Considering Ways to Optimize Weekly Selinexor Dosing for Myeloma

Jack Khouri, MD

Assistant Professor

Cleveland Clinic Lerner College of Medicine

Case Western Reserve University

Cleveland, OH

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

CASE SUMMARY

• Mike is a 60-year-old man diagnosed with IgG-κ multiple myeloma; 60% plasma cells; translocation 14;20
• Medical history: hypertension controlled with lisinopril
• He previously received:
  • Daratumumab (Darzalex), bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone; autologous stem cell transplant; and lenalidomide maintenance with a complete response (CR); time to relapse of 5.5 years.
  • Daratumumab, carfilzomib (Kyprolis), dexamethasone; achieved a CR lasting for 13 months, treated for 15 months total
• After receiving CAR (chimeric antigen receptor) T-cell therapy for 16 months and achieving a stringent CR, Mike’s disease relapsed.
• Mike, his wife, and his oncologist met to discuss his treatment options now that he has relapsed for the third time.

Targeted Oncology^TM: What are some of the approved options for Mike after 3 lines of therapy?

Jack Khouri, MD: The main approval for selinexor [Xpovio] comes from the BOSTON study [NCT03110562] that looked at early relapsed multiple myeloma. This was for those at first relapse to third relapse, and patients were randomly assigned to either bortezomib/dexamethasone [Vd] or selinexor/bortezomib/dexamethasone [SVd]. The primary end point was PFS [progression-free survival], which is common in these relapse/refractory myeloma studies.

How did patients with early relapsed multiple myeloma do on the BOSTON trial in terms of efficacy and safety?

If you look at the Kaplan-Meier curves, the PFS was better with SVd vs Vd [median PFS, 13.93 vs 9.46 months, respectively (HR, 0.70; 95% CI 0.53-0.93; P = .0075)].¹ The drug here was given weekly at a dose of 100 mg for selinexor. Many know that the initial study [STORM (NCT02336815)] investigators gave the drug twice weekly and the dose was high; a lot of patients had toxicities.² It caused anorexia, low appetite, weight loss, nausea, and diarrhea, so a lot of gastrointestinal and constitutional adverse events [AEs], which is why in BOSTON the drug was modified from 80 mg twice a week to 100 mg once a week. It did seem to be better tolerated.¹

If you look at the AEs, they were better when the drug was given once weekly. The fatigue was still considerably high, but it was better than when it was given weekly. Again, nausea, diarrhea, and cytopenias were seen. Hyponatremia is something that I see. It's a syndrome of inappropriate antidiuretic hormone [SIADH] picture with this drug.

It's important to control the nausea with selinexor when you use it, so what I try to do is I put the patients on 2 antiemetics. I put them on olanzapine [Zyprexa] every day. If they're on it at that time, I asked them to take at least 5 mg of olanzapine every day, and then ondansetron [Zofran] as needed. Many people's nausea gets controlled with this regimen. Usually the patients are on dexamethasone with this, [and] I always ask them to take the dexamethasone before their selinexor that day. So that's enough, that's a third antiemetic that helps with the nausea that comes with it.

What is some advice you would give for managing AEs with SVd?

With the first cycle, patients tend to have a lot of AEs. If you manage them well during the first cycle, the second cycle and beyond are definitely better. Patients do adapt to it, and their AE profile gets better on this drug. A lot of them get dehydrated the first cycle, because they're not eating or drinking much, so we bring them in for intravenous hydration. We start it high and lower the dose if they can't tolerate it. If there's hyponatremia, I give them salt tablets. It's very similar to an SIADH [problem]. Whenever I see hyponatremia, I start them on that, and I tell them to eat more salty foods and crackers and so forth. But if you can manage to make sure patients are tolerating the first cycle, they manage to do OK with the second cycle and beyond. That's important to get them through that first cycle.

CASE UPDATE

After discussing the various options available to him, Mike and his oncologist decided to proceed with selinexor, pomalidomide [Pomalyst], and dexamethasone (SPd) allow time between subsequent B-cell maturation antigen–directed therapies

Which selinexor combinations may have been relevant for this patient’s treatment?

The STOMP study [NCT02343042] showed selinexor in different combinations. The BOSTON study was with bortezomib—this one had different cohorts, and each cohort gave the drug with a different plasma cell–directed agent. It was given here with lenalidomide, with pomalidomide, with bortezomib, carfilzomib, or with daratumumab. If you look at the numbers, the best responses and the best PFS were seen with carfilzomib,³ which is why, if someone is willing to come for infusions and I want to give selinexor to them, I prefer to combine it with carfilzomib.... I tend to start low [for dosing] to see how they tolerate because carfilzomib can cause nausea and with selinexor, you have to be careful with the nausea. Then, if they do well, I can increase the dose of either the carfilzomib or the selinexor, but that's a good combination that I try to use every once in a while.

The dosing again, is always once a week. Although the initial label was twice-a-week dosing, we always do once a week now; it's better tolerated. With pomalidomide, I usually start at 40 or 60 mg of selinexor, and with carfilzomib either 60 or 80 mg of selinexor. The main reason for that is pomalidomide can cause cytopenia, so thrombocytopenia and neutropenia, more so than the other plasma cell agents, and selinexor can cause thrombocytopenia and neutropenia. So we do see more cytopenias with the combination of selinexor and pomalidomide, which is why we tend to start a little bit lower on the selinexor when combined with pomalidomide.... It's trial and error, you start the patient and then based on how they feel, you can lower or increase the dose.

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. 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

3. Schiller GJ, Lipe BC, Bahlis NJ, et al. Selinexor-based triplet regimens in patients with multiple myeloma previously treated with anti-CD38 monoclonal antibodies. Clin Lymphoma Myeloma Leuk. 2023;23(9):e286-e296.e4. doi:10.1016/j.clml.2023.06.001