ASH 2020: Immunotherapy in relapsed/refractory multiple myeloma
Dr Robert Rifkin - Rocky Mountain Cancer Center, Denver, USA
Prof Sagar Lonial - Emory Cancer Institute, Atlanta, USA
Prof Evangelos Terpos - University of Athens, Athens, Greece
Dr Nina Shah - University of California, San Francisco, USA
Dr Eric Smith - Dana-Farber Cancer Institute, Boston, USA
RR: Good day, and I’d like to thank all of you for joining this ecancer review of the recent American Society of Haematology meeting. Today we’re going to focus on some exciting developments in the area of the treatment of relapsed and refractory multiple myeloma. Specifically, which is a bit unique to this conference, we’re going to focus on immunotherapy. So today I’m delighted to be joined by an international panel and we’ll just go around the room and have them introduce themselves. Dr Terpos.
ET: I’m Evangelos Terpos, I am a Professor of Haematology in the Plasma Cell Dyscrasia Unit of the Therapeutics Department in the University of Athens School of Medicine in Greece.
RR: Dr Lonial.
SL: I’m Sagar Lonial, Professor and Chair in the Department of Haematology and Medical Oncology at Emory University in Atlanta, Georgia.
RR: And Dr Shah.
NS: Hi, I’m Nina Shah, I’m from the University of California, San Francisco in San Francisco California.
RR: And finally, from the other coast, Dr Smith.
ES: Hello, I’m Eric Smith and I’m a myeloma and cell therapy physician scientist at Dana-Farber in Boston.
RR: Well thank you all for joining me in this very condensed review of ASH. This was an exciting year. I’m a community oncologist at Rocky Mountain Cancer Center and a member of the US Oncology Network and Vice-Chair of Haematology Research and the myeloma disease lead. So I think that this is terrific and I’ll present a bit of the community view and then we’ll get to hear the exciting things that are going on.
This year there were quite a number of presentations on immunotherapy and I think you’ll hear about some new targets. All of us are familiar with BCMA but you’re going to also hear about the G-protein receptor family, C group 5, which is a new, novel target in myeloma cells. In addition, there were a number of trials with dual inhibition therapies with BRAF and MEK as well as bispecific antibodies, CAR T and a whole host of other things. So what I’d like to do is just kick things off real briefly by reviewing a trial in progress and then we’ll go ahead and present clinical results from others.
Specifically, I’d just like to summarise very briefly the DREAMM-7 protocol. All of the audience is familiar with belamaf and this is a study, a phase III study, comparing belantamab mafodotin, which we will just go ahead and call belamaf, and it’s a BCMA maturation targeted antibody-drug conjugate. We’re going to be comparing that to another combination, so it will be BVD versus DVD, or daratumumab Velcade dexamethasone. The only reason I highlight this is this is a high priority trial that’s in progress and recruiting actively now. It’s exciting because it really represents the advancement of belamaf into the clinic and we’re now getting much better at giving the molecule and understand its unique side effect profile. So I really won’t dwell further on DREAMM-7.
Now what I’d like to do is turn to Dr Shah who is going to discuss very important aspects of BCMA directed CAR T-cell therapy and, importantly, an issue that I think is vital during the pandemic and that’s quality of life domains. So, I’ll go ahead and turn things over to Nina.
NS: Thanks so much. This year we presented an abstract relating to the quality of life outcomes for patients who received the b2121 BCMA directed CAR T-cell also known as Ide-cel now. Although we already know the actual data from the efficacy of how the CAR T-cells did, the question is did the patients themselves do better? There had been data at EHA presented this past year on primary quality of life domains and here, this year, we’ve presented the secondary quality of life domains. Something interesting that we found was that across the board emotional functioning, social functioning and in symptoms versus GI symptoms, and overall global health status generally was lower than the usual population at baseline. But by the time people had gotten their CAR T and gone on for about nine months you could see that there had been a significant improvement in many of those domains and certainly not a lowering of any of those domains or a worsening of any of those quality of life functions. What we were able to see is that this one-time treatment, which might be able to give people maybe a year’s worth of time where they are not having other chemotherapy, actually might improve their quality of life as well which is an important outcome measure in clinical trials, it’s not just about efficacy. Ultimately I don’t think that the quality of life data is going to say, ‘You should use this CAR T versus that CAR T,’ but rather it will tell you, ‘You may want to choose a CAR T versus BiTE or ADC,’ and that’s one of the things we can get out of this data and use for future applications.
RR: So I think that’s very exciting, especially in the pandemic era where we’re all confined to home and quality of life has obtained a whole new meaning.
RR: Dr Smith, what do you view as one of the most exciting developments of ASH this year? Is there a particular abstract or presentation that stood out?
ES: Hi, thank you. Yes, if I could just briefly comment on Nina’s presentation and then I’ll answer your question. I think it’s phenomenal that Nina and others are looking into this and anecdotally I’ve certainly had patients who have received CAR T-cell therapy echo what Nina’s findings have shown and that is these patients are not coming to the oncologist, they are not on any cytotoxic chemotherapy, once they’ve recovered they are really enjoying their life as they did from years earlier.
Regarding your question in terms of other abstracts at ASH, I think some of the most exciting data has come out from two bispecific abstracts with new targets beyond BCMA. Of course there’s a lot of interest with BCMA CAR T-cell therapies, BCMA antibody-drug conjugates and BCMA bispecifics but there have been two abstracts which I’m sure we’ll go into in more detail, one targeting GPRC5D that you mentioned at your beginning, which is of near and dear interest to my heart as we described that target. The data from the Janssen group is particularly encouraging. The other from the Genentech group targeting another antigen that is specific on myeloma cells which is FcRH5 and also there there are some early encouraging signs.
RR: Yes, so this is very exciting. It’s a year when targets from the laboratory are starting to move into the clinic. Dr Lonial, what’s going on in Atlanta that’s exciting in myeloma?
SL: If I had to summarise the ASH myeloma continuum, I think this year was really more about the BiTEs and the bispecifics. We saw four or five different BCMA targeted bispecifics or T-cell engagers that all looked very active. The adverse event profile was pretty modest compared to the activity that we saw and I’m going to go out there on a limb and say I think it’s going to give CAR T-cells a real run for their money. Because I think the ability for patients to receive this as an outpatient with minimal therapy, and the unknown right now remains to be seen whether the responses will be durable. So long-term follow-up is really exciting but when you combine that with the FcRH5 and the GPRC5D data out there, I think there are so many immune targets in myeloma now that we really should be able to figure out how to eliminate the clone and result in long-term disease control through a combination of different modalities.
RR: I think that’s excellent. Dr Terpos, you had a big presentation at ASH here which didn’t really have CAR Ts or bispecific or other things but yet I think it’s a very important abstract. Would you like to summarise that briefly for all of us?
ET: First of all, I think that this ASH meeting makes us understand what would be the standard of care within the next couple of years, even in Europe, which is not so easy to use all the drugs that are available in every line of treatment. Due to this ASH meeting and the abstracts that were presented, daratumumab based combinations seem to concur first line and this, even for Europe now, is the standard. It seems that the belamaf combinations probably will go to the second line, followed by immunotherapeutic new agents with bispecifics or CAR T-cells, especially bispecifics with so many abstracts for very effective bispecifics this year. So probably when they go to the phase II, or even phase III studies, we are going to see them after or even after transplant for the patients who have high risk disease and are MRD positive after the very effective drugs that we have at first line, for example dara-VRd plus transplant plus consolidation and maintenance. So possibly after transplant if these patients at high risk may have MRD positivity then possibly bispecifics or CAR Ts may help on that.
We presented an EMN study, European Myeloma Network study, the so-called APOLLO study, which compared daratumumab pomalidomide and dexamethasone versus pomalidomide and dexamethasone. This was the phase III study that was needed in order for dara-pom-dex to have approval, mainly in Europe. You know that it has been approved in the US, based on phase II data. So we’ve seen that that triplet, as in the majority of daratumumab additions in other standards of care, managed to increase the progression free survival with a hazard ratio of 0.63. It was 12.4 months for dara-pom-dex versus 6.9 for pom-dex in relapsed/refractory myeloma patients who had received up to three prior lines of therapy. We also had a subgroup of patients, but they had to be lenalidomide refractory, who could have the dara-pom-dex or pom-dex at second line and we’ve seen also with a hazard ratio of 0.66 that the combination was very effective also in this cohort of patients. The toxicity was not much higher compared to pomalidomide and dexamethasone. I want to mention that because I was one of the co-PIs of this study that we’ve seen some increase in the infection rate initially but then when we used for the first treatments levofloxacin antibiotic prophylaxis then the signal vanished and there was no problem at all with infections in this study. This makes very important, at least for this combination, rather pomalidomide based combinations, that possibly for the first three months the use of levofloxacin antibiotic prophylaxis is totally obligatory in order to reduce the infection rate dramatically.
RR: I think that’s very important and I’d like to go back to what Dr Lonial said in that all of these things now we hope are becoming much safer and much easier to administer and hopefully will make their way soon into the community. Maybe we could go around the room a little bit, starting with Dr Smith, and see who his centre is actively looking for and then where he sees his near and dear molecule to his heart moving out into the clinic and trials. Then we’ll go around because, as all of you know, in the community we still see the majority of myeloma patients. We refer as often as we can to our clinical trials and others but we’re really looking forward, as just about everybody is, to how these are going to integrate into community and everyday practice. Dr Smith, pick up with your favourite molecule.
ES: Thanks so much. I think those are really excellent points to consider. So I’ll discuss a little of the CAR T-cell therapies broadly in terms of how they are viewed from a toxicity perspective and might make their way to work with community physicians. CAR T-cell therapies overall, there are some scepticism about the safety and particularly about older patients and the requirement for their fitness in order to be able to be referred for these therapies. It’s really important to point out that when targeting BCMA in multiple myeloma, and we don’t know if it’s the target or the disease or because of our earlier interventions, has been far more tolerable than targeting CD19 in large cell lymphoma or in ALL. It’s really the rare case for a patient to need intensive care level intervention for toxicity from these therapies. So I do think as that message filters down into the community older patients and more and more patients will realise that this is a one-time therapy that does require conditioning chemotherapy but I do see it being used more and more in the outpatient setting as these therapies do become approved and we gain more experience with them. A big part of that is our understanding now that we can intervene early at the first sign of fever and that those interventions both can cut off cytokine release syndrome to prevent it from becoming more severe and, at the same time, not interfere with the expansion of the T-cells or the efficacy down the road. These were lessons that we’ve learned over the years and this is still a very new therapeutic modality.
Specifically regarding GPRC5D that I mentioned, the bispecific data seems really promising and tolerable and that’s a new target for immunotherapy of myeloma for sure that will have a lot of interest. GPRC5D targeted CAR T-cells trial based on my work is open at Sloan Kettering now where I recently left and hopefully we’ll see that expand to multi-institution studies. But the idea of a combination of targets, BCMA and GPRC5D or even the FcRH5 is very exciting as we can hopefully eliminate myeloma cells that may be low for one or the other antigen but not low for both and have an impact on the durability of these therapies.
RR: Thank you, I think that’s great. We actually look forward to participating in the phase III trial of your favourite drug. Dr Shah, where do you think things will go and how can we get this into the communities and, if you will, out of the hospitals which are full of COVID patients?
NS: Yes, I think this ASH was really great for us to understand that there are so many options available for these novel targeting agents. There are a lot of CAR T candidates, there are a lot of bispecifics and there are new targets for bispecifics. So where I see CAR T going potentially is just in the second line. It’s going to move up from being a fifth line, sixth line, our last tool, but really go into the second line and maybe bispecifics will also go there. If there was failure on BCMA directed therapy then people could get something against GPRC5D or more optimally, as Eric described, potentially combining targeting both of those in order to have a more durable response. So all of these things suggest that we’ve actually moved to a new era of myeloma treatment, we’re not just going to rely on chemotherapy, or even just targeted therapy, but we actually have immunotherapy with new targets. I would say that one of the things that we learned this ASH is that 60% is the new bar for single agent activity because all of these agents in phase I, some of them not even reaching their RP2D yet, had around a 60% activity. I just thought that was so amazing in single agent, you just don’t see that. So that’s just something that maybe we’re getting spoiled but that seems to be a new bar to beat.
RR: It’s nice to see the bar go up. Sagar, what do you think is going to happen in the future once they stop shipping vaccine from your home city and we can get back to myeloma research?
SL: Yes, I think there are two stories. The first that was really interesting was an abstract that was presented in phase I of the Poseida BCMA directed CAR T cell, that one, and one that Nina has presented in the past which is the bb21217. What I like about both of those is they are taking the original CAR concept and trying to improve persistence which, to me, is the big issue with CARs in myeloma. Eric and Nina may disagree with me on this, but I think the biology of myeloma is so different from ALL and diffuse large B-cell lymphoma that persistence or multiple doses are likely going to be what we need to do if you want to go with a single target. Eric’s idea of targeting two is really exciting to see results as well. But what I like about both the Poseida, which is a vectorless CAR T-cell, which is really exciting because that will dramatically reduce the cost of a CAR T-cell product, or the 21217 which really tries to switch the phenotype or activation set-up of the CAR T, those to me really represent part of the future of cell therapy, taking what we already know and building on it to try and improve persistence.
I suspect where we’re going to go in the next five years is rather than four cycles of triplet or quad induction and consolidation and indefinite maintenance, I think we’re going to go to more of a HyperCVAD-like regimen where you’ve got block A and you’ve got block B, you’ve got different drugs in block A from block B, you try and take these non-cross-reactive agents, put them together and then ultimately come to consolidation, maybe with high dose melphalan, maybe with CAR T-cells, I don’t know. Then give limited duration maintenance, just like you would in ALL, with the hopes of completely eliminating the clone. And that’s our work for the next ten years, I think.
RR: So, Evangelos, are you ready to take that on in Greece? How do you see this spreading in Greece and throughout Europe?
ET: I think it is important to have the bispecifics because, as you know, one of the major issues in Greece and also in other European countries is that we don’t have so many approved by JACIE allogeneic transplantation units for the CAR T-cells which is something that is definitely needed from the companies in order to open the CAR T studies. Not only the CAR T studies but also in lymphoma and ALL, standard treatment now with the CAR Ts, all the countries use allogeneic transplantation units for the CAR Ts, which is a low number in every country. So even the very, very rich countries in Europe like Germany don’t have in every big city big allogeneic transplantation units for CAR Ts aend this is a problem. In Greece we have only two of them, on in Athens and one in Thessaloniki, the second major city. So, for us, it is a real problem. So the bispecifics for us seem to give a solution on that. I am very happy seeing such good results and, as Nina mentioned, we’ve seen that even with new bispecifics like talquetamab that has a totally different target in myeloma cells than the BCMA, the response rate was up to more than 70% as monotherapy. I think that this is extremely important because we are going to see more and more BCMA-targeted treatment to go up front like either monoclonal antibodies like the belamaf but also CAR Ts or other bispecifics. So we need other targets and that’s why I’m extremely happy.
So we are going to open two bispecific studies now in our centre and I am very happy that other Greek and other European centres will participate, centres that don’t have the opportunity to have CAR T-cell studies, mainly because of the lack of JACIE approved allogeneic transplantation units. I believe that the bispecifics probably will fit better in the European environment.
RR: Well, thank you very much. I think it’s interesting, maybe, as we start to conclude to go around the room, I haven’t heard anybody mention NK-directed CAR T-cells yet which may prove to be something that’s very exciting. Then I liked Sagar’s hypothesis, and Eric’s, that hopefully at some point this is not going to be a continuous therapy disease forever and that hopefully with the advent and approval in the United States and other places of MRD testing with next gen sequencing, maybe if you get three negative MRD tests over a year we could stop therapy. So I guess what I’d like to do is get concluding thoughts going around the room, maybe starting with Dr Smith.
ES: Thank you, it’s been a great conversation. I think NK therapies, NK CAR T-cell therapies, and off-the-shelf CAR T-cell therapies will be extremely important for the cell therapy field moving forward. Allowing those therapies to be really administered quickly and easily by hospitals will enhance their accessibility and the likelihood that patients will be referred to them, that will be certainly for the future of CAR T-cell therapy and, just to reiterate, that’s the goal. We’re trying to eliminate every last myeloma cell, prevent the need for lifelong therapy. And your point about multiple MRD testing is exciting, we clearly have evidence that the deeper response the more durable response, and it will be exciting as well to have blood-based MRD testing which is another field that’s making some really incredible advances to allow that kind of monitoring.
RR: Thank you Eric. Dr Shah, any thoughts?
NS: Yes, I think that understanding the utility of allogeneic NK and other types of approaches to CAR T will rest on understanding why we aren’t curing myeloma yet. Is it because we have the wrong target or because the cells are disappearing like Sagar was saying. Once we know that then we can understand what the goal can be. For example, it may be more difficult to keep allogeneic cell sources persistent than it would be autologous but, then again, these allogeneic cells if they’re immediately available and are from a more fit immune donor, then maybe those could do a better job up front. So it really depends on what we find as the reason for why we aren’t curing these diseases. I completely agree with Eric, I would love to see blood-based MRD analysis because this will help us to direct our therapies, better understand when we have to start and stop. And I look forward to hopefully the FDA combining or allowing for MRD to be one of the clinical trial endpoints so we can get answers a little bit sooner.
RR: Thank you. Dr Lonial.
SL: Yes, thank you. I agree with everybody, it’s been a great conversation. The one sort of note of caution I might add to the excitement over MRD was we saw two studies now with long follow-up that suggested that single time point MRD does not necessarily make up for intensity of therapy. If you had to look at the second headline on ASH myeloma after T-cell engagers, which was the first headline, the second headline was transplant is not going away. Because we saw data from two large trials that demonstrated the continued benefit of transplant, despite the fact that response rates and MRD negativity rates looked similar at early time points. So the question about sustained MRD negativity should replace the discussion on just MRD negativity. The second is I think we really need to look at 10-6 as the right endpoint. To me, 10-5 really is nothing more than a regulatory endpoint – it helps us get drugs approved quicker so we don’t have to wait seven years for PFS. But if we’re really going to talk about discontinuation of therapy it needs to be sustained MRD negativity. I like what you said, Dr Rifkin, about perhaps three time points in one year. I might say three time points over two years, to me, is more sustained and that it needs to be at 10-6 in order to really be useful for clinical decision-making.
RR: Thank you Sagar, I think that’s very useful. I’m a big fan of 10-6 as well. Dr Terpos, where do you see NK CAR Ts and MRD testing going in your neck of the woods?
ET: Thank you Rob and also thank everybody for the great discussion. I think that the NK CARs is a future treatment that may give us very good results, either where bispecifics may fail or even to have more safer ways to give the CAR T technology in earlier phases of the disease. But this, of course, has to be proven in clinical studies. Regarding the MRD, I totally agree with Sagar that we need 10-6, don’t forget also the imaging MRD that has to be improved. The PET/CT will be FDG-PET possibly is not the optimal, although it’s the best that we have to date. Possibly other tracers have to be used but we need to identify them because the extramedullary disease is a real problem in many patients that have achieved a bone marrow MRD negativity even at the level of 10-6. We have seen several patients achieving this threshold and then to have extramedullary disease somewhere else. Sometimes it cannot be captured by the standard FDG-PET so I wanted also to mention this – we need to improve the imaging MRD also.
And also we need to have the MRD definition, sustained MRD, as a target for approval of the drugs because otherwise in the first line therapy with new treatments like dara-VRd or dara-KRd plus transplant, one or two even for the high risk plus consolidation and maintenance, we may need now seven or ten years to see an approval if we continue to have PFS as an endpoint. I believe that as more and more studies suggest that this PFS correlates with the depth of MRD, I believe that at least sustained MRD needs to be the target for the approval of new drugs.
RR: I’d like to thank all of you very much for participating in today’s discussion. I think it’s a very exciting ASH and if you do, unfortunately, contract multiple myeloma we have so many more targets than we did even just a few years ago. I think there’s a bright future with everybody’s cautionary notes that just MRD negative times one is not good enough. Hopefully by using the combination of things, as outlined by Eric and others, that someday, realistically, we might be talking about curing myeloma although I don’t think any of us have exactly done that yet. So, once again, on behalf of ecancer I’d like to thank all of you for participating in today’s discussion.