Paul Richardson, MD
Dana Farber Cancer Institute
Interview Date: August 3, 2018
Myeloma research is moving quickly, with more treatment approaches being developed by researchers. Dr. Paul Richardson shares a mid-year myeloma update to catch us up and provides a treatment overview for early precursor condition myeloma and for newly diagnosed and relapsed/refractory patients. Dr. Richardson provides an update on the latest in immunotherapy research including CAR T, bi-specific antibodies, APRIL monoclonal antibodies and immunomodulator drugs. He describes how two new drugs (selinexor and venetoclax) are being used in clinical trials and how a new drug called melflufen could be used in place of melphalan for stem cell transplant. Dr. Richardson also describes key strategies using currently available drugs in the clinic. This show and Dr. Richardson’s deep myeloma expertise stresses why it is key for myeloma patients to be seen by myeloma specialists at each decision point in their care. (Many terms were used during the show that may be unfamiliar to patients, so we’ve added a thesaurus at the end of the show.)
Dr. Richardson on Myeloma Crowd Radio
Jenny: Welcome to today’s episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I’m your host, Jenny Ahlstrom. We’d like to thank our episode sponsor, Takeda Oncology.
Now, later on in the program, if you’d like to ask questions, you can dial 347-637-2631, and then I will prompt you at the end of the show how to ask the questions.
Today is a very exciting show in that we’re talking to Dr. Paul Richardson. I just spoke with him a few seconds ago. He may be delayed slightly because of the clinic. So we are going to go ahead and give an introduction for him.
We have been working really hard this summer to introduce a product called HealthTree. We’ve now been to 37 cities in the United States and are coming to the East Coast. I look forward to doing that throughout the late summer and then into the fall. So keep watching on the www.myelomacrowd.org/healthtree page to see where those meetings are going to be held. HealthTree is a software tool that I wanted when I was diagnosed.
In looking at the landscape of myeloma care, not everybody has access to a specialist like Dr. Richardson and it’s really important. Several studies have come out now showing that patients live longer when they’re seen by a myeloma specialist. A University of North Carolina study showed that patients who are seen by a myeloma specialist within the first year of diagnosis actually live 39% longer. I think if there were a drug helping us live 39% longer, we would all be taking it.
The Mayo Clinic also did a study showing similar impact for centers that treat more than over even ten patients. It really makes a difference in your care to have a specialist on board. So what we’re trying to do with HealthTree is provide three different benefits. Number one is to help patients understand the most advantageous and recent and latest therapies that are available to them really at every stage of their disease. So whether you’re newly diagnosed or whether you’re relapsed or refractory to different drugs, what options do you have in terms of treatment?
Similarly, we want patients to be able to find clinical trials, so we’ve integrated this HealthTree product with SparkCures. Many of you are familiar with it – our last show was with Brian McMahon of SparkCures. So it’s not just treatment options that are available in the clinic but also treatment options that are in clinical trials at centers that could be anywhere close to you or some distance from you.
The third benefit of using HealthTree is that is that we are a whole community of myeloma patients contributing to myeloma research. It’s very difficult to aggregate patient data because if you ask a facility to do it, they want to protect the data because of HIPAA laws. It’s just a very difficult thing to be able to share data. So when we as patients decide that we can collaborate our data and help the research community take a look at it in an anonymized way, we can really make some major advances and help the research community cure us faster.
So with that, I would like to give an introduction to Dr. Richardson. Dr. Richardson, if you’re on the line, please press 1 on your keypad.
Dr. Paul Richardson is the Clinical Program Leader and Director of Clinical Research of the Jerome Lipper Multiple Myeloma Center. Dr. Richardson is also the RJ Corman Professor of Medicine at the Harvard Medical School.
Dr. Richardson holds leadership positions in many professional organizations and is on the Editorial Board of the Journal of Clinical Oncology, Journal of Oncology, The Oncologist, Clinical Cancer Research and British Journal of Hematology. He’s a prior chairman for 5 years on the the Multiple Myeloma Research Consortium and serves on the Steering and Project Review Committees. He was a member of the ASCO Hematologic Malingancies Subcommittee and currently chairs the Multiple Myeloma Committee for the Alliance for Clinical Trials in Oncology. Dr. Richardson’s honors include the George Canellos Award for Excellence in Clinical Research and Patient Care, and The Tisch Outstanding Achievement Award for Clinical Research, as well an honorary Fellowship of the Royal College of Physicians (UK), given in recognition for international contributions in multiple myeloma and stem cell transplantation. He was a co-recipient of the Warren Alpert Foundation Prize in recognition of the successful therapeutic targeting of the ubiquitin-proteasome pathway. Dr. Richardson was also a co-recipient of the Accelerator Award for contributions to clinical research and patient enrollment in MMRC studies, as well as for the Research Center of the Year Award in 2009. He was ranked by Thomson Reuters Science Watch amongst the top 19 investigators at DFCI for the most highly cited research. Most recently, he was a co-recipient of the ASH Ernest Beutler Prize for clinical science and translational research in the development of proteasome inhibition as an effective treatment strategy for multiple myeloma in 2015; the COMY Award in 2016, and the IMF Robert A. Kyle Lifetime Achievement Award in 2017. (updated post-show)
Dr. Richardson has published more than 340 articles and 260 reviews, chapeters and editorials in peer-reviewed journals such as the New England Journal of Medicine, Blood, the Journal of Clinical Oncology, Leukemia, and many more. He’s a key contributor in constructing and implementing clinical trials both early and later stage. His primary research interest is in new therapies. He was a leader in the clinical development of bortezomib, lenalidomide, and pomalidomide and additional research leadership includes his work on panobinost, second generation proteasome inhibitors such as ixazomib and marizomib, monoclonal antibodies such as elotuzumab and daratumumab and comination therapies such as RVD (lenalidmode, bortezomib and dexamethasone).
While we’re waiting for Dr. Richardson, I’d like to just share a little bit more about why we decided to do the HealthTree product. In terms of finding a cure for multiple myeloma, there are many researchers like Dr. Richardson who are working very hard for us. Dr. Richardson, specifically, helps bring these new therapies into the clinic and has been really a key driver of running large-scale clinical trials which is key and important for development of new drugs. But as we look at how to apply currently available treatments in the clinic appropriately, the experts know in a very sophisticated way how to do this. They’re very savvy because they see hundreds of patients on an annual basis.
When I was diagnosed, I was seen by first a general oncologist. The protocol that he wanted to use was probably two to three years behind what the norm was if you had gone to a specialist. Now that we’ve been to so many cities across the country, it’s been fascinating to see your experience because everyone’s myeloma experience is just unique and different. We’ve seen now patients in rural communities and big cities. We’ve seen patients who have never seen a specialist and patients who consult with a specialist and patients who go to a specialist. We’ve seen many different ethnicities, and both tech-savvy patients and patients who are unfamiliar with the tech. It’s been an amazing experience to get to know you as patients and understand better your myeloma journey.
What I would like to see as a patient in doing this project is I want to see patients that look similar to me with maybe some similar genetic features and to see what they did for treatment and to see what the outcomes were. Because if we can see this as patients and then combine it with expertise from the myeloma specialists, we’ll be able to identify patients who are being cured. Many of the myeloma researchers that I’ve spoken to say that a certain percentage of myeloma patients are being cured. It may be small. It may be like 10% or 15%. But it’s really important to know who and why and what are the features. Why are people getting better outcomes? Sometimes it could be just the nature of the disease. Sometimes it could be other factors that we just aren’t aware of yet. So that’s what we’re really working to accomplish in creating this HealthTree product.
I’m really pleased to announce that we are almost to 600 patients in the system. If you would like help on this, we will be developing a new program called the Myeloma Coach Program which will provide one-on-one help similarly to how we’re doing this in these HealthTree workshops across the country because we realized there’s a wide range of support that people need to be able to use this tool. We realized that it was very important to do this in a system where it was safe and protected with the patient data that it was using anonymized data and that we, together as patients, are all contributing to help one another. Sometimes patients ask, “Well, if I had a really good outcome with a very long remission time, should I participate?” The answer is yes, you should participate because your story could help inform someone else on their journey. I’ve had other people say, “I really enjoy using HealthTree because it’s a place where I could put all of my information in one place.”
We’re now working on pulling lab value data from the labs and being able to integrate that into the systems. So you could collect and gather all of your labs into one place as well as things like your treatment history and your prior outcomes and your side effects. It’s been fascinating to go and talk to different organizations and doctors. I’ve shown this now to probably 25 different myeloma doctors in a demo. Their eyes get wide. They appreciate what we’re doing because it would help inform them especially because many myeloma patients go and attend and see a variety of doctors. They might go to a specialist for some of other labs, and then they might go to another doctor locally and get all of the rest of their labs performed. So now, they have things in two places. Sometimes there is an online portal. Sometimes there’s no portal. Sometimes it’s all in paper format.
We’ve been to a variety of cities, as I mentioned. In these cities, we sit down and work with patients to help them understand the tool. So it’s not a difficult or a challenge for them. One of the reasons that we decided to do this inside of a nonprofit was that because we didn’t want there to be any motivation, I guess, to do anything that was misaligned with just finding a cure for us as patients.
So in doing this project, my husband and I decided to do this. Actually, we had thought to do this many years ago. My husband’s brother had passed away from leukemia. After that experience with his leukemia, we realized what not to do when going through a cancer experience. We didn’t ask questions. We weren’t prepared as a family. We watched him go through that very challenging and difficult experience. It was about 12 months from the time he was diagnosed till the time he passed away. It became really evident that we needed to have more information when we were navigating his care.
So when I was diagnosed five years later and we were in the same hospital, getting similar advice like delay a transplant and things like that, we decided to approach this radically differently. When we did that, we decided to be very educated about our care and how this hypothesis, the data, was an important piece of it. So as we’ve created this tool, we decided that it was most important that it would to build trust with our peers as myeloma patients. This had to be a system that was based on trust. So we have done everything in our power to do that. I don’t take a salary and haven’t for the six years since I’ve started the Myeloma Crowd and won’t because it would be my dream one day to have a cure for myeloma and be able to shut it down and have us go on our way and do the things that we would love to be doing in this life that are not my myeloma related. I think we all feel that way as patients.
So we tried not to do this project. We contacted other myeloma foundations to see if they’d be interested in doing it. We contacted pharmaceutical companies to see if they could do it and they could not. We’ve talked to individual researchers at their institutions and because they can’t share patient data, they weren’t in a position to do it. So after talking to many groups, including the IBM Watson Team and Google Health and Microsoft HealthVault and others that you would think could work on a project like this, we really made a determination that we would have to do it ourselves.
In these workshops, we’ve crossed the country. It’s been fascinating. We’ve continued to improve the product. We listen every time we go. We iterate every time we go. The product is becoming better. Thanks to all of you. I just have to say how grateful I am for that.
Dr. Richardson, are you on the line?
Dr. Richardson: I most certainly am. I’m so sorry, Jenny, I’ve been on the call since 11:05 and it’s past 11:20.
Jenny: Well, I’m sorry that you had to listen to me then because people wanted to listen to you and not to me. So for some reason, it did not show you as being in the studio. So I’m thrilled that you’re here. We are excited to have you. Thank you. Let’s go ahead with the program because I’ve given an introduction for you.
Dr. Richardson: I just heard your very kind introduction and when you were doing those lovely bio, I think that bio is a little bit a few years old. I just wanted to especially acknowledge one award which you didn’t mention is just because it reflects patients and so close to me is the Robert Kyle Lifetime Achievement Award in myeloma which is really to reflect patient care. My simple reason for mentioning it is because I just want to acknowledge the IMF, in particular, as well as, of course, a wonderful partnership with the MMRF, but at the same time the IMF and, in particular, the Robert Kyle Award which my team actually received on my behalf at the IMF meeting in Madrid about a year or so ago. I think that it’s just because it’s totally focused on the patients. That for me, personally, was the most important. It was an enormous honor to receive that. So I just wanted to add that. But having said all of that, I just — and it was also lovely that my team received it on my behalf.
Jenny, I’m so sorry for the confusion on the connection. I know you’ve got an hour of radio time, approximately. I’m happy to make it up if we need to run it over the noon hour. So that’s absolutely fine. But if I can take my lead from you, Jenny, as to how you would like to conduct the discussion this morning.
Jenny: Well, I appreciate it. I’ve had people say that you are a living angel. So in mention of that award, I really believe that there are many, many caring myeloma specialists. That’s why I feel so strongly that patients need to see people like you because the expertise that you have but the concern you have for patients is really unparalleled. So just thank you for everything you do.
Why don’t we start by talking about this idea of the mid-year advances in multiple myeloma? I was talking to another doctor who said — I used to be able to go to myeloma updates every two years, and I can’t do that anymore. It’s at least every six months. So this is our six-month update. The last one we had was really around ASH. There have been many major meetings like the EHA meeting, the European Hematology meeting, and the ASCO meeting in June and other meetings, BMT meetings and things like that. So maybe we want to have you give an overview for the type of patient first, smoldering myeloma, newly diagnosed, first relapsed or heavily relapsed. Then let’s talk about the individual, different types of technologies. Maybe we’ll cover that while you’re talking about those particular things.
Dr. Richardson: Absolutely, Jenny. You made me blush with that comment. I’m far from it, but I just want to say one thing. I’m blessed to work with a fabulous team. In particular, my nursing colleagues as well as my physician colleagues. We’re, as a result of that, able to God-willing provide the best we possibly can for our patients. But thank you, very kind words.
The discussion today then I think hopefully will be best framed by starting with what myeloma is all about in the various forms of it and what options we have for our respective patients. So I think one incredibly important sort of starting point is that myeloma is an incredibly heterogeneous disease. What makes it even more challenging is that it changes within a patient over time. So not only is it different between patients, but it’s also different within a patient over the natural history of the illness. That makes it particularly challenging for patients’ families and caregivers alike.
Having said that, it’s very important to understand the nature of your own individual biology in conjunction with your caregiver in terms of understanding where you are in the spectrum of the illness. So starting with that, there’s obviously the recognition that there’s this importantly defined entity of monoclonal gammopathy of uncertain significance which means exactly what it says – that the M protein is discovered, but its exact significance is not clear. Over time, it may evolve into something more challenging.
The good news is we’re getting better and better at defining what MGUS is and what risk may come with it. This allows us a variety of strategies in going forward and dealing with it. Now, I want to especially acknowledge my colleague Dr. Irene Ghobrial who’s been a pioneer in this what we call precursor setting where she and others have looked very hard at how we can try and head off these challenges going forward in terms of identifying higher risk patients, and then with some of the newer agents that we have, which are much less toxic drugs we had available before, be able to try and sort of proverbially place a stitch in time to save nine.
Now, high-risk MGUS is one category that is currently under evaluation. But for the majority of MGUS patients, it’s simply a matter of observation carefully with your caregiver and being aware of lifestyle choices and so forth that could be very helpful in reducing stress and inflammation that may be at least, as far as we know, potential drivers of the process.
Smoldering myeloma is a slightly different entity in that it represents a sort of next step in the spectrum of the illness where myeloma becomes a little more established but isn’t nonetheless inflicting any damage to end organs structures. What I mean by that are bones, kidneys, bone marrow, et cetera. So a patient may have an elevated number of plasma cells in the bone marrow and may have a significant protein detectable, but is experiencing no ill effects from the process.
Now, the critical thing here is understanding where in the spectrum of the smoldering picture you may lie. In that context, if you have what we consider a low or standard risk smoldering disease, it may be very appropriate to just monitor you very carefully. Sometimes we use a bone strengthener to compensate for any bone demineralization that may occur. These are the so-called bisphosphonates which may be helpful. But, obviously, if you have higher risk smoldering disease which looks like it’s evolving into a more active process, again a number of investigators including Irene are exploring strategies in this setting to reverse that process using some of the exciting new biologically derived drugs that we have such as the monoclonal antibodies, the immunomodulators and oral proteasome inhibitors as one example as well as others. So that’s an exciting area.
Now, in terms of active disease, that represents a very clear entity. The good news there is that we’ve got much better at defining that. So we don’t wait for your disease to become aggressive and do you actual harm in the absolute sense. We kind of can predict when it starts to make you more anemic, the protein can get to a higher level, the light chain can particularly escalate. There are parameters in the bone marrow as well that guide us that then tell us whoops we need to get going and really try and put a lid on the process as quickly as possible. That’s the so-called newly diagnosed category with active disease where a whole host of options exist.
Now, obviously, after initial treatment, after intensifying therapy to maximize response and then moving to maintenance, which is now a standard of care, we look to maintain remission for as long as possible. Jenny, as you alluded to, in myeloma, because treatments have gotten that much better and that much less toxic in the long term, patients are enjoying remissions for longer. So there’s the tantalizing hope that in the future we may see an increasing fraction of patients in whom their disease may effect — and I use the term very carefully – a functional cure. What I mean by that is that the disease can essentially be kept in remission on a relatively almost continuous therapy but essentially other problems for the patient may become more of a worry than actually the disease itself.
A parallel is in prostate cancer, for example, wherein certain prostate cancer patients can enjoy living with a disease for many, many years and worry about different things. I hesitate to use that analogy only because I’m always eternally humbled by myeloma. So I think one has to be very careful. But having said that, your point is very well taken, Jenny, that for an increasing subset of patients, a proportion of patients, long-term remissions that results in a high quality of life and continuous therapy being part of it, but nonetheless disease control for many, many years. That I think is the exciting piece.
Now, having said that, when disease comes back, that’s defined as first relapse. In that setting, we then start to use other treatments to bring back remission and further continue treatment, continue disease control for as long as possible. So that constitutes first relapse. Now, typically, that lasts now for many years — thank God — because of these newer drugs that we’re so fortunate to have for many years, or sometimes a little bit less, but sometimes many years. We then sometimes inevitably see that the disease will come back after a period of remission, after initial relapse. That’s where we move into second and third relapse and fourth relapse. These are the patients who are described as relapsed/refractory or heavily relapsed, as you wrote in your program notes, Jenny. In that setting, the challenges become very considerable because we have to then bring to bear multiple drugs typically in order to bring the disease process under control.
Just to share with the audience, the reason for that is because as myeloma relapses, it becomes more and more diverse in its nature. Its genetics become more and more unstable. It, therefore, becomes more challenging to bring under control. Earlier in the disease, it can also be highly genetically varied. That’s for sure. For example, my superb colleague Dr. Nikhil Munshi has done some beautiful work in the genomics of myeloma and some very exciting work he’s about to publish in Nature, actually looking at smoldering versus active disease in partnership with our colleagues in France. But at the same time, what he’s shown is that you can have in your cancer as many as 5,000 mutations at the time of diagnosis. Then when the disease comes back, they can be as many as 12,000 mutations. That’s a big therapeutic challenge. How do we throw a net around it?
So that’s why we use multiple drugs in the more heavily relapsed setting. Increasingly, we’re using multiple drugs in first relapse. Now, of course, in newly diagnosed patients, we’re moving into an era of at least three drugs, sometimes four. We also use what I call the “Coast Guard” which are the bisphosphonates or the anti-bone resorptive agents like denosumab. In initial treatment, we sort of have an Army, Navy, and Air Force which is typically a steroid, immunomodulator and a proteasome inhibitor. The Marines, in my view, are the antibodies; they can often be added. Then the bisphosphonate — excuse the metaphor but I think it’s helpful — is the Coast Guard. So you have basically all your assets in place to control your disease a diagnosis. Then typically as the disease evolves and as it unfortunately may come back over time, we may then use additional drugs and additional assets to bring the process under control.
Now, obviously, in terms of treatment for younger patients, autologous stem cell transplant is a standard of. This involves using a very tried, true, and tested warhorse melphalan which we give at a high dose. In order to make that safe, we rescue the patient with autologous stem cells. This serves the role not only of allowing the melphalan to be tolerated, but also helps reset the immune system within the patient. As a result of that, the patients can enjoy some remission and some durable disease control. I think it’s fair to say that the role of autologous transplant is evolving not least of which because we have such exciting other treatments which are essentially also immune based, be they antibodies, immunomodulatory treatments, proteasome inhibitors and so forth.
As I counsel my patients, for younger folks, autologous transplant is definitely a very important option. But one size does not fit all. We’re learning that stem cell transplant can work very well for some patients, but unfortunately in others it’s not so good. We’re trying to figure out who benefits best from it because it’s obviously very helpful in the right patient, but for the patient who may not be able to tolerate it well and may have both long term as well as acute side effects, it can be very challenging indeed. So we’re seeking to better tailor that approach in our younger patients.
So that, in a nutshell, is a kind of walk through MGUS, smoldering, newly diagnosed, first relapsed, and heavily relapsed patients, Jen.
Jenny: That’s great. I know in MGUS in that situation, I’ve seen now some clinical trials actually open in that situation beyond Dr. Ghobrial’s PCROWD study, and even some that are considering treatment. Is that true?
Dr. Richardson: Yes, that’s correct. That’s the MGUS high-risk group that I mentioned because in those folks, transforming into smoldering is high, and then smoldering into active disease is also equally high. So for that reason, the idea is a stitch in time will truly save nine. I think it’s important to remember that the stage of any cancer, be it myeloma or otherwise, is a function of biology over time. So essentially, if you have MGUS that’s high risk, it may only be a matter of time before you become active disease in a relatively short order. I think that’s why I particularly applaud Irene and her team for the work they do in going into a space which is important to define; i.e., those folks with early, early precursor illness that may evolve.
But I think it’s also very important to step back and be very cognizant that the vast majority of patients with MGUS do just fine for many years. The last thing we need to worry about is myeloma. This is where I love the strategy of stress reduction, weight loss exercise, healthy diet, and so forth. Funny enough, obviously, that has tremendous benefits in terms of general health anyway. So essentially, a healthy MGUS patient is probably healthier than a patient without any MGUS, if you see what I mean.
Jenny: Absolutely. Thank you. That’s a great broad overview. Thank you so much.
Well, let’s talk about some of the specific therapies that are coming out into the clinic because now that we have a little more expertise with them. Let’s start with the CAR T technology because I know at the most recent ASH, everyone was thrilled with these very high, 90% sometimes, response rate in some of the early CAR T studies. Now, we’re seeing that some patients are staying in remission, some patients are relapsing. So can you speak to just an update on the CAR T cell technologies, the ability for patients to get into those studies, some of the new, I guess, remission statuses that might be open for patients? Because the first studies were multiple lines of therapy. So when is that coming? What other strategies could be used to keep people in remission, understanding that these patients that were first on the trials were heavily treated?
Dr. Richardson: That’s a lovely question, Jen. I think CAR T therapy holds enormous promise and is exciting as a forward direction in the immunotherpy of this disease, recognizing that immunotherapy is a broad category. It doesn’t just include CAR T technology, but it includes monoclonal antibodies, particularly monoclonal antibodies that build on the success of elotuzumab and very importantly on the game-changing nature of daratumumab.
So I think that we’re in a very exciting time because beyond these antibodies, beyond CAR T, lie these so-called biphenotypic or also have a term BiTE applied to them. These biphenotypic antibodies that try to do multiple things at once. Then, of course, we combine those with immunomodulatory drugs, the IMiDs, which have been an immunotherapy unbeknownst to us, arguably, for some time. In fact they were classified as IMiDs years ago, but their immune function has really become apparent over the last decade. It has been very, very important. Maintenance with lenalidomide, for example, has born great fruit. I think it’s important to understand that immune therapy has been part of the repertoire in myeloma for a long time. In fact autologous stem cell transplant was an immune strategy in the very beginning. Essentially you cyto-reduce the tumor burden with melphalan, give back autologous stem cells that reset autologous immunity. In fact, back in the 80’s, one of my mentors, a wonderful man who sadly passed away many years ago, but his name is Tim McElwaine, he actually developed high dose melphalan and stem cell support and Tim also then developed the idea of targeting it with interferon as a strategy of keeping the disease away using an immune treatment. So immune therapy in myeloma has existed for a very long time. The tantalizing clue for immune therapy came from allogeneic transplant where we saw some stunning successes with allogeneic transplant initially and as we broadened the approach what we realized was allo was certainly helping a small subset of patients but unfortunately the majority encountered unacceptable graft vs. host disease which made the approach very challenging, but still, there are a small but real number of patients who benefit from allo transplant approaches in the highly selected clinical trial situation and we now do that. Therein lies the clue that immune therapy can work because CAR T therapy obviously builds on that in a much more sophisticated and clever fashion because it is specific to the patient by manipulating the T cells ex-vivo as it were and then reinfusing them as you know, so they target the disease particularly with BCMA being probably one of the most exciting targets to date. CAR T has shown phenominal results but I think we have to be a little bit careful because when you see results from a CAR T trial, it has to be remembered that there is a waiting list to get into the study and that the results tend to reflect those patients who get into the modality and are able to receive the treatment. And then you see fabulous results with response rates of 90% or above. It in no way diminishes the promise of the approach, I just thinkit is very important to understand that with a hundred patients in line for CAR T, perhaps 20 or so are able to get into the program and those folks then benefit and it’s wonderful but it’s important to note that. You realize the clinical trial experience reflects that whereas other clinical trials for example typically if you enter a trial, everyone is counted and even if treatment fails the patient within the first month, they are counted in the assessment. CAR T is different because of the way it is done. You can’t do it that way. You see a response rate of around 90% is fantastic and most recently my colleague Dr. Noopur Raje presented at ASCO the maturing information around the bb2121 platform, which seems to be a remarkably good one targeting BCMA. What she showed very nicely is that reponse rates are dramatically high. The duration of disease control unmaintained (and that is an important point – it is not maintained), is about a year on average. That is obviously remarkable because the patients are so, so ill when they are treated. But it’s also important to recognize that they are then not maintained. So I personally think that as CAR T evolves, that we can integrate maintenance strategies. This will make a big difference to the duration of disease control. Particularly as you point out, Jenny, as the technology is brought in earlier. In our own patients in our own program (sharing patients from colleagues who have gone through the CAR T and my own patients who have been in line for a variety of different programs and in different settings), my own impression of CAR T is that it has great promise and we’ve got a ways to go, however, but I think particularly the idea of CAR T therapy that is designed to enhance memory, CAR T therapy that can be readily partnered with maintenance strategies – I think these are going to be hopefully available very soon. I would anticipate whilst the protocols are now obviously in overdrive, I’m really hopeful that we will see an approved approach to CAR T therapy for myeloma patients in a year or so if all goes well. It’s important to note though, in lymphoma and leukemia where the CAR Ts are approved, the benefits are striking. But just as we think about allo transplant, allo transplant in leukemia and lymphoma is curative. Allo transplant in myeloma generally and unfortunately hasn’t been. And so in CAR T therapy in parallel fashion, I think we need to realize it may be challenging to control disease over the long term unless we use very clever maintenance strategies and also finally the CAR T therapy obviously has to be geared up in a way that will allow us to make it more available to more patients and that’s not a small challenge.
Jenny: No, not at all and it’s very difficult because it’s all personalized because it’s your own cells and then they are engineered. So a few questions about what you said about CAR T cell therapy. Talking about maintaining the response, are you talking about multiple infusions or are you talking about standard myeloma drugs as maintenance therapy following, or what do you mean by maintenance therapy?
Dr. Richardson: I personally think in terms of a variety of strategies that may be helpful there. An obvious one would be taking immunomodulatory drugs that are so successful post autografting and in non-transplant settings as well as maintaining patients. An obvious place would be after CAR T therapy would be to give a maintenance strategy as long as it could be done safely to a CAR T patient to maintain their remission. There are a variety of CAR T strategies that are also looking to build the CAR T platform. In other words that it’s not just a BCMA target but it’s enhanced in some way. And you can think even hypothetically of different CARs being partnered together. Again, I think the field is very, very promising and I’m very hopeful for it. It’s important what I share with my patients at least is to recognize its promise but also recognize some of the challenges. I think what I’m particularly excited by is that fact that it is brought earlier and can be shown to endure more durable disease control, particularly with maintenance strategies, it may become something that we use in a much more widespread fashion over time.
Jenny: As you looked at these early results coming out of the CAR T therapies, why are people relapsing? What’s happening? Is it T cell exhaustion, or what else is happening? Maybe you can explain.
Dr. Richardson: Of course, Jen. I have to preface this by saying I don’t consider myself a CAR T expert by any means. I’ve got wonderful colleagues who lead the charge there in our own program specifically my partner, Dr. Nikhil Munshi. But I will share with you that there are a variety of patterns of treatment failure. I think at the end of the day, we just have to recognize that myeloma can be highly resistant to these strategies in the same ways it proved resistant in the allogeneic setting whilst we were able to cure patients with leukemia and lymphoma. I will stress though that in CAR T, it doesn’t in any way diminish its promise because, to your point, there may be opportunities to reinfuse more T cells. There may be opportunities to augment T cell function, not just with immunomodulatory drugs but arguably with other strategies such as checkpoints and others which may be able to help, recognizing that we’ve learned some tough lessons with checkpoint inhibitors that you have to be very careful about side effects.
Jenny: Right. Well, it’s a new technology so, of course, you as researchers are going to be learning over time what to do and how to manipulate that. It’s a great beginning. I am just excited about what will happen in the future to watch it, but I appreciate the update.
Now, you talked about bi-specific antibodies. Maybe you want to give us a short overview of that. Then I think I’d like to interject the monoclonal antibodies and what you referred to a little bit earlier after that.
Dr. Richardson: Yes, Jen, and I would completely agree with how you beautifully phrased the CAR T platform, so ditto, completely agree with you. So in terms of bi-specifics, obviously these are relatively early in development. They’re nowhere near as advanced as, for example, our work has been with BCMA-targeting antibodies with immunotoxins or with, for example, the antibodies like essentially daratumumab, isatuximab, elotuzumab, and others. The bispecifics though offer this opportunity to capture two sorts of function as we engage tumor cells and so enhanced therapeutic indices accordingly. The scientific promise behind them is real.
The way to think of them in the simplest terms, just to make them understandable, is that they’ll capture several components of the immune system to optimally target the tumor cell. They’ll do it as one antibody as opposed to multiple. I think that’s what makes them very attractive. I think that the safety profile from them appears to be really quite good. Some of the early bispecific antibody data in Phase 1 has been remarkable and arguably not the sort of 90% response rates necessarily of CAR T but not too far behind, which is great news because these are off-the-shelf antibodies. They’re not the sort of thing where you have to wait a month or so to get your CAR or less perhaps depending on the technology, but nonetheless you can simply use them off the shelf. So they have a real promise of doing that.
Durability of response and progression free survival data are still rather immature in that regard, so I think we have to wait and see. But the early data on bi-specifics is very promising, and importantly the tolerability appears good. There is some evidence of the same kind of immune reactions that we see with CAR T, the so-called CRS, Cytokine Release Syndrome. This is very important for patients to know. It’s not a trivial side effect. It’s a function of immune system really revving up. Generally speaking, it’s manageable. In the CAR T setting, they’ve gotten much better in managing it but unfortunately can be quite severe from time to time, and that requires real expertise in handling it. Having said that, it’s a sign that the treatment is doing its job. But like all side effects, you have to be very careful. But bi-specifics I think are very promising.
Jenny: You mentioned earlier monoclonal antibodies, daratumumab, elotuzumab, but now you have more expertise using them in the clinic, multi-year expertise. You mentioned that others are being developed. Do you want to expand on that and why you think those are so promising and now how they’re being used earlier in the clinic?
Dr. Richardson: Absolutely. Well, I think talking of the other antibodies, I think it’s very important to recognize some of the promising data around BCMA-targeting antibodies in which a chemotherapeutic is target as is partnered with the antibody. The specific example of that is the 916 antibody, currently under development by the GSK team. This antibody has been very impressive actually in terms of its activity in very refractory patients. It’s very clever because what it does is it targets BCMA. It delivers its payload. Then when it gets inside the myeloma cell, it also triggers additional antigenicity by the myeloma we think that further activates the immune system against the tumor. So the 916 molecule has shown great promise in that space.
I think separately, we’ve seen a number of other BCMA target in antibodies by different sponsors coming through the pipelines that look really promising as well. So those are antibodies to which a chemotherapeutic is attached and to which they go for BCMA which appears to be very important. This is a so-called B-cell maturation antigen which is highly expressed by myeloma and a very important functional target. In that spirit, as you’ve got on your list here, APRIL, which seems to be part of that pathway as well. That’s particularly exciting as well because the idea is there that by targeting APRIL — again, not to confuse everyone with lots of acronyms — but APRIL is a linked pathway to BCMA that’s very important in myeloma biology, and that too appears to be highly targetable.
To your question, Jen, though about the other antibodies that we’ve got in the repertoire that are really much well established, obviously, we have a daratumumab targeting CD38. As I mentioned earlier, that’s been truly a game changer in terms of outcome. It’s really transformed the relapsed/refractory space for our patients for the better. It’s become very widely used now both in the United States and in Europe. I think the word of caution though is unfortunately daratumumab does fail. There are patients in whom it runs out of benefit for, and there are patients in whom it doesn’t work. As a result of that, they face a major challenge because once daratumumab has failed a patient, it’s a particularly challenging space.
The good news is there are other antibodies in the strategies designed that can actually help us in that regard. I do want to mention elotuzumab because I think it’s an important antibody that given the success of daratumumab has sometimes been a little bit forgotten, and that I think is a mistake. Elo has its own definite role. Elotuzumab is a true immunoadjuvant. It stimulates the immune system against the myeloma through so-called natural killer cells which we realize are really important to fight myeloma through so-called natural killer cells which we realize are really important to fight myeloma. It does so through a funky pathway called SLAMF7 signaling lymphocyte activating molecule F7. Apologies for these funky acronyms, but I think they’re —
Jenny: That’s okay.
Dr. Richardson: SLAMF7 has the right ring to it because basically what elo does is come along, activate the natural killer cell. SLAMF7 is also attached to the myeloma. But unlike the SLAMF7 receptor in a natural killer cell, which is activated via a protein called EAT2, basically the EAT2 protein is absent in the myeloma cell. So what that means is that the natural killer cell is activated as the protein suggests to eat the cell is supposed to. The myeloma is tagged and targeted to be eaten. The natural killer cell comes in and does its work. All of this is turned into overdrive when you combine it with immunomodulatory treatment. We’ve had some remarkable results combining elotuzumab not only with lenalidomide originally but most importantly with pomalidomide. Pomalidomide is possibly more of a natural killer cell activator than lenalidomide is. Then that context results with pomalidomide combined with elotuzumab in patients who are refractory and therefore in need of an effective treatment have been remarkable.
My colleague Meletios Dimopoulos presented an oral session at EHA on our behalf where he showed results from our multi-center international trial where we looked at pomalidomide and dex versus pomalidomide, dex and elo and showed that for heavily pre-treated refractory patients, the addition of elo to pomalidomide and dexamethasone improved progression-free survival by about six months, which may not sound like a great deal but as an average that’s impressive. Most importantly, it’s a platform for future success.
Jenny: Would you ever use pomalidomide first in that situation if you’re getting such good results, or would you always start with the Revlimid and then if somebody feels that, then move to the pomalidomide?
Dr. Richardson: Well, that’s a great question. I would simply say to you that pomalidomide is probably best used in the relapsed setting for the variety of reasons. One, lenalidomide is an absolutely effective and highly validated IMiD. It’s been shown time and time again to be successful in myeloma. It’s been associated with substantial survival benefit. For example, lenalidomide maintenance post-transplant engenders around two and a half years of survival benefit. There are very few drugs that can fall into that category. So I would be very reluctant to say len should be replaced by pom up front when you have such successful data from len. But I would say to you that pom is a great next step if len fails. This data with pom-elo I think is particularly attractive because you might say to yourself, for example, if a patient receives a dara-based therapy earlier in their treatment course and unfortunately the dara-based treatment then fails them, arguably you could come in with pom-elo and probably need other drugs too to be fair such as bortezomib or a similar proteasome inhibitor like carfilzomib or something along those lines. In other words you might want to bring in additional drugs that would help you get response.
In the proteasome inhibitor family, we not only have obviously carfilzomib, which is a very potent, effective drug but we also have ixazomib which is an oral pill, very well tolerated generally. That’s another opportunity or another option for patients after initial treatments have failed.
Jenny: Can I ask a question about the monoclonal antibodies? As we were working to fund different programs, we ended up funding a CAR T research that was going after two targets: BCMA and CS1 together. I look at these monoclonal antibodies, and now there’s one by this GSK drug that’s being developed towards BCMA. We have daratumumab targeting CD38. We have elotuzumab targeting CS1. Would you ever see these being combined? Because right now it doesn’t seem like anyone ever uses daratumumab and elotuzumab together.
Dr. Richardson: Obviously, CS1 is the other word for SLAMF7. I think that’s a great point. I think the thing about dara is that its effects on natural killer cells are a little bit less clear than elo is. Elo is pure on the natural killer side of things or that’s exactly what it targets. Dara may have less of a stimulating effect to natural killers than elo does. So the rationale of combining the two is very promising. I think obviously we want to see results of studies to do that. I know studies exploring this are planned or underway.
Jenny: Yes, well, it’s pretty early with just that, GSK is really early in clinical critical trials also. Can you go ahead and explain APRIL a little bit better? Because I think many people have not heard of it. They don’t understand what it does, including me.
Dr. Richardson: It’s complicated biology, but I think the way to think about it is it’s a pathway that’s very important in myeloma biology. It’s linked to BCMA. It may be just as important to target as BCMA. Really what may be very relevant is targeting both, sort of building off what you talked about earlier about CS1 and CD38. So I think that as an opportunity, we, for example, are participating in a clinical trial looking at APRIL as a target. The preclinical work, I especially want to acknowledge my colleague Dr. Yu-Tzu Tai in the laboratory setting who’s done some beautiful work with APRIL, showing that it’s a very important pathway in myeloma. So for patients, sometimes it can get very confusing with all these names and targets and so forth. I think it’s relevant to say that it’s in the BCMA space. It’s related to BCMA. It is a very important target we think. Strategies going after it are now under evaluation with hopefully early results will reflect the promise we see from the laboratory.
I think the important message for patients overall is that BCMA, APRIL, CD38, CS1 or SLAMF7 are all important targets. What folks need to know is there are a variety of new drugs going after these. For example, in the CD38 space on the back of daratumumab is coming a new CD38 targeting antibody, isatuximab. That actually is a little different to dara and has different characteristics clinically. It has different side effects clinically. It may also have different effects in terms of therapeutic differences because it targets the apoptotic pathway for killing myeloma cells more than some of the immune effectors that dara does. As a result of that, we’re able to exploit that potentially as a next antibody in the CD38 family to use. So I think the good news for patients is multiple antibodies, multiple strategies, all with the goal of overcoming this challenge of resistance that can emerge over time.
Jenny: Well, that’s wonderful. I don’t want you to feel rushed because I’m happy to stay, to continue, because we still want to hear from you on lots of additional topics. Maybe we talk about selinexor and venetoclax next because those seem like they’re further along in the clinic or in clinical trials anyway. You already have quite a few results back from some of those.
Dr. Richardson: Yes, I’m delighted to for you and the listeners, Jen. Let’s perhaps touch first on venetoclax because I think that’s one that is really a very exciting new development. It’s just a pill being developed primarily in leukemia because it works on the Bcl-2 target. What venetoclax is being shown to do is really deliver benefit in the leukemia setting and probably will be FDA approved for that relatively soon in a variety of different leukemias as you know.
In myeloma, it’s been really interesting because the original goal was to go after the 11;14 mutation that exists in the important subset of patients. In the data, they are certainly very promising. But what’s been realized is you don’t just have to have 11;14 to benefit from venetoclax, particularly when you combine it with proteasome inhibitors like bortezomib. For that matter, other ones that are now under study, those lovely data at ASCO on combining venetoclax with carfilzomib.
So I think that venetoclax will advance because it is a very well-tolerated pill, in my experience. I’ve been now using it for a little while. It’s an obviously off-label or in the context of clinical trials. I would say that it’s generally well tolerated. Frankly, I think it’s an important adjunct. The dose in myeloma is being explored. You go from 50 up to 400 milligrams a day, but some studies now are looking at higher doses between 400 and 800 a day. That’s a lot, but it does seem to be well tolerated — generally speaking, well tolerated. I think venetoclax is very exciting. I think we’ll see lots of new information about that.
The studies have been led by my colleague Shaji Kumar at Mayo. My own my partner here at Dana-Farber, Jacob Laubach, is embracing a number of the trials here together with others where we’re looking at it with venetoclax combined with other drugs but also excitingly venetoclax with ixazomib, for example, which gives us an oral approach in patients which is interesting.
Jenny: Oh, nice.
Dr. Richardson: I agree. This is an MMRC trial which Shaji is leading. As part of the MMRC, we’re obviously partnering on that study. So it’s an exciting new approach. So that’s venetoclax.
Selinexor is quite different. It’s also a pill, but it targets specifically a brand new area which is the selectively export – well, it is a selective inhibitor of nuclear export proteins. Nuclear export proteins are absolutely vital in tumor biology and certainly critical in myeloma biology to the way the cancer cell functions. The so-called impact of a sign of a selective inhibitor of nuclear export proteins is quite profound pre-clinically. Selinexor constitutes the first-in-class oral selective inhibitor nuclear protein. Basically, as a single agent combined with steroid appears to be quite active even in very refractory patients. The challenge for it is actually its tolerability in terms of the GI toxicity in particular that can be associated with issues and fatigue. But the very good news is that it’s gotten a lot more manageable with dose adjustment schedule change. Funny enough, when you combine selinexor with the proteasome inhibitor, in particular bortezomib, the side effect profile is encouragingly favorable.
So I think we’re very pleased with that. It’s going very well and that’s the so-called BOSTON study. That’s going very well where we’re looking at a combination of selinexor with bortezomib and dexamethasone versus the standard approach setting. But I did want to mention the so-called STORM study which is looking at the effect of selinexor alone with dexamethasone for relapsed/refractory disease. That’s been led by my colleague Sundar Jagannath at Mount Sinai. Sundar has shown beautiful data there where it’s quite active even in the most refractory patients. So I think it’s very exciting. It’s a completely new pathway.
So I think it’s very interesting, Jen, because as we focus on immunotherapy and I think rightly so, being an incredibly important new target, it’s also important to remember these other targets because just as venetoclax is showing great promise, so selinexor is in the same space as a “new target.”
In that same spirit, it’s worth mentioning to the audience that at our own center, for example, we’re looking at a new novel targeted cytotoxic called melflufen. This sounds something new, something old. Well, in a sense, it’s old because it’s derived from melphalan, but it’s actually very new because it’s very different to melphalan. It’s a true alkylator, but it’s an alkylator that’s highly targeted and designed to be selectively and preferentially held in the myeloma cell versus other tissues. It’s taken up by the cell and kept in the cell because myeloma uniquely is enriched for peptidase which converts the pro drug into the active moiety. Basically, the melflufen itself then just sort of circulates otherwise, and other cells don’t hang onto it in the same way as myeloma cells do.
It’s a new idea, but it’s really bearing fruit in terms of what we’ve seen in terms of activity. It seems to be working when all other drugs fail patients as well in the same way as both selinexor and, for that matter, venetoclax have as well.
Jenny: What stage of clinical trials is that being used right now?
Dr. Richardson: It’s very similar to selinexor. Selinexor is coming out of Phase 2 and in Phase 3. Melflufen is in the same category. It’s in Phase 2 and in Phase 3.
Jenny: Interesting. That’s fascinating. Well, thank you for sharing that because I didn’t have that on my radar. That’s really interesting.
Dr. Richardson: Just to give you a little bit of background, it’s originally from the Karolinska Institute in Sweden. That’s where the science was done. We’ve been very fortunate, my colleague, Dr. Dharminder Chauhan has done the preclinical work here at Dana-Farber with Ken Anderson, my mentor’s partnership with Ken Anderson and the lab team who also — of course, Ken has been the mentor and guide to Tai in all the monoclonal antibody work I just touched on as well. With the lab partnership, we then brought it forward into the clinic. We’re very pleased with how it’s performed, recognizing that any drug has side effects. But the side effect profile interestingly of melflufen, apart from suppression of blood counts, appears to be generally very manageable unlike melphalan where you, for example, can get mouth sores, diarrhea, mucositis, and so on. We don’t see that with melflufen because of this unique mechanism where it’s kept by the tumor cell. It’s not held onto by normal tissue.
Jenny: It would replace the melphalan as a transplant drug?
Dr. Richardson: It’s a very intelligent question, Jen, and that’s possibly yes. My colleague Sergio Giralt in Memorial is looking at an idea of just that because obviously one of the dangers of transplant is by standard tissue damage. One of the most challenging is, of course, secondary leukemia risk and MDS and so on. Perhaps, we don’t know but perhaps melflufen, by being preferentially taken up by the myeloma, doesn’t then have the same long-term consequences to stem cells. But we don’t know that, so I want to be careful. We certainly don’t want to get ahead of ourselves there. But that’s obviously a very interesting area of study.
Jenny: Right, that would be revolutionary for transplant if that’s the case, if that ends up happening.
Dr. Richardson: Yes, I think so. I think in fairness to transplant, that would be fabulous. I think also that what’s going to be revolutionary in that space with the same principle is what we are touching on earlier which is CAR T, where essentially CAR T is seeking to do the same thing without necessarily the same amount of chemotherapy. So it will be very interesting to see how those two approaches pan out. I’m quite sure we’ll meet both. I don’t think it will be one versus the other. But I think at the same time, it will be much better to have more options than less.
Jenny: Right. Now, I’ve heard a lot about imaging or MRIs, PET scans being really used as a prognostic tool to help assess disease status, kind of like we’re using minimal residual disease testing or trying to detect how much myeloma people still have. Do you have any thoughts on that?
Dr. Richardson: Yes, I think it’s a fabulous approach in a clinical trial setting, MRD testing. I think it helps us with the regulatory challenges of getting drugs approved as quickly as we can by showing clinical benefit. So I think that MRD is a great research and regulatory tool because what it allows us to get insights to the future in terms of clinical benefit. I think MRD testing in regular clinical practice is something we need to be a little bit more careful about because there’s a lovely saying in medicine that “a fool with a new tool is still a fool.” What the implications are of MRD therapeutic choices, I think one has to be careful.
For example, we’ve shown that in our randomized studies of transplant patients, transplant early versus transplant late, if you achieve a very high-quality response regardless of whether you have a transplant or not and in particular, if you’re MRD negative, you do just as well whether you have a transplant or whether you keep it in reserve. That’s incredibly helpful to know. However, what we do know though is that in our early studies, patients who are MRD negative within three years, about 20% of them have relapsed. So how reliable then is the tool in the long term? Some of the more high-sensitivity tools that we now have in MRD I hope will get us there.
Again, I want to especially acknowledge the numerous investigators involved in MRD who have done such a great job. But I think we also have to be careful and say, well, look, it’s great for clinical trials. It’s great for getting drugs approved faster. But perhaps in everyday clinical practice, we need to be just a bit more careful, maybe wait a little bit and see how all the data unfolds before it becomes something that we use routinely in every setting. Because I’m a bit struck by the fact that I have patients who are MRD positive essentially. They are VGPR (very good partial response) patients who are in very good response for literally a decade and they do just fine. I’m equally struck that I have patients who have gone for a complete remission, achieved an MRD functional equivalent or they’ve been MRD negative in the context of a year of a clinical trial and their disease has come back with a vengeance very quickly. So I think one has to just be aware that understanding how you adapt treatment to MRD testing remains something that’s in evolution. So I think some care around that is probably wise.
Jenny: Yes, myeloma is so tricky. What about imaging as a tool?
Dr. Richardson: Well, imaging is great. I love the question because MRD testing without imaging is only half of the story, for want of a better word. You can test for MRD and if it’s negative, that’s great news.
The other thing is that the other piece of the imaging is critical because that really does help us understand because remember, multiple myeloma is called that for a reason. You can have lumps and bumps of it hiding that you can’t necessarily see just on a blood test or on bone marrow. So I think imaging is very important. PET/CT, in particular, may be helpful although again it’s not one versus the other. It’s the whole constellation.
I’m also reminded of a wonderful comment that I got recently from a very dear friend and patient colleague, Jim Omel, who’s a very remarkable man. He’s a physician/patient and a great advocate in myeloma. Jim also isn’t crazy about the term MRD as in “minimal residual disease” negative because no one quite understands what that means. I think measurable residual disease is a better term. I love Jim’s suggestion. It was his, obviously, of measurable residual disease, MRD, versus minimal disease because I think itof the idea of imaging, because imaging obviously is a measure or provides a measure of what’s going on. So I think as part of measurable residual disease assessment, imaging plus minimal residual disease assessment with marrows makes sense.
Jenny: Yes, absolutely. Jim is a wonderful, wonderful advocate for all of us. He’s terrific and a good friend. So my last question I guess would be about what progress is being made in the genetics of myeloma? I know the Compass study by the MMRF did a lot to identify different patterns and evolutions and things like that. What else are we learning about myeloma genomics? How do we put that together and give a 360-degree view of the patient and not just look at genetics? Or put it in context, I guess.
Dr. Richardson: Yes. I think that’s a really good point. I think that what’s true is that the issue is that the tumor is part of the story. The microenvironment, the neighborhood, the immune milieu is the rest of the story. I think that as we think about genetics, we have to think in those terms that it’s not just the tumor, it’s the host. I think that that becomes a very important part of understanding the complexity. As I mentioned earlier in our discussion, how the disease evolves over time changes within a patient as much as it does between patients. I think that that’s a critical point.
It’s a great question you raised, Jenny, because it allows us to think in those terms. It’s all very important to recognize that therapeutics can have an impact on that. What I mean by that is — and this is a concept that is not always shared — that we’re blessed with the antibodies, we’re blessed with immunotherapies, we’re blessed IMiDs, proteasome inhibitors, new drugs, small molecules, and so forth. Therefore, we have to be very careful with therapeutic choices, that we don’t just obviously eliminate disease, but we do give our patients the best quality of life. By that, I mean that their host milieu is also preserved optimally.
That is very important because at the end of the day, this impacts directly on how patients do. If the immune system of a patient is well preserved, if their organ function is well preserved, if the treatment they have maintains a homeostasis with their disease even if they’re not MRD negative, isn’t that good? I think that needs to be better understood because as I said earlier, in the context of transplant, there are certain patients who benefit from it and do extremely well, and there are others who unfortunately run into real difficulties. We probably need to recognize the importance of that because, for example, in our trials, we’re showing that the ability to keep maintenance going after transplant is different to those who don’t necessarily get transplanted. It’s actually generally easier to maintain patients who don’t necessarily have a transplant first and keep it in reserve. However, of course, whether they benefit more from the transplant being early versus late in the context of disease reduction is the other aspect to think about.
So to your point, this idea of understanding tumor and host, understanding the complexities of the patient’s milieu, immunological and otherwise, is a very important area of research.
Jenny: Yes, that’s why this disease is just so complicated. I know we’ve talked about a lot of things that are also complicated. This is why I suggest people go and talk to people like you for their care because there is such a depth of expertise that’s just stunning.
Well, I do want to leave some time for caller questions, if that’s okay with you, If you do have a question for Dr. Richardson, you can call 347-637-2631 and press 1 on your keypad. Go ahead with your question.
Caller: Oh, yes. Hi, Dr. Richardson. This is Adrian. It’s wonderful to hear your update. It’s probably the most lucid and eloquent update I’ve heard in a while. I actually have two questions. The first one is what is your experience with using dara in combination with pomalidomide and dex in a post-transplant setting for maintenance?
My second question is a bit more philosophical. There’s some research inspired by evolutionary theory arguing that attacking myeloma with all the armamentarium is probably not the best strategy because then the clones that are more resistant and more active will then essentially give them a chance to overcome the evolutionary battle by diminishing all the clones that are more susceptible to treatment. So the argument would be don’t hit myeloma with all you’ve got. Try to maintain some form of equilibrium in which the really aggressive clones will not have a chance to proliferate. That’s also somewhat consistent with your clinical experience talked about a patient that lived a long time in VGPR as opposed to patients that achieve spectacular results initially but then relapsed. So the philosophical question is where are you on the spectrum of real aggressive treatment up front versus aggressive but not overwhelming treatment with the hope of maintaining a really long-term equilibrium or metastable equilibrium between the various clones?
Dr. Richardson: Adrian, it’s so nice to hear your voice. Thank you for your very kind comments. Thank you for your very intelligent questions as always. So Jen, it’s my privilege to be part of the team looking after Adrian. He’s an absolutely super person, a great, great patient partner.
Caller: Thank you.
Dr. Richardson: No, no, it’s true, Adrian, absolutely. You’ve touched on some critical points. I think that the daratumumab question is really interesting. Let’s start with that one then we’ll move into the next part of it.
Dara, as I mentioned earlier, has just changed the therapeutic landscape in myeloma. I would argue being sort of functional equivalent of Rituxan as has been used in the lymphoma space. The thing is that once dara unfortunately fails a patient, then we’re kind of in a challenging space. I think that the maintenance strategies with dara are very important to study. I think they could dramatically enhance outcome. The trials would suggest, for example, Castor and Pollux would suggest that the long-term use of dara is feasible and in the relapse setting clearly results in clinical benefit.
So I think there’s a very strong argument for looking at dara-based therapy as a part of a continuous therapy strategy. But I think in the early newly diagnosed post-transplant setting, we have to be a little bit careful and wait for the results of our clinical trials to be sure about how those are placed. The reason why is dara obviously is a CD38 targeting antibody and obviously CD38 is a stem cell marker. So we have to particularly post-transplant I think, see how the information pans out.
So far, in studies like Cassiopeia, which is a superb effort led by my colleagues in France under the auspices of Philippe Moreau and others, has been shown to be really quite successful and quite safe so far, which is great news. But, obviously, we’ve got other trials ongoing that we hope to get more information. In our own Alliance group, we have the GRIFFIN trial led by my colleague Peter Voorhees has done a fantastic job with this, which is sort of currently ongoing in transplant patients to see how the dara behaves. So I think we need to be a little cautious about saying what happens in situation X means it’s going to be just as good in a situation A because obviously there’s B, C, D and E between. I think we just have to see how that all pans out, but so far so good regarding daratumumab’s role as a continuous therapy agent.
The challenge, for me, personally in the clinic right now, Adrian, is when dara fails a patient, then things can get very challenging. I think that’s just something to bear in mind. It doesn’t mean you keep it necessarily in reserve for everyone, but it does mean that you have to think rationally about sequencing because to your next point, which I think it’s such an important one. The evolutionary philosophical question, I think it dovetails very nicely with what you just asked about dara because the question then becomes do you use everything up front that’s best, or do you adopt a certain amount of therapeutic parsimony in order to make sure you’ve got guns in reserve if things fail?
I think that’s an incredibly important question. We’re studying it and trying to better understand it. In the clinic map, I tend to use my clinical experience and a very holistic view of the patient to make that call because I’m very struck that I have patients in my practice, to your exact point, who are doing very well on relatively minimal therapy over many years. I’m equally struck that multiple drugs thrown at patients with an aggressive phenotype unfortunately sometimes fail, and that can be very difficult to control.
I think we’re getting better at this though. I especially acknowledge colleagues who are really pioneers in the field of genomics in understanding who does badly and who you need to attack with full-court press. When I mean who to attack with full-court press, I’m talking about the disease obviously not the poor patient. The best example there is deletion 17p. To use a very high-level example, del 17p is a real menace. There are different varieties of it. When it’s around, in my experience, you have to be very thoughtful. That doesn’t mean that you transplant everyone with deletion 17p because, in fact, p53 mutation, as you know, Adrian, from our discussions, kind of enriches for resistance to alkylator therapy and chemotherapy in particular.
So I think that we have to be a little careful about what we put into that mix. But certainly, if I’m looking at the deletion 17 disease, I will think very creatively to put a PI in the mix and IMiD in the mix and an antibody. We’ve also got HDACs that are very effective against 17p mutation. H stacks will be the approved drug being panobinostat and a variety of others under study that I think have real promise as well. The reality is that you want to put all of these sorts of strategies together to try and target something as ominous as 17p.
11;14, of course, gives us the option of venetoclax which is a gentler treatment. I use that as an example because it’s an example you might have a better biology, arguably, although 11;14 is important to note can be expressed in plasma cells leukemia which means it’s a different animal there. I use it as an example as a teaching point, that a mutation in a particular setting may be very different in another setting. So 11;14 in plasma cell leukemia means a very different thing than 11;14 means in someone else.
So to your philosophical point about evolutionary pressure, I would say it’s extremely complicated. The more you know, the more there is to know. The good news is that we’re better understanding it. We’re better understanding the implication of clonal tiding and the idea of clonal heterogeneity. The really important message for everyone on the call is thank God for the treatment options we have which mean that we can be more tailored in what we do.
Caller: Thank you.
Jenny: Yes, absolutely. Okay, we have one more question. We have a hard stop in just a few minutes. We have one more caller question, go ahead with your question.
Caller: Hi. This has been probably one of the most informative shows that I’ve listened to. Jenny, how long has it taken you to get up to speed on myeloma?
Jenny: A long time. Many years.
Caller: Yes. So for the average patient and caregiver, we’re completely lost and a lot of this information is hard to understand and put in context. What other tools or ideas do you have for us to get up to speed so we can be able to better understand the context of this content as it relates to care?
Jenny: Well, I think what we could provide, especially for a show like this, Dr. Richardson, is links to kind of a thesaurus so as people go through the transcript, they’d be able to link out to the variety of things. It’s tough when we’re doing a show like this especially because we’re covering so many topics in a very short period of time. So I think we’ll provide that for this show in particular.
Caller: That would be an amazing resource.
Dr. Richardson: I’m so sorry, I didn’t mean to interrupt you. I just want to say thank you so much for your kind comment. I think that again as to touch on the philosophy of what you’re kindly pointing out, I think that the benefit is that we are very fortunate to have very strong patient advocacy in myeloma which has made a great difference from the IMF, MMRF to Leukemia & Lymphoma Society, also to Jenny’s efforts and other groups. It’s been really lovely to see that. I think that Jenny I think captured it perfectly that given the complexity of this disease, not only between patients but within patients, the ability to have access to the latest information and the complexity of any individual patient’s situation is really critical. I think that’s why I would put in a big plug, if your resources allow, being able to come to specialist centers because it can be very helpful. I think all email tools and all the literature that’s available, there’s nothing better than being able to sit down face to face with a person and have time to go over these things.
Caller: Well, thank you. Jenny and the Myeloma Crowd just do an amazing job. Listening since the beginning and I’ve seen the progress and the knowledge and the growth and this amazing resource that’s available to patients. Thank you both for your efforts, and I’ll sign off.
Dr. Richardson: My privilege.
Jenny: Well, thank you so much. Dr. Richardson, I completely agree. I always suggest the patients see a myeloma specialist just for this very reason: the disease is complicated. You really need people who are seeing hundreds of cases per year and running these clinical trials on it, because you’re seeing both sides. You’re seeing the science, and you’re seeing the research and the clinical application of that research.
So thank you so much for participating today. I apologize for our technical issues we had at the beginning, but you were stellar as usual. We just really appreciate your efforts. On behalf of us all, thank you so much.
Dr. Richardson: Well, Jenny, Jenny, please it’s truly my privilege. It’s my honor to help, frankly. I just want to acknowledge your work and just say thank you for all you do. Thank you in particular to all the people on the call taking time out of their Friday to listen. It’s been a true pleasure. I look forward to helping going forward.
Jenny: Yes, thank you so much. Thank you to our listeners for listening to Myeloma Crowd Radio. We encourage you to tune in next time to learn more about the latest in myeloma research and what it means for you.
MGUS (monoclonal gammopathy of undertermined signigficance): MGUS is an early precursor condition and can be present years before a myeloma diagnosis. Only a fraction of MGUS patients will develop active multiple myeloma.
Smoldering Myeloma: An early precursor condition that can occur prior to a myeloma diagnosis. Typically, only high-risk smoldering myeloma patients are treated and it is suggested that they are treated in the context of a clinical trial. Not all smoldering myeloma patients will progress to active myeloma.
Relapsed Myeloma: When myeloma returns after treatment.
Refractory Myeloma: When myeloma stops responding to a particular treatment.
PCROWD study: A study at Dana Farber led by Dr. Irene Ghobrial to study early myeloma conditions including MGUS and smoldering myeloma. Patients can join by sending in blood and bone marrow samples without traveling to Boston.
CAR T: A new treatment for myeloma currently in clinical trials. T cells are removed from an individual patient, engineered to target a specific protein on the surface of myeloma cells (in most US trials this target is currently BCMA) and given back to the patient. Currently in Phase I and II studies.
Monoclonal antibodies: Antibodies that hit one target. Currently approved monoclonal antibodies include daratumumab (targeting BCMA), elotuzumab (targeting CS1, also called SLAMF7). Future monoclonal antibodies are in development.
biTE: An antibody that is bi-specific, or hits two targets instead of one.
Immunomodulators (IMiDs): Drugs that kill myeloma and enhance the immune system at the same time. Currently available drugs in this class include Thalidomide, Revlimid and Pomalyst.
BCMA (B-cell maturation agent): A protein that has become a popular target for myeloma treatments including CAR T and monoclonal antibodies.
CS1/SLAMF7: A protein that has become a target for myeloma treatments including CAR T and monoclonal antibodies.
Selinexor: A new drug in development for relapsed/refractory myeloma patients.
Venetoclax: A new drug in development for relapsed/refractory myeloma patients. It was originally thought that it was best for patients with the 11;14 translocation, but it may be appropriate for all myeloma patients.
Melflufen: A new drug in development that provides a targeted delivery of melphalan to cancer cells. Melflufen is currently in phase III studies for relapsed/refractory multiple myeloma.