Using Novel Mechanisms of Action as Myeloma CAR T Bridging Therapy

Selecting bridging therapy for chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma is an unanswered question with no single preferred regimen. Beyond ruling out therapies that could interfere with the administration of CAR T cells, hematologists have multiple options. However, using agents with a novel mechanism of action not yet tried against the disease is considered a reasonable approach, as was discussed by Binod Dhakal, MD, associate professor of medicine at the Medical College of Wisconsin, during a live Case-Based Roundtable event in Salt Lake City, Utah.

Dhakal described the basis for using 2 particular agents that would otherwise be used in later lines of therapy: selinexor (Xpovio) and talquetamab (Talvey). Data from a small number of patients in each case show that patients who receive these agents can successfully be bridged to CAR T-cell therapy and achieve lasting disease remission.

This is the second of 2 parts. Read part 1.

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Targeted Oncology: What is the basis for using selinexor as bridging therapy?

Binod Dhakal, MD: Selinexor is an XPO1 inhibitor. XPO1 is overexpressed in cancer cells, and the nuclear export of the tumor suppressor protein is expressed through XPO1; the tumor suppressor proteins are excluded from nuclear circulation into the cytoplasm, and that minimizes and decreases the level of tumor suppressor proteins in the nucleus.¹ Selinexor blocks that XPO1 pathway and can increase the accumulation of the tumor suppressor protein in the nucleus. That’s why selinexor has increased efficacy, as it can get into cancer cells.

Right now, it is currently approved for adult patients with bortezomib [Velcade] and dexamethasone, in patients with at least 1 prior therapy, based on the BOSTON study [NCT03110562], and the late-line approval is based on the study [STORM (KCP‐330‐012; NCT02336815)] which looked at selinexor and dexamethasone combination with at least 4 prior therapies after exposed to everything and refractory to 2 proteasome inhibitors, 2 immunomodulatory agents, and anti-CD38 antibody—a very late relapsed patient population.²

However, for selinexor as bridging therapy: you use selinexor because of the different mechanism of action. Could it have impacted the T cells? We don’t have large-scale data, but we have mechanistic rationale and small-scale data that it doesn’t impair the T-cell fitness.³ You can increase the activation of T cells: for example, increase the CD8 and granzyme B expression.^3,4 That is a potential mechanistic basis for using selinexor to as a bridging therapy.

In 45 heavily treated patients, selinexor was given prior to BCMA [B-cell maturation antigen]–directed CAR T, and doesn’t seem to impact the CAR T outcomes, because you want to make sure that you don’t want to use something that can impact the CAR T outcomes.⁵ This is something that needs to be considered as a potential holding therapy.

What data support using talquetamab as bridging therapy?

Talquetamab…is a different class of drug; it is a bispecific antibody. It targets the antigen called GPRC5D which is an orphan receptor that is present in almost all plasma cells.⁶ This is the [research] that we were able to do using the multicenter retrospective study, where we used talquetamab bridging before CAR T: 34 patients were included in the analysis, almost 89% of patients underwent CAR T.⁷ These patients are very heavily treated, to a point that you would think twice before you give CAR T. Before talquetamab, we didn’t have a lot of good options for these patients. The fact that we [gave] talquetamab and almost 90% are able to go to CAR T is remarkable.

Most of the patients responded to talquetamab, 71%, and after they received the CAR T, 88% responded to CAR T, and more than half were in complete response or better. Toxicities related to talquetamab were manageable. There are many grade 1 and 2 cytokine release syndrome [CRS] and immune effector cell–associated neurotoxicity syndrome [ICANS] toxicities. Talquetamab-related toxicities also went down [in severity] and resolved at the time of the last follow-up.

Talquetamab has T-cell directed toxicities, and there are GPRC5D-related toxicities. Both could be a concern, especially if you’re using this for the long term. But here, with a short duration of talquetamab, you have those toxicities but they go away after the longer follow-up.

Similarly, in the patients with high disease burden, if you debulk the disease, we stabilize the disease, and that’s why you don’t see lot of CAR T–related toxicities as well. There were not high rates of high-grade CRS or high-grade ICANS, and also, they resolved quickly.

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_{DISCLOSURES: Dhakal previously reported being a member of advisory boards for Janssen Pharmaceuticals, Bristol Myers Squibb, Kite Pharma, Arcellx, Sanofi, Pfizer, Karyopharm, Menarini, Genentech, and Legend Biotech, and received consulting fees from Genentech, Pfizer, and Legend.}

REFERENCES

1. XPOVIO® (selinexor) mechanism of action for MM. XPOVIO HCP. Karyopharm Therapeutics Inc. Accessed January 28, 2026. https://tinyurl.com/yc2v3apa

2. Xpovio. Prescribing information. Karyopharm Therapeutics Inc; 2025. Accessed May 11, 2026. https://tinyurl.com/y8vz238m

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

4. Khouri J, Sborov D, Rossi A, et al. Focusing on selinexor for holding and bridging prior to CAR-T in relapsed/refractory multiple myeloma. J Clin Med. 2025;14(12):4071. Published 2025 Jun 9. doi:10.3390/jcm14124071

5. Costa BA, Dima D, Mark T, et al. Impact of prior selinexor exposure on outcomes of chimeric antigen receptor t-cell therapy for relapsed/refractory multiple myeloma: an exploratory analysis. J Clin Med. 2025;14(4):1316. doi:10.3390/jcm14041316

6. Cho SF, Yeh TJ, Anderson KC, Tai YT. Bispecific antibodies in multiple myeloma treatment: A journey in progress. Front Oncol. 2022;12:1032775. doi:10.3389/fonc.2022.1032775

7. Dhakal B, Akhtar OS, Fandrei D, et al. Sequential targeting in multiple myeloma: talquetamab, a GPRC5D bispecific antibody, as a bridge to BCMA CAR-T therapy. Blood. 2025;146(17):2063-2072. doi:10.1182/blood.2025029773