Interpreting Outcomes With Dose-Reduced Selinexor in Relapsed Myeloma

At a live Case-Based Roundtable event during the 2025 American Society of Hematology (ASH) annual meeting, Joshua Richter, MD, discussed the evolving role of selinexor (Xpovio) in the treatment of relapsed/refractory multiple myeloma. Richter addressed several critical clinical questions, ranging from the rationale for using selinexor in patients who have yet to receive T-cell redirection therapies to specific strategies for optimizing patient outcomes through dose modification.

The discussion centered on practical dosing insights derived from the phase 3 BOSTON trial (NCT03110562) comparing selinexor, bortezomib (Velcade), and dexamethasone (SVd) with bortezomib and dexamethasone (Vd), including how to manage “marrow fatigue” and the surprising efficacy data associated with proactive dose reductions.

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Targeted Oncology: How does selinexor fit into sequencing with T-cell redirection available in later lines?

Joshua Richter, MD: We all want to get to some T-cell redirection, whether it’s chimeric antigen receptor [CAR] T-cell therapy or bispecific antibodies. You can’t talk about myeloma without talking about T-cell fitness. I like to call it the N-minus-1 therapy; what are you going to do as the launching pad to [T-cell redirection]?

How do you select the starting dose of selinexor?

Sixty to 100 mg is the sweet spot. I usually don’t start less than 60 mg. That doesn’t mean I don’t end up there [with some patients]. For older, frailer patients I start at 60 mg. With pomalidomide [Pomalyst], you can’t go higher than 60 mg; that’s the maximum tolerated dose. With carfilzomib [Kyprolis], I usually start at 80 mg. But one of the things that I’ve come to learn is if in your head, you’re saying 80 or 100, give 80 mg. If you’re saying 80 or 60, give 60 mg. When I’m on the fence [I give] the lower dose, because you get better synergy.

How did the BOSTON trial of selinexor approach dosing differently from before?

There is a lot that we learned from BOSTON, and there’s a lot that we’re still learning. There was a time where bortezomib was intravenous twice weekly. Now…it’s once weekly subcutaneous, and selinexor is the same way.^1,2

…For the most part, in the relapsed [setting], we’re using triplets, and…it’s really a doublet plus dexamethasone. You need 2 people to move a couch. If you’re going to have 1 person move a couch, you need Arnold Schwarzenegger in his prime to move it. That’s what led to our original dosing strategies in STORM [NCT02336815] for selinexor. There was a time not that long ago that the level for the FDA for approval for myeloma was an overall response rate between 22% and 30%. In order to get that monotherapy…to respond, you needed to crank the dose. There’s a dose response curve, so we gave 80 mg twice a week, [like] just 1 giant guy trying to move a couch. We learned that when you get 2 people, one on each end, it’s a lot easier to move.

[Now] we give selinexor once weekly. In clinical practice, I never use this exact schema. First of all, BOSTON is done on a 35-day cycle [which I find] too confusing. I do every treatment is on a 28-day cycle …Again, not part of this study, but I always give 3 weeks on, 1 week off, in much in the same way that we use the immunomodulatory drugs [IMIDs], lenalidomide [Revlimid] and pomalidomide, because you get marrow fatigue if you keep them on. My personal experience with selinexor is that if you don’t give a week off after the first 2 cycles, you have to stop anyway because they’re too thrombocytopenic, or you run into trouble. I found that if you give 3 weeks on and 1 week off, it’s a lot easier to keep them going. But that’s my experience.

BOSTON was head-to-head, weekly SVd vs Vd, and the overall response rate was higher and median duration of response is better.¹ The median overall survival was not reached. From an intention-to-treat standpoint, the median progression-free survival [PFS] was improved from around 9.5 to 14 months [HR, 0.70; 95% CI, 0.53-0.93; P =.0075].

What rationale is there for dose reduction of selinexor?

There are drugs in myeloma that we dose reduce and there are drugs that we don’t. Lenalidomide is the archetype of drugs we dose reduce. You will see someone in clinic on lenalidomide, they will be neutropenic, and you will drop them from 25 to 15 mg or 15 to 10 mg, and you won’t think twice about it. How often do we dose reduce carfilzomib? Most of us have had someone at 56 mg/m² [and] they have some problem. We don’t drop them to 45 or 36 mg/m². We switch it to bortezomib and switch it to ixazomib [Ninlaro], and we get rid of the drug.

It turns out that selinexor is very much like the IMIDs. It’s a drug that is designed to be dose adjusted. As hematologists, we love the concept of dose intensity. …For a curable modality disease, that makes a ton of sense. But for diseases where we’re treating it almost in a chronic fashion, longitudinal dose intensity has a purpose. Instead of giving them 80 or 100 mg and having them peter out, giving them 60 mg to keep them longitudinally on therapy leads to better outcomes.

How did the dose reductions affect efficacy outcomes in BOSTON?

We compared patients who did dose reduce vs those that didn’t, and the patients that dose reduced had a much-improved PFS from around 9 to over 16.5 months.³ It’s actually a better drug when you use it that way. When we look at PFS overall, we saw some impressive data. One of the things that strikes me is medians are some of the worst statistics that could ever be used in myeloma. …The standard deviation in myeloma is so huge because it’s the most heterogeneous disease.

Which patients performed the best with the BOSTON regimen?

This was published by María-Victoria Mateos, MD, PhD, at ASH 2 years ago.⁴ She looked at certain subgroups and found that certain subgroups performed way better than the 14 months. One of them was one prior line of therapy. BOSTON was 1 to 3 prior lines. If you look at 1 prior line, the median PFS was 21 months. But when she looked at proteasome inhibitor [PI] naive, the difference was striking. In someone who would have gotten DRd [daratumumab (Darzalex), lenalidomide, and dexamethasone] upfront had a median PFS of around 9.5 months.

The median PFS for selinexor, bortezomib, and dexamethasone was 30 months.⁴ When we talk about 14 months in early relapse, nobody gets excited. Next-generation technology is getting us 30 to 40 months—isatuximab [Sarclisa] or datatumumab plus carfilzomib, and dexamethasone—but not when you’re CD38 refractory. CAR T probably get you that as well. Those come with a whole host of other problems. Not everyone’s going to be eligible for CAR T due to access, age, comorbidities, etc.

But in the subset of patients for BOSTON, those who were PI naive—not all of them got DRd up front—but PI naive was a 30-month PFS.

There are other regimens you can give. Thanks to the recent approvalof DREAMM-7 [NCT04246047],⁵ you can give belantamab mafodotin [Blenrep], bortezomib, and dexamethasone. It’s a great regimen, but with all the ocular [toxicity] and the risk evaluation and mitigation strategy, it’s a more complicated regimen to give, and especially if you have an older patient who needs to drive back and forth for treatment that does not work if they cannot see well.

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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. Jagannath S, Delimpasi S, Grosicki S, et al. Association of selinexor dose reductions with clinical outcomes in the BOSTON study. Clin Lymphoma Myeloma Leuk. 2023;23(12):917-923.e3. doi:10.1016/j.clml.2023.08.018

4. Mateos MV, Engelhardt M, Leleu X, et al. Impact of prior treatment on selinexor, bortezomib, dexamethasone outcomes in patients with relapsed/refractory multiple myeloma: extended follow-up subgroup analysis of the BOSTON trial. Eur J Haematol. 2024;113(2):242-252. doi:10.1111/ejh.14223

5. Blenrep approved by US FDA for use in treatment of relapsed/refractory multiple myeloma. News release. GSK. October 23, 2025. Accessed February 24, 2026. https://tinyurl.com/arpwwz7f