Age, Disease Burden Are Factors in Early Use of Selinexor in Multiple Myeloma

Jonathan L. Kaufman, MD

David Bankes Glass Multiple Myeloma Professorship

Professor, Department of Hematology and Medical Oncology

Emory University School of Medicine

Medical Director and Section Chief, Ambulatory Infusion Centers

Winship Cancer Institute of Emory University

Atlanta, GA

CASE SUMMARY

• A 76-year-old man was diagnosed 5 years ago with multiple myeloma (IgG-kappa)​
• Hypertension well controlled with lisinopril​.
• He noticed a progressive decline in his stamina, and now presents to his physician with bone pain and fatigue​.
• Serum free light chain lambda at diagnosis was 8842 mg/L​
• Standard risk by fluorescence in situ hybridization​
• ECOG performance status of 1; IMWG (International Myeloma Working Group) Frailty Status: Intermediate-Frail​
• Based on age and risk status, transplant is not preferred for this patient​.
• He received daratumumab (Darzalex), lenalidomide (Revlimid), and dexamethasone (DRd) with a complete response​.

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Three years later​

• He reports increasing fatigue and bone pain when having his annual check-up with his oncologist​.
• PET scan – shows uptake in multiple bony lesions on ribs and femur​.
• The patient wishes to continue therapy and is interested to hear what options remain​.

DISCUSSION QUESTIONS

• In patients with newly diagnosed multiple myeloma not eligible for transplant, how should we sequence therapies?​​
• Is it better to use DRd first and choose the second-line therapy based on whether the patient is refractory to bortezomib (Velcade) or lenalidomide?

LOUAY HANNA, MD: What about selinexor [Xpovio], bortezomib, and dexamethasone [XVd]? We have strong data in the second line, especially if this patient needs [therapy for] high disease burden.¹ You want some completely new mechanism of action. I would think XVd might be a better option. But if this patient had soft relapse on 10 mg of lenalidomide, I wouldn’t say they’re completely resistant to IMiD [immunomodulatory imide drug]. So maybe they could receive carfilzomib [Kyprolis] and pomalidomide [Pomalyst] or bortezomib plus dexamethasone, or lenalidomide, bortezomib, and dexamethasone.

JONATHAN L. KAUFMAN, MD: I’m glad you mentioned bortezomib, selinexor, and dexamethasone…. [The BOSTON trial (NCT03110562)] is exactly the one that you mentioned. There are a lot of phase 3 data in this situation but this is one of the trials that was not talked about.

MAURIZIO BENDANDI, MD: Why does this patient have heavy tumor burden on relapse? I would expect the disease not to be explosive, since he was on DRd…. I don’t know that I would engage in selinexor in a 79-year-old patient who most likely is going to have GI [gastrointestinal] toxicity. I understand they’re 2 different mechanisms of action, [but] selinexor is not an easy medication.

SHEBLI ATRASH, MD: Selinexor dosed at 160 mg a week, meaning 80 mg twice a week, got the reputation of nausea, vomiting, and GI problems [in the STORM trial (NCT02336815)].² I can tell you [that with] a dose of 40 mg a week or 60 mg a week, you still get great efficacy with very minor GI toxicity.

KAUFMAN: I say this all the time—we learn so much more about a drug after the drug is approved. [The BOSTON] study used selinexor weekly, continuous dosing every week at 100 mg. But exactly what Dr Atrash said, we don’t use 100 mg every week; we use 40 mg to 60 mg for 3 out of 4 weeks. We don’t have randomized data [comparing dose levels], but I’m able to maintain efficacy. This study in this similar patient population [showed benefit of] bortezomib, selinexor, and dexamethasone vs bortezomib and dexamethasone [Vd].¹

BENDANDI: But how many patients in this study were [aged] 79? Even reduced-dose selinexor, at [the age of] 79, is not an easy medication in my opinion.

KAUFMAN: Let’s say the patient is aged 75, or they started when they’re 70 and now they’re 75. Or a patient was transplanted and was progressing was on the PERSEUS [NCT03710603] regimen 2 or 3 years later on daratumumab/lenalidomide. There would be a variety of agents that could come in.

BENDANDI: I started using selinexor [soon] after it was approved in the second line with bortezomib, but for [a patient aged] 79, it’s not easy.

KAUFMAN: No, we agree. [In terms of the outcomes with BOSTON], there was benefit in the primary [end point] with a statistically significant, clinically significant 4-month improvement in progression-free survival [(PFS) 13.93 months median with XVd vs 9.46 with Vd], but I don‘t think these are the key data.¹

There was a somewhat higher [objective] response rate: 76% [with XVd] vs 62% with Vd. The median duration of response is 20 months vs 13 months, respectively. In 76% of patients [treated with XVd], you‘re looking at a year and a half of benefit. [Although] we don’t have the [subgroup data] for the older patient population [of 75 or older], for those patients who hadn‘t had a prior proteasome inhibitor [PI], there was a 30-month [median PFS with selinexor] vs 10 months [without it]. It looks like there’s something there because that’s the key with these patients who we’re seeing now with the DRd. These are very small numbers, less than 50 patients in each arm [with no prior PI], but that looks good.

If you’ve ever used selinexor, there’s hematologic toxicity and non-hematologic toxicity. [I believe] 100 mg is not the right dose once a week. I don’t think 80 mg is the right dose; I think it’s somewhere between 40 mg and 60 mg, and I typically give it 3 out of 4 weeks. That’s been my approach for how I use this medication.

Patient selection is critical here. For a frail 79-year-old, maybe [they should not be selected, but it could be used in] a fit younger patient who is refractory to daratumumab and lenalidomide, and maybe a patient [who] hasn’t seen a PI for whatever reason. This patient hasn’t seen a PI…and I agree they need a PI.

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