EVENT REGION Ohio
PARTICIPANT LIST Arun Kumar, MD | Mark Knapp, MD | Kasra Karamlou, MD | Timothy Moore, MD | Bachar Dergham, MD | Baidehi Maiti, MD, PhD | Samir Abraksia, MD
CASE SUMMARY
A 76-year-old man was diagnosed 5 years ago with IgGκ multiple myeloma (MM). He had hypertension that was well controlled with lisinopril. He presented to his physician with bone pain and fatigue. At diagnosis, his λ serum free light chain level was 8842 mg/L and clonal bone marrow plasma cell percentage was 50%; fluorescence in situ hybridization classified the disease as standard risk. His ECOG performance status was 1, and his International Myeloma Working Group frailty status was intermediate-frail. Based on the patient’s age and risk status, a transplant was not preferred.
The patient received daratumumab (Darzalex), lenalidomide (Revlimid), and dexamethasone, and he had a complete response. He was able to resume daily walks, perform more activities around the house, and travel more frequently.
Three years later, he reported increasing fatigue and bone pain during his annual checkup with his oncologist. A PET scan showed uptake in multiple bony lesions on his ribs and femur. He wished to continue therapy and was interested to hear what options remain.
QUESTIONS
- How do you counsel patients with relapsed/ refractory (R/R) MM on selinexor (Xpovio) as a treatment option?
- If you use selinexor, what steps and supportive care do you proactively perform to improve tolerability?
- What is your approach to dose reduction?
- What is your approach to nausea/vomiting prophylaxis and hydration?
KUMAR: The cytopenias were the most prominent [adverse events (AEs)].1 I won’t be using selinexor in the second line, but maybe in the third or fourth.
KNAPP: I’ve used it in the third-line setting and beyond. I haven’t used it in the second line. I tend to use elotuzumab [Empliciti] with pomalidomide [Pomalyst] and dexamethasone. I find that’s kind of a fairly well tolerated regimen with few AEs.
KHOURI: Has anyone used selinexor in the first relapse?
KARAMLOU: I have. I think the biggest thing is dosing. I usually go below the recommended dose. I usually either start at 60 mg or 80 mg once a week. I always give them antiemetics prior, and I watch the patient’s weight closely because of the weight loss. That’s another big thing that you have to watch when you put patients on selinexor. But usually in my experience, if you go at the lower doses rather than the 100 mg, most patients seem to tolerate it a lot better.
MOORE: I agree; [I put] my first patient…on the recommended dose, and the patient did terribly— and she’ll never go back on it again, even at a reduced dose. Starting low and gradually increasing it is the way to go.
MODERATOR SIDEBAR
Q:What were the adverse events (AEs) observed with selinexor (Xpovio), bortezomib (Velcade), and dexamethasone in the phase 3 BOSTON trial (NCT03110562) of patients with R/R MM?
JACK KHOURI, MD: The majority of the [AEs] were hematologic— 60% had any-grade thrombocytopenia, approximately one-third had anemia, and 15% had neutropenia.1 Fatigue was common: Forty percent of the patients had it. Gastrointestinal [GI] AEs were common; almost half of the patients had nausea, and more than 70% [combined] had nausea and diarrhea. Approximately one-quarter of the patients had weight loss, and decreased appetite was also seen in about one-third. So GI toxicity, weight loss, and hematologic toxicities were seen, and there was a significant number of patients who needed dose modification on this study [89% with selinexor vs 76% with bortezomib/ dexamethasone]. The drug in this study was given at 100 mg, which was a little bit different from the prior study [STORM; NCT02336815].
KHOURI: I fully agree. That’s the main message here: The drug works, but you have to give it in a very wise manner. The key to it is to start low. I would not start at 100 mg like what [the BOSTON study (NCT03110562)] did. I tend to do 60 mg or 80 mg [of selinexor] once a week with bortezomib [Velcade], and I tend to use 2 antiemetics with it. I give olanzapine every day for everybody and ondansetron [Zofran] as needed. I tell the patients that the nausea that happens with selinexor can be gut related and brain related, which is why I tend to use ondansetron and olanzapine.
I watch their weight very carefully. They’re with us once a week getting bortezomib at the infusion center, so I check their complete blood count and comprehensive metabolic panel. Hyponatremia is something that we see with the drug. The mechanism is still not clear, but it [could] be some version of SIADH [syndrome of inappropriate antidiuretic hormone secretion], maybe with some dehydration. If they’re not eating and they’re hyponatremic, we ask them to eat salty things at home. If they look dehydrated to me, I give them some intravenous fluids when they come for their bortezomib.
I tend to hold the drug if their platelet count is less than 50,000/μL. That is when I drop the dose to a lower dose level. If they’re not at 50,000/μL, I tend to hold and wait for them to get better, and then I restart at the same dose level because many patients can get better after the first cycle. It’s always the first cycle that’s hard to keep patients on track with, but once you get them through the first cycle, they do well afterward. I start with 60 mg or 80 mg; if they’re responding, I tend to keep them on the same dose. If they’re responding with no issues, you don’t have to dose escalate. If you don’t see a good response after the first or second cycle and their safety profile is OK so far, you can escalate and see what happens.
DERGHAM: In the package insert, when you use it as a doublet, you use it twice a week at 80 mg, but when you use it with bortezomib, it’s 100 mg once a week. And it was kind of puzzling which one is the accurate one.2 At some point, I thought 80 mg once a week would be the standard for both regimens, and I do exactly what you do. I add the olanzapine automatically to those patients.
KHOURI: They used to do it twice weekly, but the drug was not tolerated. That dose was not the ideal dose. But I think [giving it] once a week and starting low and incrementing [are key]. If you have to, if the patient is responding, keep them on the same dose with olanzapine and ondansetron as needed.
KUMAR: What dose of olanzapine are you giving, [and do you give it] every day?
KHOURI: I know some physicians do it for just 1 day before, on the day of the drug, and then the day after. I tend to keep the patients on [daily] because I’ve seen patients having relapse of their nausea a couple of days after their selinexor. I tend to just keep them on it every day, 5 mg at bedtime. You can start with the day before, the day of, and the day after and see how the patients does. In my experience, they have their nausea later in the week after they got the drug.
MAITI: When you do use selinexor, do you give prophylaxis for infection, and if they have neurologic complications such as confusion and dizziness, how do you manage that?
KHOURI: Confusion and dizziness could be related to their sodium. I’ve had a few patients admitted to the hospital for management of their hyponatremia. Some patients can fall at home because they’re hyponatremic and they’re confused. I usually admit them, and I’ve restarted the drug on a few of those patients at a lower dose. And I instructed them to eat more salty things, and they did fine. The key is to just make sure that they’re hydrated at home and eating some salty food, and that can help.
I usually give acyclovir for these patients because they’re already on bortezomib and carfilzomib [Kyprolis], but that’s about it in terms of infection prophylaxis.
MAITI: If you have a good response on selinexor but patients are losing weight, what do you do?
KHOURI: I reduce the dose. If they’re responding, if you started at 60 mg or 80 mg, I would just reduce it to the one just below it, and patients can regain their appetite when you reduce the dose. Rarely I’ve seen a couple of patients who are not able to tolerate even 40 mg. But usually they [improve], and there are a lot of dose levels that you can use, which is a good thing with this drug. I’ve used mirtazapine if I keep them on a low dose and they still have no appetite, and it has helped some patients.
MAITI: When I read about selinexor, it did say it can have ophthalmic toxicity, some blurry vision in approximately 10% of patients,2 so I wondered whether that’s something you encounter.
KHOURI: No, I don’t see that. I don’t usually send my patients to ophthalmologists unless they have issues, which can happen from other things, and I wonder whether some of that could be related to dexamethasone-related cataracts or something else. But it’s not standard of practice.
In terms of toxicities, STORM [NCT02336815] was the initial study that looked at the doublet of selinexor and dexamethasone, and the dose was 80 mg biweekly. There were hematologic toxicities; more than half of the patients had thrombocytopenia of grade 3 or 4.3 High-grade neutropenia was also common. With BOSTON, we did 100 mg once a week, and the hematologic toxicity was not as pronounced,1 and these are the dose levels [Figure 12]. I tend to start either at 60 mg or 80 mg, and I increment to 100 mg if I have to. If I don’t have to, the response is OK, I tend to keep the same dose. There’s a 40-mg dose level that I use in patients who have more frailty, and [I use it] more commonly with carfilzomib or pomalidomide, based on some of the data that we have. With bortezomib, I tend to do 60 mg or 80 mg. [Although] 40 mg works, it doesn’t work as well as 60 mg or 80 mg.
[The Tisch Cancer Institute at] Mount Sinai did some digging into the BOSTON study of selinexor, bortezomib, and dexamethasone vs bortezomib and dexamethasone, and they looked at the outcomes of patients who had dose reductions.4 They found that the response rates were better than those of patients who did not have dose reductions. That was probably related to the fact that you could keep the patients on the drug longer, and…because they stayed on it for a longer time, they were able to get more benefit from it that way.
So do not shy away from reducing the dose of the drug, or [you can] start low and see what happens. If you can keep these patients on the drug longer, you can get more benefit from it. [It was found that] 81% of the patients who had dose reduction responded vs 66% who did not have dose reduction, and mostly those are the patients who had to go off study because of tolerability [Figure 2].4 It is important to make sure that patients tolerate and stay on the treatment so that they can get more benefit from it.
ABRAKSIA: Patients who had their dose reduced have a longer progression-free survival [median, 16.6 months vs 9.2 months; HR; 0.5678; 95% CI, 0.3614-0.8919; P = .0065].4 To me, that’s because they’ve stayed on the drug longer. Is that the point?
KHOURI: Exactly. The key is not to keep them on a high dose that they can’t tolerate that you have to just discontinue or dose reduce. It’s better to keep them on a tolerated dose for as long as you can. The longer you can keep them on it, that’s what’s going to benefit them.
ABRAKSIA: That seems to be a concept in oncology in general.
KHOURI: Yes, I agree. But many think that…the high dose is what’s going to help, and then you take the patient off the drug, and they don’t get enough time on the drug; that may compromise their response. That’s what this subgroup analysis shows from the BOSTON study. If you can keep them on a low dose for as long as you can, this is the key, as long as they’re responding.
REFERENCES:
1. Xpovio. Prescribing information. Karyopharm Therapeutics Inc; 2022. Accessed April 18, 2024. https://tinyurl.com/3m3mu6h3
2. Grosicki S, Simonova M, Spicka I, et al. Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. Lancet. 2020;396(10262):1563-1573. doi:10.1016/S0140-6736(20)32292-3
3. Chari A, Vogl DT, Gavriatopoulou M, et al. Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019;381(8):727-738. doi:10.1056/NEJMoa1903455
4. Jagannath S, Facon T, Badros AZ, et al. Clinical outcomes in patients (Pts) with dose reduction of selinexor in combination with bortezomib, and dexamethasone (XVd) in previously treated multiple myeloma from the BOSTON study. Blood. 2021;138(suppl 1):3793. doi:10.1182/blood-2021-146003
