番茄社区

The (Xpovio) in combination with bortezomib (Velcade) and dexamethasone for the treatment of adults with multiple myeloma who have received at least one prior therapy. The approval was supported by the phase III BOSTON study, which was recently and presented at December's American Society of Hematology (ASH) virtual meeting.

番茄社区 has brought together three expert leaders in their field: moderator , is joined by , and , for a virtual roundtable discussion; and this second of five exclusive episodes explores their thoughts on selinexor and the BOSTON study.

Episode one: Early Transplant or Delayed? Multiple Myeloma Experts Debate

Episode two: Selinexor OK'd for Myeloma, But Does That Make It a Good Drug?

Episode three: Many Questions Surround GRIFFIN Study

Episode four: FORTE Raises Question of Excessive Treatment in Myeloma

Episode five: CAR-T for Myeloma Excites at ASH, but Questions Remain

Following is a transcript of their remarks:

Vinay Prasad, MD: I'm back with Aaron Goodman and Dr. Al-Ola Abdallah and we're talking about selinexor. Aaron, selinexor, good drug or great drug? How would you characterize this drug?

Aaron Goodman, MD: I would characterize it as an awful drug.

Prasad: Awful drug?

Goodman: Yes.

Prasad: And why is that, sir?

Goodman: Well, $2,200 to $4,000 a month, so it's clearly not cheap, yet to date there is no data that it makes the patients live longer and the toxicity profile, I would say, is not favorable. The drug company would like to remind us that it does have a novel mechanism. That's about it to me.

Prasad: Novel mechanism of action, I hear a lot of that. In fact, we talk most about mechanism of action when efficacy and tolerability are quite poor. Dr. Abdallah, any thoughts on selinexor? How do you think about this drug?

Al-Ola Abdallah, MD: Again, I keep saying the same word all the time. We really require from a pharma company like Karyopharm to think about doing real randomized clinical trials. When we say real randomized clinical trials, do we have lack of myeloma treatments for our patients? No, the answer, we don't. We just need to know where do we put these types of treatments. If we believe this type of drug is good enough as a combination therapy or as a single agent, why are we not seeing it as a randomized clinical trial to see exactly how effective it is in myeloma? And I agree with Aaron. We need to know exactly not only the efficacy, also the side effects, the toxicity, to learn more, is it really good or is it not good. That's the whole purpose of doing the randomized clinical trial.

Prasad: Now, the makers of this product will point out that they have done a randomized clinical trial. It's called BOSTON and it randomized patients with selinexor, Velcade and dexamethasone, or Velcade-dexamethasone, which I think is not a very popular second-line regimen in this country, particularly for people who received Velcade in the first line. Dr. Abdallah, any thoughts on the BOSTON study, a PFS benefit from selinexor-Velcade-dex versus Velcade-dex in one or multiple subsequent lines of therapy?

Abdallah: I can give you a best answer for that. If you ask me exactly how many relapsed myeloma I treated with Velcade-dex for the past five years, I'll tell you two patients, maybe, and two of these patients are frail and not candidate for a clinical trial, so we don't...

Prasad: In other words, you think it's a straw man control arm, an unacceptable control arm, in your mind?

Abdallah: Not acceptable at all. I don't know if there is any myeloma doctor who for the past five years treated any patients with Velcade-dex.

Prasad: Well, they might have if they enrolled a patient on the BOSTON study. Aaron Goodman, what are your thoughts on the control arm of the BOSTON study?

Goodman: Well, I mean at least they did a randomized trial. I think that's the only thing you can give them a reward for. I'm just going to say it, I don't think it was ethical for centers in the United States to enroll in that study. I'm not a myeloma KOL. I do treat a lot of myeloma, but I have been to many of their talks and nowhere in the recommendations at first or second relapse is doublet therapy with Velcade-dex recommended for the treatment of our patients, especially when I believe 60% of those patients had already received Velcade-dex. If they truly consented patients for this study, I can't imagine what that consent talk looked like, re-treating with a doublet with the two therapies that they have seen.

So, yes, a big surprise. They added a drug with a novel mechanism that had some sort of plasma cell activity and they combined it with Velcade-dex, and there was a modest improvement in progression-free survival. Who cares? It doesn't tell me what to do clinically at all. I will never use that regimen because it's been proven to be superior to a regimen that we don't use in clinical practice in the United States, so it's a useless study.

Prasad: It's proven to be superior to an inferior regimen.

Goodman: Yes.

Prasad: I think it exposes one of the major paradoxes of multinational, global, randomized controlled trials, which is they help neither people in global countries nor people in this country. Let me put it to you this way. In global countries, they already struggle to afford drugs like revlimid and daratumumab, and they are very unlikely to be able to afford a new drug like selinexor. The results of this clinical study are not going to help those places because they're not going to have ready access to a drug like selinexor, I would guess, on average.

Meanwhile, this trial doesn't help us in the United States because we don't give Velcade-dex as second-line therapy, so it doesn't inform our clinical practice. It's a trial that answers a question that neither country is facing, not a lower-middle income nation nor a very wealthy nation, and I consider these trials deeply problematic. We can run randomized trials all day in oncology, but if our control arms are nothing like how we practice, they don't provide information for any of us who see patients day-to-day. Dr. Abdallah, thoughts?

Abdallah: Well, also another thing about this trial, but one of the most common things that now we are using revlimid as maintenance therapy, only 39% of the patients were exposed to revlimid, not refractory to revlimid. If you look at a lot of trials now, the APOLLO trial, all these trials are showing that patients who are not refractory versus refractory there's a difference in progression-free survival.

Prasad: Sure.

Abdallah: I'm wondering exactly how much is this effective in those patients in that population. We have to be very careful about these type of studies and unfortunately who are the physicians who are going to use it? They're not going to use this study after failure of maintenance revlimid. They're going to definitely try to exhaust other options like daratumumab and all of these treatments, and then use the selinexor-Velcade-dex, which we don't know exactly if it's going to be effective after triple refractory. Or is it going to be the same median progression-free survival as they claim? That's the biggest problem that we're going to face and I agree with you, it did not benefit at all for us, and I don't think it answered any of the questions. Can this overcome things like a proteasome inhibitor refractory or even IMiD refractory? It did not answer that and unfortunately most of our patients are IMiD refractory now. This kind of like could be a trial that will not give the best answer for this case, so that's also a big negativity of the BOSTON trial.

I just want to add, also, in regarding the developing country, it's a very expensive drug. Don't forget about the supportive treatments that you have to give for these patients...

Prasad: Good point.

Abdallah: ... IMiD for GI toxicity. The only time I use IMiD in the patients is for VRD-PACE, and my patients don't have nausea and...

Prasad: ... containing regimens. Yeah, of course.

Abdallah: If you look at the BOSTON trial -- it's not my study, it's their study -- and you look at the side effects and toxicity, you can see that how many of these patients got a grade 3 nausea. It was over 8% and that's after using the drugs like IMiD. You can see exactly the weight loss was higher in these patients, so I don't see that in my myeloma patients where I give a very toxic regimen like VRD-PACE comparing to selinexor. That's really very challenging for my patients because we are trying to be very effective.

The reason we don't want to -- I know a lot of physicians don't like to do the transplant -- is because of the mucositis. So why are we giving a drug that can cause GI symptoms, which it was the reason why we stopped using drugs like panobinostat in the past, diarrhea and rash.

Prasad: Yes. Absolutely. I think what jumps out at me about a drug like selinexor is not the novel mechanism of action. I don't spend a lot of time watching YouTube videos of the molecular mechanism of drugs. What jumps out at me is the toxicity and tolerability for patients reported in all the clinical studies, including rates of grade 5 AEs in the initial study. Dr. Goodman, any last thoughts on selinexor?

Goodman: Yeah. For a drug that we do not know makes patients with myeloma live longer, at the very least, all we can ask for is that it makes them feel better. Clearly, it does not do that and they charge you quite an expense for that.

My final thoughts on this drug is it has currently no role in the treatment of patients with multiple myeloma in the United States, outside of the penta-refractory patient with no clinical trial options who, after a very thorough informed consent processes, is willing to try another treatment.

Prasad: That's true. For that patient, they can also consider VTD-PACE and some salvage cells if you have them on hand. There are lots of other things I'd think about, but thank you, gentlemen, for this conversation.

Comment