Paul Richardson, MD
Dana Farber Cancer Institute 
Interview Date: July 31, 2019

Selinexor, by Karyopharm, was recently approved in the myeloma clinic for use in myeloma patients who have relapsed after other lines of standard myeloma treatment. Learn why selinexor was approved early, when it should be considered, how it can be best combined and how to manage side effects early and successfully. Dr. Paul Richardson of the Dana Farber Cancer Institute joins Myeloma Crowd radio to share how early FDA access approval works and why this drug was selected for early approval. For myeloma patients who have relapsed after proteasome inhibitors, immunomodulators and monoclonal antibodies, selinexor provides another option for effective care. 

Thanks to our episode sponsor

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 GlaxoSmithKline for their support of Myeloma Crowd Radio.

Before we get started with today's show, I'd like to just share a quick update on the software tool we created called HealthTree. We now have over 4,400 patients who are using HealthTree. You might notice that we are introducing a new design. In HealthTree, you can gather together all relevant information about your myeloma in a single place. This is important especially if you're being seen at multiple facilities. It helps bring together all your information to make your doctor's visits easier. It also helps you better understand what type of myeloma that you're dealing with. You can see treatment options that are personally relevant at every stage of your myeloma that you can then discuss with your doctor, find clinical trials you're eligible to join, which narrows down your list of the clinical trials from 450 open myeloma studies to about ten to 20 more personalized studies. You can find financial help, answer researcher survey questions to advance insight into care and see what -- and soon, you'll be able to connect with myeloma patients who have similar genetic features to you. We call this the Twin Machine. You'll be able to see what others had for treatment that have similar features to you and how they responded to therapy in an anonymous way. We'll have more to come, including a doctor in researcher portal, so experts like Dr. Richardson will be able to learn from aggregated anonymized results.

Now, onto today's program and Dr. Richardson. Today’s show represents ever-growing myeloma treatment arsenal. The development happening in myeloma therapy is truly stunning. It’s a testament to outstanding researchers like Dr. Paul Richardson, who worked tirelessly to ensure that new treatments are taken through this very lengthy process from an idea to an actual working therapy. I think the average time that that process takes is typically 17 years. And I'd like to introduce Dr. Paul Richardson to today's show about the new FDA approval of a drug called Selinexor by Karyopharm. Welcome, Dr. Richardson. Thanks for joining.

Dr. Richardson: It’s a pleasure.  

Jenny: Thank you so much for joining. Let me give you a little introduction before we get started. Dr. Paul Richardson is RJ 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 the 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 Foundation for clinical trials and the Myeloma Steering Committee Member of the National Cancer Institute. He is 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 distinguished myeloma specialist who's a very influential figure in the new drug approval process in myeloma having led large Phase III clinical trial efforts for approval such as bortezomib and leading Steering Committees and Oncology Drug Advisory Committees for myeloma therapies such as 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 and is the recipient of the Robert A. Kyle Lifetime Achievement Award by the International Myeloma Foundation for his work that's resulted in significant advances in research, treatment and care of myeloma patients around the world.

Dr. Richardson, we know you are at the forefront of bringing new therapies and caring for patients. It's a wonderful blend and amazing expertise. We're just so thrilled that you joined us today.

Dr. Richardson: No, Jenny. It’s my privilege. Thank you very much for the invitation. You’re most kind with your introduction. I just want to simply say it’s just been a privilege to be part of a great team of investigators from across the board, from the very beginnings with bortezomib through to lenalidomide, pomalidomide, ixazomib, daratumumab, elotuzumab and then of course to the drugs, panabinostat and the ones that we sort of listed the most recently, selinexor being approved a few weeks ago. But I just especially want to acknowledge all patients and families who make all of that possible, not least of which because patients participate in these clinical trials which takes tremendous courage and commitment. That partnership is essential to the progress we've made.

So I just wanted to especially share that with you, Jenny, because that's essentially the privilege of what we do. It’s being able to all move together in this mission to improve outcome. It's particularly nice to be able to share this kind of moment with you, Jenny. I especially want to acknowledge your contributions and your team's contributions to research and progress in myeloma. Thank you, Jenny.

Jenny: Well, thank you. It's so stunning. I mean it takes so long for a new drug to come from an idea to development. This last year's ASH, I was just so stunned by the number of companies and the number of trials that are open in myeloma. When we started this program, we really wanted to promote clinical trial participation because all these therapies that you've helped bring to the clinic, Pomalyst and Revlimid and all these other drugs that are core drugs now that you use in myeloma and we're taking in myeloma, just happened because of that process because you're leading things forward and patients are participating. So it's truly a partnership that patients should consider at every stage of their disease.

Dr. Richardson: I agree. It's something to be cherished in so many ways. But it's also an area of great, great challenge, I think, as we go forward because -- to help with the listeners, obviously these ideas come from patient laboratory science, which can be extremely laborious and intensive. That process can be very long. I think what then happens is that the target acquisition as we call it, a specific biological target in myeloma, it can then be in turn treated with appropriate drug classes, be they small molecules, antibodies, immune therapies and so on. Then we translate that to the bedside. And I think that translation to the bedside has always been the most challenging part of clinical researchers. For all the clues that we have from our preclinical work via the laboratory to animal models and then into the clinical setting, that interface with clinical researches is an area of exquisite vulnerability in the sense that for the ten shots on goal that we may have from the lab, it remains a reality that actually when we translate that to the clinic, whilst it was certainly so much better than we were before, there are a number of clinical trials that fail, that don't show the benefits. Then we need to be able to move quickly on to new strategies for our patients.  

I think the good news in myeloma, though, is that those have become increasingly less common compared to say 15, 20 years ago where clinical trials could fail with a higher rate than we see now, which is actually I think very good news. I think that the good news is that we're getting better at being selective in our targets but please, it’s important to recognize how much work goes into that process before we then bring, as you say, the new agents to the clinic. It's a very long process to echo the point you just made.

Jenny: Yes, I agree. Whatever patients can do to help speed that along I think is helpful. Well, today, we're talking about a specific therapy that was recently FDA approved for the use in myeloma. It's a drug called selinexor. Maybe we should just start with a broad overview of what it is and how it's been developed over the last few years for multiple myeloma

Dr. Richardson: Thank you, Jenny. Well, selinexor I think is particularly intriguing because it's been entirely novel mechanism of action. It's a small molecule inhibitor that disrupts the ability of the cancer cell to export it from the nucleus - what we call a tumor suppressor proteins - which essentially are critical in suppressing the genetic translation from the gene to the protein product, essentially which is how a cell, a cancer cell grows resistance and survives. That process, that transcription, that whole downstream process is in the normal cell controlled by this whole family of what we call tumor suppressor proteins. These nuclear proteins are critical in suppressing malignant behavior. Malignant cells, therefore, export these protein so that they can actually be able to transcribe and translate the gene product into an actual cellular effect.

Now, what's so interesting about this is that what selinexor and the drugs in this class do is they selectively inhibit these nuclear export proteins in a way that keeps the proteins inside the nucleus and so stops the malignant cell from behaving as badly as it is prone to do. I suppose a good analogy I'm going to borrow from one of my colleagues which is it's almost as if at home, a rave is going on and the parents have left the house. And that's the malignant cell. What happens is with these inhibitors is that they keep the parents at home. And the parents at home turn it into a wine and cheese as opposed to a rave.

So essentially, I think that is quite useful because it explains how we're able to keep those proteins inside the nucleus in a way that then suppresses the malignant genotype being translated to the malignant phenotype. And it's very potent in actually killing the myeloma cell in doing that. What's so interesting is though, unfortunately, normal tissues are also affected by this because essentially, this nuclear export mechanism is also relevant to normal cellular function but to much lesser degree. And why that becomes important is in a moment to explain why it may be that in combination, selinexor is particularly effective as opposed to just a single agent. But how this drug works is essentially to inhibit the export of proteins from the nucleus that otherwise suppress the malignant genotype and phenotype. And by doing that, it actually triggers program cell death and causes the myeloma to obviously perish.

Now, why it’s so important is because it's also particularly effective in the setting of highly resistant myeloma. We have evidence in the lab of a particular effect on, for example, p53, which is an important mechanism reflected by 17p deletion at a cited genetic level in the cancer. And that in turn codes for p53 mutation. That particular target is very relevant in the aggressive myeloma. So for that reason, it’s those kinds of abnormalities in the myeloma cell that we see more commonly in relapsed refractory myeloma in which other treatments have failed the patient that they typically overexpress these particularly dangerous genes. And interestingly enough and important enough, selinexor is a mechanism. And the preclinical setting appears to be particularly effective at targeting that kind of gene product.

So recognizing these as laboratory experiments, the one always have to be taken with a pinch of salt, it's important to recognize that this appears to have been translated to the clinic because what we've been able to see is that selinexor, challenging as it is to give as a single agent, is nonetheless effective in patients in whom unfortunately, all other available therapies have failed. And that's why we obviously had the very important accelerated approval just before July 4th

I think one of your questions was, Jenny, how long has this been in development? And I would simply say that the original groundbreaking work was done about a decade ago under the guidance of a remarkable preclinical scientist, Sharon Schechter. She and her colleagues in the laboratory developed these classes of drug and brought it forward. She's actually a founder of   Karyopharm who is the pharmaceutical company who produced selinexor.

Jenny: That's fascinating. I remember doing a show on this I think, gosh, probably four years ago when it was just going through the development process. You're right. It just takes so long. You explained how it acts differently from other classes of myeloma therapies. You touched on the fact that even though it has single agent activity, it might be more effective in combinations. And that's typically how things are given in myeloma, in combination. How does it work in conjunction with the other therapies, like the proteasome inhibitors or the immunomodulators and things like that?

Dr. Richardson: Yes, great question, Jenny. I would say that this has been the very exciting part of it. Just to explain, lots of patients listening may say, “Well, my goodness, why does it take so long?” It takes longer because you have to be super careful. You not only have to be super careful, but this kind of scientific detection and identification of an active molecule it requires time and effort. This is the simple fact.

I think what's so interesting about selinexor is that when we first started using it in the clinic, it clearly as a single agent was active, but it clearly had substantial side effects. And I mentioned earlier, a pinch of salt. One of the biggest side effects was this very low sodium that we see with its use. We also see fatigue. We also see low platelet count and so forth, which represent side effects that probably reflect an effect on normal test use that in some way is modulated by this inhibition of these key proteins from the nucleus.

What we found is that when you combine the drug with drugs like proteasome inhibitors and in particular, bortezomib, intriguingly, the side effect panel changes dramatically in a way that's favorable. What we've found is that it may lie in the following mechanisms that proteasome inhibition in itself may actually alter the behavior of this nuclear export mechanism in normal cells. It may alter it subtly in myeloma as well, but not to the extent of killing -- in fact, it enhances the killing of the myeloma. But actually, in the setting of normal tissues, the effect may be favorable. And what I mean by that is when we've combined bortezomib with selinexor, we've seen clinically that this combination is well tolerated. And a lot of the challenging side effects of selinexor like nausea, fatigue, low sodium, et cetera are more manageable. And one of the other aspects of it may also be frankly that we're able to give the selinexor once a week for example and still retain efficacy because we're basically combining it with the proteasome inhibition. And as a result of that, we're seeing a synergy.

For that reason, combination strategies with, for example, bortezomib in particular and proteasome inhibitors more broadly have been highly effective. I think that's one of the important messages for listeners because certainly, since the approval, personally, I have been recommending the use of selinexor. It’s certainly with dexamethasone which is according to the label. But most importantly that actually combined with drugs like bortezomib for example, it can be much better tolerated and also more effective.

In terms of other drugs like daratumumab and the immunomodulatory drugs and so on, clearly, there've been lots of studies looking at this. And the most important being, the STOMP trial, which was a multi armed study in which various combinations were explored. In STOMP, the clear signals with the proteasome inhibitors, that was the one that was really exciting. That led to what's called the BOSTON study, which has currently actually been very active and accrued and so on. We’re very much looking forward to data emerging from Boston soon. In fact, that's one of the reasons why FDA were able to feel confident with the accelerated approval. It’s because they had data (at least safety) from BOSTON that was favorable.

In any event, other parts of the STOMP study and in particular combined with daratumumab for example, selinexor can actually work at least additively if not synergistically with daratumumab. Interestingly, again, the side effect profile when you combine the drug can be more manageable because you can use less selinexor this frequently. But also, I do think, however, there was a mechanistic interface with proteasome inhibition that may be quite specific to that partnership. So how I've been thinking of the drug is selinexor plus a proteasome inhibitor plus other drugs. It’s how I've been thinking of it going forward

Jenny: That's fascinating. And I know that that's why on some of these trials you might run a Phase I trial on a single agent, but then you might run a Phase I trial of a drug in combination with other drugs because it's the first time you've used it in that particular combination. What are the other combination drugs in the BOSTON study that selinexor is being used with

Dr. Richardson: It’s just the bortezomib and dexamethasone. So the BOSTON study is a randomized comparison of selinexor plus bortezomib and dexamethasone compared to bortezomib and dexamethasone. It's in a much less heavily pretreated population than the original STORM trial. And the STORM trial, which we were very much part of and it’s of course the basis to accelerated approval. It's being led by my colleagues, Dr. Ajai Chari and Dr. Sundar Jagannath, from Mount Sinai. The STORM study was designed to test the drug in a real area of exquisite medical need, which was patients in whom all the major drug classes had failed them. So they were resistant to proteasome inhibitors, resistant to IMiDS, resistant to daratumumab-based therapeutic treatments like it.

In that study, these patients are also called “triple class refractory” and typically what we call penta-exposed, so their disease has been exposed to multiple agents, including the PIs, the IMiDS and CD38 targeted therapy. And in this group of patients, a response rate of about a third was seen in combination with low dose dexamethasone. At the time, I think a lot of people, who perhaps aren't so familiar with myeloma therapy, were a little bit nonplussed with a “so what” comment. Well, actually, that's very important for those patients who benefited. And for those patients who did respond, these were durable and an important subset.

So as you can imagine, Jenny, that was the rationale for the original accelerated approval. But it was supported by this BOSTON study that was done earlier in the disease which obviously takes longer time to mature and read out. So the strategy of accelerated approval make great sense in that context in my opinion.

Jenny:  And these are for patients who, by that point, by the time they're just penta-refractory or resistant to pretty much all major standard of care myeloma drugs. They've picked up these additional mutations that you talked about, like the p53 and the deletion 17 or whatnot. Their diseases evolved to become an even more aggressive disease by that point.

Dr. Richardson: Yes. I think that's right. Jenny, if I may, just to add another point, I mean I think doing studies for patients who are triple class refractory and penta-exposed is very challenging area to offer patients’ treatment because their disease is so resistant. Unfortunately, they are  so ill. Frankly, I think the sponsor, Karyopharm in this case had the courage to do that. And that was meeting an unmet medical need. And I think what I particularly was impressed by is that the the FDA really listened to what the issues were. I thought that was a very important part of the Oncology Drug Advisory Committee discussion. It was that there was a real recognition of just how challenging this patient population are.

One thing that was interesting in that ODAC discussion, which is probably worth sharing with listeners is there was somewhat of a focus on the impact of dexamethasone in this setting. And I think one has to be very clear about that. There is absolutely no evidence that dexamethasone in this population on its own has meaningful activity. And there was one very important clinical trial recently done in Europe called the ADMYRE study where they looked at a novel drug called Aplidin, which is not being studied in the US anymore, was for a while, clearly active, but for a variety of complicated reasons, it’s just probably not going forward in the US, although interesting enough, it's approved in Australia. When you combine Aplidin with dexamethasone, how does it compare to dexamethasone and the dexamethasone patients in that trial? And this was a large Phase III study. These were less heavily pretreated patients than STORM. But nonetheless, they'd had at least three lines of prior therapy. The response rate to dexamethasone once a week was a negligible 2%. The duration of disease control was only about a month. Obviously, we have the highest level evidence that steroids in this type of population have no meaningful benefit on their own.

I think that's an important point to share, Jenny, with listeners because at the ODAC, that was a point of contention. I don't do Twitter, but I heard on Twitter that apparently, dexamethasone was being discussed. I think it's important to share with patients who know this only too well. Dex alone in this setting really has no meaningful activity. So I think that for that reason, that process was very important to have that discussion and share that dialog.

Jenny:  And if Dex were effective in that way, you probably wouldn't be triple class refractory. So by that stage, it's like not working.

Dr. Richardson: Of course, of course. I would use your analogy. I think sometimes metaphors are very helpful to clarify things. I think Dex in this setting is like WD-40. It's just oil that helps the wheel turn a little better, but you've got to have the wheel. The fact of the matter is that the Dex is only contributing to the ability for that wheel to turn. And I think that the perseveration on Dex conferring activity in this setting for people who are in the clinic, seeing patients three days a week and caring for them as I do, that's clearly not what's making a difference here.

Jenny: Right. Well, before we talk about the trial results that I'd like you to share, can you go back and explain this FDA accelerated approval process? Because I think in general, most myeloma patients don't understand that process or how somebody gets through that process or what that looks like.

Dr. Richardson: I'm delighted, Jenny. I give FDA enormous credit here because their goal is to bring drugs as quickly as possible to patients who need it. And as we know, in the context of clinical trials, these have to be rigorous. There have to be eligibility criteria, we call them, for the safety of the patient first and foremost, but also because from a drug development point of view, there has to be a very strict approach to what we call regulatory science. And I use that term broadly to explain that this requires entry criteria. It requires measurable disease. It requires safety parameters that can lead to a reliable signal from a clinical trial as to the efficacy of the drug. And that's terribly important. An accelerated approval pathway is a mechanism provided by the FDA, which I think is incredibly helpful. What it does is it provides a mechanism where there is clearly a signal from a particular drug that it's active, that it's working despite the fact that other treatments have failed and that it has a reasonable safety profile that would justify it being made available to patients in the setting of unmet medical need and on the understanding that ongoing trials in earlier stages of disease, which are the gold standards, where they're comparing the new drug to a standard of care in a randomized perspective's fashion are ongoing.

Why that's very important is because it helps the FDA understand what the real effect is of the drug as it stands versus in combination and at the same time as the reassuring confirmation of whatever was seen in the more advanced setting. Usually, when it comes into that Phase III setting, the drug is actually able to do much more. For example, when we think about bortezomib, it was actually approved on the accelerated approval pathway in 2003. The response rate back then was around 30% in patients in whom all of the treatments at the time had failed them. And that was a single arm trial, which it was my privilege to be part of with a number of other key investigators. And we got FDA approval for bortezomib because at the same time, we'd launched the APEX study, which was a randomized comparison of high dose Dex, which was the standard of care at that time versus bortezomib alone in less heavily pretreated patients. So FDA were able to provide us with access to bortezomib in very sick folks whilst we conducted the APEX study to prove the benefit of bortezomib compared to high dose Dex, which was the standard back in 2003-2004.

So an accelerated approval mechanism is an incredibly important way of giving patients access to a drug whilst the full approval process is underway. I think this is important to share with your listeners how this works because it means that, for example, in a community setting, as opposed to a patient having to go to a clinical trial to pass all the entry tests necessary, meet all the entry criteria, a clinician or provider and the patient can in the community setting try these drugs to help that patient in that particular context without having to necessarily go through the rigor of a clinical trial in order to gain access.  Unfortunately, you can often be excluded from treatment on that basis. So the accelerated approval mechanism, to me, is absolutely essential. I particularly want to acknowledge FDA because it's a very difficult task, but they do an exceptional job of sorting that out. And particularly, we're very lucky in the myeloma world that we have a super FDA team we work with. They do really listen. Also, they have very high standards appropriately. But at the same time, they're very receptive.

Jenny: It seems like the FDA is working harder to identify earlier ways and faster ways of just making sure safety is okay, but also moving things forward more quickly. I just feel that in the myeloma pipeline that you're seeing. Does myeloma get any special treatment because it falls within that orphan disease designation for the FDA fast track approval or no

Dr. Richardson: I believe so. Yes, I believe it does. I think obviously, the good news in the myeloma review team at FDA is that they're seasoned hematologists and oncologists. And the leadership there is particularly good in my opinion. That's with Doctors Nicole Gormley, Ann Pharrell. Ann Pharrell is actually the division leader. Then of course with the overall leadership of Dr. Rick Pastor, who in my opinion is just second to none. He's exceptional. And I think the important point is that they understand the disease. And what's most important is they have a keen understanding of cancer. They know what it means. They know what it means to patients and families. They know how deadly end stage myeloma is. So they realize how important it is for us to have access to these newer agents provided that meets key standards of efficacy, which reflects both activity and of course, safety.

Jenny: Right. And when patients have run out of options and have nothing else to turn to, examples like this are really important. What you said before, now the local oncologist can use this. That's so important because 80% of myeloma patients are really being seen in the community oncology setting.

Dr. Richardson: Exactly. And they don't have access to clinical trials. The idea of expanded access, compassionate use programs is very well intentioned. But it's important to note that that is also a question of feasibility and scale because especially in the current environment between institutions and the regulatory processes at work in each respect to the hospital academic center, so-called compassionate use program is very difficult to execute actually. It's not as simple as sometimes is thought. And expanded access programs are of course very important potentially. But they are not a substitute for access in the accelerated approval setting in my opinion because speed is the key. And for a patient who is triple class resistant, penta-refractory, having to wait for an IRB approval for months is just not an option. Getting drugs within a week or two is what you need. And that's when drugs that got accelerated approval can be used quickly. Of course, in a way in which also patients and most importantly their providers are well educated so they know how to handle the drug and what to do with it.

I think what's also important to share, Jenny, with listeners is also these treatments are often a bridge to next treatment. And I think that's a very important concept to understand because especially in cancer like myeloma, which is increasingly we're seeing prolongation of survival, which is wonderful and along the disease control periods with all of the various drug classes we have, unfortunately, at the end of the day, we still have an incurable disease in the long term. So this idea of bridging next therapy is so important because it gives us the ability to, God willing, be able to see benefit from a treatment that lasts long enough for another treatment then to become available or a patient to stabilize well enough, see some recovery accounts, recovery parameters to then be able to go on to another protocol, for example. So I think sometimes the nuances of all of this are not so easy to immediately see on the face of it. But as you dig deeper into what this means, that's the kind of benefit that's also very important to appreciate

Jenny: Well, I think that's very important because even in today's landscape, if a patient had run out of all options and could use something selinexor to get them another six months until they can get into a CAR-T trial or something like that would be helpful. It feels like with myeloma, you're playing a chess game at all times. You just have to take these continual moves

Dr. Richardson: I agree

Jenny:  And that can be another move into something else. So I completely agree with that strategy.

Dr. Richardson: I so agree. Thank you, Jenny.

Jenny: Well, that was a good point. Thank you for bringing it up. When you talk about results, trial results, you had mentioned the bortezomib response rate. What types of response rates did you see or are you seeing in the current studies of selinexor? How does that compare to other response rates that you might see in a myeloma drug that's already been approved? Then I noticed in some of the data that what you were saying earlier that patients with some high risk features responded even better to that. Do you have numbers on those or can give us some estimates about that?

Dr. Richardson: Absolutely, Jenny. I think what's very important to share is that in the context of single agent experiences, active drugs in myeloma have traditionally had about a 20 to 30% response rate typically in combination with low dose dexamethasone. I mean the best example of that would be something like pomalidomide for that matter. Another example would be carfilzomib and dexamethasone and even daratumumab. When we built that study from accelerated approval to then subsequently full approval, the initial response rates to daratumumab monotherapy with dexamethasone as part of premedication and so forth is a solid 30 to 35%. So a rule of a third is about right. What I think is so compelling about selinexor is that we saw a response rate of around a third, around 30% despite the failure of the other drugs. And that's I think a critical point

So that being said, obviously we want to do better in combination. I think what was also important is when we looked at the STORM study and looked at those patients who responded, their survival for the responders was quite remarkable. And some patients saw disease control for up to 18 months, which was really, really striking in such a difficult to treat population. Obviously, for those patients who unfortunately didn't respond, the survival was very short. The challenge with looking at that though is that this is a single arm trial. So because of that, you can't necessarily compare, but you can at least infer.And what we also did in this setting was we did some analysis from what we call Flatiron data, which are data that was derived from electronic medical records. And it looks at community- based practice. And what we were able to do there was look at what happens to patients who are typically triple class resistant, penta-refractory. What are their outcomes? And what we are able to see in a case matched control analysis was that actually, on average, we improved outcome, disease control survival by a factor of about a third that we almost doubled in actually five months versus ten months. And I think in that context, well, if that's not definitive, it's suggestive. And I think that is helpful for us to see that kind of signal. So to your point, Jen, we saw activity in this heavily pretreated refractory population, an important signal. The proof though of real benefit and real efficacy will be much earlier. And that's obviously the value of the BOSTON study and other trials alike, which are happening in much earlier stages of disease. So I think those are important points to share.

The question that you ask about high risk cytogenetics is a very important one. And that is clearly true that we saw in the percentage of high-risk patients in which this study was enriched for them because of the nature of their disease. We saw a response rate that was consistent. It wasn't dramatically lower in the higher risk patients. It was actually very similar. And we did see durable disease control. But I want to stress that unfortunately, high risk disease still remains very difficult. There's no question about that one area of disease that we're seeing real problems where there's what we call extramedullary relapse, which is disease of myeloma that recurred outside the marrow compartment. And that's a particularly challenging area. We've looked at this subset in the STORM study. We do see activity there too, which is important. There are interestingly larger studies in different settings of similar patients where we're seeing also some important signals from other drugs as well that are still in development. So we're very hopeful that we're meeting that need in the longer term as well.

Jenny:  Well, that's fascinating. Okay, that's great. So now that it's FDA approved, what indication was it FDA approved for?

Dr. Richardson: Well, Jenny, it's approved for patients in whom they've had all three major classes of drugs, proteasome inhibitors, immunomodulators and CD38 targeting antibodies. So they basically had PIs, IMiDS and monoclonal antibodies fail them. In those patients, the selinexor is approved for use. Right now, the label has to follow the study. So it actually talks about selinexor with low dose dexamethasone. And that's very appropriate.

In clinical practice, obviously as we discussed before, there is, I think, a strong rationale for thinking about combining it with other drugs as well. I think the side effect profile is worth spending some time on because it's a very difficult drug to give, especially on its own because it's got this potent side effect profile. But in our experience at our center, it’s been manageable as long as one is very proactive. I think the productivity focuses on antiemetic treatment, focuses on hydration being absolutely key and careful monitoring, monitoring of sodium, monitoring of platelets. In fact, the sponsor has done a very good job in my opinion of pulling together good management guidelines that are now readily available to providers to help manage this. And they involved several types of antiemetic (anti-nausea) fluids as I've mentioned, careful attention to serum sodium levels, monitoring of platelet count and so forth and recognition that fatigue is a very challenging side effect of this drug. But if you reduce the drug and adjust schedule, in our experience, you can start at a certain dose level and drop quickly. You can actually see disease control and at the same time better tolerability.

Jenny: Okay, great. I think what I noticed too is that some of the side effects were more common to the solid tumor side of the side of oncology

Dr. Richardson: Yes, that’s a good observation. 

Jenny:  While myeloma patients might not be that familiar with that, most doctors treating solid tumors deal with GI effects and things like that. Well, maybe you want to comment on that.

Dr. Richardson: Well, I think that, for example, patients who are undergoing treatment for, say, colorectal cancer with intensive chemotherapy that is typically based on what we call platinum-based chemo run into tremendous side effects from these approaches. And the GI doctors are expert at managing those with aggressive hydration, three to four drug regimens for antiemetics and so on. And I think we can learn a lot from them in this context. But I think having said that, my own experience with the drug has been with close involvement of the nursing team and a recognition that you can't just prescribe this drug and say, “Come back and see me in three or four weeks.” I mean that's just not the way to manage this drug. We have two to three visits a week during treatment to make sure things are going well, regular phone calls. It is an outpatient therapy. I want to stress that. But at the same time, this is a drug that has to be monitored carefully. And patients have to be carefully counseled and followed. And as I mentioned before, the essence of hydration and the essence of antiemetic management is really fundamental to making the drug fulfill its potential. And as I said, it's really interesting

Jenny: Can you explain what antiemetic is? because I'm not familiar with that phrase and probably most patients are not either.

Dr. Richardson: Oh, I'm sorry. I was talking about solid tumor patients most certainly are anti-nausea drugs. Basically, one of the side effects of selinexor is that it makes you lose your appetite. And patients regularly report that one of the biggest side effects is they do feel nauseated. So you have to work hard on that. And the good news is that we have a whole array of antiemetics that are very state of the art brand new that work. Again, what is important is that the sponsor has a very proactive algorithm that's provided to prescribing physicians and nurse practitioners and others so that we can really be ahead of this rather than learning as we go along. And in our experience from the clinical trials, which is where obviously we've used selinexor, it's been very effective in managing those side effects.

As I mentioned before, one of those interesting things though is that when you combine the drug with proteasome inhibitors, these side effects are substantially less of a problem, which is so interesting and very important.

Jenny: That is fascinating. I've never heard about lowering of side effects by combining with another drug. So that is really interesting.

Dr. Richardson: To be fair, I think that’s probably underappreciated, but it happens with other combinations too because essentially, what you do, Jenny, is you're able to use less of each drug to achieve more. And it's the essence of synergy actually. But I suspect and I don't know, but we have a hunch that perhaps with proteasome inhibition and selinexor, it's a little bit more than that. And it's to do with this XPO1 mechanism, this new transport protein pathway that there may be some effect that's more specific that may in fact help with normal tissue response to the new transport protein inhibitor.

Jenny: One more comment. I heard when the drug was going through that ODAC process or the FDA process, it sounded like some of the side effects could be reversible, whereas in some classes in myeloma therapy, you don't see that. You see permanent side effects. But that was the comment that I remember.

Dr. RichardsonWell, I think the important point is that when you're always assessing side effects in such a sick population as those patients who are treated in the STORM study, it's very important to recognize what the baseline range of challenges and complications are. So for example, recognizing that infection is the biggest threat for our patients anyway because of myeloma itself, which is not part of treatment but from the immune system being disrupted by the myeloma, that the biggest cause of death amongst our patients regardless of therapy is actually infection.

So when you look at side effects and you look at treatment related mortality in the STORM trial, what's very important to note is that there are no organ specific toxicities to the drug. What I mean by that is – carfilzomib for example, fantastic proteasome inhibitor really does work. It's powerful. But there is no doubt there is a cardiac signal with that drug. It has a cardio toxicity and we know that. Fortunately, it's not common, but it's real. And I think with selinexor, there were some specific side effects that are challenging. But to your point, Jenny, they're manageable and reversible. Obviously, a cardiac toxicity, that's catastrophic. It's a disaster. The point is that in the context of selinexor, generally speaking, the side effect profile in our experience at least was manageable and reversible. So your point's well taken

But I also want to make sure patients understand this. I’m no way saying that some of these other drugs are dangerous. No, not at all. The reality is they're very effective. But like with all anti-cancer agents, there's this therapeutic index as we call it. And I think it's very important to appreciate that. Unfortunately, in myeloma, we're very lucky that almost all our agents have a good therapeutic index. Just some have side effects that you have to be very careful about and others, you can afford to be a little bit more relaxed about. And perhaps we've got a little, to your point, solid tumor oncologists to deal with this day in, day out. To some extent, we're lucky because we don't have to. But now perhaps with drugs like Seli, we have to be more vigilant.

Jenny: Yes. I think just an awareness from patients, knowing ahead of time what to watch for is really critical. And I remember being on even my consolidation therapy and just not having any clue what I was feeling and why it was associated with side effects of the drugs. And six months into it, I mentioned it. And they're like, “Why didn't you say something earlier?” I should have. I should've said something earlier. So sometimes, we as patients just need to speak up. Then things can be adjusted for our benefit.

Dr. Richardson: That's true, Jenny. If I may also, another comment just to add to that, it's important to recognize also that side effects can be dynamic. In other words, they can evolve over time. So some of our drugs, I'm specifically focused on lenalidomide and the diarrhea that's associated with lenalidomide, that can emerge later in treatment with lenalidomide. It’s not an acute side effect. It's something that emerges over years of use. That's well recognized now. We treat it with things like colestipol and it really works. And my point is that that's another point to share with listeners. In the case of selinexor, it's the opposite. It's almost like all the side effects are front ended. Then as you establish a dosing schedule that a patient can tolerate, then things seem to settle down. So it's a different algorithm that the side effects are early and unchallenging and then they can settle down. Whereas with some of all the drugs, which are very well tolerated generally, sometimes you can see the side effects emerge later.

Jenny: Well, let's talk about what the clinical trials are looking like. You mentioned the Boston study, how that's ongoing. What other trials is this drug being used in? And where do you see this heading?

Dr. Richardson: Well, there are a whole range of combination trials that are ongoing. And I think the important point about selinexor is that because if you use less of it and on a less frequent schedule, it's much better tolerated. The good news is also when you combine it with other drugs, we see evidence of synergy preclinically and then at least in the clinic so far, additive as well as possible synergistic effects. Well, again, we're waiting for the mature results of all the trials to be sure of that. The important thing is that selinexor is being studied in other diseases too. And one of the areas that it's showing very striking activity is in lymphoma. And this is an important validation, I think, of the target and the drug. And it's one of the reasons why in the hematologic oncologic community, the whole drug class is gaining considerable attention because again novel mechanism completely different to anything else in this space.

And at the same time, it's not just one hematologic cancer. It is in others. And it's being tested also and being looked at in other tumor types including solid tumors. One area it's potentially going into as one example is into glioblastoma because there's evidence it crosses the blood-brain barrier and that it exploits a target in GBM, which is a horrible disease. And we fortunately have a number of drugs that have come from the myeloma space that are going into GBM including one that people may forget called marizomib, which was a proteasome inhibitor that is still in development in myeloma but has now primarily focused in GBM and hopefully will come back to myeloma if all goes well. Interestingly, selinexor is also being developed as an opportunity in GBM because in glioblastoma multiforme as it's called, it’s such a dreadful disease and frankly we are very, very challenging to treat

Jenny: Amazing. Well, that's great that it can be widely used. I think there are a lot of drugs that probably are like that, that might be effective in myeloma and are being used in other cancers. And we just need to find those that we can bring to the myeloma clinic. I will leave some time for some caller questions. If you have a question for Dr. Richardson, you can call (347) 637-2631 and press 1 on your keypad. We’ll have a few caller questions. Then we'll wrap up at the end if that's okay.

Caller: Hi, Dr. Richardson. Before, you mentioned that there are compassionate use programs and that it is better have this drug FDA approved. Can you just explain what a compassionate use program is and what hospital has to do to become part of it? Then just a second question, on top of that, I was wondering why it might make this actually hard for the patients.

Dr. Richardson: Right. It's an excellent question and I hope you can hear me, Jen. Can you hear me?

Jenny: Yes, we can.

Dr. Richardson: Beautiful. Sorry because I just always worry about mutes and so on. Yeah. Compassionate use requires a use of a drug that usually has what we call single patient IMDs assigned to it, which means that you have to issue an IMD for each single patient's use. And compassionate use typically for IRBs is allowed for up to two to three patients on any one particular drug at any one institution.

So what then is often a much better approach is what's called an expanded access program. That’s very difficult to administer again to a regulatory standard with a full framework of what's essentially a protocol because expanded access becomes a protocol essentially. So that's a tremendous resource commitment on the one hand. And it's also required a great deal of organizational development. Now, that's probably quite handy in the setting of an in-hospital drug. If you've got a drug that you would administer in a hospital inpatient, that's one thing. It's substantially more challenging for an outpatient approach.

So compassionate use, we do use. I've used this in the past in different settings. I've used expanded access actually very successfully, typically for inpatient administration of drugs. I'll give you an example. We developed a drug called defibrotide for the use of a treatment of a deadly syndrome called VOD/SOS, which complicates transplant. And there, because the approval process was long and challenging, we used an expanded access program to give patients access to free drug. And it was a very successful approach. That’s an inpatient drug for patients in whom the complication was occurring as part of their transplant. And that was because that was successful. Other uses in the setting of drugs in the broader sense -- and I also would stress VOD/SOS is quite rare. It's not a common problem fortunately. It's in ten to 15% of transplants. So it's very distinct. It's in an inpatient setting that we typically see it. So it lends itself as a disease entity to that kind of approach.

And also frankly from a resource point of view, nuances specific to defibrotide, that was how it was best taken forward. And FDA were very supportive of that. So I think that's an example of how you can use Expanded Access Programs (EAP) and compassionate use successfully. I think it's much more difficult to translate to a bigger disease in a bigger setting.

Caller: Okay. Thank you.

Jenny: Okay, great. Thanks for your question. That was something I was actually wondering too. I think patients can get really confused when it comes to compassionate use and expanded use programs. And there is a burden on the hospital and sometimes on the patient to ask about those things and get it through the process. So thank you so much for explaining that.

Dr. Richardson, I have a question because you mentioned this earlier. You mentioned that it might be particularly helpful for the p53. So if patients have a deletion 17, is that something? And let's say they're having a difficult time and they're relapsing after therapies. Was that something that you would choose to use? Or how would you apply that for deletion 17 patients?

Dr. Richardson: Yes, it's a great question. I think the good news is that we have an array of drugs that are active in 17p deletion now. And they range from proteasome inhibitors in particular. For example, carfilzomib is very active in 17p deletion patients as is ixazomib, which is obviously an oral drug and very, very well tolerated generally speaking. Of course, bortezomib has activity in 17p disease as well. Pomalidomide does. Clearly, the antibodies do, be it both Elo or Dara. And the more recent data with isatuximab suggests activity as well. Selinexor seems to be very more specific in terms of the preclinical modeling, which has shown activity in this mechanism of inhibition of nuclear export proteins. And this particular mechanism for p53 mutation is vital to how it works. So I personally think selinexor, particularly in combination, is a drug strategy I would favor in someone with 17p deleted disease in the setting of relapsed refractory disease. The good news though to stress is that there are other combinations as well available to patients in which 17p targeting works. For example, histone deacetylase inhibitors like panabinostat, they work in in 17p deleted disease.

Jenny: Interesting. I'm just curious about this now that I've been listening to you because when you talk about less of each drug to have a greater impact, when you look up the triplet versus quad type of applications -- let's say you have a proteasome inhibitor, an immunomodulator and you're on Dex or using Dara or something like that or you have Dara with it and you add a little bit of a selinexor or something like that in the p53. In the p53, would you or do you typically drop the dose on everything and combine the quad? Or do you just have a higher level of the triplet? Do you know what I'm saying? I'm just curious about strategies.

Dr. Richardson: Yes. Well, I think it's an incredibly important question. I think the beautiful thing about quads is that you can use obviously all four components of the therapeutic approach to drive response. And that does mean that you can use less of each to generate more. And it's an important strategic approach. The interesting thing is that some patients, however, get considerable benefit from a doublet or triplet without necessarily pulling all four together. Sometimes, I approach this somewhat sequentially. And I'll give you an example. One of my patients has particularly difficult disease. She has lots of extramedullary challenges. And she did very, very well on the combination of carfilzomib, pomalidomide, dexamethasone and daratumumab. Then once we had excellent disease control in most other aspects, she started to develop extramedullary escape. But it wasn't actually particularly dangerous. It was more subtle with just a few sights of disease. And we simply added cyclophosphamide. And in that context, she is now responding again. So you use it sometimes in that kind of way to bring disease under control depending on what the setting is. So clearly, in her quad approach, it’s needed. At the same time, we've got clinical clues that we needed to add a fourth drug and we did. And she's tolerated it very well. We've been able to do that. So she was a real example of how we think of these things.

Jenny: Well, to me, this is the precise reason that you go see a myeloma specialist because this is so nuanced and so complex. And you have to be watching. Every patient is different. Their genetics are different. Their responses are different that unless they have someone like you who is watching over their responses and knowing what to apply when, I think it's almost just impossible to get great care unless you have somebody like that on your team. So I am a huge believer in consulting with a myeloma specialist, especially at diagnosis. If you're not close to an academic center, please go to a myeloma specialist at an academic center when you're diagnosed and when you relapse because as you can hear, there is so much knowledge from you, Dr. Richardson and from other myeloma specialists that just is unparalleled.

Dr. Richardson: Well, thank you, Jenny. It's all privilege to help. And I think in that spirit, I very much really appreciate working with my community colleagues to do exactly what you're describing. And I think that's one of the critical points though. I'm living the analogy I use. It's a bit like being the football coach and your own doctors, your quarterback. Then you need a coach on the touchline who could actually help with the play. So I think that's the way to think about it in terms of a structure. We work as a team. But the critical point is that you've got to coach on the touchline or on the sideline guiding the quarterback as to what to do.

Jenny: Yes. Well, that's fabulous. Thank you so much for joining us today. We really appreciate you taking some time out of your busy schedule to join us and explain this new therapy. We're very excited that it's coming to the clinic as yet one more option that patients can consider especially for heavily relapsed patients. And we're just thrilled that you took the time to join us today. Thank you so much.

Dr. Richardson: No, it's absolutely my pleasure. Thank you very much. Thank you.

Jenny: 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.