of your response, was this would be your backbone. So the question Phil raised at the end of his talk was what do you add to it and that’s legitimate. That’s where MRD may matter – what do you reasonable add to it, recognising that these other therapies add complexity, potentially side effects and of course cost. So the other issue then becomes we’ve got a standard – how do we then rationally add to it going forward?

SL: Right. So, as we talked, we’ve talked a lot about the transplant and the maintenance, salvage therapies are obviously very important. We had four new tools last year, there was data presented today on ixazomib, the oral proteasome inhibitor. Very interesting study from the Mayo Clinic group with an all-oral combination and their favourite drug, cyclophosphamide.

PR: I think it gets to your point, though, Saga. The data was very impressive – ixazomib clearly is active, clearly it works. But it is interesting, the premise from Martha Lacy who presented was cyclophosphamide is a cheap partner. That may be true but, at the same time, while the tolerability of ixazomib and its efficacy were very striking I share your view that immunomodulatory therapy as part of proteasome inhibition as a partner makes so much more sense. Whilst clearly ixazomib cyclophosphamide dex is promising and the tolerability is excellent, again it’s good to see this kind of information because it helps us choose treatments and for those patients, for example, who might be intolerant of IMiD therapy this obviously is a great alternative. I personally, though, am struck that again and again we’re seeing that the three drug platform matters. No sooner had we heard from Martha than we got a very nice presentation from Amrita Krishnan in relapsed refractory disease showing that when you combine ixazomib with pomalidomide in double refractory patients you see great activity and excellent tolerability. What was one of the lovely parts of her talk was at the very end she showed a picture of one of her patients on the study who’d had a great response, double refractory, he’d just climbed Mount Kilimanjaro. I thought that said it all, that’s where we’re going with these oral regimens and this patient looked fantastic on the top of Mount Kilimanjaro. Apparently, as Amrita put it very amusingly, he was on his week off. That was just terrific.

SL: Right. The role of low dose alkylators is increasingly getting pushed out and not only is the IPD data that you presented really interesting but in view of the data that we’re going to see on Sunday, combining dara with a proteasome inhibitor, you could talk about ixazomib with dara as a potential combination. There are so many other better, less cytotoxic ways to think about treating that it’s hard to get enthusiastic for a long term about that.

PR: I agree and the other thing that was so interesting in the relapsed refractory session, Sagar, was there were a couple of sections worth mentioning. Marivi Mateos presented a very interesting story about a drug you and I know, Aplidin, which is derived from a marine source, a sea squirt of all things. It’s not clear exactly how it works, it’s a novel apoptotic, it targets a variety of pathways that seem to be very meaningful because in fact the pre-clinical work was done by Constantine Mitsiades. Marivi led the phase II single agent study which we participated in and we clearly saw a response. The question then was where do you go from there. The drug kind of idled for a while but then moved into a phase III study against high dose dexamethasone. Interestingly whilst that obviously was very much a non-US study for a variety of reasons, not least of which because the sponsor, the PharmaMar based in Spain, but in any event by report, and we’ll hear data about aplidin at ASH, that study was positive in favour of aplidin. The data from Marivi Mateos was quite compelling – phase I double refractory patients, including patients who had received daratumumab and daratumumab had failed them, she reported responses even in those patients. So overall around a 55% response rate and even more strikingly a sustained response rate even in patients with a double refractory and monoclonal antibody resistant disease. So it always invites the question that we’ve got a lot of drugs to choose from but let’s not forget those that have a signal that may be worth pursuing.

SL: No, it’s really interesting and a lot of exciting advances for patients. We’re cementing some of the concepts that perhaps our groups have held high for a while. It’s nice to have large data sets to support them. As we get better drugs with more targeted approaches the role of transplant and timing continues to be an important question.

PR: Yes, I agree, Sagar. If I may on one thing finally, in the relapsed refractory space a very nice presentation from Andre, from the MMRC of carfilzomib pom – great results and striking, basically PRs or better at 80%. To your point, and this was raised in the discussion at the session, early versus late transplant depends on what you can salvage with. You can keep transplant in reserve if you’ve got fantastic salvage regimens and when you’re looking at Andre presenting data with car-pom combined 80% response rate, you realise you’ve got salvage options. So for a patient who has that and they say, ‘Look, I’d rather keep my transplant in reserve,’ that seems a perfectly reasonable approach.

SL: Good, well an exciting first day and thank you for tuning in to for these updates from the first day at ASCO.