Going Nuclear: The Role of XPO1 in Multiple Myeloma
Join myeloma experts Dr. Paul Richardson, Dr. Joe Mikhael, and Dr. Sundar Jagganath for a discussion of recent advances in patient care. You will learn how inhibiting a key protein, XPO1, is impacting the current treatment paradigm.
Full Webinar Transcript Below:
Tanya Lewis: Hear from our expert panelists on theevolving treatment landscape of Multiple Myelomaincluding the role of XPO1inhibition and potential combinations ofdifferent mechanismsfor future clinical development. Today’s webinar will be moderated byKaryopharm’s executive vice president and chief medical officer Dr. Jatin Shah. Dr. Jatin Shah will be joined by Dr. Joseph Mikhael from the International Myeloma Foundation and the Translational Genomics Research Institute at the City of Hope Cancer Center, Dr. Sundar Jagannath from the Tisch Cancer Institute at Mount Sinai Hospital, and Dr. Paul Richardson from Harvard Medical School and the Dana Farber Cancer Institute.
Our esteemed panelists have been paid by Karyopharm for their time preparing for and presenting at today’s webinar and the views they express are their own and not those of Karyopharm or the institutions for whom they work. During our program today Dr. Mikhael will discuss the evolution of the treatment landscape of multiple myeloma. Dr. Jagannath will then review the results of the STORM study where the XPO1 inhibitor Selinexor was evaluated in patients with advanced, heavily pre-treated multiple myeloma. Finally, Dr. Richardson will describe evolving areas of interest and mechanistic combinations and rationale for further clinical development. With that let’s get the program underway! I’d like to turn things over to Karyopharm’s chief medical officer, Dr. Jatin Shah.
Jatin Shah: Thank you so much Tanya. As Tanyamentioned my name is Jatin Shah, I’m the chief medical officer here at Karyopharm.We’re very excited to be hosting thispresentation todayto discuss the dynamic treatmentlandscape in multiple myeloma,including discussions on the mechanismof diseaseand re-treatment strategies. We’ll alsotake a close look at XPO1 inhibitionand its role in multiple myeloma, including a review of the clinical datafrom the first XPO1 inhibitor evaluated in multiple myeloma.So, we’ll end with a review of somepromising combinations of differentmechanismsthat warrant further clinical evaluation.
I’d now like to welcome Dr. Joseph Mikhael to describe the evolution of a very dynamic treatment landscape in multiple myeloma. Dr. Mikhael is a professor at the translational genomics research institute at the city of hope cancer center, the chief medical officer of the international myeloma foundation and director of myeloma research and a consultant hematologist at the honor health research institute.
Dr. Mikhael: Thanks, Jatin. Thanks for being so thorough. As I typically say my name’s Joe I’m here to give the talk, that’s about all people need to know but, I’m very privileged to join this fantastic crowd and I find it interesting that I’ve been the one to give the history lesson here in myeloma. I guess I’m showing more and more gray hair all the time, Jatin, so they’re getting me to do the walks down memory lane now. My young colleagues Sundar Jagannath and Paul Richardson I know will hopefully share with me in this little history lesson as we go through.
So as was discussed, I’m really here to tee things up to have us thinking a little bit about really the remarkable history we’ve had in myeloma. I mean those of us who are myeloma geeks, we talk about this all the time, but you know we’ve really not seen another cancer have the kind of transformation that myeloma has had over the last decade. And so my objective here is really to have a quick walk through the history but specifically thinking a bit more about single agents and the role that they have played with obviously single agent activity, in that history and in doing so help us understand how important mechanisms are in multiple myeloma. How we are not overcoming this disease with one simple mechanism but many in combination but each of those ones must have a significance and of itself.
We will remember that, and I was really actually hoping in time for this talk that I could have updated this slide working with Shaji Kumar and others we’re almost ready now to add the next line of improving survival and myeloma. I always call this the happy and sad slide. The happy slide part of it is that every time we measure survival in myeloma it continues to increase, and you see this blue line climbing and it’ll almost land halfway between it and the black line above it. The sad part of the slide is that there’s still a gap between the myeloma cohort and the non-myeloma cohort so we we’ve doubled, and in some circumstances triple the average survival of myeloma over this period of time and we continue to see that improvement carrying on.
So I’m not going to go too far back in history and I’m just going to briefly mention these that you know going back to the 40s we had urethane melphalan, which frankly still has one of the most impressive single agent activities of any drug and myeloma made its appearance and soon thereafter cortical steroids. The 70s frankly didn’t bring us a lot in myeloma I mean it may have brought the world bell bottoms and the bee gees and whatever else pervaded the country at the time but it really didn’t bring a whole lot in myeloma therapy. Until the 80s when the notion of autologous stem cell transplant, and Sundar and Paul both have tremendous history in this work, really started to demonstrate its benefit in myeloma. And then just before the turn of the century we really started to see the benefit of more biological novel approaches with thalidomide demonstrating at least a 30 single age activity. Obviously, these numbers can vary based on what study you look at I’ve tried to give us some generalities. Then really this mushrooming over the last 20 years now has seen things changed hall’s tremendous work in multiple studies really introduced to us in the early 2000s. bortismith with really 38 percent single agent activity in patients that had relapsed most of whom had been through transplant or had some kind of alkylating therapy and soon thereafter we saw the other immunomodulatory drug come after thalidomide in the form of lenolidomide. And then not too long later and there are many people on this call who are involved with its development of course, including Michael himself and carfillsmith where now every time we’re looking and this is an important caveat that I want you to notice. When we start looking at the single agent activities of these drugs, we’re noting them in patients who were refractory to everything that we’ve seen up until now.
So in a sense they’re not being compared hair to head they’re being now compared further along the line and as we know myeloma evolves. With each line of therapy, the marrow is more beaten down with each line of therapy patients are older and less able to tolerate therapies as we move each line of therapy so it’s becoming an increasingly difficult environment. I know that there are a lot of football, fans here it’s almost like thinking it’s one thing to win a game during the regular season but then you start getting into the playoffs and deeper and deeper into the playoffs you know you’ve got more challenges. There you’ve got more difficult opponents as it were and so we saw with carphyllsimid and pomalidomide that these two agents if you will cut their teeth in single agent activity in patients previously treated with immunomodulatory drugs and chromosome inhibitors. Of early stage in 2015 it was a bit of an odd year because we saw two drugs that actually didn’t have single agent activity but clearly did in combination pandeminous state and elotuzumab approved and then daratumumab which now was demonstrating itself in a double refractory disease to prosome inhibitors and immunomodulatory drugs. Exsasmid was approved in combination but the very first studies that Paul and shaji kumar published also demonstrated single agent activity.
So as we look at this before we go beyond 2015 let me just give you my simple Dr. Joe’s take on what we learned if you will. Through that process what I would figure as the recipe as it were for success that single agent activity had to be present that not that agents that don’t have single agent activity don’t have a role but their role is significantly limited that one has to demonstrate as I’ve shown efficacy and heavily pre-treated disease. That it has to be compatible if not even almost if you will promiscuous to be able to partner with different drugs. So it’s one thing to have a response rate and that’s what these percentages are referring to overall response rate so partial remission and greater which would include very good partial remission and complete remission. But now being able to partner with other drugs to enhance that response rate but also not to increase toxicity so to have tolerable and manageable side effects that when two drugs are combined together you’re not amplifying the neuropathy or amplifying the cytopenias per se and then these drugs need robust phase three data in earlier use you cut your teeth you prove yourself by yourself in heavily refractory disease but then later on you need to show that you can combine with others in a large phase three trial comparing to the to the standard of care that you can add a significant benefit.
The other feature that becomes important and there are drugs unfortunately that haven’t met this metric being able to continue the drug we’ve come to appreciate that myeloma is really in many ways a chronic disease and we don’t always have to treat every patient forever but continuous therapy comes important and if there’s a certain toxicity that causes you to stop a drug earlier on it can impair its ultimate benefit. And then of course the hope the dream is that a drug can not only prove itself and relapse disease and start to work its way back through earlier relapse but indeed make its way to the big leagues as it were right up into front line therapy so that’s kind of my take on it.
As we’ve seen different drugs do this and then to demonstrate this a little bit more we published a paper a few years ago looking at all the different drugs that had been reported at the time so this is 2014 and really saw that cut off in fact up until then no FDA approval had been granted to a drug that didn’t have single agent activity of greater than 20 percent. Not that that’s a magic number but it is a significant number nonetheless.
And as I mentioned the disease becomes more aggressive we all have seen a version of this slide before where we know myeloma can harbor multiple clones and with each relapse become more resistant and this becomes important because it’s influencing the way we think about this disease that we don’t save the best to last that sounds great for a romantic song or movie but not really ultimately in myeloma as we are in the field moving our best therapies earlier on to combat the disease earlier.
So lastly in our history lesson as I have a few minutes left here we’ve come to obviously understanding where we are and who’s hosting us today isn’t Selinexor and so again now we have another agent that’s cut its teeth in not just double class refractory not even just triple class refractory but truly Penta refractory disease. So median eight lines of therapy still has a 25 response rate and that’s where it’s difficult to compare these numbers but I give them to you to help you understand the significance of these drugs. This this several months ago issa tuxed was approved i had the privilege of leading the first in human study in that drug where we showed a 24 single agent response rate obviously amplified with pomolidomide and it’s approved only in combination. Then just literally a few months ago bolantemab similarly to cell and x or triple class refractory disease but not mandating Penta refractory disease with a 31 response rate median seven lines. And who knows what’s to come over this coming year. Obviously I’m not going to be a profit and predict the future but we expect to see car t cell therapy melfon fulfinamide or the artist formerly known as melfluffin ibertamide by specific therapies and others to come. So it speaks to us of mechanism and many of you have seen the slide and even shared this kind of slide.
Before and i’m not going to go through it in detail but just to remind you that this this disease is not just about the tumor it’s not just about its own self it’s how it interacts with the environment the pathways within the cell and the pathways without the cell become really important as we look to the future engaging t cells and natural killer cells and others becomes really important because the mechanism of myeloma is by no means one simple cml like approach.
So as I come to the end here we’ve seen, this tremendous evolution in myeloma and I’ve listed here in red what has been a standard for a number of years. In green what over the last 12 months or so we have now added to our armamentarium of now introducing more dare to map frontline cell and xor and relapse disease esotuximab. In purple what we’ll likely see in the coming year as we continue to study this disease more and more. So at this point I’m happy to turn it back to you Jatin and trust that this quick history lesson with relevance and single agent has been of value and I’ll turn it back to you boss.
Jatin Shah: Thanks so much Joe. So really thanks so much Dr. Mikhael really appreciate that walking through the history of myeloma, providing that context for these improvements in survival and these really due to new classes of drugs both new drugs and new classes of drugs. So that’s really helpful to understand where we came from and where we’re headed. I think the recipes have successfully provided for my loan agents is a key thought process to really kind of help understand that, so that’s great lots of things for us to consider as we move forward but really helps contextualize all the data in this dynamic landscape. So i think we’ll have some questions at the end for you.
What I’d like to do now is welcome Dr. Sundar Jagannath. Dr. Jagannath is the director of the myeloma multiply aluminum program at the Tisch cancer institute within the mount Sinai medical center. A professor of medicine at the Icahn school of medicine at mount Sinai. Dr. Jagannath was a principal investigator of the storm study which was a phase 2b single arm open label study of Selinexor and dexamethasone in patients with advanced heavily pre-treated multiple myeloma. The FDA granted accelerated approval on July 3 2019 to selinexor based on the storm study. I’m really honored and privileged to have you join us today to review the clinical data Dr. Jagannath.
Dr. Jagannath: Thank you very much Jatin. I hope you all can hear me. So we heard Joe said that Selinexor cut its teeth on this particular storm trial. It is déjà vu you know going in front of FDA, presenting the strong data and getting the accelerated approval. So let’s see why I’m all excited about Selinexor.
See once the eukaryotic cell organized the nucleus and separated with nuclear membrane then the transportation between the nucleus and the cytoplasm then they needed the chaperoning so the proteins cannot go in and out very easily they usually needed an exportin or importin important to bring them in. Export them to export out among this exportin one is a major nuclear export protein and this is important because all the tumor suppressor proteins or a majority of them, they are exported out of the nucleus into the cytoplasm. Once you export them then of course the tumor suppressor protein is not in the nucleus, the cell can continue to multiply so exporting is an important way to export all the tumor suppressor protein. And that’s being said the cancer cells have a lot of exportin one because they want to continue to multiply so they throw out all the tumor suppressor protein out. The other one is the you know eukaryotic initiation factor for e this is a translation initiation factor for e this binds to messenger rna of oncoproteins. Like c make bcl excel etc and they are also need to be exported and there the protein mic and all has to be produced because the messenger rna has to go in. So glucocorticoid receptor that’s an important for the glucocorticoids you know dexmedson to bind to glucocorticoid receptor and then goes into the nucleus and then binds to the glucocorticoid receptor elements. So if you block this whole activity with you know small molecule orally active selective inhibitor you know that’s what Selinexor is then what happens is all of this activity is stopped so the tumor suppressor protein accumulate in the nucleus. The oncoproteins are not translated anymore and the steroid could be retained with a glucocorticoid receptor.
So this is why you will find that this is quite effective in the treatment of myeloma but i believe this would be quite effective in many other cancers too because it’s not just for myeloma. The exportin one is over expressed in many cancers and this mechanism is very very unique and this is an important drug and it will turn out to be important in many other diseases. As I said it is over expressed in myeloma and there has been publication correlating the poor prognosis and drug resistance with over expression of the exportin one so Selinexor is the first in class orally available selective inhibitor.
And now we’ll see how this ends up being very effective in myeloma. So this is a pivotal storm trial part two and 122 patients were enrolled on this part two expansion you know expansion study in Penta refractory myeloma before they were triple refractory and some Penta refractory. But the study was designed only to have Penta refractory myeloma enrolled on this study so the key inclusion criteria as you can see was quite liberal because these are advanced myeloma. Quite often they come in with renal impairment so you have to keep the renal clearance quite liberal 20 milliliter or data which is actually a ckd stage four so these patients with greater than 20 milliliters per minute were allowed to participate in the trial and these patients have had so much treatment so we allowed anc as low as 1 000. I know and that’s already great too you know neutropenia and then you have platelet at 75 000. So that’s grade one thrombocytopenium using cdc criteria and hemoglobin 8.5. So you could see we were allowed patient almost in grade 2 ctc criteria into the study so it doesn’t take much to push them into grade 3 and that’s important in this advanced patient. The patients were all exposed to velcade and carpal zoom lenovolt and dexamethasone alkylators glucocorticoids. But they were also exposed to their tumor man and that’s important and the primary endpoint is overall response rate so it’s important for FDA for an accelerated approval. It is the response rate which is the key so the primary endpoint for the study was overall response rate. But of course we looked at the duration of response progression free survival overall survival and most importantly, the safety. The medication was given in high doses because in Penta refractory we were using a single agent Selinexor with the dexamethasone so it is 80 milligram twice weekly with the dexamethasone’s on 20 milligram twice weekly which will come to 40 milligram once a week.
And so it is you could see this i would call as high dose Selinexor or dexamethasone treatment and this was given to patients until progression of disease or intolerability. So 122 patients were enrolled but the FDA looked at very closely and they found that 83 patients really met all the Penta refractory because patients are referred it is very difficult to document whether they were truly refractory to revlimid and to pomonamide etc so this is the fda went through this comb through this database and they thought 83 patients met at 68 of the patient met the Penta refractory population. And in this group you can see age 40 to 85 you know with a median age of 65 and you know the time from diagnosis could vary seven years but it could be from one to 23 years creating clearance i already alluded to. Patients less than 30 milliliters per minute but allowed five percent height is cytogenetics and almost more than fifty percent of the patient but this group by definition all of them are functionally high risk because the next option is hospice so this is our functionally high risk patient to keep in mind. In addition to the traditional genetic markers as high risk and many of these patients by the time they come they have eco performance status you know not that great so you could see ecog a person of the patient were there and many of them had symptoms so they’re all eco one more than half of the patient where econ one or more and they have quite a bit of co-morbidities because of prior treatment exposure and the toxicity from priority treatment exposure as well as the age of the population you have cardiac coronary artery disease hypertension renal impairment. All of them comes into play so quite a bit of comorbidities are there and if you look at the prior treatments by definition you know fda combed through you could see refracted pi image data to mum and steroid 100 percent refractory to carcinoma pulmonary direction. These are second generation prolisomine beta and immunomodulator molecule and direct remember 100 refractory to 2 pi 2 emitted and direct map which is the definition for Penta refractory 100. So you can see that these were really refractory patient population and this is where joe said that the hurdle to climb you know the high gem bar is really high in patient with pen type of fracture.
So what did we get? You know joe said as you have to cross 20 well we did overall response rate of 25 but clinical benefit respond that is the minor response and better is another 12 percent so you have 37.3 of the patient and i will tell you why. Clinical benefit response or even minor response was meaningful to this Penta refractory patient later on. When we talk about overall survival now if you look at it you know the median eight lines of prior treatment you know two patients had progressed even after car t cell therapy because they were all coming into clinical trial patients wanted to be on cutie so the patients had failed Kathy and then came to the study. The median time to response is very fast you know one month and this is critical to understand. You know because once you know the patient is responding in a Penta refractory the motivation of the patient the motivation of the physician to support the patient. do those modification ask them to stay on the drug becomes very clear so the first month is critical if the patients are going to really benefit from this treatment you have to be you know monitoring the patient closely and also be a real advocate for this in keeping the patient on the study.
Median duration of response you could see 3.8 months. And if you look at any reduction in the monochrome protein so there are patients who had you know so-called stable disease but actually had reduction in the paraprotein less than 25 so if you include anybody did they show any response 66 percent of the patient had reduction in the paraprotein quantified reduction in the paraprotein.
Now this is the overall survival the red let’s focus on the red. Now that’s all 83 patient and the median overall survival is 7.6 months now if you take patients who had overall response which is blue and the black one is sorry overall response is black pr or better and then you have the blue which is a minor response. So here you could see as long as the patient had minor responses are better or the partial response are better they did equally well in terms of survival and the median is not reached and that’s very important. That in such an advanced that we had a great impact on the life expectancy and then you look at the green to say really these are advanced patients. If they didn’t respond to the drug the median life expectancy was very short 2.3 months showing that this population truly was otherwise you would have had the patient who didn’t respond still go on and surviving but that’s not the case here.
The adverse reactions are shown on these slides. You know hematologic most common is thrombocytopenia and then non-hematologic you see fatigue, nausea comes up the weight decrease nausea, vomiting and diarrhea. Hyponatremia they’re all shown there and grade three or greater is mainly hematologic you could see thrombocytopenia and anemia coming there otherwise you have fatigue and some nausea they start going down at grade three they’re all in a single digit in terms of nausea vomiting diarrhea. They’re all in single digit so you have fatigue and hyponatremia. They are in the 22 percent neighborhood we’ll talk about a little bit more in the next slide.
So the question is how do we manage the adverse event for these patients so side opinions we can do dose reduction give them drug holiday instead of giving these drugs you know you got rumored this is high dose in an extra 80 milligram twice weekly and you can always give one week off. You can reduce the dose, you can give it once a week 100 milligram if the patient is showing a response so that is a dose modification becomes important how to support the patient through in the first month you know because these are Penta refractory patient. If and you’re allowing patients with platelet count of 75 or coming in or patient already in grade 2 neutropenia 1000 are above coming in you may want to use growth factor support for these patients or even platelet support for these patients. That’s important so that at the end of one month because the response is very rapid you will know whether the patient is benefiting or not and as their response the amount of cancer goes down in the bone marrow so the tolerance goes down so the tolerance goes down for two reasons. Number one there is response so the myeloma goes down so the bone marrow reserve goes up and number two you are able to dose modify so the tolerance goes up so we can handle the cytopenia. The next one is the gastrointestinal you know this is where we have learned as this drug we have used now we know we can use undone citron which is the phyt ht3 on antagonist. I usually give them three times a day for the first couple of days automatically around the clock rather than waiting for them to complain of nausea and then using a lanza pain or zyprex at bedtime. It is also very helpful for these patients and then you can use you know uh rolapitent which is the nk1r antagonist which is only once every two weeks that helps very well it’s called varubi. It helps with the nausea phenomenally well you know these were not effectively used during the particular study but now we are using it routinely and we find the tolerance is better and of course you want to make sure the patient is having adequate hydration and nutritional supplementation. Fatigue you know you may want to follow the patient closely for the fatigue this is important and especially they may be mildly dehydrated they’re nausea they did not eat or they didn’t drink so keeping them well hydrated supporting their anemia. All of that will help some people have used you know methylphenidate or Ritalin to help with these patients but i’m not usually advocating that. And then of course hyponatremia easily handled with the normal selling in your infusion center or giving them salt tablets. Now it is Paul Richardson’s role okay I’ll sign off. Back to you Jatin.
Jatin Shah: Well thanks so much Dr. Jagannath, appreciate that for reviewing this data with us today. Your leadership on this study importantly i appreciate reviewing the mechanisms of action as this is key with this new field is new class of drugs to really understand this new method of action and the science is powerful. As you saw the clinical data you reviewed so thank you for that.
I’d like to now welcome our third speaker Dr. Paul Richardson. Dr. Richardson hails from the dana farber cancer institute where he’s a clinical program leader and director of the clinical research at the jerome lipper multiple myeloma center. Dr. Richardson is also the rj cortman professor of medicine at the Harvard medical school. Today Dr. Richardson will review the mechanistic rationale for combinations in relapse refractory myeloma. Dr. Richardson…
Dr. Richardson: Thank you very much Jatin and it’s lovely to join everyone and thanks so much for a wonderful set of introductions from the one hand just now Sundar and of course just before that Joe. As you heard so nicely from Sundar we’ve got a platform of a novel mechanism of action which is absolutely critical in this triple class refrig refractory penta exposed population of patients but obviously as a single agent having demonstrated that important signal and particularly looking at the responder analysis and those patients in that category as to how long disease was controlled was particularly striking. The question then becomes what do we do in terms of combinations because clearly in my opinion that’s absolutely the way forward so with that in mind my I wanted to do a quick background to share with our audience. You know as we think about multiple myeloma it’s very appropriately named it is truly an incredibly heterogeneous group of diseases encapsulated in one terminology and it’s highly complex of diagnosis but it’s even more so at relapse because of obviously genomic events and what we call clonal evolution. And on the right side of the slide here i show whole genome sequencing courtesy of my colleague my super colleague nikhil munshi from a patient of ours in one of our clinical trials who basically had whole genome sequencing done at diagnosis where there are over 5000 mutations and then after induction emission therapy transplantation, consolidation and maintenance the patient then relapsed and that relapse there are 12000 mutations. So you can fully appreciate that this extraordinary complexity of disease is something that we really have quite a task to overcome. So the fact that we have a novel mechanism action with Selinexor uniquely in its place space and the idea of putting a combination strategy in place really makes sense to try and get our hands around or a net around this disease process.
Now this just goes into more detail over that exact whole genome sequencing and i just bring it out visually for you because i think in that last diagram it’s a little bit less clear but as you can see 5000 mutations of diagnosis and it moves forward hopefully… here we are yep twelve thousand so the critical point now what’s interesting here. And a point that’s worth making is that actually the signal in terms of the mutagenicity of this particular patient’s disease is quite complex and points to a very adverse pattern emerging after therapy. So it actually also matters what we do in terms of our treatment because there’s certainly the hypothesis that there is actually now some substantial data behind that certain treatment strategies can actually engender even greater genetic change in the disease and that’s why again this whole novel mechanism action that’s driven by Selinexor or is I think particularly attractive.
Now another basic sort of background point is that there’s a critical interaction between plasma cells and the bone marrow micro environment. This is an older slide from a very nice review a few years ago by Antonio Colombo and my mentor Dr. Ken Anderson but what you can see here as illustrated well is this interaction not just between the tumor cell and the bone marrow stromal cell but critically also with the bone micro environment as well as other aspects of the physiology and micro environment within which the disease lives. Very specifically the immune milia as we’re beginning to better understand it and this is actually a construct that sort of drives that question: how do we use the multi-modality targeting of myeloma in the context of this micro environment to improve outcome? And i show this to you because it’s now such a well established platform for us in terms of how we think about myeloma therapeutics and you can see as you go around the grid here starting at a at the bottom where we’re looking at producer inhibition as a platform of therapy and then moving to the space of antibodies. And then as we think about this into the more complex immune micro environment that we can target and then finally a variety of strategies that can target the epigenetics of the disease. And then as you swing around to category e you can look here at what we’re thinking in terms of dendritic cells and checkpoints but what’s so impressive and important and obviously this particular schematic anti-seize and the success of cell and x-ray in this space. We now have an entirely novel mechanism of action to add to this particular construct of multiple approaches to the to the combinatorial strategies in targeting myeloma.
Now this is not get an older slide but i just show it to you to give you where the idea of these rational combinations has been built over a many years of hard work in the space of novel drugs for myeloma and this is from a few years ago from a clinical cancer research review where we schematically hypothesized that you had a rationale for putting together varieties of novel drugs and as you can see in that context we now have third generation immunomodulatory drugs. We have of course next generation proteasome inhibitors including cough ulcemic and also exacerbate and most importantly we now have monoclonal antibodies. So as we think about combination strategies I think this illustrates very well how we might then rationally try to put together new mechanisms action particularly in heavily pre-treated patients.
Now we have multiple options now available and the critical thing is that they have different mechanisms of action. I’m sorry that this doesn’t project terribly well but what I’ve illustrated here obviously is Selinexor in the key position but also balance mathem here and also in the same context isotaximab and elotuzumab. But in any event you can see now that we’re in a position with 12 normal drugs that we can think rationally about different mechanisms of action to augment the outcome.
Now in terms of thinking more about XPO1 and the novel mechanism action of Selinexor I think it’s well worth sharing some of this information high XPO1 levels are clearly correlated with poor prognosis for our patients. And in that regard strategies aimed at targeting this pathway may be therefore of particular importance.
Now we’ve already heard very nicely about mechanism action but just a few endpoints of emphasis to bring out in terms of inhibition of XPO1 it’s critical to understand that XPO1 overexpression enables the cancer cell to escape tumor suppressors and actually in that context escape pathways for induction of apoptosis and this clearly as i mentioned correlates not only with poor prognosis but clearly underpins drug resistance. And then in terms of inhibition the inhibition of XPO1 classically impacts tumor cells by what we think are three core mechanisms obviously increasing the nuclear levels and activation of tumor-suppressed proteins. A critical construct in myeloma but I think what’s also very important that it traps the oncoprotein messenger rna in the nucleus leading to reduced oncoprotein levels so that whole mutagenic thrust that I tried to emphasize and show you earlier is suppressed by this mechanism and in that same context there’s the retention of the activated corticoid receptor in the nucleus which is why you heard so nicely from sundar about the combination of Selinexor with steroids was particularly important actually because this mechanism may be particularly relevant in that setting. I think what’s particularly attractive as well is as you think about these particular tumor suppressor proteins that are relevant in myeloma. There is the classical pathways of nf kappa b signaling and c mic that may be modulated through this mechanism so that underscores certain pivotal drugs we use. Either immunomodulatory drugs on the one hand and proteome inhibitors on the other so it’s actually no surprise then that there’s synergistic activity in combination with potassium pomalidomide and lenolidomide and we see this not only in vitro but in vivo. As I’ve mentioned already there’s this signaling pathway from dexamethasone that’s very relevant now I think one other key point to bring out here is also evidence that’s emerging about what i consider one of the most vulnerable populations we have: those with 17p deletion and clearly we have a lot of pre-clinical information that supports the notion that Selinexor and the inhibition of XPO1 may be vital in going after that particular mechanism.
Now in terms of XP1 and inhibitors in combination with image leading to reduce tumor growth I just want to show you some preclinical information from a variety of colleagues. This is having very nice for clinical data in mm-1s cell lines where you can see obviously the impact of vehicle none and in that same context you can see that there is clear synergy when you combine saline xl with lenolidomide. So there’s an effect from Seli alone. There’s an impressive effect from lenolidomide alone put the two together and it’s even better.
Now in that same context what about monoclonal antibodies well if you think about how monoclonal antibodies work it’s a very rational hypothesis particularly with cd 38 targeting that there would be synergy potentially with XPO1 inhibition and why so because daratumumab and antibodies like it have multiple mechanisms of action in the way that they actually engender myeloma cell death. And it’s not just simply through the immune system but it’s also through direct apoptotic mechanisms as well so there’s a strong rationale why there should actually be synergy with Selinexor and in this particular experiment you can see here that the use of Selinexor or in combination with naratumumab resulted in a potent inhibitory effect on cd138 positive myeloma cells derived from myeloma patients in the newly diagnosed setting and that’s what’s really also interesting is that in the non-myeloma cells and this is critical. There was no exacerbation of effect on again non-malignant cells so a very important observation here in this particular study… and then again more preclinical data which i think is particularly visually impressive to me anyway and impressive scientifically about the potency of XPO1 inhibition combined with proteasome inhibitors. And I think in terms of understanding mechanism one of the really nice things to sort of realize is that protozoa inhibition potentiates the inhibition of XPO1 by Selinexor because there is actually increased nuclear localization of icaf b and inhibition of nf kappa b which are these absolutely pivotal pathways in myeloma biology. And this graphic illustrates this extremely nicely and i think is particularly visually obvious if you look at the synergistic effects of Selinexor or combined ear in combination uh with potassium in these myeloma sorry in these proteasome inhibitor resistant myeloma cell lines.
So if we then look further at this and look not only at bautism but you can see on the left here vortisimid having a profoundly synergistic effect. If you look at the vehicle and look at vortezumib and the blue line what’s interesting actually in this model system is Selinexor actually is that much more impressive in terms of tumor volume on its own compared to vortex which is very interesting in my view but again when you combine the two there’s clear synergy. And of course the same observation is made for clophilsometh even more so in my opinion for carfilzomib recognizing obviously these are different cell lines someone has to be careful but it’s still striking to me the synergy that we see with southern exile pre-clinically with cocktails. And then i think intriguingly um this is a very nice experiment which shows the potential role of XPO1 inhibition or the use of a selective nuclear export protein inhibitor. In this case altimex or elsa as I’ll call it for short in this particular pre-clinical system. And what you see here is an interaction with venetoclax which clearly shows that the combination of elsa with venetoclax enhances apoptosis and leads to loss of chromogenicity and colony assays.
I want to share with you just a story around a patient in whom my next choice of drug is going to be Selinexor she has very aggressive disease that’s now 17p deleted and she expresses 11 14. and unfortunately on maximal doses of carboxymite, dexamethasone cyclophosphamide and venetoclax. So that’s about as powerful platform as we can put together by the way. Unfortunately she relapsed after rbd daratumumab and so it was particularly worrisome because daratumumab had failed her. She now has aggressive disease that’s on the march and i’m combining Selinexor with my next repertoire of drugs to challenge her now exactly on the basis of some of this information here because it may be a very rational approach in the management of her disease.
In any event I think intriguingly this combination data points that with our major classes of drugs, the proteasome inhibition, immunomodulation and antibodies there is a strong rationale for combining with Selinexor and very importantly in the setting of venetoclax that may be equally important too. Why I’m so fascinated by that personally is that venetoclax constitutes in my opinion a very important advance in translocation 11 14 positive disease. One of the worries is when it fails what do we then do and in this setting it’s very interesting to see pre-clinical information like this because that may guide us with rational strategies perhaps even to prevent that in patients who have this particular translocation and do so with drugs like Selinexor.
So these are my conclusions and they’re more a sort of broader thing for discussion, but as you can see and as I think all of us are familiar innovations with chromosome inhibitors immunomodulators monoclonal antibodies and i should also mention histone theocetylase inhibitors as well have produced significant improvements in clinical benefit. And recent approvals in my view and will augment this now it’s very relevant to share with you 12 novel drugs in the last 20 years or so over 28 new approvals for combinations and indications and of course we have great new immune therapies coming which may be agnostic to mutational thrust and obviously baseline immune function is key to the barrier to that success. Therefore you know it’s an important thing to target but whilst i do think we’ve got monoclonal antibodies and immune therapies that are so promising we also have to recognize that they fail and as we think about how we go after this I think it’s particularly exciting that we have entirely novel mechanisms actions such as Selinexor such as venetoclax and other drugs that will be available to us. So in my opinion the combinations of integrating these novel mechanisms of action and so improving on what you saw so nicely from Sundar in terms of a baseline signal can actually become a reality and as we further approach this. The refinement of prognostics so for example if i use my patient example how can we better understand how she may or may not do? How can we best combine drugs for her can we look at her immune profiling and then of course in patients who achieve high quality responses and achieve true complete remissions how can we use tools like mrd to better inform our treatment choices. I think I’ll close their chat in the interest of time and thank you. Thank you for everyone’s attention.
Jatin Shah: Excellent thanks so much Dr. Richardson for reviewing the evolution of the field based on the science driving these rationale combinations. Clearly lots to think about here as a myeloma treatment landscape continues to involve. Again I want to thank Dr. Mikhael, Dr.Jagannath, and Dr. Richardson, the tour de force from our expert panel reviewing a field which is rapidly evolving reviewing the clinical data of XPO1 inhibition with Dr. Jagannath and really Dr. Richardson for laying out a bright future with rational accommodations. One question did come up and so for those folks who put questions in the chat who have captured all those and if we have your contact information we’ll follow up on that. Just one question for Dr. Mikhael, with all these new drugs and i think for the panel how do you see the field evolving? Where we get the most out of all of our tools with these new classes of drugs
Dr. Mikhael: Yeah no it’s a great question Jatin and one that we discuss at length and I’d be interested to see of course what my colleagues think but maybe just share the principle which is I think this notion that we would ever save the best for last has really kind of moved away from our thinking there’s always been this tension in myeloma you know are you of the cure camp or the control camp. You know are you the bar logie Jagannath let’s you know get in there we’re gonna find him we’re gonna get him, you know give everything up front or the raj Kumar mayo kind of treated like hypertension just enough to control it to try to keep a lid on it and i think everyone recognizes that both extremes are probably not ideal but i think the field is tipping more towards combining as Paul beautifully explained. Multiple mechanisms of action when there are several clones or potentially several clones up front because that first remission is often the longest remission. So i think we’re gonna see a strategy, it may not be all exactly in first line that’s sometimes called the one two punch you know the frontline therapy and first relapse are thought of almost as a combination as it were a strategy that together we’ll be using multiple mechanization as evidenced by going from doublets to triplets and almost definitely soon to quadruplets. that’s kind of the principle I’ll see if you know, Paul and Sundar want to chime in with more detail than that.
Dr. Jagannath: Well you put it succinctly. I believe in curing myeloma and not keeping it as a chronic disease or just i want to give two drugs at a time and keep them around and things like that. I want to cure and get the patient back that life and quality of life and get going. so i think you will eventually come to it whichever way you look at it and I will stop there.
Dr. Richardson: Well um I think I can sort of take a sort of position somewhere in between those and i think I do agree with Joe. I think combinations of treatments are essential going forward because they give us in my opinion the best chance of clonal control and avoiding this kind of mutational thrust that can actually generate very adverse outcomes. In the longer term I think somebody touched on a very important point, minimal disease functional cure and quality of life and i think that’s why I come somewhere in the middle because i think it’s very important to recognize how critical that is and whilst I think in our younger patients with excellent performance status and really you know are free of comorbidities that preclude intensive therapies those approaches make sense. Although we all already recognizing the evolution of that therapeutic space because as we move to car t and novel immune strategies and we move away from some of the older approaches that were great war horses in the past but maybe less attractive going forward because of long-term consequences. So as we put all of that together I think that something like Selinexor or with an entirely novel mechanism action really is attractive because bringing that earlier, you know how do we then optimize the biological effect that that can have? And what I’m very struck by Jatin is that for example in Sundar’s presentation and storm the twice a week dosing of Selinexor was active but challenging. Now frankly we routinely use it weekly and we use it weekly in combination and it’s much better tolerated and I think that points the fact that we can move much earlier and of course we have the excellent data from Boston which shows that that’s a feasible approach that can translate into clinical benefit. So I’m very excited about this combination strategies and I think they are going to provide us with the vision that Sundar is looking for which is you know functional cures.
Jatin Shah: Well excellent thanks so much for great, discussion great viewpoints there. One of the questions that came up in the chat was actually a manager of extra medullary disease when a patient was diagnosed with a myeloma or pancreas and a mass or pelvis. Any thoughts on just approach to myeloma with extra medullary disease doctor Jagannath? We’ll start with you.
Dr Jagannath: Yeah I mean in the context of this meeting ceremony or ceramics works well even an extra medullary disease. To put it out there in terms of statement number two, extraordinary disease especially in pancreas and liver generally are you know worse prognosis. Quite often these people have elevated ldh and when they presented aggressively like that in the olden days we would have resorted to d sub chemotherapy. It is a lymphoma like regimen or vdt pace and it often puts them into remission. Nowadays i have to say that even the extra medullary disease are you know amenable to newer agents such as bi-specific and car t-cell therapy too. So i think we are getting many more treatment argumentation but today i just wanted to say that cylindrical works in extra medullary disease and and cell mix also crosses the blood-brain barrier. so this is one of the few drugs that crosses the blood-brain barrier so those are all important things to keep in mind. Any drug that is you know is able to penetrate and goes to the cns and goes into you know all these different organs is more effective for extraordinary disease.
Dr. Richardson: Also yeah and I’d love to build on that because i mentioned 17p before. We know an extra dollar disease that 17p tends to be enriched so in my opinion Selinexor constitutes an excellent choice for extra medullary disease as part of a combination approach for all the reasons that you heard so nicely from Sundar, Jatin. But in addition to that because the genetic profile of this type of disease is typically enriched for 17p and of course i think there’s such compelling evidence that uh 7×4 is outstanding in that setting and sorry joe no not at all i mean you captured i was about to focus on that point because as i do think is important i think that’s where the combination is particularly important is. As Sundar said unfortunately not all extramedullary disease is the same. Sometimes we speak about it as this sort of phenomenon that is unifying but it really isn’t necessarily the difference between de novo and relapse when someone for example has a oligosecretory or room as non-secretory disease and only presents an extraordinary disease. And also the location of it makes a difference and when we see it in the liver and we see it in the pancreas it is often tragically very terminal. So in those situations absolutely we need agents that can penetrate into those areas. Sometimes we also you know add radiation or other forms of localized treatment to try and enhance that effect but it’s a it’s a tricky situation and it’s challenging to deal with.
Jatin Shah: Excellent thanks so much for a great discussion, again, great insight and feedback on that question. A very difficult disease treat very difficult to treat the disease and with that, you know i think just want to wrap up and thank again all of our panelists for their joining us today and tremendous insights. And a great conversation, we’ll continue this dialogue. And with that I’ll turn it back over to our host for today’s program Tanya Lewis.
Tanya Lewis: Great panelists I’m really excited about the future and i’d like to thank you Jatin and thank all of you for joining us today. We appreciate the time and tremendous insights provided by our esteemed panelists. We hope that all the attendees benefited from today’s presentation. We’re excited to share that there will be future events like this one. Please visit our website and follow us on social media for more information on upcoming events. This session has been recorded as well and you will be able to revisit on our website and youtube page at any time. We hope to see you again for one of our upcoming webinars.
Thank you all again for joining us and enjoy the rest of your day! Thank you very much everyone thank you, thank you very much bye-bye.