Prof Heinz Ludwig – Wilhelminenspital, Center for Oncology and Hematology, Vienna, Austria
Prof Wee Joo Chng – National University Cancer Institute, Singapore
Prof James Chim – Queen Mary Hospital, University of Hong Kong, Hong Kong
HL: Hello, we are here at the occasion of the EHA meeting 2017 in Madrid with ecancer. My name is Heinz Ludwig, I work at the Wilhelminen Cancer Institute in Vienna, Austria and my distinguished colleagues, Dr Chng and Dr Chim will do their introductions themselves.
WJC: Thanks for the invitation. My name is Wee Joo Chng, I’m from the National University Cancer Institute of Singapore.
JC: My name is James Chim, I’m from the Queen Mary Hospital, University of Hong Kong.
HL: So the question is, which is of highest relevance, what is new in relapsed refractory myeloma? I would like to address this question to Dr Chng please.
WJC: Yes, I think in the last couple of years really it’s been a fantastic couple of years for myeloma patients. There have been a number of very exciting drugs that have been approved and these were predicated on very good results from phase III studies. One of these agents is carfilzomib which has been shown to be better when combined with Rev/Dex than Rev/Dex in one study, the ASPIRE study as well as in another study in a head to head comparison with Velcade shown to be better than Velcade in the treatment of relapsed refractory myeloma patients. So those were excellent. Then also we have now an oral proteasome inhibitor, ixazomib, that was shown in the TOURMALINE study when combined with Rev/Dex was better than Rev/Dex and that’s led to its approval as well. In addition to those, daratumumab is one of the very exciting agents, the first monoclonal antibody that we have targeting CD38. What these approvals is now currently giving us physicians treating patients in Singapore, where all these drugs have been approved just this year, is there are a lot of choices, there’s a lot of hope for the patients but as practising physicians the challenge is how to use these drugs because there is no head to head comparison, they all seem to be effective. Then from the patient’s perspective is how to get access to these drugs because they are actually very expensive in a lot of the Asian countries where it’s not reimbursed and patients have to pay for it. So those are the challenges in the next while.
HL: So you mentioned the challenges, Dr Chim, how do you select treatment for an individual patient with relapsed refractory myeloma?
JC: First of all, in Hong Kong still we have very difficult access to these novel agents, especially when there are not many clinical trials conducted in Hong Kong. But now we are lucky that some of these drugs are actually licensed and approved in Hong Kong, they can be purchased. For example, carfilzomib is already available in Hong Kong but of course at quite a pretty expensive cost. Ixazomib is so far not yet licensed yet; I assume that they are likely to be licensed in Hong Kong early next year. The other drug that we have access to is actually pomalidomide, so we had lenalidomide for a number of years and now we have pomalidomide, so we have access to these agents. Of course, again, the patients have to pay for themselves. So therefore, although despite that, these trials are conducted elegantly in these randomised controlled phase III trials. They showed that, for example, carfilzomib or ixazomib in combination with lenalidomide and dex produced very superior results as compared to the control arm that was lenalidomide and dex. But still we may not be able to use both of these agents, for example carfilzomib, together with lenalidomide which are pretty expensive for the patient and is not yet reimbursed in our country. So in that connection we may actually consider to use less expensive versions like combining carfilzomib with a cyclophosphamide or just carfilzomib with dex in that connection.
HL: Dr Chng, you enrolled several patients into the TOURMALINE-MM1 study, can you tell us a little bit more details about the study and the outcome?
WJC: Yes. TOURMALINE-MM1 is a randomised study in relapsed refractory myeloma with patients having previously been treated with one to three prior lines of treatment where one arm is ixazomib plus Revlimid/Dex and the other arm is with Revlimid/Dex. The study reported positively with a significant improvement in progression free survival; overall survival benefit not seen yet but usually today we need much longer follow-up to be able to see that effect. The drug is generally quite well tolerated compared to bortezomib which is another proteasome inhibitor that we use a lot today; there is a much lower incidence of neuropathy, it’s an oral drug so it’s convenient for the patient. One of the interesting signals from that study is that it appears in the high risk patient that ixazomib can overcome the poor risk effect such that the high risk patient actually has a similar outcome to the standard risk patients treated on ixazomib. So ixazomib is one of the interesting new drugs and we need to find ways to use it for our patients. But like James said, ixazomib/Rev/Dex is a challenge to give in our patients. So in that regard I’m very excited by the poster that you’re presenting at this meeting where you combine ixazomib with Thal/Dex.
HL: Yes, we just showed the results from a phase II study employing ixazomib/Thal/Dex in relapsed refractory myeloma patients. I must say the combination, even with thal, is very well tolerated and we had the follow-up is quite short, to be honest, it’s only 6.5 months at this point of time. The response rate is close to 50%. When we look at quality of life, quality of life is maintained, it’s even improving with continuous therapy and we have ixazomib maintenance implemented in this study so there are eight cycles of induction and then one year of ixazomib maintenance. This is very well accepted by the patient and we also participated in the TOURMALINE-MM1 study and, of course, patients were randomised, as you know, into ixazomib/Len/Dex or Len/Dex but usually as a physician you know into which group the patients are randomised because some agents, particularly the triple combinations, make more toxicity. But we were not able to distinguish who was randomised to ixazomib/Rev/Dex versus Rev/Dex alone. I’m not sure, is this your experience as well?
WJC: Yes, it’s my own experience as well. The drug is really quite well tolerated. I would just also say that we are also involved in the current maintenance study which is placebo or ixazomib alone and again most of the time you have no idea whether the patient is on the placebo or the drug because it seems to be very free of side effects.
HL: Usually when you have a phase III trial which shows better response rates, equal activity in high risk and low risk and standard risk patients, better PFS, you want to have confirmation of this data. So would you like to comment on the China extension study?
JC: I don’t have a lot of information about that study because it conducted in mainline China. But in this connection I think that, as far as the TOURMALINE study is concerned, I believe that ixazomib being an oral agent is very convenient, that’s the beauty of this drug. But at the same time it causes some GI upset, especially diarrhoea. So actually I’m pretty interested in Professor Ludwig’s design that it’s combined with thalidomide which gives rise to constipation, it may actually partially offset the GI side effects.
HL: So we use a very low dose of thalidomide: 100mg in the fit elderly and 50mg in the elderly aged 75 or older. With this low dose of thalidomide you manage your patients very well and there is no excessive toxicity. I agree the China extension study has not been published in full detail but there was only a poster at the International Myeloma Workshop in Delhi recently. What is interesting, and I think it’s always rewarding if you have a large study with several hundreds of patients you want these results to be confirmed. The China extension study actually confirmed everything that has been seen in the TOURMALINE-MM1 study; in effect they even excelled the outcome because the PFS was significantly better but in addition to that in the Chinese patients there were also several benefits seen after a short follow-up. So it’s very rewarding and with ixazomib we have now a new drug which will be taken up by our patient community with significant enthusiasm because you can go with this drug for a very long time with only minor toxicity or no toxicity at all and it will be implemented in different protocols, I’m sure, and these studies are ongoing.
JC: In fact I’m more excited by the data from daratumumab in combination with either Revlimid/lenalidomide/Dex or bortezomib/Dex because it seems that, for example in the POLLUX study when daratumumab is combined with lenalidomide and Dex compared with a control arm that is lenalidomide/Dex only. So actually the response rate is at 90% and actually more the VGPR or above, the frequency of more than VGPR, is actually 40%. So I think it’s really encouraging, the [?? 10:22] and the progression free survival is not yet reached.
HL: What you’re implementing is that we also move, in myeloma, to a lymphoma-type therapy. We have the standard backbone and this will be augmented by an antibody, so by daratumumab or other antibodies.
JC: But in fact I think daratumumab is slightly different, say for example from rituximab that we use for CD20 positive B-cell lymphoma, the reason being that it has multiple mechanisms of action in addition to induction of direct dara induced apoptosis in the CD38 expressing plasma cells. They also induced apoptosis while this complemented cytotoxicity and also enabled ADCC, that is antibody-dependent cellular cytotoxicity, and also ADCP, that is antibody-dependent fatal cytosis. In addition to all that it also actually alleviates or actually removes the inhibition of the myeloma specific T-cells in the bone marrow microenvironment, the reason being that all these MDS, myeloid derived suppressor cells, and regulatory T-cells and also regulatory B-cells inside the bone marrow that inhibit the function of these myeloma specific T-cells are actually expressing CD38 as well. So that’s why the CD38 antibodies have got a wide ranging mechanism of action. So possibly it may account for this excellent result that we see in these randomised controlled trials.
WJC: But I must say that in the abstract that was presented yesterday as an oral presentation it was somewhat disappointing to me that it still doesn’t overcome the high risk genetics. So although it significantly improved the outcome of high risk patients the standard risk patients were doing a lot better on the dara arm. That is still a significant area of unmet need. We have now analysed ENDEAVOR data for cytogenetics, there’s no overcoming of the high risk, daratumumab doesn’t seem to, which is why it is interesting to see this signal in ixazomib. That needs to be replicated in other independent, larger studies to see whether it’s really, truly a unique thing to ixazomib or not, which will be very important.
HL: But this was confirmed today by Shaji Kumar’s presentation who presented a long-term follow-up of his phase I/II study using ixazomib/Rev/Dex. What he found is continuous improvement in outcome with long-term ixazomib therapy without any significant toxicity. So, as you mentioned, this drug is really very interesting and I hope it will change at least the way we also handle maintenance therapy in the future, particularly in the high risk patients.
JC: Actually, looking into the future I think actually we’re entering into the era of immunotherapy. For example, daratumumab is just one example and then we actually have anti-PD-1, the PD-1/PD-L1 axis is very important, not only in solid cancers but also in a wide range of haematological malignancies including myeloma. So that’s why we see some pretty impressive data from the use of the anti-PD-1 antibody pembrolizumab together with Revlimid and dex, although these are still premature. But then it seems that even in lenalidomide refractory patients still the response rate is almost 40% so it’s quite impressive. So I believe that immunotherapy is coming into becoming a very important option, not to mention that we have also CAR T-cells, chimeric antigen receptor T-cells. Currently the best antigen in myeloma is the BCMA, so this is the B-cell maturation antigen that can be targeted. And also there are actually a lot of clinical trials going on with different manufacturers of the BCMA targeting CAR T-cells. I just wonder whether in the future we may be able to target additional antigens in addition to BCMA because the BCMA is also actually expressed in certain other haematopoietic cells.
HL: Yes, as you mentioned there are trials ongoing combining a checkpoint inhibitor with an antibody against membrane antigen. In the future we could also envisage using two different antibodies against epitopes on myeloma, as is done in breast cancer, for instance. So what impressed you most regarding the CAR T-cell presentations here which have been shown to the audience today or yesterday?
WJC: Very impressive yesterday was the presentation from the Chinese group on their CAR-T results. This was the same abstract that was presented at ASCO just last month. They show a very high response rate, actually I think the response rate was PR and above in 100% of cases with close to 50% or more achieving a CR. Interestingly enough for that piece of data, and this was a question that was posed to the presenter, was that in almost all the patients the CAR-T actually do not persist in the patient, they all disappear after about six months or so. But yet they have five patients that have remained in CR going out more than a year. So this is somewhat interesting because in most of the ALL CAR-T study with CD19 the long-term remission is associated with long persistence of the CAR-T. So I’m not sure whether this means that either the CAR-T that is infused or manufactured is a bit different or that myeloma patients may have a slightly different biology. But that data is very impressive and, in fact, this afternoon we’ll hear another presentation on a different CAR-T programme but I think this is the future potentially.
JC: Yes, actually that study is actually conducted by our researchers from Xi’an Jiaotong University. So basically they have nineteen patients, if I remember correctly, eighteen of them are evaluable and actually they achieved an overall response rate of 100%. 95% of these evaluable patients are actually entered into near-CR or more. So this is a very remarkable result and actually what I notice is that in these CAR-T cells, because the B-cell receptor has to be conjugated [?? 17:20] to the signalling molecule of course but also to costimulatory molecules so we can use CD28 or 4-1BB or actually together. So this possibly together is a third generation. What I noticed is that they used 4-1BB so they didn’t mention about CD28, so possibly this is second generation CAR-T cells. I’m not sure whether actually 4-1BB is an important costimulatory molecule so I’m not sure whether it may actually help to contribute to this very remarkable result and also possibly the persistence of the CAR-T cells inside the patient. But anyway I agree that we still have to see the long-term results but it is truly remarkable in this connection.
HL: If we would have an antibody or, let’s say, a bispecific antibody producing similar results what would be your preference?
JC: My preference, of course, CAR-T is very demanding, it requires a GMP standard over a high level about technology, about the genetic engineering, it has to be very exact. So I believe that, for me, it’s easier to use a bispecific antigen engager. So I’m actually looking forward to the emergence of these drugs in our locality. Obviously currently I notice that they have actually bispecific antibodies are targeting BCMA on one side and also CD3 to engage the T-cells into action. So I do look forward to this trial.
WJC: In that regard I would just say that in the ALL story the advantage seems to be with the CAR-T in terms of longer term disease control because the drug is temporary. But I also agree that logistically it’s always easier to use an antibody than a CAR-T because it’s very, very expensive and also a very involved process. But in myeloma we’re lucky to have all these platforms currently undergoing clinical trials and we’ll surely know in the next few years which would be a better platform to go with.
HL: This is a very excellent statement for closing our session. The future for myeloma patients looks very bright and for us as myeloma physicians. So we are grateful for all these developments, we are grateful that we can take part in these developments and we are looking forward to much better therapies and to be able to cure the majority of patients and, in the end, all of our patients affected by this disease. Thank you very much to this expert panel. Thank you for listening. Thank you ecancer for having us here. Thank you very much.
