Early Intervention Enables Control of Selinexor AEs in Multiple Myeloma

At a live Case-Based Roundtable event during the 2025 American Society of Hematology (ASH) Annual Meeting, Joshua Richter, MD, discussed the safety and practical considerations when using selinexor (Xpovio) in the treatment of relapsed/refractory multiple myeloma.

Richter discussed the cytopenias and other high-grade toxicities that were reported with selinexor and how his management approach has evolved as newer trial data have been released and clinical experience has developed. He also discussed how co-medications such as antiemetics can dramatically change the tolerability outcomes with this therapy and in turn enable greater antitumor responses.

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This article is part 2 of a 2-part series from a Case-Based Roundtable event.

Targeted Oncology: How do you address hematologic toxicity associated with selinexor?

Joshua Richter, MD: There are certain tropisms that we know about [regarding] the hematologic toxicity for selinexor, and the main one is thrombocytopenia. It turns out that XPO pathway inhibition blocks TPO pathways. It blocks it in such a profound way that if we go back to the original STORM study [NCT02336815] when we were giving selinexor twice weekly, that blockade of TPO is so powerful you cannot overcome it with TPO agonists. You could give full 10 mg/kg romiplostim [NPlate], [but] it doesn’t do anything. That’s how potent it is.

If, on the other hand, you give once weekly selinexor, you can overdrive that with TPO mimetics, but you have to ratchet up the dose. As opposed to the package insert for romiplostim of 1 mg/kg, 2 mg/kg, 3 mg/kg…you [have] to ratchet up quickly. But in general, there’s a tropism for thrombocytopenia.

We see thrombocytopenia with the SVd [selinexor, bortezomib (Velcade), and dexamethasone] regimen,^1,2 but grade 3 or grade 4 thrombocytopenia is not a problem. The patient doesn’t necessarily feel anything when they have 40,000 or 50,000 platelets/μL. We get gun-shy, or we say, “Let’s hold for a week.” But the patient doesn’t come in saying they feel horrible. They don’t come in with neutropenic fever because they have a platelet count of 40,000/μL.

The other nice thing about that is that when they’re on a non-IMiD [immunomodulatory drug] regimen, you don’t have to [deal with situations] where your 80-year-old patient is on a DOAC [direct oral anticoagulant] for some reason, [such as] atrial fibrillation. You’re giving them chemotherapy. They have 100,000 platelets/μL, [so] you go ahead and treat them. They have 80,000/μL; you go ahead and treat them. [Then] they’ve got 40,000/μL. Why does their physician give them that DOAC again? They had 6 heart attacks. I think we don’t talk about that enough. That’s a real-life problem I know that I deal with all the time. You have someone on chronic therapy, and here we are as hematologists calculating vascular scores to know if we can continue. But you don’t have to worry about that with a non–IMiD-containing regimen.

What approaches are there to managing nonhematologic adverse events (AEs)?

The gastrointestinal [GI] toxicity is interesting. We’ve learned a lot about the GI toxicity in selinexor, and it’s part of the reason why the numbers are a lot lower than they used to be.^1,3 Part of it is that once weekly is far better than twice weekly. The other is that we’ve learned to be proactive, not reactive. Nausea is one of those things where once patients get it, you’re behind the 8-ball, so being proactive is better.

I like to think about toxicities for drugs being proximal or distal. For chimeric antigen receptor T-cell therapy, proximal is cytokine release syndrome and immune effector–cell associated neurotoxicity syndrome, and distal is infection and cytopenias. Most of our drugs have distal toxicity. When they’re on lenalidomide [Revlimid] for 7 cycles, and you get a call from the nurse that they are here for their daratumumab [Darzelex], but their absolute neutrophil count is 300/μL, you’ve got to drop the dose. The toxicity for selinexor is proximal. Those first 3 cycles are the ones you’ve got to get them over. Once you get them over those first 3 cycles, it’s smooth sailing—at least that’s my experience—because now you can start backing off on all the antiemetics that you [gave to] them.

One of the things that was interesting is the hyponatremia story. If you go back to the original paper, there was a lot of grade 3 hyponatremia.³ Now, a couple things about that. One is, a lot of the patients in STORM had advanced myeloma. When you have [increased] paraprotein, pseudo-hyponatremia becomes an issue. The other is…the Common Terminology Criteria for Adverse Events [CTCAE] lists everything from stubbing your toe to a heart attack [as] grade 0 to grade 5. Grade 1 hyponatremia is the lower limit of normal of your [laboratory results] down to 130 mEq/L. There is no such thing as grade 2 hyponatremia, and the CTCAE grade 3 starts at 129, for reasons that make no sense at all.

We would have patients come in with 128 or 129 mEq/L [but] asymptomatic who had to be stopped on therapy. They used to recommend hydration, and then we started realizing, maybe we can overcome this with salt tabs. One of my favorite nephrologists did a study, his own personal analysis. He looked at how much sodium was in a salt tab versus how much sodium was in a packet of soy sauce. There is more sodium in a packet of soy sauce than there is in a salt tab. What we started recommending was that patients order food and use soy sauce or their favorite salty snack. It turns out [what is] a lot better than dragging the patient in for constant hydration is just making sure their salt intake is good.

What co-medications do you give with selinexor?

When we do prophylactic antiemetics, we have learned a whole lot. Our nurse practitioners figured it out, and then they told us what we learned. If you look at the original STORM study, the overall response rate in STORM was 26%.³ At Mount Sinai, the response rate was 53%. It wasn’t patient selection; the biggest difference between our practice and the rest of STORM was the use of NK1 agonists like aprepitant [Emend]. Ninety-seven percent of our patients were on an aprepitant-like drug vs 18% for the rest of the group. Personally, we give a lot of rolapitant [Varubi]. It’s not a commonly used drug, but rolapitant is [given at] 180 mg every 2 weeks and has the fewest drug-drug interactions with selinexor. Or if you have access to netupitant/palonosetron [Akynzeo], you can give [it] and dexamethasone and reduce the pill burden. But being aggressive upfront with these medications, at least for the first 3 or 4 cycles, got patients over those issues, and then it was much easier to treat them, and we ended up having high response rates.

…Rolapitant is a drug I had never heard of because I think we all give either aprepitant or fosaprepitant. Rolapitant is a drug that, it turns out, has the fewest drug-drug interactions. Our standard order set is, we order selinexor—I give everything on a 28-day cycle, 3 weeks on, 1 week off—and rolapitant at 180 mg every 2 weeks, at least for the first 3 cycles.

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_{DISCLOSURES: Richter previously reported consulting/advisory roles for AbbVie, Bristol Myers Squibb, Genentech, Johnson & Johnson, Karyopharm, Pfizer, Regeneron, Sanofi, and Takeda; and speaker's bureaus for Adaptive Biotechnologies, Bristol Myers Squibb, Johnson & Johnson, and Sanofi.}

REFERENCES

1. 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

2. Xpovio. Prescribing information. Karyopharm Therapeutics; 2022. Accessed February 24, 2026. https://tinyurl.com/5f6ucusr

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