Selinexor‐based regimens for the treatment of myeloma refractory to chimeric antigen receptor T cell therapy

Chari, Ajai; Vogl, Dan T.; Jagannath, Sundar; Jasielec, Jagoda; Unger, Thaddeus J.; DeCastro, Andrew; Shah, Jatin J.; Kauffman, Michael; Shacham, Sharon; Jakubowiak, Andrzej

doi:10.1111/bjh.16550

Cited by 13 publications

(14 citation statements)

References 14 publications

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“…The response rates with these triplets can range from approximately 50-80% and toxicities are those seen with the individual agents. Of note, the responses in the post CAR-T setting have been validated in other patients who had responses with selinexor containing triplet regimens, with remissions lasting nearly as long as their CAR-T remissions [44].…”

Section: Selinexor In Multiple Myeloma (Mm)mentioning

confidence: 96%

Targeting Nuclear Export Proteins in Multiple Myeloma Therapy

2020

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Multiple myeloma (MM) is an incurable malignancy of plasma cells with a clinical course characterized by multiple relapses and treatment refractoriness. While recent treatment advancements have extended overall survival (OS), refractory MM has a poor prognosis, with a median OS of between 4 and 6 months. Nuclear export inhibition, specifically inhibition of CRM1/ XPO1, is an emerging novel treatment modality that has shown promise in treatment-refractory MM. Initially discovered in yeast in 1983, early clinical applications were met with significant toxicities that limited their utility. The creation of small molecule inhibitors of nuclear export (SINE) has improved on toxicity limitations and has led to investigation in a number of malignancies at the preclinical and clinical stages. Preclinical studies of SINEs in MM have shown that these molecules are cytotoxic to myeloma cells, play a role in therapy resensitization, and suggest a role in limiting bone disease progression. In July 2019, selinexor became the first nuclear export inhibitor approved for use in relapsed/refractory MM based on the STORM trial. As of May 2020, there were eight ongoing trials combining selinexor with standard treatment regimens in relapsed/refractory MM. Eltanexor, a second-generation SINE, is also under investigation and has shown preliminary signs of efficacy in an early clinical trial while potentially having an improved toxicity profile compared with selinexor. Results in ongoing trials will help further define the role of SINEs in MM.

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Section: Selinexor In Multiple Myeloma (Mm)mentioning

confidence: 96%

Targeting Nuclear Export Proteins in Multiple Myeloma Therapy

2020

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“…Intriguingly, combining them with CAR-T cells also achieved encouraging outcomes, with the improved cytotoxic activity and cytokine production of CAR-T cells (225,226). In particular, the recent clinical studies showed that the R/R MM patients resistant to anti-BCMA CAR-T cell therapy could also benefit from selinexor-based regimens and carfilzomib-based regimens (227,228), and a study reported that anti-BCMA CAR-T cell therapy combined with lenalidomide was effective in the R/R MM patients who had previously relapsed after anti-BCMA CAR-T cell therapy (229). Ibrutinib, a well-known Bruton's tyrosine kinase inhibitor, has been approved for the treatment of CLL and MCL.…”

Section: Improving Anti-tumor Efficacy Of Car-t Cell Therapy Through ...mentioning

confidence: 99%

CAR-T Cell Therapy in Hematological Malignancies: Current Opportunities and Challenges

et al. 2022

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Chimeric antigen receptor T (CAR-T) cell therapy represents a major breakthrough in cancer treatment, and it has achieved unprecedented success in hematological malignancies, especially in relapsed/refractory (R/R) B cell malignancies. At present, CD19 and BCMA are the most common targets in CAR-T cell therapy, and numerous novel therapeutic targets are being explored. However, the adverse events related to CAR-T cell therapy might be serious or even life-threatening, such as cytokine release syndrome (CRS), CAR-T-cell-related encephalopathy syndrome (CRES), infections, cytopenia, and CRS-related coagulopathy. In addition, due to antigen escape, the limited CAR-T cell persistence, and immunosuppressive tumor microenvironment, a considerable proportion of patients relapse after CAR-T cell therapy. Thus, in this review, we focus on the progress and challenges of CAR-T cell therapy in hematological malignancies, such as attractive therapeutic targets, CAR-T related toxicities, and resistance to CAR-T cell therapy, and provide some practical recommendations.

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“…An evaluation of Xd plus carfilzomib or bortezomib in patients with rapidly progressing MM after undergoing CAR-T therapy has been reported [58]. While the study was small, results suggest that XKd or XVd may offer therapeutic benefit for these patients who have exhausted available treatment options.…”

Section: Xd + Pi After Car T-cell Failurementioning

confidence: 99%

“…Importantly, the most common non-hematologic toxicity of selinexor -fatigue -is generally a problem of tolerability but not safety in the way that the vital organ toxicities seen with other MM agents are more a matter of safety. Given the BOSTON results with the convenient once weekly XVd regimen, the NCCN listings for XVd, the all-oral XPd regimen and once weekly XDd regimen [68,69] and the use of once weekly XKd [70,71], the future use of selinexor is likely in the well-tolerated and highly synergistic multi-drug combinations, which utilize less frequent but still-efficacious dosing. The substantially lower rates of both hematologic and non-hematologic toxicity seen across the multiple arms of STOMP, as well as the confirmatory data of BOSTON, are both reassuring and encouraging in terms of tolerability and therapeutic potential.…”

Section: Expert Opinionmentioning

confidence: 99%

Selinexor for the treatment of patients with previously treated multiple myeloma

Jagannath

Chari

et al. 2021

Expert Review of Hematology

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Introduction: Multiple myeloma (MM) is an increasingly treatable but still incurable hematologic malignancy. Prognosis has improved significantly over recent years, although further advances remain urgently needed, especially for patients with heavily pre-treated and resistant disease for whom there are limited options. Selinexor is a first-in-class, oral, selective inhibitor of nuclear export (SINE) compound that triggers apoptosis in malignant cells by inducing nuclear retention of oncogene messenger RNAs (mRNAs) and reactivation of tumor suppressor proteins (TSPs). In clinical studies of patients with relapsed and/or refractory MM, selinexor has demonstrated both manageable toxicity and encouraging efficacy.Areas covered: This review will provide an overview of the mechanism of action of selinexor as well as the efficacy and safety data from clinical studies using selinexor for the treatment of multiple myeloma. Expert opinion: Long-term outcomes for patients with MM will continue to improve due to numerous recent and imminent therapeutic advances, although critical areas of unmet need remain. Oral selinexor is likely to contribute to the meeting of these needs and the further advancement of MM therapy in a meaningful way.

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Selinexor‐based regimens for the treatment of myeloma refractory to chimeric antigen receptor T cell therapy

Cited by 13 publications

References 14 publications

Targeting Nuclear Export Proteins in Multiple Myeloma Therapy

Targeting Nuclear Export Proteins in Multiple Myeloma Therapy

CAR-T Cell Therapy in Hematological Malignancies: Current Opportunities and Challenges

Selinexor for the treatment of patients with previously treated multiple myeloma

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