15th International Myeloma Workshop

What is the potential for using monoclonal antibodies in multiple myeloma?

Prof Sagar Lonial – Emory University, Atlanta, USA
Prof Pieter Sonneveld – University Hospital Rotterdam, Rotterdam, Netherlands
Prof Jesús San Miguel – University Hospital, Salamanca, Spain

SL: I’m Dr Sagar Lonial and we’re here live with ecancer news at the 15th International Myeloma Workshop in Rome. I’m joined by my colleagues Dr Sonneveld and Dr San Miguel and we’re going to talk a little bit about some of the highlights from the meeting today. So let’s get started talking a little bit about the one area that I know people are really excited about and that’s monoclonal antibodies. We’ve got at least two or three, two that are potentially imminently approvable and I think the mechanisms of action are actually quite unique and multifactorial, not just enhancement of immune function but also ADCP potentially, CDC and even direct cytotoxic effect through binding and interaction with CD38, for instance. What do we know about their activity as single agents and in combination?

JSM: Regarding single agent elotuzumab has not shown activity as single agent, only in stable diseases but in combination with lenalidomide, dex we have already the data of a large, randomised trial showing superiority. As far as anti-CD38 monoclonal antibodies are concerned as single agent they have clear activity. Approximately one third of patients that have been refractory to all previous treatment have responded to the anti-CD38 monoclonal antibodies. The most mature data respond to daratumumab but there is also similar data now with another monoclonal antibody.

SL: What about combinations? What do we know about trying to make these drugs even better?

PS: Combinations, as Jesús mentioned, with len-dex for example but also with proteasome inhibitors, they seem fairly promising. Right now there are studies ongoing or have already been completed like CASTOR and POLLUX with either an IMiD or a proteasome inhibitor that we have to wait for the results. But the results that we know of, preliminary, are very promising. There are trials now planned or ongoing in the newly diagnosed patient that will also explore these combinations of proteasome inhibitors plus an IMiD plus daratumumab and for elotuzumab the same thing.

SL: Right, I think it’s really exciting. So I think our centres have probably treated a lot of patients with each of these antibodies. What are the unique pitfalls or classical antibody related things that practitioners need to be aware of as they get out there

JSM: Probably the first one is the infusion reactions. Approximately two-thirds, even more, of the patients have infusion reactions. The good news is that they are mild, only grade 1/2 and they are well controlled if you pre-medicate appropriately these patients. The second problem could be the interference that you may have with a monoclonal antibody when you assess the response because the monoclonal antibody may give you a false band in the electrophoresis that may confuse as a residual paraprotein. Also you can have problems with the red blood cells when you are doing the typing for the transfusion due to the monoclonal antibody. But we have learned already quite fast how to handle these problems.

SL: Yes. Anything you want to…?

PS: Those are practical problems and people have to be aware of them. So if you don’t do the blood typing before giving daratumumab you have to rely later on on genotyping rather than phenotyping. Another thing I would like to mention is that with daratumumab it’s of course important that the CD38 expression on the target cell is there, in this case the myeloma cell. There are myelomas that have lower or even low expression of CD38 and what people in the lab have discovered is that you can increase the expression of CD38 in the tumour cell by treating the cells with ATRA, all-trans retinoic acid. This seems also a promising way to improve the efficacy of daratumumab. We will start a trial shortly where patients will have daratumumab monotherapy and then later on with ATRA pre-treatment and we’ll look at the expression of CD38 in the cell. So this is…

SL: Yes, really amazing laboratory data that really identified that. That, coupled with the data from, I think, the same group that also suggested that expression is directly linked to response really speaks to things that try and upregulate CD38 expression.
PS: Exactly, so that’s an important issue.

SL: Yes, OK. Well let’s switch gears a little bit and talk about the new proteasome inhibitors. We’ve talked about lots of different ways to give bortezomib – IV, sub-cue, weekly, twice weekly, but what do we know about the right way to give carfilzomib and what else is new on the front in terms of oral proteasome inhibitors?

PS: If I may start with carfilzomib, this is a very effective and potent proteasome inhibitor. We have used it in both relapsed patients and in a trial for newly diagnosed patients. It’s well tolerated, it’s rapidly effective and so far we have not entered major problems with the administration. So it can be done on an outpatient basis and patients tolerate up to six or eight cycles of carfilzomib in combination with one or two other drugs quite well. So both with len-dex or with thal-dex we have seen good results and minor toxicity.

SL: Tell me about the concerns that certainly flowed out there about heart failure, cardiac issues, shortness of breath. Have you found that in the phase III trials that you’ve run to be an issue?

PS: It’s definitely an issue. I think we should not underestimate this because the cardiac effects may occur suddenly and unexpectedly in patients. So you have to monitor your patients, you have to check them for pre-existing cardiac disease. I can say that in the carfilzomib thal-dex trial that we did in 120 patients so far, newly diagnosed patients, we have two cases where patients developed cardiac problems, one was a patient already with cardiac disease and the other was new. So we keep an open eye for it because it’s not frequent but if it occurs it’s serious.

SL: And what do you think, have both of you had experience looking at 2036, 2056, once a week, twice a week, what do you think we’re going to end up using in real practice?

JSM: I think we are looking forward for the once a week for convenience for the patient. In fact there is an ongoing trial that will try to answer this question but for convenience for the patient it will be much better the once a week if the activity is preserved.

SL: OK.

PS: I agree, definitely.

SL: And ixazomib, tell us about the oral proteasome inhibitors.

JSM: Yes, ixazomib is the twin brother of bortezomib, the advantage is that it’s not only oral but also the incidence of peripheral neuropathy is significantly lower as compared with bortezomib. It has shown efficacy as a single agent even in bortezomib refractory patients and in combination with len-dex we have already a phase II trial showing a high activity not only during the combination but also as part of the maintenance increasing the quality, the depth of response. Probably this is the rationale why so rapidly several randomised trials, the TOURMALINE project trials, have been activated in combination with len-dex, more than 700 patients in each of the trials that are currently being conducted, in combination with len-dex in newly diagnosed patients and in the relapsed setting and as maintenance after transplant and also after conventional induction for the elderly patients not candidate for transplant. Probably we will soon have data on these very important randomised trials.

SL: Yes, I think it’s really interesting, especially the maintenance aspect could really make things a lot more convenient. So I’m going to ask the provocative question, in induction therapy if you’ve got great second generation proteasome inhibitors and you’ve got great IMiDs where have the alkylators gone from induction? Not transplant, just from induction.

PS: I think we have learned that the alkylator, say melphalan, is not a good partner for lenalidomide, look at the MPR studies. So now that len has been established as a solid first line treatment, len-dex for patients, especially the non-transplant eligible patients, I think alkylator is not the first choice anymore. So combinations of an IMiD with steroids and possibly also an oral proteasome inhibitor is probably the future.

JSM: OK, although I will accept this I am not so, so convinced.

SL: I knew you wouldn’t agree on this.

JSM: As you know, I am really a big supporter of melphalan because I think this was the first drug that demonstrated clear activity in myeloma. In fact, the data that we have when we compare VTP versus VMP in the non-transplant candidate showed that although in the short term the responses were higher with VTP, the long-term follow-up the survival was better. And we should not forget that melphalan, as other alkylators, may target precursor cells that may translate into prolonged survival. And it’s a cheap drug which is very important.

PS: I’m not saying that melphalan should be deleted from every treatment. But your VMP versus VTP was with, let’s say, older drugs.

JSM: Oh yes.

PS: Thalidomide is older. Now we have the lenalidomide IMiD which is better than thalidomide, we have the oral proteasome inhibitor. I think this is the way most investigators think this has to be explored.

JSM: No, no doubt, but…

SL: Alright, the controversy will continue. So let’s switch to HDACs. This has been an area where we’ve started and stopped and started and stopped. We were all excited about PANORAMA-1 and then everybody started criticising the difference in PFS. But I think we’ve had some new data in the last six months, or new reviews of the data, that it really identified who the better patient populations may be.

JSM: Yes, and this was a very interesting observation that has been presented at ASCO and here also in this meeting showing that in patients that have received two or more lines of therapy and have been previously exposed both to proteasome inhibitors and IMiDs, lenalidomide, the difference in PFS is almost 8 months because the response when you have the panobinostat is maintained and the PFS is maintained while in the control arm it’s significantly lower. Then I think this is very important news also. And this was the basis for the approval both by the FDA and EMA in this cohort of patients.

SL: Yes, I’ve been really struck by the ability of the HDACs to overcome either active drug resistance or emerging drug resistance. And the patients that seemed to gain the most benefit from PANORAMA-1 were exposed to an IMiD, exposed to a PI and had had two prior lines of therapy. So those are patients you could argue are well on their way to drug resistance. So that’s where we saw the biggest bang.
PS: In addition, I fully agree with what you say, in addition there are now also selective HDAC6 inhibitors that show great promise in the lab and also in early trials in relapsed refractory patients.

JSM: And excellent tolerability which is important.

SL: Right. I think ricolinostat certainly fits that bill, the ability to be selective for HDAC6, not specific, as I think too specific may be a problem as well. But its combination attributes, both with proteasome inhibitors and with IMiDs is really quite striking as well. So let’s talk a little bit about genomics and updates to new methods of MRD assessment. I know you gave a really nice talk today about some of this, how does that fit in with where we’re going?

PS: I think most myeloma doctors now agree that genetics, genomics, play a role in prognosis of patients. This is something that we learned from leukaemia. So FISH is now more or less established but there are next steps ahead like a more broader interpretation of the genetic data, of the biology of myeloma. For example, by using newer techniques like gene expression or genomic sequencing, genome sequencing, and we will learn from those results how the biology of the myeloma, how it works into the prognosis ultimately. And also if we can predict a response to specific drugs based on the biology of the myeloma. So this is important. In addition MRD is another important prognostic analysis and test that can be done somewhere after initial treatment, maybe after induction or after a transplant or after the end of maintenance treatment. I think we still have to learn what’s the best moment, whether it is a split-second analysis or a more continual analysis. There are trials ongoing where this will be analysed and for the moment I would like to say that it looks like MRD assessment is important for prognosis. You can identify patients with remaining tumour load, they are MRD plus; patients where you cannot identify surviving cells, MRD negative and the key question now is which method should we use, is it flow cytometry or exome sequencing? So it’s important that both techniques will be incorporated in clinical trials and that they can be compared and that we know, hopefully, in a few years which is the method to use.
SL: To me that message is really the key one, which is I think we’re in the learning phase of what to do, we’re accumulating the data. I’m not sure I know what to do with somebody who is MRD positive at two years out from an auto-transplant who is otherwise fine or who is two years negative out from an auto-transplant who is MRD negative and doing fine as well. I don’t know, do you all feel like we have the data to make treatment decisions based on that information yet?

JSM: No, unfortunately we have not yet this data and this is similar to what has been done in ALL. I think ALL is a model for many things and one is how to use appropriately minimal residual disease. We are using continuous treatment, it’s needed for everyone, minimal residual disease probably can contribute to this. We have already identified a subgroup of patients, those with high risk cytogenetics, that after transplant are MRD positive. This patient has a hopeful prognosis, we already for these patients do immediately they have minimal residual disease positive we do something else. But, apart from this category of patients, for the rest I think we need, yes, to conduct prospective clinical trials including MRD.

PS: Yes, this is what has been lacking so far, trials specifically designed to answer the question what does it mean MRD positive or negative. What if you apply regimen A or regimen B to those situations?

SL: OK, so as we’re wrapping up let’s touch on the new definitions of myeloma and perhaps the new staging system.

JSM: We have recently created guidelines in which for treatment of myeloma you not only will have the CRAB criteria but also if you have more than 60% plasma cell without CRAB or a free light chain ratio more than 100 without CRAB or more than one focal lesion on MRI, this is active myeloma because the risk of transformation is more than 80% and these are clear candidates for active treatment.

SL: It’s a big change but I think it’s well needed.

PS: Yes.

SL: Do you want to touch a little bit on the revised international staging system?

PS: Yes, I think that’s also a major step forward. So rather than using one prognostic parameter like cytogenetic abnormalities or ISS, now we know that combining those and other parameters like LDH and age, for example, that they may significantly improve the prognostic impact of those staging systems. Recently IMWG has made a big effort to combine the data from a lot of trials and based on that a revised ISS was constructed. But there are also other examples before that show the same picture. So by combining clinical factors with genetics and age we will be able to better classify the patients into all the range from good to standard to low risk and high risk.

SL: Yes, I think it’s really an important paper to look at because the new staging is not just two numbers any more, it really does take a little bit of time to learn it. And I think you’re right, incorporating genetics really makes it a more modern staging system. Alright, well thank you. It has been a great meeting.

JSM: Thank you very much.

SL: And thank you for tuning in to ecancer.tv. We hope you’ve enjoyed this session and look forward to additional sessions in future meetings down the road. Thank you.