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How the BOSTON Study Impacts Myeloma Patients

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Published on July 2, 2020

How does the BOSTON study impact Myeloma Patients

Great news from the BOSTON study offers relapsed and refractory myeloma patients a new treatment option. Dr. Paul Richardson, Dana Farber Cancer Institute, and Patient Power co-founder, Andrew Schorr explain the results and impact of the BOSTON study.

Patients living with relapsed and refractory myeloma have often tried several different treatment options, the BOSTON study results offer new hope to patients who have already been through the standard treatment options.

This program is sponsored by Karyopharm Therapeutics. This organization has no editorial control, and Patient Power is solely responsible for program content.

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Transcript | How the BOSTON Study Impacts Myeloma Patients

Andrew Schorr:
Hello, and welcome to Patient Power. I'm Andrew Schorr, and we're visiting with really, a world renowned researcher and clinician in multiple myeloma, and that's Dr. Paul Richardson. Dr. Richardson, welcome back to Patient Power. Just so everybody knows, what is your affiliations there in Boston?

Dr. Richardson:
Oh, thank you, Andrew. And it's my privilege to be with you. I serve as the Clinical Program Leader and the Director of Clinical Research at the Jerome Lipper Myeloma Center here at Dana-Farber Cancer Institute in Boston, and I'm the R.J. Corman Professor of Medicine at Harvard Medical School. And the reason that's lovely to share with you is because R.J. Corman Railroad is on the calendar behind there, and he's a former patient, much loved patient of mine passed away some years ago, and then just below that calendar is a wonderful picture of another very lovely patient of mine and his wife, James Bond, and his wife, Kathleen. So it's great to be on Patient Power and to be in my office and for that to be a background to our conversation.

Andrew Schorr:
Yeah. Thank you. Well, as far as the background, you have loads of clinical data and research data all over your office, and I wanted to talk to you about one specific study. So there's data that's come out of something where you were a senior investigator, the BOSTON study. Help us understand the BOSTON study. Who was it for? What were you trying to find out? What did you learn that can help at least a subset of myeloma patients?

Dr. Richardson:
Well, thank you, Andy. And it was a privilege to be part of the BOSTON trial, which was a multicenter international trial presented by my colleague, Athanas Dimopoulos as an oral session at ASCO. And similarly as a major presentation at EHA. Essentially, the construct behind the BOSTON study was to build on the very exciting data generated in the so called STORM study, where we were able to demonstrate selinexor (Xpovio) twice a week as an oral medication combined with dexamethasone (Decadron) was very effective in the treatment of relapsed and refractory penta-exposed triple-class resistant myeloma. Now that's quite a mouthful, but essentially that's really end-stage disease, and the patients who participated in that trial really had no available currently available options. And so we saw a signal of response there, and to their enormous credit, FDA granted the drug accelerated approval based on the substantial duration, durability and depth of responses that were seen in the subset of patients who responded in the STORM trial.

Now, that was around 30%, 25 to 30%. That obviously constitutes an exquisite area of unmet medical need. The BOSTON study was absolutely crucial, because this move, this promising new agent from this very, very challenging space of relapsed refractory myeloma that's penta-exposed and triple-class resistant into treating patients with relapse refractory myeloma, but much earlier in their course. And this is critically important, because selinexor represents a first-in-class oral agent that targets a unique pathway in myeloma, and they mainly that the nuclear export protein exportin 1 (XPO1). Now exportin 1 is not unique in myeloma, but it's an incredibly important pathway that myeloma uses, and it's used by other cells too. One of the challenges to selinexor, which it actually very specifically blocks that pathway, is the toxicity associated with the twice a week oral administration of drugs, was quite challenging and required tremendous amounts of attention to detail around antiemetics and supportive care. In the BOSTON study, the drug was administered weekly, and this was the very innovative step in the trial with weekly bortezomib (Velcade).

And the reason that was done was to simplify and generate truly real-world environment, in which the combination could be given. And most importantly, to maximize not only benefit, but critically address the issue of side effects and tolerability. The control arm, obviously had to offer patients a standard of care and that standard of care was classically given bortezomib with dexamethasone in early relapse, and this was on a twice a week schedule. So much more intensive in that regard, but comparing the two drug platform to the three, and with the less frequent bortezomib with the less frequent dexamethasone combined with the weekly selinexor would the three drug combination actually prove superior to the more intensive two drug combination. This is a very courageous trial in that sense, and I think what I particularly like about the study is that it was truly real world.

We have participation from across the globe and countries in Eastern Europe. We had centers in India contributing to the study. So this truly was an international and real world effort. The results in a nutshell, as presented by Athanas, demonstrated a clear progression-free survival advantage to the three drugs over the two, and the gain was around four and a half to five months in favor of a three drug platform compared to the two. But what was striking to me, is that the response rates were much higher and the quality of responses were higher in the three-drug platform. And very importantly, in pre-specified analysis, we looked at high risk patients and other specific subgroups of poorer prognosis and saw that the clinical benefit in those subgroups was particularly favorable. And then what was really interesting, Andy, was that in the side effects space, clearly the weekly administration of selinexor was far better tolerated than the twice weekly had been in the more advanced setting.

And most importantly, the neuropathy was substantially less because the bortezomib was being given weekly, and we also think because selinexor has some important anti-inflammatory properties, that it may in fact be reducing some of the more severe high-grade neuropathy by virtue of the nature of the drug. Now, I think it's very important to understand that this... Particularly now in the current environment that we're so challenged by, by COVID where you have to minimize patient visits, weekly visits and so forth, and minimize obviously, side effect issues and maximize efficacy. This kind of a weekly schedule is obviously a very... Has substantial practical advantages.

Andrew Schorr:
All right, let me go over some of this with you, because it sounds pretty significant. So we had a breakthrough drug that was approved earlier for the sickest people with a new mechanism of action.

Dr. Richardson:
Right, exactly.

Andrew Schorr:
The idea was, could it work for an earlier group of patients?

Dr. Richardson:
Right.

Andrew Schorr:
Could it be used in combination to be effective with the side effects? And the answer was yes.

Dr. Richardson:
Absolutely. And I want to build on this, Andy, because the original STORM studies were designed to just look at the combination of selinexor and dexamethasone. Now laboratory studies, including at our center, had shown that the selinexor target exportin 1 was very important. And that if you combine selinexor with steroids and other drugs in the preclinical setting, you could enhance activity. Now, the studies that actually informed BOSTON, were the so-called STOMP studies, these are very important. I want to especially acknowledge the investigators involved in those trials, because essentially in those studies, selinexor was combined with standard of care agents like bortezomib, like carfilzomib (Kyprolis), like daratumumab (Darzalex). And because of that, a signal emerged that suggested synergy, and also the weekly schedule was actually much better tolerated. There was a very nice presentation, for example, on selinexor and carfilzomib by Dr. Cristina Gasparetto at EHA last year as an oral session that illustrated this. It was particularly nice.

Then there was a very nice presentation of selinexor and pomalidomide (Pomalyst) at last year's ASH meeting. This particular one, this was by Dr. Christine Chen, from Toronto. Christine showed really nicely that the combination of selinexor, and indeed pomalidomide was both efficacious and also better tolerated, but these were relatively small stuff. So Dr. Gasparetto's work with selinexor + daratumumab, selinexor + carfilzomib, and Christine Chen's work with selinexor + pomalidomide, again, small cohorts of patients, but an informative, better result in striking responses. BOSTON was a step up from that as a very large phase III effort, multicenter and international, and actually required by the FDA appropriately, because if you're going to get an accelerated approval from a single long trial, even if they're in this population of patients with exquisite unmet medical need and new prognosis, was extremely guarded. Nonetheless, if you only have a single arm study, you've got to have supporting randomized studies earlier in the disease that can then validate the observations initially made. And so this is very, very important.

Andrew Schorr:
So just to explain to patients then. So the FDA approved selinexor for the sickest people first.

Dr. Richardson:
Yes, exactly.

Andrew Schorr:
And then wanted more data.

Dr. Richardson:
Absolutely.

Andrew Schorr:
This trial, the BOSTON trial delivered that and with a positive result?

Dr. Richardson:
Yeah. Yeah, and I think that's exactly right, Andy, and I think as you look in the current randomized phase III space in myeloma over the last six months or so, we've been very lucky and so fortunate in myeloma that we've had so many positive phase III trials, but in fact, in the last six months, we've had a number of phase III studies, where surprisingly some of the results have been less impressive than were expected in favor of the more novel, more powerful combinations. And there are a number of examples of this, but in fact, this is why I think BOSTON was a breath of fresh air, that here we are with a nice well-designed well-conducted phase III, where an impressive, clinically important progression-free survival advantage was seen. What I particularly liked about it was that toxicity was reduced because that's a very important real world consideration.

I have to stress though, it wasn't that selinexor was without side effects. Absolutely not. You needed to be very proactive, and in the U.S. setting, it's very important to realize that the nausea, fatigue, anorexia associated with its use, and you can get some vomiting too, if you don't get ahead of it. These are very important side effects to address proactively, and in the study, we actually only required that [inaudible] be used and then next generation drugs could be used if needed. I think, in those of us who've been using the drug and using the combinations, it's very important to actually use at least two antiemetic agents and use dexamethasone to really get ahead of the nausea and any kind of anorexia early, because from a patient perspective, even once a week can be challenging unless you do that.

Andrew Schorr:
Okay. Well, as a cancer patient who's dealt with nausea, when you talk about antiemetics, I know you do want to stay ahead of it. I think the good news is, you have a large trial, well controlled. You're learning how to use a new class of medicine in combination with others to make a difference for a wider group of myeloma patients. Dr. Paul Richardson, thank you-

Dr. Richardson:
Andy, I would like to add one more point if I may, I'm sorry, because I think it's very important that we put a note. In this study crossover was allowed. So if you were on the control arm of the study as a patient and unfortunately bortezomib and dexamethasone didn't help you as well as we would have hoped it to do. You could then add selinexor to it. So obviously that was dealt separately than the first group, the first primary endpoint of PFS, because obviously that's what the FDA are looking for, for clear, unequivocal evidence of clinical benefit.

What was really nice in the trial, was if you're on the control arm and unfortunately your treatment failed you, you could then have the selinexor added to see if that could restore benefit. Now, data on that are obviously coming and emerging and we'll be reporting on that, but even with that crossover, there was actually a trend in survival in favor of the three drugs. So I think that's an incredibly important platform, because what that tells us, is that the clinical benefit associated with this entirely novel agent, a new mechanism action is very important.

Andrew Schorr:
All good news, I think, in offering hope to a wider group of patients, and with a skilled myeloma specialist such as yourself, managing side effects and having really effective combinations to fight the myeloma, Dr. Paul Richardson from Dana-Farber Cancer Institute. Thanks for being with us and explaining the results of this very significant BOSTON study.

Dr. Richardson:
Thank you, Andy. My privilege and my pleasure. Thank you.

Andrew Schorr:
I'm Andrew Schorr. Remember, knowledge can be the best medicine of all.


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