Dosing Considerations for Selinexor in R/R Multiple Myeloma

Joshua Richter, MD

Associate Professor of Medicine

Tisch Cancer Institute

Director, Multiple Myeloma

Blavatnik Family-Chelsea Medical Center at Mount Sinai

New York, NY

(previous article based on this event)

Targeted Oncology^TM: What monitoring is needed for patients receiving selinexor (Xpovio)?

In general, the monitoring was recommended what we do for all of our therapies: complete blood count, [standard blood] chemistries, making sure patients are not losing weight, then giving hydration as needed especially if the [route of oral administration] intake is not good, and [prophylactic] antiemetics all the way around [including 5-HT3 receptor antagonist and other antinausea prior or during treatment].¹

What can be observed about the dosing and toxicity of selinexor based on the different doses used in the STORM [NCT02336815] and BOSTON [NCT03110562] trials?

I will go over the difference in grade 3 and 4 toxicities. [However, we should] avoid doing [direct] cross-trial comparisons. Looking at the STORM versus the BOSTON study, there were a lot of differences. STORM was a more heavily pretreated group of patients with a median of 7 prior lines of therapy, whereas patients in the BOSTON trial received 1 to 3 prior lines. In STORM, investigators gave 80 mg twice weekly, whereas in BOSTON, they gave 100 mg once weekly.^2,3

I think a lot of our conceptions about selinexor came from STORM, [since] it was the first experience many of us had. But we see that when you move the drug [earlier], give it in combination, and give it once weekly, there are improved rates of at least the hematologic toxicities. Thrombocytopenia of grade 3 or 4 goes from 58% [in STORM] to 39% [in BOSTON], neutropenia and nausea dropped to single digits [in BOSTON], and fatigue and hyponatremia dropped as well.

The CTCAE [Common Terminology of Adverse Events] is very interesting in terms of hyponatremia. The CTCAE, which has a listing of every adverse event, grades it 1 through 4 in worsening severity. Hyponatremia grade 1 is lower limit of normal to 130 mEq/L. There is no such thing as a grade 2 hyponatremia in the CTCAE. Grade 3 starts at 129 mEq/L, and I can tell you, because I’ve accrued many patients to STORM, a lot of those patients would be asymptomatic with a blood sodium of 128 mEq/L or 129 mEq/L that counts as grade 3.

How are dose reductions performed for selinexor, and what are their expected outcomes?

As far as dose reductions, I think for the most part, [it’s recommended to] dose between 60 mg and 100 mg once weekly, depending upon the partner drug, and dropping the dose by 20 mg for every dose reduction. So, if you start at 100 mg, you can go to 80 mg. If you start at 80 mg, you can go to 60 mg, and then ultimately down to 40 mg.¹

There was a post hoc analysis [from the BOSTON trial] of patients and clinical outcomes when selinexor was reduced.⁴ One of the things that this brings up is something we see in multiple myeloma, that there are certain drugs that we’re all comfortable with dose reducing. We dose reduce lenalidomide [Revlimid] all the time. Carfilzomib [Kyprolis], on the other hand, is a drug we often don’t dose reduce. When patients get toxicities from carfilzomib, oftentimes—not always—we [discontinue] the drug. Selinexor is a drug that benefits from monitoring and dose reduction when necessary.

If you compared the progression-free survival [PFS] with patients who had dose reductions with those that did not, you had a PFS that goes from 9.2 months [with bortezomib (Velcade) and dexamethasone] to 16.6 months [with selinexor, bortezomib, and dexamethasone], with an improvement in overall response from around 66% to over 81% [with the addition of selinexor].⁴

How has selinexor been investigated in other combinations?

In the phase 1b/2 STOMP trial [NCT02343042], selinexor was combined with dexamethasone and another drug used in multiple myeloma. This is an umbrella trial where we have patients on selinexor/lenalidomide/dexamethasone, selinexor/pomalidomide [Pomalyst]/dexamethasone, selinexor/bortezomib/dexamethasone, selinexor/carfilzomib/dexamethasone, and selinexor/daratumumab [Darzalex]/dexamethasone.

In all of these studies, the selinexor is administered once weekly, and although the other drugs are given in standard fashion, the dosing of selinexor differs depending upon what the partner is.^5-8 When you combine selinexor with daratumumab or bortezomib, the maximum tolerated dose is 100 mg once weekly. Combine it with carfilzomib, it’s 80 mg once weekly. Combine it with an immunomodulatory drug like lenalidomide or pomalidomide, it can generally be given at 60 mg once weekly.

_REFERENCES

_{1. Xpovio. Prescribing information. Karyopharm Therapeutics Inc; 2020. Accessed March 20, 2023. https://bit.ly/3FArFSR}

_{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}

_{5. Gasparetto C, Schiller GJ, Tuchman SA, et al. Once weekly selinexor, carfilzomib and dexamethasone in carfilzomib non-refractory multiple myeloma patients. Br J Cancer. 2022;126(5):718-725. doi:10.1038/s41416-021-01608-2}

_{6. White DJ, Chen CI, Baljevic M, et al. Once weekly oral selinexor, pomalidomide, and dexamethasone in relapsed refractory multiple myeloma. Blood. 2021;138(suppl 1):2748. doi:10.1182/blood-2021-148759}

_{7. Lentzsch S, Lipe B, Tuchman SA, et al. Efficacy and safety of selinexor-containing regimens in patients with multiple myeloma previously treated with anti-cd38 monoclonal antibodies (αCD38 mAb). Blood. 2021;138(suppl 1):1651. doi:10.1182/blood-2021-150232}

_{8. Mo CC, Jagannath S, Chari A, et al. Selinexor for the treatment of patients with previously treated multiple myeloma. Exp Rev Hematol. 2021;14(8):697-706. doi:10.1080/17474086.2021.1923473}