Dr Paul Richardson - The Dana–Farber Cancer Institute, Boston, USA
Dr Wenming Chen - Beijing Chaoyang hospital, Beijing, China
PR: Hello, my name is Dr Paul Richardson and it’s my pleasure to welcome you to this edition of ecancer here at the ASH 2017 annual meeting in Atlanta, Georgia. I’m the RJ Corman Professor of Medicine at Harvard Medical School and serve as the Clinical Programme Leader and Director Of Clinical Research at the Jerome Lipper Multiple Myeloma Centre at Dana-Farber Cancer Institute in Boston, Massachusetts. It’s my pleasure to be joined today by actually Professor Wenming Chen who is based in Beijing. Wenming, welcome.
WC: Nice to meet you.
PR: In that context, Wenming, we are basically going to be talking about three or four important abstracts from the meeting today. Between us we’re going to talk about ixazomib based therapy in the context of newly diagnosed patients; discuss a little bit of data around daratumumab combined with up front RVD therapy; talk about daratumumab monotherapy in the context of smouldering myeloma, those will be the three that I deal with, and then basically I’ve asked Wenming to tell us a lot about BCMA and APRIL and look at some very exciting new data from China in the CAR-T space. We are also introducing you to a very international approach now to ecancer where we’re seeking to reach out to our viewers, not only within Europe and the United States but across to China and to Asia. So we’re also going to try and frame our discussion in the context of how we care for our respective patients in the US, elsewhere and, of course, in China in Beijing with Wenming. So with that in mind, I wondered if I could ask you, Wenming, to start and tell us a little bit about what you thought about this abstract on the first in class APRIL antibody and its preclinical evaluations done in this particular paper presented to us.
WC: Thank you. I’m Wenming Chen from Beijing Chaoyang Hospital, Capital University of Medical Sciences and also director of the Multiple Myeloma Research Centre for Beijing so I’m happy to meet with you.
PR: I know that your expertise as a BCMA guru is in the space of the combined infusion of CD19 and BCMA specific CAR-T therapy. Now, at the meeting we’ve heard a great deal about CAR-T, there has been breakthrough information from the Bluebird Bio group with their phenomenal data from the CAR-T platform they use and they’re reporting a 94% overall response rate, a 50 % CR rate with very manageable side effects. So that’s a tremendously exciting dataset. We, of course, have from your own team and your own colleagues in China wonderful data from the LEGEND team of over sixty patients, I believe, with outstanding response rates and great tolerability with a bispecific approach. So, if I may, tell us a little bit about this CD19 and BCMA specific chimeric CAR-T.
WC: So in China there are many centres that all do CAR-T BCMA with relapsed and refractory myeloma patients. They reported at this year’s ASCO and EHA meetings so this is very effective and nearly 100% of patients achieved a PR or a CR, so it’s very powerful and very effective. Some patients achieved a response and maintained their response for one year so it’s very powerful, BCMA. I don’t know, maybe in China the result is better than Bluebird, so for Bluebird maybe there are different patients here in China than in other countries, I don’t know. Now in China we do the combined CD19, the CAR CD19 and the CAR BCMA, for the myeloma patients. In this meeting the China group reported that ten patients have received the CAR CD19 and the CAR BCMA and of the ten patients eight patients achieved a PR and two patients achieved a CR so it’s very effective for the patients. But because there is not for a long time it’s just that the trial is coming up for one year so the prolonged response rate is just about three or four months and it needs time to follow up for the patients that can achieve the response for a longer time or not. For the safety it’s very safe, very safe. You know with CAR about the CRS, most of the patients achieved a grade 1 or grade 2 CRS, only about 20% achieved more than about a grade 3 CRS so it’s very safe.
PR: So, in summary, we’re seeing a very exciting although early signal in terms of this bispecific CAR approach. Which does make sense, doesn’t it, using two targets and, at the same time, the rates of CRS appear low but we have to be careful because these are early days. I do agree with you that there is a key aspect to interpreting these data between the two studies. In the US population very heavily pre-treated, multiple novel agents; I suspect in China it’s a little different because the access to novel therapies is different in China.
WC: Yes, in China it appears that it’s also heavily treated, if the patient’s sensitive to the drugs they also come on the myeloma drugs to treat them, even if they’re previously resistant. So we use the CAR-T and also the CAR-T is sensitive for the plasmacytoma. That is reported in the centres that reported that that the patients with plasmacytoma received a BCMA CAR-T and they responded.
PR: So there are a lot of exciting aspects. In terms of the CAR-T data, though, I think it’s fair to share with our audience that it’s been really a remarkable day here at ASH with the oral presentation from the Bluebird Bio team resonating with what we’ve heard from our Chinese colleagues in a different setting previously. So the landscape for CAR-T therapy remains early and we have to be aware of the side effects, not least of which CRS and the neurological syndromes that can be life-threatening but, at the same time, remarkable and I would argue clearly a major breakthrough in our field. So, with that in mind, there are other exciting things. Just to share with you that there is a BCMA antibody drug conjugate, the so-called GSK’916, that has been presented by my colleague Suzanne Trudel, demonstrating a remarkable monotherapy signal in highly refractory patients of 60% at MTD and, interestingly enough, a response rate of over 40% in daratumumab refractory patients, which is quite noteworthy in itself, with minimal toxicity other than some grade 1/2 corneal ulceration in a subset of patients manageable with steroid eye-drops and at the same time thrombocytopenia and fatigue. So early days for GSK’916 but very, very promising indeed and representing a very different approach to CAR-T with an off the shelf antibody drug conjugate that could be administered every three weeks in a broad fashion and obviously complementing what we’ve heard so nicely. So, with that in mind, I’m going to spend a little bit of time on ixazomib maintenance, a lovely paper presented by my colleague Thannos Dimopoulos, looking at ixazomib in actually non-transplant eligible patients to be specific, or those not undergoing transplant. To cut to the chase here, the use of ixazomib at a dose range of 3-4mg once a week basically post-induction remission therapy associated with excellent outcomes with superb tolerability in this pooled analysis from a variety of different trials. What’s very clear is that the PFS for the study group as a whole is very solid at approaching 36 months, or three years, and that in those patients post-induction remission therapy receiving maintenance the PFS signals are approximately two years. So, all in all, exciting and promising data. Now, I wonder, basically, Winming, if you could share with me in China what your strategies are for maintenance. What do you do for maintenance in Chinese patients?
WC: In China usually we use thalidomide for the maintenance. Mostly patients use thalidomide for the maintenance and from September of this year bortezomib and lenalidomide can be covered by the insurance so after that we can use lenalidomide and bortezomib for the maintenance.
PR: So in China thalidomide used but now for those patients who benefit from insurance coverage, they can receive lenalidomide and bortezomib. Great to hear, very similar to what, obviously, is being done around the world and in the United States as well and Europe. So, on that note, would you see ixazomib having a place in your Chinese practice with maintenance?
WC: Yes, I would, I would approve. Next year I will be able to use ixazomib for the maintenance because of the convenience and the less side effects.
PR: I agree, I’m delighted to hear that. And also I just want to acknowledge the remarkable contribution from you and your colleagues in China to the ixazomib RD combination used as part of TOURMALINE. There was a Chinese study and it was our privilege to co-author the manuscript where we saw real benefit in Chinese patients to lenalidomide, ixazomib and dexamethasone in the relapsed setting.
WC: Yes, for the patients that the combination works, the RD, the patients that also we can prolong the PFS.
PR: Absolutely, and it was a 10 months PFS difference which was remarkable.
WC: And overall survival.
PR: And in survival, yes. Absolutely, that was the striking point was that in the Chinese study we saw an OS difference in favour of the three drugs over the two very early which is remarkable. So, good, thank you so much again for that excellent work, Winming. So now moving on to the other data that we wanted to talk about today which revolves around daratumumab use in a variety of settings. First in the up-front setting and transplant eligible patients my colleague Peter Vorhees in partnership with the Alliance Foundation for Clinical Trials, the so-called AFT of which it’s my privilege to be part, have led a remarkable study and we report here on the safety run-in of RVD daratumumab followed by transplant, RVD consolidation with daratumumab and then dara-R maintenance. In that context this is now moving into a randomised phase II where patients either receive RVD transplant, consolidation and R maintenance or exactly the same but with daratumumab interwoven. Peter reported yesterday, in fact, at the meeting that this combination approach was highly effective in terms of its overall efficacy signal, albeit early and in a 16 patient cohort, but also in that context very favourable tolerability and excellent stem cell mobilisation and so forth. We need to wait for the randomised phase II to really comment more on the efficacy signal but, speaking for myself as we are, at Dana-Farber, a lead enroller to the trial at the moment, we’re very pleased by the safety of this approach. Certainly in those patients receiving daratumumab we’ve seen great activity and similarly, in fact, we’ve seen similarly good activity for RVD but we think hopefully the daratumumab will make a bigger difference in the long term. Judging by results at this meeting we would expect daratumumab to add substantially to the platform. I should mention that at the meeting we have a late breaking abstract tomorrow from my colleague, Dr Marivi Mateos, and a European study group, comparing VMP to VMP daratumumab and the remarkable PFS difference is quite striking, isn’t it Winming? I’ll ask you, if I may, daratumumab’s position in China. How are you using daratumumab in China?
WC: Daratumumab is not available in China so maybe just for clinical trials beginning next year, daratumumab with Velcade and dexamethasone.
PR: So you’ll be doing that on clinical trial but hopefully in China you think daratumumab will become approved and available in the future hopefully?
WC: Maybe two years later.
PR: Really? Oh dear. Well I hope it’s sooner than later because it’s obviously a wonderful antibody and it’s proving transformative in outcome. But for Chinese patients we need to move hard to get it available to them. In that same context we do want to mention that daratumumab monotherapy has been tested in the CENTAURUS study for smouldering myeloma and my colleague from Ohio State, Dr Craig Hofmeister, presented a lovely abstract on this which was basically a smouldering myeloma study with the senior leadership of Dr Ola Landgren where essentially they were able to administer daratumumab to a smouldering population and identified 123 patients, no less, with 41 patients in each arm, looking at various doses and schedules of daratumumab. Significant clinical benefit, as reflected by duration of response in terms of progression free survival as well as excellent safety in this study. What was interesting is that the results that they showed with essentially long PFS etc., with PFS rates of 98%, 93% and 89% respectively, is that longer therapy was better in terms of PFS control, intermediate was somewhat in between and obviously the short exposure was more modest at 89%. What I’m very struck about is that the efficacy of this approach was associated with great safety, minimal in the way of side effects which is very encouraging. Fascinatingly, a similar smouldering study presented by Marivi Mateos was much more aggressive, looking at KRD transplant, KRD and then KR maintenance. That study showed very similar results in terms of PFS although obviously differences in toxicity. So exciting data there. Tell me basically, Winming, how do you treat smouldering patients at the moment in China?
WC: In China there is usually a directive that high risk smouldering patients are very eager to treat and therefore for intermediate and for low risk no treatment. For the high risk you usually use lenalidomide dexamethasone for this kind of patient. Sometimes we use the bortezomib or dexamethasone for treatment. But most of our patients we don’t treat.
PR: I see. Obviously in the United States and in Europe it has been established that lenalidomide maintenance until progression is associated with survival benefit. There is data at this meeting confirming that from both the UK, with the Myeloma XI study data showing remarkable benefit to lenalidomide maintenance, again regardless of response, and at the same time we’ve got German data suggesting the same, that in other words even if you have CR you should be on lenalidomide maintenance. Even MRD negative patients who ultimately may relapse should benefit from continuous therapy. When do you think in China lenalidomide maintenance will be available?
WC: Now it’s available. Because lenalidomide is covered by the insurance so the physicians use lenalidomide longer and longer, so we can use lenalidomide for maintenance.
PR: As we discussed a moment ago. So you’re very kind. Well, if I may, I think that brings us to the end of our discussion today on these critical abstracts. I just wondered if you had anything to add, Winming, to these comments in terms of particularly the CAR-T therapy? Any closing thoughts?
WC: For the CAR-T it’s very effective in [?] maybe, depending on the patients MDS negative. For the patients it’s very [?] so the patients cannot receive CAR-T because, as I said, the efficacy is very important. Therefore the patients [?] can use the CAR-T, it’s very suitable for these kinds of patients.
PR: So do you see CAR-T therapy in the future replacing stem cell transplant?
PR: Yes, I agree. It may well be and if the field evolves we go there. On that note I think we’ll close on a very positive note to say this year’s ASH meeting has been once again a plethora of new and exciting advances in myeloma. We now have a very international flavour, we always have, in fact, to what we do in myeloma research but it’s particularly lovely to have colleagues from China as part of our discussions to reflect on the research efforts that are being made in Asia and all around the globe to not only provide outstanding new treatments to patients in Europe and the United States but also in a global sense as well. So thank you very much for your kind attention.
WC: Thank you.
PR: Again, Winming, a pleasure to see you and be with you.