Roundtable Discussion: Vescio Debates the Sequencing of Selinexor in Relapsed/Refractory Multiple Myeloma

Robert A. Vescio, MD

During a Targeted Oncology Case-Based Roundtable event, Robert A. Vescio, MD, medical director, Multiple Myeloma and Amyloidosis Program, Samuel Oschin Comprehensive Cancer Institute at Cedars Sinai Hospital in Los Angeles, CA, discussed the case of a 78-year-old patients with relapsed/refractory multiple myeloma.

YEH: I don’t do repeat bone marrow [biopsies] because I don’t see a point to doing that. If the patient is having a lot of pain, I might get an MRI just to make sure the patient doesn’t have a cord compression. But in general, if they’re progressing, I just go ahead with the second-line treatment.

CHARU: I usually would do the imaging when they progress just to have a baseline as to what’s happening, at least when they progress.

GREEN: If it’s been a few years that the patient’s been on therapy and since her last imaging if she’s asymptomatic I would still get a bone survey just to see that there’s no progression of lesions.

VESCIO: There are a lot of differences of style with this. I don’t tend to repeat the bone marrow biopsy, but I know some of the academic centers or some people tend to. That’s just how it was done years ago but I don’t know that it changes the patient’s [treatment]. Usually, the abnormalities you see on the initial bone marrow biopsy are what made the original myeloma cell in the patient. Additional mistakes usually are mutations like RAS mutations and you’re not going to really see those with a new FISH test on a new bone marrow analysis.

So I tend not to do so many bone marrows, plus patients don’t like them too much. I don’t do as much imaging either, but I think I should and sometimes I’ve been burned. It’s certainly rational to repeat imaging just to make sure, especially if her protein spike went up a lot. But I know if somebody feels fine and they were doing well and it’s a biochemical relapse, it’s unusual…to ever find anything wrong.

SHIN: When would you consider enrolling bone agents like bisphosphonates or denosumab [Xgeva]?

VESCIO: I think all patients with multiple myeloma who are started on treatment should get a bone-protective agent. I certainly have had exceptions, but [for] a…relatively asymptomatic patient with a normal bone density and no lesions, I’m not sure they need to be [on a bone-protective agent].

Then the question—a very hard one—is: For how long do you give it? I know if you give it indefinitely, the risk for osteonecrosis of the jaw certainly goes up, and if you keep doing it monthly their risk increases substantially as well. I tend to stop it after a while if they’re in remission, and I usually don’t go more than 2 years. Then [I] either stop or, if they really had a lot of bone problems at the beginning, I’ll do it every 3 months for a while.

CHARU: When you start the treatment, you do it every month?

VESCIO: I do it every month. I use the zoledronic acid [Zometa], and denosumab is easy; patients like it. I will say what makes me pause is that the zoledronic acid stays in the body longer, so I always wonder if somebody’s going to have years of disease. Maybe with the zoledronic acid you do it for a while then you stop and it stays in the body for years. Rather than the antibody-drug conjugates, the denosumab tends to wear off. Thinking about [patients with] low aggressive myeloma, I tend to give a little more zoledronic acid, figuring their disease isn’t that bad and the drug is going to hang around for longer. But it’s a style thing, there’s no right answer.

CHARU: What about in patients who don’t have too many bony lesions?

VESCIO: I think you should because I think you can get away with it. When all these studies were done the drugs didn’t work so well. Now we have drugs that work quickly and I always get a bone density test; so if they don’t have lesions, I get a bone density test. If they show osteoporosis and if they even show significant osteopenia, then that’s a reason to start. This person [in this case] needs to be treated. She’s becoming anemic. She went from remission to a substantial protein spike. I don’t think there’s any controversy that something needs to be changed.

So how do you decide what to do? What type of backbone would you consider if she’s progressing on a CD38 monoclonal antibody?

YEH: [Because] the patient’s been on immunomodulatory imide drugs for so long and [has] high-risk features, I’d probably want to change it to a proteasome inhibitor just to see if that would work. Then [I’d] just keep the CD38 and maybe add dexamethasone back on.

VESCIO: I think there’s a rationale for basically all of them. Obviously, if somebody’s progressing very slowly, sometimes just substituting lenalidomide for pomalidomide [Pomalyst] would make sense. It seems like [the patient is] progressing a little more rapidly than that, so that does make [bortezomib/pomalidomide/dexamethasone] a reasonable option. Nobody picked the selinexor and 1 picked elotuzumab [Empliciti], which would be fine as well.

YEH: There’s such a crowded field in the second line. There are so many better options, so I’m not sure why we put selinexor [as an option]. Maybe for the patient [with del(17p)], but even with that I’m stretching it.

GREEN: I think it does give you another option and it is an oral drug, which at least has some advantages as opposed to some of the alternative second-line agents, which may be a little easier in terms of the convenience factor.

VESCIO: If you give patients a choice of intravenous treatment vs a pill, they generally want the pill, if it’s covered. Sometimes they don’t like the pills because it’s not covered fully, but I think with this drug it’s been covered pretty well.

JANG: To me, this is more like a third- or fourth-line agent.

I think with the existing treatment I can squeeze in 2 lines of treatment before I give the selinexor.

CHAND: I was thinking about ixazomib [Ninlaro]. When the medication first came out, I think there was some mention about the del(17p), and ixazomib seems to work well in those patients. It’s a much better-tolerated drug and it’s given orally. I don’t think I’m looking forward to using selinexor as a second-line treatment. I would probably use it more down the road for [a patient with del(17p)]. I’m just curious to know what your thoughts are.

VESCIO: Ixazomib…has to be the most convenient drug. It’s 3 pills a month and patients love that. It’s certainly effective as a proteasome inhibitor. I have my doubts whether bortezomib at day 1, 4, 8, and 11 compared to oral ixazomib [is less effective]. My suspicion is that the bortezomib would be more potent. But then again, that’s a lot of shots and a lot of trips [to the clinic] and patients tire of that. I don’t have a ton of patients on ixazomib, but [I’ve added] it to lenalidomide and dexamethasone…when somebody maybe had bortezomib before. It worked, but they stopped because of convenience or neuropathy and then the disease slowly creeps back.

Again, the convenience factor is important. I will say [that], very off label, I have a couple of patients with very easy-to-fix myeloma [who are] on monotherapy with ixazomib just because bortezomib worked great. But they don’t want to take the shots and they didn’t tolerate lenalidomide and they don’t want to come to see me very often. So they’ll just take pills and will wait for the infusion treatment later. Ixazomib certainly has its place, but I don’t know that this patient [in the case] is really progressing rapidly. But I don’t tend to think of it when patients are progressing symptomatically; I tend to use the other proteasome inhibitors for those [patients].

CHAND: What’s the lowest dose that you’ve used for selinexor? Is it 40 mg?

VESCIO: It is 40 mg. I wanted to switch to 60 mg but [the patient] wouldn’t let me. He’s on 40 mg, however, and is responding. He’s about 3 months into the treatment but he had a profound response in the first month with 100 mg. It’s at least an eighth-line treatment in him so it’s beyond this. Pretty much every approved drug’s been given. It’s been good so far for him and he is tolerating it, but he might be able to up the dose to 60 mg later.

The people I’ve talked to throughout the country…tend to think 60 mg is the magic number. But there are people long term, I’ve heard, that have done really well when they reduced it to 40 mg and [who are still responding to the treatment].

CHAND: Do you routinely give these patients antiemetics or something like that?

VESCIO: I think you have to. We educate them [on the adverse events. I give them granisetron [Sustol] with the selinexor and…5 mg of olanzapine [Zyprexa] at night and then they do the olanzapine 2 nights in a row with the dexamethasone and I just have them continue it that first week until I know they’re going to tolerate the treatment. Then, if they do OK, we readjust from there. I think with this drug it’s better to give too much at the beginning than too little, because if they feel crummy then it’s a psychological thing too; they’ll feel crummy the next time as well that they take it.

Also, consider hydration. [This treatment] can cause hyponatremia.…My very first patient…had some edema at the time and so he really avoided salt. But he was on the 100-mg twice-a-week dose, which was the original dose for heavily treated patients. He [experienced] some hyponatremia because of the diarrhea he had and other reasons. [Patients] need to maintain their hydration and maintain their salt intake [so be mindful of that].

[Selinexor] does cause some thrombocytopenia and neutropenia as well. We’re all pretty comfortable with adjusting based on that. If it causes significant thrombocytopenia, you have to lower the dose. Just remember, all these things we’ve done in patients who had essentially normal counts when they started. Sometimes we’re not so lucky with patients. They start off in their fifth line [of treatment] and their counts are not so good to begin with. So you’re going to have to use your judgment. I’ve certainly had patients I was more aggressive with than what you would see here because their disease forced me to be a little more aggressive.