Paul Richardson, MD
Dana Farber Cancer Institute
Interview Date: June 1, 2020

Myeloma progress continues in 2020 as additional therapies continue through the clinical trial process. This is great news for myeloma patients. One of the best mid-year meetings is the American Society of Clinical Oncology. Held virtually this year, Paul Richardson, MD of the Dana Farber Cancer Institute shares updates on key announcements. This includes the difference between two triplet combinations - Kyprolis/Revlimid/Dex vs. Velcade/Revlimid/Dex which had surprising results. He also shares updates on the monoclonal antibodies isatuximab and daratumumab. Dr. Richardson reviews CAR T data about the bb2121 CAR T therapy expected to be approved as the first CAR T in myeloma. He also reviews additional therapies that were recently approved, like selinexor, or others that are close to approval like venetoclax (for 4;14 myeloma patients) and a new antibody drug conjugate called belantamab mafodotin. It's key to stay up-to-date on approvals and clinical trials so you know what's coming in myeloma care. It's exciting! 

Thanks to our episode sponsor GlaxoSmithKline

Jenny: Welcome to today’s episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I’m your host, Jenny Ahlstrom, and we’d like to thank our episode sponsor, GlaxoSmithKline, for their support of Myeloma Crowd Radio. Thank you all for joining us so early this morning.

Now although many places are still dealing with the complexities of the coronavirus (I think we’re all still doing that, unfortunately), myeloma progress is still happening. We’ve heard from many myeloma doctors now that treating your myeloma should take priority. The virtual meeting at the American Society of Clinical Oncology or ASCO this last weekend was a perfect place to hear about mid-year updates. We need to know what they are so we can get great myeloma care in spite of or even in context of what is going on globally. 

In today’s show, we have Dr. Paul Richardson from Dana-Farber to give us an update, and we welcome him to the program. But before we get started, we would like to share an introduction.

Dr. Paul Richardson is the R.J. Corman Professor of Medicine at Harvard Medical School, and the attending physician in the Division of Hematologic Oncology and the multiple myeloma and bone marrow transplant service at the Dana-Farber Cancer Institute. Dr. Richardson is the Clinical Program Leader and Director of Clinical Research for Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute. 

He’s also Chairman of the Multiple Myeloma Committee for the Alliance and Alliance and Alliance Foundation for Clinical Trials, and Myeloma Steering Committee Member of the National Cancer Institute. He’s Editorial Board Member for Publications such as Clinical Cancer Research, Journal of Clinical Oncology, American Journal of Hematology Oncology, Journal of Oncology, and many, many others.

Dr. Richardson is a very distinguished myeloma specialist who’s influential in a new drug approval process in myeloma having led very large Phase III clinical trial efforts for approvals like bortezomib, lenalidomide, pomalidomide, ixazomib, and leading steering committees and oncology drug advisory committees for myeloma therapies like panobinostat, daratumumab, carfilzomib, and selinexor.

Dr. Richardson received the Earnest Beutler Lecture and Prize from the American Society of Hematology or ASH for his translational advances and achievements, and enabling clinical science in multiple myeloma. He’s also recognized and appreciated by the Patient Advocacy Community as a recipient of the Robert A. Kyle Lifetime Achievement Award by the International Myeloma Foundation for his work that’s resulted in significant advances and research treatment in care of myeloma patients around the world.

Because we have the HealthTree platform in place, and we now have over 6,000 patients who have registered in that platform, it was very easy for us to invite many myeloma patients to join our coronavirus study. In that study, we’ve had over a 1,066 patients joined to date. If you would like to join that study and fill out the survey questions around the coronavirus and how that has affected you in your myeloma care, we would love it. 

That helps inform the Myeloma research community, there’s a series of probably 40 to 50 questions, depending on what’s happened there, but we would very much like to know how you have been impacted as a patient in terms of your care, have you changed care, have you done more telemedicine? They’re very easy questions to answer, and that would be very helpful to the whole myeloma community. We would be very excited about that.

In addition, we are in the process of building some new features inside of HealthTree and building out HealthTree University. Let me just share what HealthTree University is. It is the world’s largest online educational platform for all multiple myeloma patients. Currently, we have 13 lessons in there. We plan on having up to 30+ courses about multiple myeloma, and each course has a set of lessons. For example, the last course that we just did actually has 35 lessons in it. This is an amazing platform that you can use to educate yourself on multiple myeloma. 

I also want to highlight, while we’re waiting for Dr. Richardson, I want to highlight that we just completed a webinar about HealthTree. I think a lot of people were surprised at the ability HealthTree has to help you manage your care. It’s not just a single data registry, and it’s for you. That’s why we built it. It’s to help you understand certain things that you can do to manage your disease. 

In HealthTree, you can track your myeloma in a single place. For example, if you get treated at multiple centers, you can include your information there in all your labs. Some of the locations, if they’re on Apple Health, those labs can be pulled in automatically. You can also add your genetic features and your prior treatments and outcomes and all of that. Once you do that, once you add information, then we open up benefits to you. I think Dr. Richardson is on now. We will have him join. 

Dr. Richardson, thank you so much for joining.

Dr. Richardson: Oh, Jenny, it’s my pleasure. Thank you so much to your patience this morning. We’ve had a very busy morning already with the brave new world we’re in right now with a very long series of Zooms that started around 7:00 this morning. Sorry to be slightly behind joining you, but we were on a very important research discussion just a few minutes ago.

Whilst we’re all facing such challenging times in every sense, it’s great to see the research engines still moving forward. Apologies for perhaps being just a couple of minutes behind joining you, but all very much in a good cause. It’s a pleasure to join you, Jenny, and especially after the data presented over the weekend and on Friday in the myeloma space at ASCO.

Jenny: Oh, I know. Well, no. We completely understand. We’re just so appreciative that you’re working so hard for us all. It’s just terrific and we don’t mind. Let’s go ahead and get started. I think it might be best if we break this up into like precursor conditions first, newly diagnosed myeloma, relapse refractory myeloma. There’s so much to cover. I know it’s going to be difficult for you to keep it simple for all of us, but because this is like a firehose of updates, but we’ll offer that challenge to you, because I know it’s not easy.

Dr. Richardson: No. I greatly appreciate it, Jenny. It’s just a pleasure to share with everyone. I think the broad overview that as we face the enormous challenges of the impact of COVID and the pandemic and both -- and the real challenge that poses for our patients in every way, and above all, everyone, please stay safe in this very difficult time.

I think we have to frame a conversation around myeloma advances, Jenny, in the context of understanding what the impact of COVID is going to be on a therapeutic landscape everywhere, but very importantly in myeloma because I think by way of backdrop, we all are realizing that multiple myeloma patients are very vulnerable to the complications of COVID should they become infected.

We know that in cancer patients broadly, mortality is higher. We know that in myeloma patients in particular, there may be a higher influence of serious complications. That means that we really have to focus on minimizing risk to our patients in every way. Actually, in the research environment, Jenny, to some extent repurposing in order to meet that challenge, that doesn’t just mean adapting our therapies to optimize the practicalities and safety of what we do. 

That’s obviously very important, but it also actually means in the practical sense, and certainly speaking from my own group, we’ve got an effort through the International Myeloma Society led by Nikhil, looking and understanding the incidence and severity of problems, we’ve also got a very boots on the ground type approaches in terms of actual therapeutic interventions and research that we’re doing as a whole group in this space, be it with convalescent serum, BTK inhibition, some really exciting new data around selinexor that’s emerging and targeting the vascular damage that this virus can cause. It could be a particular importance to our patients. 

My colleague Irene Ghobrial is leading an immunological effort to really understand the immunology of what’s going on, so that we can really help patients accordingly.

I want to preface our discussion by emphasizing that because obviously, as we think of all the advances at ASCO, we have to realize what do they mean in the context of what Dr. Rafael Fonseca described as the post-COVID world or how he described it was before COVID, B.C., and now what he calls A.C. which is after COVID.

I think it’s an important distinction because really, we will be living with this challenge for some time now. I think whilst there’s great promises with the vaccine is coming, the reality is that they’re not around the corner. There are still ways to go. We have to be aware of what the implications of all of this is going to be.

But with that as a preface, Jenny, I wanted to sort of agree with you that I think we can talk about a couple of things that I thought would be very important. The upfront spaces you point out, obviously some of the emerging data around smoldering myeloma, but very, very importantly about newly diagnosed disease and relapsed refractory because that’s where I felt that was really some strong and important information to share.

So Jenny, how would you like me to start? Would you like me to start by just going first into perhaps the plenary session yesterday, which I thought was particularly important. This was the KRd versus RVd study. Would you like me to start with that, Jenny?

Jenny: Yes. I think that would be a great place to start, and thank you so much for the COVID context, because we’re all living that and thinking about that in addition to our myeloma. It’s really important. As we go through, you can put everything in context, if you don’t mind.

Dr. Richardson: No. I’ll be delighted to Jenny, because it is really the gorilla in the room. I think -- I feel very strongly that the myeloma community, we have to focus on the myeloma rather than be distracted by COVID, that’s true but obviously, we realized that the absolute challenge it poses. 

In that spirit, Dr. Shaji Kumar presented yesterday at a plenary session in ASCO, which hit a real milestone in the myeloma research community, because plenary sessions of ASCO just focused really more on solid tumors than the necessarily hematologic cancers generally speaking is a very important achievement for Shaji and the ECOG team who led the ENDURANCE study. It was our privilege to be part of that. This was the ALLIANCE piece that was our component. At the same time, the SWOG group are major participants.

This represented, I think, what I consider a gold standard Phase III trial where we have the inter-group mechanism being deployed to really translate cutting edge clinical research to real world practice by virtue of the inter-group mechanism which reflects not just top academic university centers but community practices as well as a very broad national reach.

So I first and foremost wanted to acknowledge Shaji and Vincent Rajkumar’s leadership of the ENDURANCE study, and of course all the resources that come to bear through the National Cancer Institute to deliver this study. It was a long trial in the making but a very important one. I think ENDURANCE was an excellent acronym to be used.

But to simplify it for everyone, this was a perspective randomized comparison of all the lenalidomide, bortezomib, and dexamethasone versus very exciting new proteasome inhibitor relatively to bortezomib, carfilzomib, Revlimid, and dexamethasone. And obviously, both platforms have been shown in early phase studies to be really very active and there was great promise around certainly KRd that it may actually go a step up from RVd, and provide really high quality responses that could translate into clinical benefit that may surpass that provided by RVd.

Obviously, RVd was established with the early phase work that we were privilege to be part of, and then the SWOG study led by Brian Durie which very convincingly showed that RVd was a new gold standard. This was a very, very important trial. How did these two regimens perform in the real world for our patients?

The study enrolled over a thousand patients, so it was an incredible achievement and the patients who participated were really the heroes in my view of this. Basically, patients who weren’t immediately going to transplant, they were patients who generally speaking will not be considered classically high-risk in terms of their myeloma characteristics. I think that in that context, it’s important to know their work, our patients in the study who had translocation 4;14 which we would normally consider to be high-risk. And indeed, there were patients with CD38

ISS Stage 3 disease, which we also consider to obviously be higher risk by clinical criteria.

It wasn’t a study that was empty of high-risk patients, it really did contain a high-risk population as well although it was enriched for what we consider standard risk myeloma. In that context, with this study, what was particularly striking was that the progression-free survival which was the primary endpoint of the trial, was actually virtually the same - around 34 months of those regimens and I think they’re very important because what it suggested was that these were both very active regimens, both very effective, not unexpectedly bortezomib’s challenge was peripheral neuropathy, a very important one, and that was significantly higher against the RVd regimen compared to KRd.

What was very important though and particularly in the current context of what we’re facing with COVID and so forth, was the cardiovascular, renal, and thrombotic signal from the KRd platform. It was cardiovascular pulmonary renal and then thrombotic to be precise, and there under rates of significant toxicities to KRd were significantly higher than the RVd regimen. 

By virtue of actual numbers, approximately 16% of the patients on the KRd arm ran into these toxicities in a significant sense, which is obviously good news for those who didn’t, but obviously, very important to us as providers to be aware of the implications of that and in contrast for RVd, it was less than 5% so we now know very clearly that we have to think about this vascular component to KRd that we’ve known about and realized.

But this is very much a real-world study which demonstrated this to be an important challenge that we needed to be aware of. So I think that sort of arms us to therefore be better at managing that and more selective going forward, and certainly, one of the messages from the tolerability profile was KRd’s clearly very active, but we have to be careful about this particular spectrum of toxicities.

The good news though is obviously, KRd was not associated with anything like the degree of peripheral neuropathy, and there was some discussion from a number of key opinion leaders including Jesus Berdeja, who basically made the point of then someone who would have neuropathy as a worry, you know, this data would certainly support the use of KRd as a treatment of choice, whereas someone conversely who might have vascular or renal risk would be someone we would much rather pursue RVd.

The very interesting thing was also, in the classical 4;14 group of patients, there was also no difference of one regimen versus the other, both perform well. Having said that, in the Stage 3 patients, there was a signal that KRd might be more powerful in that particular subgroup. Basically, good takeaways in that both regimens were exquisitely active and effective in generating close to three years of disease control on average without transplant, and at the same time, an understanding of the tolerability of both regimens now being much clearer and allowing us to choose.

On the same meeting on Friday though, there was a presentation by the SWOG group led by Dr. Saad  and Bob Orlowski where, and again, which we in the ALLIANCE were part of, which was a comparison of the RVd +/- elotuzumab combination in high-risk disease. What is very interesting, within the high-risk population, defined by 17p deletion and adverse cytogenetics, again, the PFSs were actually very good for both groups of patients. They exceeded 30 months, but the Elo was very well tolerated, but didn’t appear to add a great deal to this setting.

I think as we think about the implications of this, we also had a very nice presentation in the oral sessions on daratumumab in high-risk disease. What was very interesting was that they were able to show, in what was called a meta-analysis of randomized Phase III trials, this is an abstract presented on Friday, but they showed the efficacy of daratumumab with high-risk cytogenetics.

Basically, longer follow-up would be probably needed, but having said that, there was a strong suggestion of benefit of daratumumab in high-risk disease. I think for patients, the important takeaway is that these triplets are performing well, the addition of antibodies particularly daratumumab may be important, and we are able to tailor off therapies even more to suit an individual patient to improve outcome.

I think that this real-world study led by Shaji, the ENDURANCE trial, was an incredibly important milestone in our upfront treatment of myeloma because it also led us to another position which I think is important. Shaji concluded that RVd should be considered the standard backbone in the upfront setting for patients going forward based on this data. 

I think that’s a very fine conclusion, but I also think the takeaway is not it’s a standard, it should be that we have options and we can tailor. In other words, we can obviously use RVd but we can also think about how we best position KRd for example, and there may be, as I mentioned, patients who clearly benefit from that, and would be therefore appropriate, and also, we can be very careful in what we do to minimize the side effects.

The final point I was going to make in this, as we think about this, Jenny, was strategic. If you think about the treatment of myeloma as a long journey, and it’s a true marathon, not a sprint, I need to have guns in the cupboard for my patients. What I want to have is if I use my RVd first, I want to then have carfilzomib to use if RVd fails. I’m sure you can see the rationale there, Jenny, that this is how we might strategically think about things, and of course, we also have ixazomib, which particularly for older, frailer patients as an oral proteasome inhibitor, which is particularly important in the context of COVID. That’s another very important string in the bow for us to have.

So my takeaway from the plenary session and then RVd-Elo study from the Elo study from the SWOG group, which again, it was a privilege to be part of, was that this reinforced the highest level, the options that we have going forward in terms of best evidence. A very positive overall message recognizing the level of information these studies provided to guide us with best choices for our patients.

Jenny: Well, that’s a very important study, I believe, because I think there’s a perception that KRd is more potent in general, and I know a lot of the doctors who have high-risk patients kind of go to that first, and so those are such interesting findings, and I wonder, for the deletion 17 or the 14;16 patients that are in the other high-risk categories, what do you think? If some of these other studies are like the RVd-Elo and the dara are being used in the high-risk, do you have any indication for other things? I know there was another study at ASCO doing isatuximab with KRd for newly diagnosed myeloma.

Dr. Richardson: Yes, that’s correct. Well, isatuximab is obviously in the CD38 family, but it has important differences in terms of how it behaves. It binds to a different epitope of the CD38 complex, and it has more of an apoptotic signal, but I think that I was very impressed with the CD38 meta-analysis showing clearly that daratumumab was effective in those patients. 

Isatuximab clearly seems to be also active in high-risk diseases, we know from our work in ICARIA and other trials, again, I would think about this in a strategic sense where I would say that for example, daratumumab is being used earlier in this diseases, when disease recurs, what do you have? What forces do you want to deploy? Isatuximab, to my mind, combined with other drugs, provides a very important addition in the CD38 space to allow us to take on relapsing disease. 

But I agree with you that the fact that we’re exploring platforms like KRd-Isa is important. We are also looking at RVd-Isa with the goal of understanding better how that combination performs and whether that has a specific role in certain subsets, for example.

I mean there is some suggestion that isatuximab might be particularly effective against certain aspects of myeloma through this apoptotic pathway, and we’re trying to better understand what that means. Conversely, daratumumab clearly established itself as a very key component of upfront treatment, with approvals which is the critical thing so that patients have access, and of course now, they’re really starting successfully the subQ program.

I think with the subcutaneous program, daratumumab now has really been positioned very nicely to become a backbone of therapy, and then these strategic considerations become real going forward.

Jenny: Yes, very much more convenient for patients than the long infusion.

Dr. Richardson: Well, true. Also very importantly, again, in the COVID era, it’s so important for us to have short clinic visit times. We have got to maintain social distancing, we have got to maintain spacing for our patients in the clinic. In order to do that, we need the convenience of this. Isatuximab of course has a short infusion time anyway by nature of its very specific pharmacology. Even by the IV route, it’s a relatively fast infusion. There are, in fact, studies looking at subQ, isatuximab also now on the way, so those hopefully will provide us some insight as to how that may be made equally convenient.

Jenny: In the newly diagnosed setting as well, I know there were some other things that were covered at ASCO, and I don’t know which ones you want to cover or don’t. But I know there were some STAMINA transplant results, and there was also an NK cell CD38 type product, if you want to cover any of that.

Dr. Richardson: Well, sure. I mean I’d love your thoughts on these too, because I’m rather like you, I’m sort of digesting a lot of this.

Jenny: Yeah, me too.

Dr. Richardson: I would simply say that I would consider all of this data very provocative, I’m looking forward to getting a little bit more granularity on the STAMINA results long-term, and recognizing that clearly, transplant remains an absolutely critical component of our therapeutic options, but in the post-COVID-19 era, how are we going to view autologous transplant, and certainly, how are we going to view tandem transplant, for example, recognizing all the caveats with that approach that we already have.

I think that whilst the good disease control in my view is the best way of minimizing risk for our patients, I also think that profound immunosuppression and hospitalization, for example, which in the context of transplant is a reality for most patients in one way or another. We have to think about transplant in the new era, and where does that belong?

I think in that spirit, I was very struck by some of the newer agent data that was presented on the Friday. I think that the idea of more convenient, less sort of toxic therapies, really becoming a focus was an incredible positive from the meeting. I thought there were a number of presentations there that I could perhaps spend a bit of time on recognizing the, you know, other experts, Jenny, I’m sure, can give you more insights as well. 

But what I wanted to focus on, if I may, was the newly diagnosed space. We had some important information there. I wanted to now talk a little bit about a couple of things, really. Relapse refractory disease, if I may, and to talk a little bit about the session on Friday which I found particularly interesting and informative.

I think what I thought was the most important presentations of the Friday session, what was in fact the CAR T data and in particular, the KarMMa study, which my colleague, Dr. Nikhil Munshi presented. What we’re sharing with the audience is a sort of critical new platform with real significant numbers of patients involved, and the most, to me anyway, the most mature information we have so far to date in terms of a large multicenter effort that’s both US and European, and sort of provides insights into the state of the art, because this is an extraordinary effort, which combine US centers with European teams, and obviously, had an outstanding team of investigators leading it.

I think everyone’s very familiar with what’s called the bb2121 platform, or ide-cel as it's now described which in a very important Phase I study, led by my colleague, Dr. Noopur Raje, she showed beautifully that we were able to establish an effective dose of CAR T’s, the response rate in the Phase I trial was quite encouraging around 80% of patients responding and complete response rate of around 45% and a median progression-free survival of about 12 months, so realizing that obviously, there was something we had to be very careful about with the sustainability of these responses.

But the good news in my mind from the Noopur study was that the cytokine release syndrome and neurotoxicity was under 10%, Grade 3 or worse, which again in the COVID era is so important to understand because cytokine release syndrome in the context of COVID is actually one of the most dangerous aspects of the virus itself. You can imagine obviously, from a clinical point of view, being able to distinguish the two in the in-hospital setting is absolutely essential.

But having said that, I think most programs have been very careful and very safe with their approach with CAR T’s to date. But in any event, this study that Nikhil presented, I was very impressed, 128 patients were enrolled in the trial.

Jenny: That’s a lot.

Dr. Richardson: Based on a lot of prior treatments -- exactly -- they were really what I would consider, again, the importance of what I described as sort of real-world practice. Will these trials translate into real-world benefit for our patients? I think that I was particularly impressed by the fact that they were able to show a dose effect from the CAR T cells, and at the high dose of 450 times 10⁶ cells the response rate was very solid at 80%, the complete response rate of around 40%. This data were important.

When you look to the whole group overall, and this is probably the more kind of real-world thing, around 70% of the patients responded, and around a third achieved complete response. Then I think what was particularly interesting to me, or important to me, was that the duration of responses around 11 months, which I think is very important because it means that you could get approximately a year of disease control, there did appear to be some degree of dose effect, so that mattered, and the progression-free survival which is a very, very discriminating endpoint for benefit was around 8.8 months.

So a very important start, and a very important data, because it really tells us the kind of work we have to do to improve on this platform, and most importantly, I think what was nice was to show that this was a very sort of safe approach in the broader sense of things because the toxicity profile was not trivial obviously, and it requires an in-patient piece.

I think what I was particularly struck by was that obviously, centers have gotten better and better at managing CAR T therapy, the incidence of neurotoxicity, especially the serious ones were still under 10%, in fact less than 6%, and that was really good to see. Obviously, with a number of new strategies that are trying to get ahead of this toxicity problem in a variety of different ways. 

Essentially whilst there were some treatment-related mortality seen is very important, it was fortunately low in number. There were only, as I recall from Nikhil’s presentation, there were very sadly only three patients who passed from CRS, pneumonia, and GI problems, but obviously, but that’s a major area of focus. But we need to obviously realize that all of our treatment platforms carry risk. 

There was, in fact, another CMV pneumonia seen in one patient who passed within about six months of the procedure, but I still think for a platform that’s generating these kind of responses, it’s very promising, Jenny. I think the question then becomes, how do we build on that? I think that then maintenance becomes variable, and how can we sustain these responses so they last longer? How can we make those more effective?

The other final caveat is making it more useable. In other words, and our own program is definitely been the issue of what we call waiting list for CAR T, and those have been real. But I think as these platforms develop, hopefully, this will become a more useable platform, and more practical.

Jenny: And then can I ask some follow-up questions about this a little bit? I know the bb2121 is in that -- originally was with Celgene and now is with Bristol-Myers Squibb, and they’re looking for approval this year, so when it gets approved for whom will it get approved? Because I know in the study, these patients were very highly relapsed, so when you talk about the side effects or even just in that, you just wonder if that was because they’ve had 15 lines of therapy already. So yes, maintenance is important but how many lines therapy, do you think, will somebody have had to have to be able to do that?

Then my second question would be, what’s the lasting impact of CAR T therapy on the immune system when patients are considering doing that during the COVID timeframe? Is that something they should be worried about? Does it last months? Just give us some context, I guess, about the impact of using CAR T in COVID.

Dr. Richardson: Yes. I think that’s an absolutely superb question, Jenny. I would simply say this, that I think it’s a major challenge right now. No question about it. What I wanted to really focus on as we go into the last 20 minutes or so of our discussion today, was the non-CAR T based platforms of relapsed/refractory disease because I think those are very important. 

But I think really, what I wanted to do by emphasizing the results of the KarMMa trial because as you know there are lots of others, there’s the Janssen platform, and Legend, and obviously, lots of exciting work being done, and really acknowledge the incredible work being done broadly in the CAR T space.

I really focused on the KarMMa study was here, you had 130 patients treated in an international trial where clearly, these were heavily pre-treated folks, they have had a median of actually, as I recall from the Nikhil’s presentation, the median number of prior regimens was six. This was really quite a heavily pre-treated population. It begs the question that if you go forward and into the future, how will these platforms behave earlier? Obviously, if we get the COVID situation under control, we already are in a better place.

I think thinking to the future, to my mind, CAR T therapy is looking something  as a cellular approach that may, as we talked about before, Jenny, may be a strategy that may replace for example the platform of autologous stem cell transplant. It may provide us with an immunologically more robust approach that improves the outcome given the strength of the signal. Obviously, we’ll have to see and then the question will be well, what happens if you combine the two? Is that even better?

We’ll have to see how that all evolves, but you raise the absolutely critical question which is you know, what’s going to happen in the COVID era? I think in that spirit, I was very much impressed by a couple of presentations. I think one that I think is really nice to share with everyone is the in the relapsed refractory space were the results of the BOSTON trial that was presented on Friday by my colleague Dr. Thanos Dimopoulos, and this was a comparison of weekly selinexor, with bortezomib and dexamethasone given weekly, which is very important because again it’s minimized compared to twice weekly, bortezomib and dexamethasone as the classic gold standard. This was in one to three prior lines of therapy.

I think as people may know, selinexor is a first in class drug by its targets called Exportin 1, and XPO1 is clearly overexpressed in multiple myeloma, and selinexor was the first clinically approved oral selective XPO1 inhibitor that actually targets this process was particularly fascinating is that selinexor also amazingly, has antiviral properties and is actually being studied prospectively for the treatment of COVID. 

In the interest of time, I should probably leave at that, but suffice to say, the initial information from that trial is looking very promising. Patients may think, oh, how on earth does that happen? Well, the thing is that Exportin is a key nuclear export protein, but not only do cancer cells exploit, but interestingly enough, so do RNA viruses, and so this may be really a stroke of serendipity, if you will, or good fortune, because you may have in here a good anti-cancer drug or anti-myeloma drug which also has potential anti-viral properties although we’ll have to see.

Jenny: I mean that’s so interesting because the study just for COVID is using low dose selinexor, and it’s believed to be anti-inflammatory as well as the anti-viral, so that’s so fascinating.

Dr. Richardson: Well, it is. Thank you, Jenny, for picking that up because the anti-inflammatory piece is very important because what’s so interesting, as we were talking earlier about side effect management, was really the implications in this trial of tolerability because one of the challenges of selinexor has been the GI toxicity and the profound fatigue and other side effects that patients report on a twice a week schedule which can be really difficult. 

Some patients do very well with it over the longer term. Others have found it simply impossible at twice a week, and you have to go weekly and you have to dose reduce. In my practice, I’ve always been combining it frankly with the results of the STOMP data with other drugs because it allows you to go less frequently.

This study really validates again at the highest level because it really shows, in a multicentered international trial, that giving the selinexor 100 milligrams once weekly, bortezomib subcutaneously once weekly, and lower doses of steroid, just 40 milligrams a week, again, compared to the classic bortezomib schedule which is twice a week with more steroids. 

In fact, twice as much steroids per week. In fact, the three-drug platform clearly outperformed the two-drug platform. That was really, I think, one of the more encouraging results of the recent beta Phase III in myeloma because if you think about it, Jenny, in our recent Phase III space, we really haven’t had any strikingly positive trials. If you think about it with ixazomib, I mean I think the RVd-Elo study and the ENDURANCE trials were incredibly important trials but they didn’t show a striking benefit to a particular approach that would actually guide us in treatment choices.

While in contrast, BOSTON shows basically at least four and a half month improvement in progression-free survival for three drugs versus the two which met the primary endpoint of the trial. But what really struck me about the data that Thanos presented was that if you looked at subgroups, you might say well, okay, selinexor’s such a challenge to give, how did clinical benefit translate in older folks? In older patients, actually, the clinical benefit, the hazard ratio is even better, and in high-risk cytogenetics, it was again even better which is obviously bought for everyone.

Then what I was particularly impressed by is that Thanos showed a frailty assessment, and in the frail group, the hazard ratio was preserved, and that worried me. I was thinking well, if we can’t give it to frailer patients, that’s a challenge. But, in fact, it was feasible, dose produced as guided by the protocol if needed. But most importantly, the frail group got as much clinical benefit as the fitter group whose hazard ratio was only slightly lower than that of the frail group.

This was the sort of highest level of clinical evidence to show the clinical benefit which we thought was particularly encouraging. Whilst the survival data remain immature, there is a trend there. What we also showed was that time to next therapy actually would reach its end point by showing a significant difference in therapy with an improvement of about six months in favor of the three-drug versus the two. Of course, no surprises, the response rates and so on were strikingly different in favor of the three drugs.

In terms of the peripheral neuropathy, Jenny, that’s what I think was really interesting. You might say well, okay, with weekly, you’re going to have lower neuropathy. We sure did. Basically, the peripheral neuropathy was cut from around 50% to 30% in favor of the three-drug arm. What was very interesting to me though was that the higher grades of neuropathy were cut down. While that may be very relevant is because we know that high grade neuropathy with bortezomib could be driven by inflammation. 

Jenny: Interesting, wow.

Dr. Richardson: So to your point, if there’s less steroid in the selinexor arm, you might expect actually for the high grade neuropathy to be more equivalent, right?  Well, actually, we didn’t see that. We saw that the peripheral neuropathy that was Grade 2 or more, was 34% for the treatment arm and 21% for the for the control arm, and 21% from three drugs, but if you looked at the Grades 3 or 4, which is the one that I worry about the most, 9% for the control arm, and half of that, 4 1/2% for the three. That trend because the numbers were small, fortunately, and I’ve always hate to see that kind of grade of neuropathy, the P-value trended, but the P-value was statistically significant to the other groups that I just described.

I think what we see is really again, a very courageous study because essentially, what we’re doing is saying the triplet is less intensive from the control arm from a regulatory point of view, there’s a chance of your study failing because you’re obviously kind of giving less to achieve more hopefully, but you might lose big time. 

The really good news for BOSTON is that didn’t happen, and the three drugs outperformed the two even though the two are more intensive, and the biggest concern which was the side effect profile with the weekly dosing of selinexor and was much better than expected, although GI toxicity remained a challenge and we continue to work on that. But most importantly, neuropathy was much less for the three drugs versus the two.

I do want to make a point about the GI toxicity. In this trial, because it was a multicenter international trial, the anti-nausea approaches were very standardized and very kind of simple. We know in practice that by being proactive with a variety of antiemetics, you can actually do a lot better with the antiemesis and the management. Again, very nice data for BOSTON on Friday, and this was, as I say, presented my colleague, Dr. Dimopoulos, and it’s a real-world regimen particularly with this tantalizing possibility that it could be helpful from this point of view of COVID was really good to see.

Jenny: Wow. That’s just better together. You just don’t know what the synergies are going to be, do you, until you try them together?

Dr. Richardson: Well, you don’t. Also, to see a surrogate gain from a drug that’s been repurposed essentially for anti-viral therapy was really, really, really gratifying I think. Because again, we want to be careful, the data still are cooking for the randomized Phase II but there are reports from colleagues in New York, who arrived at the forefront of the pandemic obviously, at Mount Sinai particular where patients were being given selinexor appropriately for their myeloma and specifically unfortunately ran into COVID, but did well actually on the selinexor. 

Whereas, in contrast, some folks who are not on that approach for very appropriate reasons, clearly were seeing a very different signal for those people unfortunately. But in any event, a nice result. 

So Jenny, I know we don’t have -- I’m very conscious of your time and your listeners’ time, and the last ten minutes, if I may, I wanted to focus on some work we did, just simply illustrate I think -- or a couple of things actually, just to talk a little bit more about relapsed refractory. Perhaps before I talk about our work because that may seem a little bit -- let me give you something a little bit broader. I did want to talk a little bit about the BELLINI trial.

I don’t know if you’ve had any questions about that, but I really wanted to mention that in that study, which was the venetoclax, bortezomib study, there’s a lot of patients that have been asking me about this, because 11;14, there’s a subgroup of patients, it’s a very important subgroup. I think I could be very quick here but just say that the clearly, the 11;14 group did very well, and those who also had this so-called entity of BCL-2 high gene expression to have an approved outcome, but particularly, the 11;14 group did well.

I think after all that we’ve been through with the ups and downs of the venetoclax journey, this was nice to see on a positive note that a simple oral pill given daily, if you have the 11;14 translocation in your disease, it’s a very important option to have.

Now, in terms of regulatory approval, Jenny, that may be a little ways off but it probably will be hopefully at least next year if not before recognizing that there’s sort of maturity of information that we have to have to make that next sort of step. But I think that was an exciting presentation from the meeting. 

In terms of other data that are relevant to this sort of new approval setting, I think the BELA-MAF data, this is the GSK-916, which obviously is the BCMA targeting antibody drug conjugate. We’ve already published the DREAMM-2 information which shows clinical benefit in this really high risk penta-refractory population. Very hopeful that that approach will be FDA approved as early as this year, at least accelerated approval pathway, because this was exclusively in very similar population to the CAR T group that I described earlier, triple-class resistant disease, as we call it, very vulnerable patients. 

Basically, in that group, we see this very solid response signal of around 35% with meaningful progression-free survival controlled, but the benefit, Jenny, of an antibody that’s just off the shelf, and again, in the COVID context, really, none of the sort of CAR T complexity of admission management and so forth just you know, once every three to four week infusions of a monoclonal antibody. The other thing about GSK is that there’s a lot of steroid that has to begin with. In fact, steroids are not required.

Jenny: Nice, very nice.

Dr. Richardson: It is very nice. The biggest challenge has been the concerns about the ocular toxicity, but I can share that I think for a much better understanding of it, we know exactly how to manage it in terms of dose and schedule adjustment. Some of the interventions we used in DREAMM-1 for example where we thought steroid eye drops may help, we now know theyn don’t, and that’s actually an important positive, because steroid eye drops can enhance cataracts which can be a blastomycosis as well as glaucoma. I think it’s very important not to use those now, but we recognize that there are other strategies that do work.

I’m very hopeful for GSK-916 or BELA-MAF as we call it, for short, because it’s a very convenient and practical approach. In that same spirit, although there wasn’t much information in ASCO per se on this, but there is an ER, we are going to be presenting data on another novel approach to targeting penta-refractory or triple-class resistant disease. 

That’s where our work with a drug called melflufen comes in, which is sometimes thought of as, you know, some people say, well, isn’t this just glorified melphalan, it absolutely isn’t. It’s very different. It’s in fact nice to sort of contextualize it with BELA-MAF because it’s a very specific way of delivering the warhead to the tumor. It’s aminopeptidase activated, it’s targeting by being lipophilic, whereas traditionally, chemotherapeutics are lipophobic which is why, especially melphalan, you have the dose escalators to get what it needs to do. But melflufen is very different, and very specifically targets extramedullary disease, we believe. That’s an important new direction.

A couple of snippets there, if I may, Jenny. But finally, as we move in sort of five minutes or so, I really wanted to talk about what I think was a session we gave on Friday morning on the new cell model we have called CC-92480 which are called 480, if I may, for short. This was a certain human Phase I study that we did that was an international trial. That really was a privilege to present this on behalf of my co-investigators because the study group was from Europe, Canada, and the United States. We were very fortunate in the -- it was really quite ambitious in that regard, because obviously, international Phase I’s are not necessarily the easiest studies to perform, but we were able to do that.

In that context, we presented preliminary results of our study. Just to explain to patients, 480 is really a fascinating drug. It’s a specifically designed small molecule but maximally targets so-called key proteins but control fundamentals of the immune response to myeloma, and at the same time, actually have a key role in terms of proliferative signaling. This is so-called Ikaros and Aiolos. 

Now, we know these very well from the successful targeting by the immunomodulatory drugs like lenalidomide and pomalidomide, but the so-called cell mods are different in that they are bigger molecules and they specifically are developed to be potent modulators of this so-called cereblon E3 ligase complex. 

Not the confuse everyone with the science, but just to emphasize that they build on the principles of lenalidomide and pomalidomide, but are a step up, so it’s important to not think of them as sort of again a glorified IMiD. That would be a mistake. They are really in a different category in my opinion. I think this supports that.

They have a much high degradation efficiency, the induction of apoptosis is much more powerful and they overcome lenalidomide and pomalidomide resistance nicely, pre-clinically, and 220 iberdomide has been the lead cell mod presented on that last ASCO by actually Dr. Sagar Lonial. 

That data has continued to look really good, but we were able to show data on 480 which is even more potent pre-clinically than 220, and we used what’s called an adaptive Bayesian dose escalation for patients which allowed us to be very responsive to both safety and efficacy, and we looked at continuous schedules versus intensive schedules, we integrated a very sophisticated approach to PK, pharmacokinetic and pharmacodynamic assessment. 

What I wanted to share, Jenny, was that special appreciation for our patients for putting up with all of this, because obviously, that evolved a lot. There was a lot of blood testing and a lot of visits to the clinic for this Phase I initially to really establish dosing schedule, but it really paid off, because we reported on 76 patients just to give you an idea, Jenny, they’re very analogous to what we’ve been talking about, classically, you know literally 90% were refractory to lenalidomide and pomalidomide, 70% were refractory to monoclonal antibodies, and everyone who had prior proteasome inhibition exposure.

This was a very, very sick -- I’m not going to say sick. This is a very vulnerable population -- 

Jenny: Right, lots of therapy.

Dr. Richardson: Exactly, and resistance. What we’re able to show is the neutropenia and thrombocytopenia were the major side effects, but they were manageable. Neuropathy, just 5% of patients, which is very low. Deep vein thrombosis, just one patient. Whilst we were very vigilant about the infection signal, this also was very manageable, and we found that Maximum Tolerated Dose (MTD) -- and also no cardiac toxicity or renal, and we were able to show that the maximum tolerated dose was just one milligram pill once a day, three weeks on, one week off, that was the best schedule. 

We figured that out really carefully. We looked at lots of different schedules. We looked at targeting the Aiolos degradation in patients and we looked at the light chain measurements and we were very careful to monitor their disease control and we found that the best schedule, the best dose was one milligram, three weeks on, one week off.

In that group of patients, we had 55% response rate including --

Jenny: That’s high.

Dr. Richardson: Yeas exactly, including the clinical benefit rate, minimal response of 64%. In that group, we had complete responses and very good partial responses. If you look at the 55% group, seven of the 11 patients in the cohort were classically penta-refractory. Of those seven patients who were penta-refractory, one had a complete response, one had a very good partial response, and two of the patients have partial responses, and one a minimal response, so you can see why we’re excited because that’s a very nice early signal.

Let’s be careful because the numbers in that group obviously are subset of an overall group. But if you look at the other one milligram patients treated on a slightly less optimal schedule, the response rate in that group was 40%, and remember, this is just a pill once a day, three weeks on, one week off.

If you look at everyone overall, because obviously, we started very low doses of 0.1 milligram, the response rate in terms of partial response is around 21% which obviously is lower and that reflects unfortunately what we learned, which is that the lower dose of the drug wasn’t as effective but the very good news is that those patients did well from a safety point of view and were able to go on to other treatments without penalty.

The important point was we dose reduced in just 22% of patients, and we didn’t discontinue 480 in any patient because of toxicity, and there were no treatment-related deaths whatsoever. That’s actually really exciting because it’s a very encouraging signal in the Phase I to see that, and it tells us, we’ve got a well-tolerated or potentially well-tolerated drug on our hands.

Then finally, we looked in the extramedullary population. It’s a very vulnerable group, I mentioned. At one milligram, we saw responses to an extramedullary disease including complete responses which was for a pill, really something. So early data, but really promising in my opinion because just the convenience of an oral therapy with a manageable side effect profile, but we’re now combining 480 with other drugs and those things were looking very promising.

Jenny: All right. Something exciting for people who are relapsing on certain other lines of therapy, so it’s nice to know that the cell mods are not just another immunomodulatory.

Dr. Richardson: Well, no, it isn’t. I think the point is, Jen, is when you’ve got iberdomide, which is 220, that appears to be really good too, and 480, which is that much more potent, it’s a next line of defense or attack depending on how you want to look at it. I think especially in the era of COVID to have this as a platform is really, really attractive.

Jenny: Yes, amazing. Dr. Richardson, I know we’re at the top of the hour, do you have time for one question, potentially?

Dr. Richardson: Absolutely.

Jenny: Or do you have a hard stop? Okay. We’ll take caller. Go ahead with your question.

Caller: Hi, Dr. Richardson. I have sort of a three-part question about CAR T-cell. First, I wasn’t sure if I understood correctly. Is there work being done on the use of stem cell plus CAR T? That’s the first question. The second question is what’s the possibility of CAR T being used instead of stem cell transplant by early 2021? And then the third part is, what’s the progress on CAR T looking at multiple targets?

Dr. Richardson: Well, those are great questions. Thank you for asking.

Yes. There are trials looking at autologous stem cell transplant going first, with CAR T to follow, and these are sort of in design and in development, the other part of your question which is you know, can CAR T come forward to replace autologous transplant, that’s certainly a vision that could be real in the long-term in my opinion.

Obviously, we have to be very thoughtful about that and see how the data guides us but when you’re seeing this kind of response signal from the platform, I think the durability of it becomes the next big challenge, and how we get there becomes key, so that gets to our third question which is there are now CAR T platforms that are being developed that have multiple targets. 

From what I’m seeing, these appear very attractive too, because BCMA is relatively far down the ontogeny of plasma cell development. It stands for B cell maturation antigen, so you can imagine that it’s downstream in plasma cell biology in some respects, and then in fact, one of the reasons we think that sometimes, the disease control when you target BCMA may be a little bit more challenging, may reflect that. Therefore, the ability to target other markers of disease and so go a little bit upstream, if you will, of the phenotype may be a very attractive strategy.

Lots to do there, I think, but excellent question.

Jenny: Great. Thank you so much for your answer, and for the question, thanks for that excellent question.

Dr. Richardson, there’s so much to cover. It’s just impossible to cover it in an hour. You covered a lot in a very short amount of time, so we really, really appreciate your willingness to join us especially at such a busy time. We know how incredibly busy you are, and I’m just so grateful for sharing your expertise with patients.

It’s so fantastic. You gave us a lot of answers. We will be writing articles on some of the findings of ASCO so you can watch for that. We’ll also do a full transcript of this show, so you’ll be able to refer back to it.

But Dr. Richardson, thank you so much for your time.

Dr. Richardson: It’s really a pleasure, Jenny. Please, very best wishes to everyone on the call and please stay safe, everyone. Thanks very much. Bye-bye.

Jenny: Well, and thank you so much. Thank you for listening to Myeloma Crowd Radio. We invite you to tune in next time to learn more about the latest in myeloma research and what it means for you.