Dosing and Toxicity Considerations for Heavily Pretreated Patients With Myeloma

Once a patient with relapsed/refractory multiple myeloma (RRMM) has cycled through an anti-CD38 antibody, a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and 2 classes of T-cell–redirecting therapy, and has decided against chimeric antigen receptor (CAR) T-cell therapy, the treatment menu narrows considerably. What remains is less a question of which drug is most active than which regimen a patient can actually tolerate and access close to home.

In a live Case-Based Roundtable event in Buffalo, New York, Brea Lipe, MD, clinical director of the Multiple Myeloma Program at the Wilmot Cancer Institute, University of Rochester Medical Center, reviewed late-relapse treatment options and moderated discussion of a case built around an older patient who had already exhausted most standard mechanisms of action.

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Read part 1 from this roundtable event.

CASE SUMMARY

• The patient is an 82-year-old woman with relapsed/refractory multiple myeloma after several lines of therapy.
• ECOG performance status, 2; International Staging System (ISS), III/Revised ISS, II; standard/intermediate-risk cytogenetics
• Deemed transplant ineligible
• Prefers to minimize hospital time and travel; would prefer not to receive CAR T-cell therapy
• Treatment history:
  • Daratumumab (Darzalex), lenalidomide (Revlimid), dexamethasone (Dara-Rd): complete response, followed by relapse
  • Carfilzomib (Kyprolis), pomalidomide (Pomalyst), and dexamethasone (KPd): very good partial response (VGPR), followed by disease progression
  • Daratumumab plus teclistamab (Tecvayli) on clinical trial: complete response, followed by relapse
  • Talquetamab (Talvey): VGPR, followed by disease progression, now presenting for further therapy

EVENT RECAP

After disease progression on bispecifics for both established targets, 2 IMiDs, and an anti-CD38 antibody, this patient has few truly novel mechanisms left to address their disease. When Lipe polled the particiapnts on next steps, 85.7% chose a selinexor (Xpovio)-based regimen over rechallenging a BCMA-targeted bispecific, starting belantamab mafodotin (Blenrep), or using an isatuximab (Sarclisa)-based combination. Lipe agreed with the group’s leanings and flagged an important caveat about the belantamab mafodotin plus bortezomib (Velcade) regimen: its signature toxicity is ocular, ranging from blurry vision to vision loss, a trade-off that could be especially difficult for an 82-year-old for whom watching television or reading may be one of the few remaining joys. She considered rechallenge with a prior bispecific to also be a weaker option here, because data suggest sequencing multiple T-cell engagers one after another tends to underperform, likely because the first exposure has already reduced T-cell fitness.

Lipe examined the evolution of selinexor and its dosing approaches. The STORM trial (NCT02336815) that won selinexor's original accelerated approval dosed it at 80 mg twice weekly in combination with dexamethasone, producing a 26% response rate but a 10% rate of grade 5 adverse events, which Lipe said was simply too toxic to use.¹

The BOSTON trial (NCT03110562), which added bortezomib and gave 100 mg selinexor once weekly, resulted in a 76% response rate and median progression-free survival (PFS) of 13.9 months, but Lipe still said she considers 100 mg too aggressive outside of a clinical trial.² In her own practice, she caps selinexor at 60 mg weekly, a dose informed by the phase 1b/2 STOMP trial (NCT02343042), which she worked on: in a once-weekly selinexor-pomalidomide-dexamethasone (SPd) comparison, the lower 40 mg dose produced a longer median PFS than the 60 mg dose, 18.4 months vs 9.5 months,³ likely reflecting better tolerability and fewer dose interruptions rather than a true biological advantage for less drug. Selinexor-based triplets after prior anti-CD38 exposure retain meaningful activity across all 3 backbone partners, with SKd showing the longest median PFS at 15.0 months in that setting, though cross-trial comparisons should be read cautiously given the small sample sizes.⁴

Lipe discussed the mechanistic appeal of selinexor as an oral inhibitor of exportin 1 (XPO1), a nuclear export protein overexpressed in myeloma cells that normally shuttles tumor suppressor proteins out of the nucleus and into the cytoplasm, where they cannot function. By blocking that export, selinexor traps tumor suppressors inside the nucleus, triggering cell cycle arrest and apoptosis, a mechanism entirely distinct from the proteasome inhibitors, IMiDs, and CD38 or BCMA-directed antibodies this patient had already cycled through.⁵ As this patient’s disease was not refractory to the backbone partners used in STOMP, the patient could be given a better chance at remission despite their challenging case of myeloma.

Tolerability determines whether a patient stays on selinexor long enough to benefit. Fatigue, nausea, and anorexia are the most common limiting toxicities, and Lipe described being aggressive about upfront antiemetic prophylaxis, using ondansetron and prochlorperazine routinely and reaching for olanzapine in select patients, reasoning that preventing an adverse reaction to a first dose is easier than helping a patient recover from it.

When it comes to other late-line therapies, Lipe noted that although she has seen less efficacy from ixazomib (Ninlaro), she believes it was underdosed in early clinical trial usage. She said she avoids bendamustine even as a last resort due to poor experiences in patients with myeloma. Selinexor-based treatment’s oral administration and preserved T-cell fitness leave later options open, including a delayed CAR T-cell therapy referral if the patient's goals change.

Lipe closed by raising a point she felt the field underdiscusses: for an 82-year-old who has already failed 2 bispecific classes, continuing to escalate therapy is not automatically the right answer, and a conversation about goals of care, including hospice, belongs alongside any discussion of the next regimen.

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DISCLOSURES: Lipe previously reported consulting or advisory roles with Bristol Meyers, Janssen Oncology, Karyopharm Therapeutics, Sanofi, Pfizer; and institutional research funding from Janssen, Cellectar, Karyopharm Therapeutics, Celgene, Amgen, and Seagen.

REFERENCES

1. 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

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. White D, Schiller GJ, Madan S, et al. Efficacy and safety of once weekly selinexor 40 mg versus 60 mg with pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Front Oncol. 2024;14:1352281. Published May 17, 2024. doi:10.3389/fonc.2024.1352281

4. 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

5. Kang Y, Neff JL, Ellero A, et al. Selinexor-based treatments are associated with increased expression of T-cell activation markers in multiple myeloma. Blood Immunol Cell Ther. 2025;1(3):100009. doi:10.1016/j.bict.2025.100009