Examining the Strongest Options for Heavily Pretreated Myeloma After Bispecific Therapy

For patients who have received multiple lines of T-cell redirecting therapy, cycling through one bispecific antibody and then another, the treatment decision in the next relapse raises a question the field has not fully resolved: if T cells have been continuously engaged and possibly exhausted over months of bispecific exposure, what is left to work with, and which agents offer the best probability of disease control in a patient who is older, transplant ineligible, and unwilling to pursue CAR T?

In a live Case-Based Roundtable event for oncologists in Orlando, Florida, Sikander Ailawadhi, MD, professor of medicine and chair of hematology at Mayo Clinic in Florida, used a second patient case to explore the post-bispecific treatment landscape and discussed the practical role of belantamab mafodotin (Blenrep) and selinexor (Xpovio)-based regimens in late relapsed multiple myeloma.

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This is part 2 of a 2-part series. Read part 1.

CASE 2 SUMMARY

• The patient is an 82-year-old woman with relapsed/refractory multiple myeloma who presents to clinic to discuss her next treatment options after several lines of therapy.
• ECOG performance status 2; ISS III/Revised ISS II; standard/intermediate risk cytogenetics.
• She has been deemed transplant ineligible. She prefers to minimize time spent in the hospital and reduce the need for frequent travel to the infusion center. Because her commute to the academic center is over an hour each way, she would like to receive therapy closer to home. She would prefer to not receive CAR T.
• Treatment history: daratumumab (Darzalex), lenalidomide (Revlimid), and dexamethasone (Dara-Rd) to complete response (CR) (February 2024) → relapse (December 2024) → carfilzomib (Kyprolis), pomalidomide (Pomalyst), and dexamethasone (KPd) to very good partial response (VGPR) (March 2025) → disease progression → daratumumab-teclistamab (Tecvayli) on trial (Dara-Tec) to CR (September 2025) → talquetamab (Talvey) to VGPR → disease progression (January 2026)

EVENT RECAP

Ailawadhi noted that the clinical situation in this case is qualitatively different from the one facing early relapsed patients being considered for CAR T. This patient has received 2 successive T-cell redirecting therapies, a B-cell maturation antigen (BCMA)-targeting bispecific followed by a GPRC5D-targeting bispecific, and has disease that progressed through both. Ailawadhi told the group that, in this setting, he would not pursue CAR T. Continuous bispecific use can deplete and exhaust T cells; a patient who has been on this trajectory for months may not have T cells that can be collected in adequate numbers or that will expand effectively after manufacturing and be effective.

The poll reflected uncertainty in the group about what to reach for instead. Approximately 45.5% of participants chose a belantamab mafodotin-based regimen, 36.4% chose a selinexor-based regimen, and 18.2% chose rechallenge with a BCMA-targeting bispecific. No participants chose an isatuximab (Sarclisa)-based regimen.

Ailawadhi framed the appeal of belantamab mafodotin in mechanistic terms. As an antibody-drug conjugate (ADC) targeting BCMA, belantamab mafodotin does not rely on T-cell engagement to kill tumor cells; the cytotoxic payload is delivered directly. In a patient whose T cells may be exhausted from prolonged bispecific use, this mechanistic independence is clinically relevant.¹ However, he told the group that he conditions any decision to retarget BCMA on evidence that the antigen is still present. At his institution, marrow samples are sent for BCMA immunohistochemical staining before any BCMA-directed rechallenge, a step he acknowledged is not standard practice outside academic centers and is not commercially available in most community settings. He said any soluble BCMA positivity is generally considered sufficient by current conventions, though the field continues to evolve on this point.

For those who chose a bispecific rechallenge, Ailawadhi noted the logic but added a caution. Switching from talquetamab to teclistamab or elranatamab (Elrexfio) could make sense if BCMA expression is confirmed and the patient has been off BCMA-directed therapy long enough, but the trajectory of disease through both target classes in rapid succession makes him skeptical. International Myeloma Working Group (IMWG) and NCCN guidelines indicate that reexposure to a drug class can be considered after at least 1 intervening line or after 6 months of benefit, and that patients may receive more than 1 BCMA-directed therapy sequentially, but an immediate switch to a second BCMA-directed agent after the first has failed is associated with lower response rates.²

For selinexor-based regimens, the data Ailawadhi reviewed support their utility in patients who have exhausted BCMA and GPRC5D options and need a mechanism that bypasses both T-cell engagement and antigen dependence. He first summarized the STORM trial (NCT02336815), which enrolled 123 patients treated with selinexor at 80 mg twice weekly plus dexamethasone, with a median of 7 prior lines of therapy, showing an overall response rate (ORR) of 26%, a median progression-free survival (PFS) of 3.7 months, and a median overall survival of 8.6 months.³ STORM established proof of concept in a population with extremely limited options, but it used a higher dose of selinexor than in newer trials. Grade 3 or higher adverse events occurred in 95% of patients and grade 5 events in 10%, a toxicity burden he attributed largely to the twice-weekly schedule.

Subsequent trials showed that XPO1 inhibition at lower, less frequent doses produces better tolerability without sacrificing efficacy when used in combination. The BOSTON trial (NCT03110562) enrolled 195 patients treated with selinexor-bortezomib-dexamethasone (SVd) at 100 mg weekly with a median of 1 prior line of therapy, achieving an ORR of 76%, a median PFS of 13.9 months, and a median duration of response of 20.3 months. Ailawadhi told the group he gives approximately 80 mg weekly in practice and uses selinexor-carfilzomib-dexamethasone (SKd) as his most common late-line combination.

The all-oral option of selinexor-pomalidomide-dexamethasone (SPd) is particularly relevant for a patient who wants to minimize infusion center visits. STOMP trial (NCT02343042) data on once-weekly SPd dosing showed an ORR of 50% at 40 mg selinexor weekly (n = 28) and 65% at 60 mg (n = 20) in patients with a median of 2 prior lines of therapy.⁴ Median PFS was 18.4 months in the 40-mg cohort and 9.5 months in the 40-mg cohort. Duration of response was not reached in the 40-mg arm. Ailawadhi cautioned against reading the PFS advantage in the lower-dose arm as a direct efficacy signal; patients on 40 mg are more likely to remain on treatment because they tolerate it better, and that tolerability advantage drives the prolonged follow-up.

A practical discussion about selinexor adoption in community practice followed. Several participants cited concern about gastrointestinal (GI) toxicity, particularly nausea, decreased appetite, and weight loss, as a reason for hesitation. Ailawadhi acknowledged the reality of these concerns, which require proactive management: prophylactic ondansetron and olanzapine before each dose, with loperamide available for diarrhea and close attention to nutritional status and weight. He noted that myeloma physicians are becoming accustomed to managing unique toxicity profiles, such as ocular toxicity with belantamab mafodotin or skin and taste changes with talquetamab, and that selinexor’s GI profile is similarly manageable once the team builds experience with it. Starting at 40 mg weekly and titrating up is reasonable for frail or older patients; 60 to 80 mg weekly is the target range for most.

Polling results from the live event reflected participants’ treatment approach in late relapsed, heavily pretreated multiple myeloma:

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_{DISCLOSURES: Ailawadhi previously reported consultancy for Celgene, Amgen, Janssen and Takeda, and research funding from Pharmacyclics, Cellectar and Janssen.}

REFERENCES

1. Bertuglia G, Di Nicola A, Gay F, et al. Current positioning and future development of belantamab mafodotin and other antibody-drug conjugates to treat multiple myeloma. Front Oncol. 2026;16:1822419. doi:10.3389/fonc.2026.1822419

2. Costa LJ, Banerjee R, Mian H, et al. International myeloma working group immunotherapy committee recommendation on sequencing immunotherapy for treatment of multiple myeloma. Leukemia. 2025;39(3):543-554. doi:10.1038/s41375-024-02482-6

3. Baljevic M, Schiller G, Mark TM, Van Domelen DR, Gasparetto C. Lower dose and weekly schedules of selinexor in multiple myeloma - updated evidence on safety and efficacy. Front Oncol. 2025;15:1649493. Published 2025 Sep 22. doi:10.3389/fonc.2025.1649493

4. 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