selinexor and Multiple-Myeloma

Selinexor is a novel XPO1 inhibitor which inhibits the export of tumor suppressor proteins and oncoprotein mRNAs, leading to cell-cycle arrest and apoptosis in cancer cells. While selinexor is currently FDA approved to treat multiple myeloma, compelling preclinical and early clinical studies reveal selinexor's efficacy in treating hematologic and non-hematologic malignancies, including sarcoma, gastric, bladder, prostate, breast, ovarian, skin, lung, and brain cancers. Current reviews of selinexor primarily highlight its use in hematologic malignancies; however, this review seeks to summarize the recent evidence of selinexor treatment in solid tumors.. Pertinent literature searches in PubMed and the Karyopharm Therapeutics website for selinexor and non-hematologic malignancies preclinical and clinical trials.. This review provides evidence that selinexor is a promising agent used alone or in combination with other anticancer medications in non-hematologic malignancies.. Further clinical investigation of selinexor treatment for solid malignancies is warranted.

Topics: Active Transport, Cell Nucleus; Antineoplastic Agents; Cell Line, Tumor; Humans; Hydrazines; Karyopherins; Male; Multiple Myeloma; Triazoles

Selinexor [Nexpovio. Despite the availability of several drug classes, relapse and refractoriness is common in multiple myeloma. Selinexor [Nexpovio

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Humans; Multiple Myeloma

Multiple myeloma (MM) remains an incurable disease despite advances in treatment options. Recently, selinexor has shown promising efficacy for relapsed/refractory multiple myeloma (RRMM), whereas its optimal timing and drug combination remain unclear. In order to assess the various regimens that incorporate selinexor, a systematic review and meta-analysis was conducted.. Clinical trials and real-world studies involving MM patients treated with selinexor were included. Pooled risk ratio (RR) was calculated to compare the rates, along with a 95% confidence interval (CI) and concurrent. A total of 16 studies enrolling 817 patients were reviewed. The usage of selinexor as the fifth-line or prior therapy achieved a higher objective response rate (ORR) (65.9% versus 23.4%,. In conclusion, using selinexor as the fifth-line or prior therapy had a beneficial impact on RRMM. The regimen of Xd plus PIs or IMiDs was recommended.

Topics: Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Drug Combinations; Humans; Immunomodulating Agents; Multiple Myeloma

Competent T-cells with sufficient levels of fitness combat cancer formation and progression. In multiple myeloma (MM), T-cell exhaustion is caused by several factors including tumor burden, constant immune activation due to chronic disease, age, nutritional status, and certain MM treatments such as alkylating agents and proteasome inhibitors. Many currently used therapies, including bispecific T-cell engagers, anti-CD38 antibodies, proteasome inhibitors, and CART-cells, directly or indirectly depend on the anti-cancer activity of T-cells. Reduced T-cell fitness not only diminishes immune defenses, increasing patient susceptibility to opportunistic infections, but can impact effectiveness MM therapy effectiveness, bringing into focus sequencing strategies that could modulate T-cell fitness and potentially optimize overall benefit and clinical outcomes. Certain targeted agents used to treat MM, such as selective inhibitors of nuclear export (SINE) compounds, have the potential to mitigate T-cell exhaustion. Herein referred to as XPO1 inhibitors, SINE compounds inhibit the nuclear export protein exportin 1 (XPO1), which leads to nuclear retention and activation of tumor suppressor proteins and downregulation of oncoprotein expression. The XPO1 inhibitors selinexor and eltanexor reduced T-cell exhaustion in cell lines and animal models, suggesting their potential role in revitalizating these key effector cells. Additional clinical studies are needed to understand how T-cell fitness is impacted by diseases and therapeutic factors in MM, to potentially facilitate the optimal use of available treatments that depend on, and impact, T-cell function. This review summarizes the importance of T-cell fitness and the potential to optimize treatment using T-cell engaging therapies with a focus on XPO1 inhibitors.

Topics: Animals; Cell Line, Tumor; Exportin 1 Protein; Humans; Multiple Myeloma; Proteasome Inhibitors; T-Lymphocytes

Multiple myeloma is currently incurable, and the incidence rate is increasing year by year worldwide. Although in recent years the combined treatment plan based on proteasome inhibitors and immunomodulatory drugs has greatly improved the treatment effect of multiple myeloma, most patients still relapse and become resistant to current treatments. To solve this problem, scientists are committed to developing drugs with higher specificity, such as iberdomide, which is highly specific to ikaros and aiolos. This review aims to focus on the small molecular agents that are being researched/clinically used for the treatment of multiple myeloma, including the target mechanism, structure-activity relationship and application prospects of small molecular agents.

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Combined Modality Therapy; Deubiquitinating Enzymes; Drug Development; Drug Resistance; Histone Deacetylases; Humans; Ikaros Transcription Factor; Immunomodulating Agents; Models, Molecular; Morpholines; Multiple Myeloma; Phthalimides; Piperidones; Proteasome Inhibitors; Treatment Outcome; Ubiquitin-Protein Ligases

Selinexor is a novel XPO1 inhibitor approved for patients with relapsed refractory multiple myeloma. When used as twice weekly dosing, selinexor is associated with significant toxicities, prohibiting its use in clinical practice. Newer combinations with other chemotherapeutic agents have evaluated less frequent and lower doses of Selinexor with aggressive supportive care. These novel combinations appear to have tolerable safety profiles while preserving drug efficacy, making Selinexor a reasonable option for patients with heavily pretreated relapsed refractory multiple myeloma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Hydrazines; Multiple Myeloma; Triazoles

In this review we highlight the most recent studies furthering the clinical development of selinexor, a novel exportin-1 inhibitor, for the treatment of multiple myeloma and non-Hodgkin lymphomas.. Three pivotal trials, the SADAL trial for diffuse large B-cell lymphoma, and the BOSTON and selinexor treatment of refractory myeloma trials for multiple myeloma, have recently led to the regulatory approval of selinexor monotherapy or combination regimens. They are complemented by several earlier phase clinical trials with iterative combinations, adding selinexor to novel therapies and cytotoxic chemotherapy regimens at various stages in the disease courses. In some, selinexor appears synergistic, occasionally overcoming treatment refractoriness, whereas in other situations appears additive. Consistent issues with tolerability are seen across trials, although consensus guidelines on their preemption and management have recently been adopted which may improve treatment success. While comparative data are lacking, the efficacy of selinexor-based regimens does not approach that of contemporaneous cellular and immunotherapies.. Selinexor is a novel and potentially synergistic therapy for lymphoid malignancies, although requires refined supportive measures and strategies to improve its efficacy. Likely, for continued success, it will need to identify niches that complement recent advances, such as bridging to cellular therapies or maintenance thereafter.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Hydrazines; Lymphoma, Non-Hodgkin; Multiple Myeloma; Triazoles

With the incorporation of novel agents in earlier lines of therapy, an increasing number of multiple myeloma patients are refractory to traditional classes of drugs. Selinexor in combination with dexamethasone has emerged as a viable option for heavily pretreated triple-class relapsed and refractory multiple myeloma (RRMM). In this systematic review, we analyzed available literature on the role of selinexor in RRMM. The Boston trial demonstrated that selinexor when combined with dexamethasone and bortezomib is associated with a better depth and duration of response without excessive toxicity, compared with bortezomib and dexamethasone alone. Similarly, selinexor in combination with carfilzomib and dexamethasone was found to have a durable response and tolerable safety profile in both carfilzomib-naive and carfilzomib refractory RRMM patients. Selinexor in combination with IMiDs (lenalidomide and pomalidomide) as well as CD38 monoclonal antibodies (daratumumab) also have promising results. Selinexor combination therapy is both safe and effective for patients with pretreated RRMM.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Humans; Multiple Myeloma; Neoplasm Recurrence, Local

Multiple myeloma (MM) is a hematologic malignancy of plasma cells that remains incurable with currently available therapies including proteosome inhibitors, immunomodulators, monoclonal antibodies, corticosteroids, and alkylators, in addition to autologous stem cell transplantation in patients who are eligible. Novel therapeutics are therefore required to improve patient outcomes. The goal of this paper is to review the role of three new agents in the MM treatment landscape: belantamab mafodotin, selinexor, and melflufen.. All three agents have demonstrated clinical activity in patients with MM. Belamaf is the first FDA-approved anti-BCMA targeted agent, showing single-agent response rates of 60% and higher response rates of 48-100% in combinations. The majority of patients treated with belamaf experience corneal toxicity which remains the main challenge with its use; however, fortunately, the vast majority of patients recover. Selinexor is also FDA approved for the treatment of relapsed MM, with single-agent response rates of 26% and combination rates of 48-65%. Gastrointestinal side effects are common with selinexor use, with roughly 65% of patients experiencing nausea, 50% anorexia, 35% vomiting, and 42% diarrhea, the majority of which are grades 1-2. Both agents have a plethora of ongoing clinical trials with data forthcoming on various combinations with standard backbone agents as well as additional novel treatments. While melflufen showed promising initial data showing single-agent response rates of about 30%, inferior survival outcomes in patients previously treated with ASCT in the phase 3 OCEAN study lead to early termination of the trial and subsequent removal from the US market. Belamaf, selinexor, and melflufen are active agents to treat myeloma. Belamaf and selinexor are current options for the treatment of relapsed multiple myeloma with improved response rates and durability when used in triplet combinations. The optimal timing of use and treatment combinations of both agents in the context of additional immunotherapeutics entering the MM landscape requires further study. Many prospective studies are in development and promise to afford further clarity in the near future.

Topics: Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, Follicular; Multiple Myeloma; Prospective Studies; Transplantation, Autologous

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.. 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.. 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.

Topics: Humans; Hydrazines; Karyopherins; Multiple Myeloma; Receptors, Cytoplasmic and Nuclear; Triazoles

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Humans; Hydrazines; Infections; Multiple Myeloma; Recurrence; Triazoles

Topics: Active Transport, Cell Nucleus; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Nucleus; Clinical Trials as Topic; Dexamethasone; Drug Evaluation, Preclinical; Exportin 1 Protein; Humans; Hydrazines; Karyopherins; Multiple Myeloma; Prognosis; Receptors, Cytoplasmic and Nuclear; Triazoles

Topics: Consensus; Humans; Hydrazines; Multiple Myeloma; Practice Guidelines as Topic; Triazoles

The progression of multiple myeloma is accompanied by complex cytogenetic and epigenetic alterations that include mutation or functional inactivation of tumor suppressor proteins and overexpression of oncoproteins. Patients whose myeloma is refractory to the three major classes of drugs including immunomodulatory agents, proteasome inhibitors and anti-CD38 monoclonal antibodies have a very poor prognosis. Drugs with novel mechanisms of action that can bypass resistance mechanisms are sorely needed for this group of patients. Selinexor represents a novel, oral agent with an innovative mechanism of action that offers a significant therapeutic advance in this group of heavily treated patients. Moreover, this novel mechanism may provide additional options for patients with less refractory disease.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Exportin 1 Protein; Humans; Hydrazines; Karyopherins; Multiple Myeloma; Receptors, Cytoplasmic and Nuclear; Survival Rate; Triazoles

Selinexor (XPOVIO™) is a first-in-class, oral, small molecule Exportin-1 (XPO1) inhibitor that is being developed by Karyopharm Therapeutics for the treatment of cancer. Selinexor (in combination with dexamethasone) received accelerated approval in the USA in July 2019 for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM). Selinexor is also undergoing clinical development in a wide range of haematological and solid cancers. This article summarizes the milestones in the development of selinexor leading to this first approval for RRMM.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Exportin 1 Protein; Humans; Hydrazines; Karyopherins; Multiple Myeloma; Receptors, Cytoplasmic and Nuclear; Triazoles

Multiple myeloma (MM) is a malignancy of plasma cells that is typically chronic, and relapse is common. Current therapeutic strategies include combination and sequential treatments with corticosteroids, alkylating agents, proteasomal inhibitors, immunomodulators, and monoclonal antibodies. These drugs prolong survival but ultimately become ineffective. Exportin 1 (XPO1), a nuclear export protein, is overexpressed in MM cells, and knockdown studies have suggested that XPO1 is essential for MM cell survival. Selective inhibitor of nuclear export (SINE) compounds are novel, orally bioavailable class of agents that specifically inhibit XPO1. Selinexor (KPT-330) is the first-in-human SINE compound. Early phase clinical trials have established the safety profile of this agent and have shown promising efficacy in combination with low-dose dexamethasone and other anti-MM agents. The combination of selinexor and dexamethasone has demonstrated activity in "penta-refractory" MM, (ie, MM refractory to the 5 most active anti-MM agents currently used in treatment). We have reviewed the available data on the molecular implications of XPO1 inhibition in MM. We also reviewed the pertinent early phase clinical data with SINE compounds and discuss management strategies for common toxicities encountered with use of selinexor.

Topics: Active Transport, Cell Nucleus; Antineoplastic Agents; Drug Resistance, Neoplasm; Exportin 1 Protein; Humans; Hydrazines; Karyopherins; Multiple Myeloma; Neoplasm Recurrence, Local; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Treatment Outcome; Triazoles

Despite significant progress in our understanding and the development of novel therapies, most patients with multiple myeloma will experience relapse of their disease. Therapy of relapsed myeloma has improved due to the availability of novel agents that are highly active against the disease. However, the selection of therapy can be challenging due to the emergence of toxicities, comorbidities and frailty. In the following we discuss our approach to the treatment of the patient with relapsed myeloma.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials, Phase III as Topic; Decision Making; Gene Expression Profiling; Humans; Hydrazines; Immunotherapy; In Situ Hybridization, Fluorescence; Multiple Myeloma; Neoplasm Recurrence, Local; Stem Cell Transplantation; Sulfonamides; Symptom Assessment; Transplantation, Autologous; Triazoles; Watchful Waiting

Despite the availability of various anticancer agents, Multiple Myeloma (MM) remains incurable in most cases, along with high relapse rate in the patients treated with these agents. The year 2015 saw major advancements in our battle against multiple myeloma. In 2015, the U.S. Food and Drug Administration (FDA) approved three new therapies for multiple myeloma, namely Ixazomib (an oral proteasome inhibitor), Daratumumab and Elotuzumab (monoclonal antibodies against CD38 and SLAMF7 respectively). The purpose of this review is to provide a detailed analysis of these aforementioned breakthrough therapies and two other newer agents, Filanesib (kinesis spindle inhibitor) and selinexor (SINE inhibitor), presented at the 2015 annual meeting of American Society of Hematology (ASH). We also describe the role of agents targeting PD-1 axis and chimeric antigen receptor T (CAR-T) cells in the treatment of MM.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Boron Compounds; Congresses as Topic; Glycine; Humans; Hydrazines; Molecular Targeted Therapy; Multiple Myeloma; Proteasome Inhibitors; Protein Kinase Inhibitors; Signal Transduction; Thiadiazoles; Treatment Outcome; Triazoles

Topics: Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Humans; Multiple Myeloma

Dose modifications in response to adverse events (AEs) can maintain tumor response and improve therapy tolerability. We conducted a post-hoc analysis of the efficacy and safety of reduced selinexor doses in the BOSTON trial (NCT03110562).. Efficacy, safety, and quality of life (QoL) in 195 patients with relapsed/refractory multiple myeloma randomized to once-weekly (QW) selinexor (100 mg), QW subcutaneous bortezomib (1.3 mg/m. In total, 126 patients (65%) had selinexor dose reductions (median dose 71.4 mg/wk). In patients with dose reductions versus those without median progression-free survival was 16.6 months (95% CI 12.9-not evaluable [NE]) versus 9.2 months [95% CI 6.8-15.5]), overall response rate was 81.7% (95% CI 73.9-88.1%) versus 66.7% (95% CI 54.3-77.6%), ≥very good partial response was (51.6% [95% CI 42.5-60.6%] vs. 31.9% [95% CI 21.2-44.2]), median duration of response was not reached (95% CI 13.8-NE) versus 12.0 months (95% CI 8.3-NE), and time to next treatment was 22.6 months (95% CI 14.6-NE) versus 10.5 months (95% CI 6.3-18.2). Mean best change from baseline on the EORTC QLQ-C30 Global Health Status/QoL scale was 10.0 ± 20.5 versus 4.0 ± 20.9. Duration-adjusted AE rates that were lower after selinexor dose reduction included thrombocytopenia (62.5% before vs. 47.6% after), nausea (31.6% vs. 7.3%), fatigue (28.1% vs. 9.9%), decreased appetite (21.5% vs. 6.4%), anemia (17.9% vs. 10.3%), and diarrhea (12.9% vs. 5.2%).. Appropriate dose reductions in response to AEs of the 100 mg selinexor starting dose in the BOSTON study were associated with improved efficacy, reduced AE rates and improved QoL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Drug Tapering; Humans; Multiple Myeloma; Quality of Life

Proteasome inhibitors (PIs), including carfilzomib, potentiate the activity of selinexor, a novel, first-in-class, oral selective inhibitor of nuclear export (SINE) compound, in preclinical models of multiple myeloma (MM).. The safety, efficacy, maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D) of selinexor (80 or 100 mg) + carfilzomib (56 or 70 mg/m. Thirty-two patients, median prior therapies 4 (range, 1-8), were enrolled. MM was triple-class refractory in 38% of patients and 53% of patients had high-risk cytogenetics del(17p), t(4;14), t(14;16) and/or gain 1q. Common treatment-related adverse events (all/Grade 3) were thrombocytopenia 72%/47% (G3 and G4), nausea 72%/6%, anaemia 53%/19% and fatigue 53%/9%, all expected and manageable with supportive care and dose modifications. MTD and RP2D were identified as selinexor 80 mg, carfilzomib 56 mg/m. Weekly XKd is highly effective and well-tolerated. These data support further investigation of XKd in patients with MM.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Drug Administration Schedule; Female; Humans; Hydrazines; Male; Maximum Tolerated Dose; Middle Aged; Multiple Myeloma; Oligopeptides; Survival Analysis; Translocation, Genetic; Treatment Outcome; Triazoles

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Disease-Free Survival; Female; Humans; Hydrazines; Kidney Diseases; Male; Middle Aged; Multiple Myeloma; Survival Rate; Triazoles

Selinexor 80 mg combined with low-dose dexamethasone (Sd) demonstrated significant clinical benefit in patients with relapsed/refractory multiple myeloma (RRMM) who had disease refractory to a proteasome inhibitor (PI), an immunomodulator (IMiD), and an anti-CD38 monoclonal antibody based on a global phase II STORM study. The present study, MARCH, addresses China regulatory needs to further validate the data from STORM in Chinese patients with RRMM.. The MARCH study was conducted at 17 sites in China, where eligible Chinese RRMM patients who had disease refractory to PI and IMiD were enrolled. Selinexor 80 mg combined with dexamethasone 20 mg was administered orally on day 1 and day 3 of each week in 4-week cycles. The primary endpoint was the overall response rate (ORR) per an independent review committee, with the null hypothesis of ≤15%. Patients who received at least 1 dose of study treatment were included in the safety population. The pharmacokinetic (PK) profile was characterized by parameter and ethnicity sensitivity analyses.. A total of 82 patients with RRMM were enrolled in the study, with a median age of 60 years. Of the 82 patients, 55 patients (67.1%) had high-risk cytogenetic abnormalities, defined as one or more of del 17p13, t(4;14), t(14;16), or 1q amplification identified by fluorescence in situ hybridization (FISH); 18 patients (22.0%) had abnormal renal function. Enrolled patients were heavily pre-treated with a median prior regimen number of 5. All 82 patients (100%) were refractory to both PI and IMiD, including 20 patients (24.4%) categorized as triple-class refractory population (refractory to PI, IMiD, and daratumumab). Ten patients (12.2%) had undergone CAR-T therapy. ORR was 29.3% (95% CI 19.7, 40.4) with a median DOR of 4.7 months. The median PFS and OS were 3.7 and 13.2 months, respectively. ORR was 25.0% (95% CI 8.7, 49.1) in the triple-class refractory population. Efficacy was consistent across various subgroups. The most frequent grade 3/4 adverse events (AEs) included anemia (57.3%), thrombocytopenia (51.2%), lymphopenia (42.7%), neutropenia (40.2%), hyponatremia (29.3%), and lung infection (26.8%). Serious AEs were reported in 54.9% of patients. No significant drug accumulation was shown following multiple administrations. No human PK ethnicity difference was identified between Chinese and western patients.. With an encouraging ORR, the MARCH study has demonstrated that selinexor combined with low-dose dexamethasone (Sd) delivers meaningful clinical benefit to Chinese patients with RRMM, including triple-class refractory patients. AEs were expected and manageable with supportive care and dose modification.. ClinicalTrials.gov, NCT03944057 (May 09, 2019); Chinadrugtrials.org.cn , CTR20190858 (June 05, 2019).

Topics: Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Humans; Hydrazines; Immunologic Factors; In Situ Hybridization, Fluorescence; Multiple Myeloma; Proteasome Inhibitors; Triazoles

This study estimated the comparative efficacy of ciltacabtagene autoleucel (cilta-cel; CARTITUDE-1), a chimeric antigen receptor (CAR)-T-cell therapy, versus 3 non-CAR-T therapies (belantamab mafodotin [DREAMM-2], selinexor plus dexamethasone [STORM Part 2], and melphalan flufenamide plus dexamethasone [HORIZON]), each with distinct mechanisms of action, for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) who were triple-class exposed to an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 monoclonal antibody.. Pairwise matching-adjusted indirect treatment comparisons (MAICs) were conducted using patient-level data for cilta-cel from CARTITUDE-1 and summary level data for each comparator (2.5 mg/kg cohort in DREAMM-2, modified intention-to-treat population in STORM Part 2, and triple-class refractory patients in HORIZON). Treated patients from CARTITUDE-1 who satisfied the eligibility of the comparator trial were included. MAICs adjusted for imbalances in important prognostic factors between CARTITUDE-1 and the comparator populations. Comparative efficacy of cilta-cel versus each therapy was estimated for overall response rate, complete response or better rate, progression-free survival, and overall survival.. After adjustment, patients treated with cilta-cel demonstrated at least a 3.1-fold and at least a 10.3-fold increase in the likelihood of achieving an overall response or complete response or better, respectively, at least a 74% reduction in the risk of disease progression or death, and at least a 47% reduction in the risk of death. These results were statistically significant.. Cilta-cel showed improved efficacy over each comparator for all outcomes, demonstrating its potential as an efficacious treatment for patients with triple-class exposed RRMM.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Humans; Hydrazines; Melphalan; Multiple Myeloma; Triazoles

Multiple myeloma is a malignancy of plasma cells with around 6000 new cases per year in the UK. Cyclophosphamide plus prednisolone is considered a standard of care for disease and symptom control in the advanced relapsed or refractory myeloma setting within the UK NHS. The selective nuclear export inhibitor, selinexor, has been relatively well tolerated in previous clinical trials and offers promise when used in combination with a wide range of other anti-cancer treatments. Here, we investigate if the addition of selinexor can improve responses to cyclophosphamide plus prednisolone without adding prohibitive toxicity.. Ethics approval is obtained. Results will be submitted for publication in a peer-reviewed journal.. ISRCTN15028850.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Cyclophosphamide; Dexamethasone; Humans; Multicenter Studies as Topic; Multiple Myeloma; Neoplasm Recurrence, Local; Prednisolone; Randomized Controlled Trials as Topic

Selinexor is an oral, selective nuclear export inhibitor. STORM was a phase 2b, single-arm, open-label, multicenter trial of selinexor with low dose dexamethasone in patients with penta-exposed relapsed/refractory multiple myeloma (RRMM) that met its primary endpoint, with overall response of 26% (95% confidence interval [CI], 19 to 35%). Health-related quality of life (HRQoL) was a secondary endpoint measured using the Functional Assessment of Cancer Therapy - Multiple Myeloma (FACT-MM). This study examines impact of selinexor treatment on HRQoL of patients treated in STORM and reports two approaches to calculate minimal clinically important differences for the FACT-MM.. FACT-MM data were collected at baseline, on day 1 of each 4-week treatment cycle, and at end of treatment (EOT). Changes from baseline were analyzed for the FACT-MM total score, FACT-trial outcome index (TOI), FACT-General (FACT-G), and the MM-specific domain using mixed-effects regression models. Two approaches for evaluating minimal clinically important differences were explored: the first defined as 10% of the instrument range, and the second based on estimated mean baseline differences between Eastern Cooperative Oncology Group performance status (ECOG PS) scores. Post-hoc difference analysis compared change in scores from baseline to EOT for treatment responders and non-responders.. Eighty patients were included in the analysis; the mean number of prior therapies was 7.9 (standard deviation [SD] 3.1), and mean duration of myeloma was 7.6 years (SD 3.4). Each exploratory minimal clinically important difference threshold yielded consistent results whereby most patients did not experience HRQoL decline during the first six cycles of treatment (range: 53.9 to 75.7% for the first approach; range: 52.6 to 72.9% for the second). Treatment responders experienced less decline in HRQoL from baseline to EOT than non-responders, which was significant for the FACT-G, but not for other scores.. The majority of patients did not experience decline in HRQoL based on minimal clinically important differences during early cycles of treatment with selinexor and dexamethasone in the STORM trial. An anchor-based approach utilizing patient-level data (ECOG PS score) to define minimal clinically important differences for the FACT-MM gave consistent results with a distribution-based approach.. This trial was registered on ClinicalTrials.gov under the trial-ID NCT02336815 on January 8, 2015.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Hydrazines; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Prognosis; Quality of Life; Survival Rate; Triazoles

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Databases, Factual; Dexamethasone; Disease-Free Survival; Female; Humans; Hydrazines; Male; Middle Aged; Multiple Myeloma; Survival Rate; Triazoles

In the phase 3 BOSTON study, patients with multiple myeloma (MM) after 1-3 prior regimens were randomized to once-weekly selinexor (an oral inhibitor of exportin 1 [XPO1]) plus bortezomib-dexamethasone (XVd) or twice-weekly bortezomib-dexamethasone (Vd). Compared with Vd, XVd was associated with significant improvements in median progression-free survival (PFS), overall response rate (ORR), and lower rates of peripheral neuropathy, with trends in overall survival (OS) favoring XVd. In BOSTON, 141 (35.1%) patients had MM with high-risk (presence of del[17p], t[4;14], t[14;16], or ≥4 copies of amp1q21) cytogenetics (XVd, n = 70; Vd, n = 71), and 261 (64.9%) exhibited standard-risk cytogenetics (XVd, n = 125; Vd, n = 136). Among patients with high-risk MM, median PFS was 12.91 months for XVd and 8.61 months for Vd (HR, 0.73 [95% CI, (0.4673, 1.1406)], p = 0.082), and ORRs were 78.6% and 57.7%, respectively (OR 2.68; p = 0.004). In the standard-risk subgroup, median PFS was 16.62 months for XVd and 9.46 months for Vd (HR 0.61; p = 0.004), and ORRs were 75.2% and 64.7%, respectively (OR 1.65; p = 0.033). The safety profiles of XVd and Vd in both subgroups were consistent with the overall population. These data suggest that selinexor can confer benefits to patients with MM regardless of cytogenetic risk. ClinicalTrials.gov identifier: NCT03110562.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Cytogenetic Analysis; Dexamethasone; Female; Humans; Hydrazines; Male; Middle Aged; Multiple Myeloma; Progression-Free Survival; Treatment Outcome; Triazoles; Young Adult

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Female; Humans; Hydrazines; Male; Multiple Myeloma; Pain; Peripheral Nervous System Diseases; Triazoles

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Boron Compounds; Dexamethasone; Female; Glycine; Humans; Hydrazines; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Triazoles

Selinexor, a selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1) and forces nuclear accumulation and activation of tumor suppressor proteins, inhibits nuclear factor κB, and reduces oncoprotein messenger RNA translation, is a potential novel treatment for myeloma that is refractory to current therapeutic options.. We administered oral selinexor (80 mg) plus dexamethasone (20 mg) twice weekly to patients with myeloma who had previous exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent and had disease refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab (triple-class refractory). The primary end point was overall response, defined as a partial response or better, with response assessed by an independent review committee. Clinical benefit, defined as a minimal response or better, was a secondary end point.. A total of 122 patients in the United States and Europe were included in the modified intention-to-treat population (primary analysis), and 123 were included in the safety population. The median age was 65 years, and the median number of previous regimens was 7; a total of 53% of the patients had high-risk cytogenetic abnormalities. A partial response or better was observed in 26% of patients (95% confidence interval, 19 to 35), including two stringent complete responses; 39% of patients had a minimal response or better. The median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival was 8.6 months. Fatigue, nausea, and decreased appetite were common and were typically grade 1 or 2 (grade 3 events were noted in up to 25% of patients, and no grade 4 events were reported). Thrombocytopenia occurred in 73% of the patients (grade 3 in 25% and grade 4 in 33%). Thrombocytopenia led to bleeding events of grade 3 or higher in 6 patients.. Selinexor-dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies. (Funded by Karyopharm Therapeutics; STORM ClinicalTrials.gov number, NCT02336815.).

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Dexamethasone; Drug Administration Schedule; Drug Resistance, Neoplasm; Exportin 1 Protein; Female; Humans; Hydrazines; Intention to Treat Analysis; Karyopherins; Male; Middle Aged; Multiple Myeloma; Receptors, Cytoplasmic and Nuclear; Survival Analysis; Thrombocytopenia; Triazoles; Young Adult

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cytogenetic Analysis; Dexamethasone; Drug Resistance, Neoplasm; Female; Humans; Hydrazines; Male; Middle Aged; Multiple Myeloma; Neoplasm Staging; Oligopeptides; Prognosis; Recurrence; Retreatment; Treatment Outcome; Triazoles

Purpose Selinexor, a first-in-class, oral, selective exportin 1 (XPO1) inhibitor, induces apoptosis in cancer cells through nuclear retention of tumor suppressor proteins and the glucocorticoid receptor, along with inhibition of translation of oncoprotein mRNAs. We studied selinexor in combination with low-dose dexamethasone in patients with multiple myeloma refractory to the most active available agents. Patients and Methods This phase II trial evaluated selinexor 80 mg and dexamethasone 20 mg, both orally and twice weekly, in patients with myeloma refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide (quad-refractory disease), with a subset also refractory to an anti-CD38 antibody (penta-refractory disease). The primary end point was overall response rate (ORR). Results Of 79 patients, 48 had quad-refractory and 31 had penta-refractory myeloma. Patients had received a median of seven prior regimens. The ORR was 21% and was similar for patients with quad-refractory (21%) and penta-refractory (20%) disease. Among patients with high-risk cytogenetics, including t(4;14), t(14;16), and del(17p), the ORR was 35% (six of 17 patients). The median duration of response was 5 months, and 65% of responding patients were alive at 12 months. The most common grade ≥ 3 adverse events were thrombocytopenia (59%), anemia (28%), neutropenia (23%), hyponatremia (22%), leukopenia (15%), and fatigue (15%). Dose interruptions for adverse events occurred in 41 patients (52%), dose reductions occurred in 29 patients (37%), and treatment discontinuation occurred in 14 patients (18%). Conclusion The combination of selinexor and dexamethasone has an ORR of 21% in patients with heavily pretreated, refractory myeloma with limited therapeutic options.

Topics: Active Transport, Cell Nucleus; Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Dose-Response Relationship, Drug; Exportin 1 Protein; Female; Humans; Hydrazines; Karyopherins; Male; Middle Aged; Multiple Myeloma; Progression-Free Survival; Receptors, Cytoplasmic and Nuclear; Triazoles

Acquired drug resistance is the greatest obstacle to the successful treatment of multiple myeloma (MM). Despite recent advanced treatment options such as liposomal formulations, proteasome inhibitors, immunomodulatory drugs, myeloma-targeted antibodies, and histone deacetylase inhibitors, MM is still considered an incurable disease.. We investigated whether the clinical exportin 1 (XPO1) inhibitor selinexor (KPT-330), when combined with pegylated liposomal doxorubicin (PLD) or doxorubicin hydrochloride, could overcome acquired drug resistance in multidrug-resistant human MM xenograft tumors, four different multidrug-resistant MM cell lines, or ex vivo MM biopsies from relapsed/refractory patients. Mechanistic studies were performed to assess co-localization of topoisomerase II alpha (TOP2A), DNA damage, and siRNA knockdown of drug targets.. Selinexor was found to restore sensitivity of multidrug-resistant 8226B25, 8226Dox6, 8226Dox40, and U266PSR human MM cells to doxorubicin to levels found in parental myeloma cell lines. NOD/SCID-γ mice challenged with drug-resistant or parental U266 human MM and treated with selinexor/PLD had significantly decreased tumor growth and increased survival with minimal toxicity. Selinexor/doxorubicin treatment selectively induced apoptosis in CD138/light-chain-positive MM cells without affecting non-myeloma cells in ex vivo-treated bone marrow aspirates from newly diagnosed or relapsed/refractory MM patients. Selinexor inhibited XPO1-TOP2A protein complexes (proximity ligation assay), preventing nuclear export of TOP2A in both parental and multidrug-resistant MM cell lines. Selinexor/doxorubicin treatment significantly increased DNA damage (comet assay/γ-H2AX) in both parental and drug-resistant MM cells. TOP2A knockdown reversed both the anti-tumor effect and significantly reduced DNA damage induced by selinexor/doxorubicin treatment.. The combination of an XPO1 inhibitor and liposomal doxorubicin was highly effective against acquired drug resistance in in vitro MM models, in in vivo xenograft studies, and in ex vivo samples obtained from patients with relapsed/refractory myeloma. This drug combination synergistically induced TOP2A-mediated DNA damage and subsequent apoptosis. In addition, based on our preclinical data, we have initiated a phase I/II study with the XPO1 inhibitor selinexor and PLD (ClinicalTrials.gov NCT02186834). Initial results from both preclinical and clinical trials have shown significant promise for this drug combination for the treatment of MM.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biopsy; Cell Line, Tumor; DNA Damage; Doxorubicin; Drug Resistance, Neoplasm; Drug Synergism; Exportin 1 Protein; Heterografts; Humans; Hydrazines; Karyopherins; Mice; Multiple Myeloma; Polyethylene Glycols; Receptors, Cytoplasmic and Nuclear; Survival Rate; Topoisomerase II Inhibitors; Triazoles; Tumor Burden

Multiple myeloma (MM) is an incurable haematological cancer. Selinexor is the first-in-class selective inhibitor of nuclear export (SINE) and was newly approved for the treatment of MM. Until now, very few studies have investigated selinexor resistance in MM. Heterogeneous nuclear ribonucleoprotein U (hnRNPU) is an RNA-binding protein and a component of hnRNP complexes. Here we found that hnRNPU regulates MM sensitivity to selinexor. Cell apoptosis assays were performed to compare selinexor-induced cell death in control knockdown (CTR-KD) and hnRNPU knockdown (hnR-KD) MM cells. HnRNPU knockdown-induced nuclear protein retention was examined by proteomics array. HnRNPU-conferred mRNA translation regulation was evaluated by sucrose gradient assay, RNA electrophoresis mobility shift assay, and RNA pull-down assay. We found that hnR-KD MM cells were more sensitive to selinexor-induced cell death in vitro and in mouse model. MM patients who responded to selinexor had relatively low hnRNPU expression. In brief, hnRNPU comprehensively regulated MM sensitivity to selinexor by affecting the localization of LTV1 and NMD3, and mRNA translation of MDM2 and RAN, which were involved in XPO1-mediated nuclear export of ribosome subunits and tumor suppressors. Our discoveries indicate that hnRNPU might be a possible marker to categorize MM patients for the use of Selinexor.

Topics: Animals; Cell Line, Tumor; Heterogeneous-Nuclear Ribonucleoprotein U; Humans; Hydrazines; Karyopherins; Mice; Multiple Myeloma; RNA; RNA-Binding Proteins

XPO1 (Exportin-1) is the nuclear export protein responsible for the normal shuttling of several proteins and RNA species between the nucleocytoplasmic compartment of eukaryotic cells. XPO1 recognizes the nuclear export signal (NES) of its cargo proteins to facilitate its export. Alterations of nuclear export have been shown to play a role in oncogenesis in several types of solid tumour and haematologic cancers. Over more than a decade, there has been substantial progress in targeting nuclear export in cancer using selective XPO1 inhibitors. This has resulted in recent approval for the first-in-class drug selinexor for use in relapsed, refractory multiple myeloma and diffuse large B-cell lymphoma (DLBCL). Despite these successes, not all patients respond effectively to XPO1 inhibition and there has been lack of biomarkers for response to XPO1 inhibitors in the clinic. Using haematologic malignancy cell lines and samples from patients with myelodysplastic neoplasms treated with selinexor, we have identified XPO1, NF-κB(p65), MCL-1 and p53 protein levels as protein markers of response to XPO1 inhibitor therapy. These markers could lead to the identification of response upon XPO1 inhibition for more accurate decision-making in the personalized treatment of cancer patients undergoing treatment with selinexor.

Topics: Active Transport, Cell Nucleus; Hematologic Neoplasms; Humans; Karyopherins; Multiple Myeloma

Selinexor (KPT-330), a small-molecule inhibitor of exportin-1 (XPO1, CRM1) with potent anticancer activity, has recently been granted FDA approval for treatment of relapsed/refractory multiple myeloma and diffuse large B-cell lymphoma (DLBCL), with a number of additional indications currently under clinical investigation. Since selinexor has often demonstrated synergy when used in combination with other drugs, notably bortezomib and dexamethasone, a more comprehensive approach to uncover new beneficial interactions would be of great value. Moreover, stratifying patients, personalizing therapeutics and improving clinical outcomes requires a better understanding of the genetic vulnerabilities and resistance mechanisms underlying drug response. Here, we used CRISPR-Cas9 loss-of-function chemogenetic screening to identify drug-gene interactions with selinexor in chronic myeloid leukemia, multiple myeloma and DLBCL cell lines. We identified the TGFβ-SMAD4 pathway as an important mediator of resistance to selinexor in multiple myeloma cells. Moreover, higher activity of this pathway correlated with prolonged progression-free survival in multiple myeloma patients treated with selinexor, indicating that the TGFβ-SMAD4 pathway is a potential biomarker predictive of therapeutic outcome. In addition, we identified ASB8 (ankyrin repeat and SOCS box containing 8) as a shared modulator of selinexor sensitivity across all tested cancer types, with both ASB8 knockout and overexpression resulting in selinexor hypersensitivity. Mechanistically, we showed that ASB8 promotes selinexor-induced proteasomal degradation of XPO1. This study provides insight into the genetic factors that influence response to selinexor treatment and could support both the development of predictive biomarkers as well as new drug combinations.

Topics: Active Transport, Cell Nucleus; Humans; Hydrazines; Karyopherins; Lymphoma, Large B-Cell, Diffuse; Multiple Myeloma; Suppressor of Cytokine Signaling Proteins

Selinexor (KPT-330) is a small molecule inhibitor of XPO1, which mediates the transport of tumor suppressor proteins, oncogene messenger RNAs, and other proteins involved in governing cell growthfrom the cell nucleus to the cytoplasm. It is overexpressed in many cancer types. Because eukaryotic translation initiator factor 4E (eIF4E) plays a critical role in protein translation in cancer cells in multiple myeloma (MM), we evaluated the effectiveness of combined inhibition of protein translation and nuclear export in MM. Selinexor, an inhibitor of nuclear protein export, dose-dependently decreased eIF4E, IKZF1, and c-MYC protein levels. Using a doxycycline-inducible-pLKO-Tet-On vector, knockdown of eIF4E significantly enhanced the antiproliferative effects of selinexor, sensitized resistant MM cells to selinexor, and increased apoptosis in MM cells. Immunofluorescent analysis of MM cells showed that the combined treatment increased the localization of residual eIF4E to the nucleus compared with selinexor-only treatment. The overexpression of eIF4E at least partially rescued the effects of selinexor in MM cells by reducing G1 cell cycle arrest and increasing the selinexor-IC50 10-fold. Moreover, the combination of selinexor with pharmacologic inhibitors of protein translation showed synergistic anti-MM effects. These results suggest a synergistic anti-MM effect of selinexor combined with eIF4E inhibitors in vitro. Our work provides a better understanding of the potential mechanism of resistance to selinexor and a rationale for combining selinexor with eIF4E inhibitors for the treatment of MM.

Topics: Active Transport, Cell Nucleus; Apoptosis; Eukaryotic Initiation Factor-4E; Humans; Karyopherins; Multiple Myeloma; Protein Biosynthesis

The increasing use of anti-CD38 monoclonal antibodies (αCD38 mAbs) for newly diagnosed or early relapsed multiple myeloma (MM), especially in non-transplant eligible patients, may lead to more patients developing αCD38 mAb-refractory disease earlier in the treatment course with fewer treatment options.. We analyzed the efficacy and safety of selinexor-based triplets (selinexor+dexamethasone [Sd] plus pomalidomide [SPd, n = 23], bortezomib [SVd, n = 16] or carfilzomib (SKd, n = 23]) in a subset of STOMP (NCT02343042) and BOSTON (NCT03110562) study patients treated previously with αCD38 mAbs.. Sixty-two patients (median 4 prior therapies, range 1 to 11, 90.3% refractory to αCD38 mAb) were included. Overall response rates (ORR) in the SPd, SVd and SKd cohorts were 52.2%, 56.3%, and 65.2%, respectively. Overall response rate was 47.4% among patients who had MM refractory to the third drug reintroduced in the Sd-based triplet. Median progression-free survival in the SPd, SVd, and SKd cohorts was 8.7, 6.7, and 15.0 months, respectively, and median overall survival was 9.6, 16.9, and 33.0 months, respectively. Median time to discontinuation in the SPd, SVd, and SKd cohorts was 4.4, 5.9, and 10.6 months, respectively. The most common hematological adverse events were thrombocytopenia, anemia, and neutropenia. Nausea, fatigue, and diarrhea were primarily grade 1/2. Adverse events were generally manageable with standard supportive care and dose modifications.. Selinexor-based regimens may offer effective and well-tolerated therapy to patients with relapsed and/or refractory MM who had disease previously exposed or refractory to αCD38 mAb therapy and could help address the unmet clinical need in these high-risk patients.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Humans; Multiple Myeloma

Selinexor is an orally available selective inhibitor of exportin-1 that has offered a new treatment option in relapsed or refractory myeloma (RRMM) either in combination with dexamethasone (Sd) or with bortezomib and dexamethasone (SVd).. We evaluated the efficacy and toxicity of selinexor combinations in the real world, post progression therapies and their outcomes. The analysis included 44 patients with RRMM treated with Sd (N = 21, 48%) or SVd (N = 23, 52%).. On intent-to-treat, response rate (ORR) among all treated patients was 29.5% (13/44, of which CR: 2, VGPR: 3, PR:8); ORR was 35% for SVd and 24% for Sd. Median PFS was 3.0 months for all; 6.9 months for responders (≥PR),2.7 months for Sd and 3.4 months for SVd treated patients. In univariate analysis, serum albumin <3.5 g/dl and LDH >ULN were associated with worse PFS (P = .001 and P = .032, respectively).The OS of the whole cohort exceeded one year while serum albumin <3.5 gr/dl and LDH>ULN were associated with worse OS. After progression to Sd/SVd, 20 patients received further therapy; on ITT, the ORR was 40% (8/20) and the subsequent PFS was 3.4 months. The most common adverse events were fatigue, thrombocytopenia and nausea, while the most recorded grade 3 or 4 side effect was thrombocytopenia; 56% (25/44) of patients required dose reduction, however, this was not associated with inferior PFS.. In conclusion, selinexor-based therapy provides an additional treatment option in the real word setting and with appropriate dosing and toxicity management a subset of patients may have significant benefit.

Topics: Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Humans; Multiple Myeloma; Serum Albumin; Thrombocytopenia

Extramedullary disease usually implies a dismal outcome in relapsed/refractory multiple myeloma patients, and requires novel treatment approaches. We designed a trial using Selinexor, a nuclear export protein 1 inhibitor, together with anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cell product CT103A to treat these patients, and describe the first two cases in this report.. Selinexor was administered with a novel two-step schedule in bridging therapy and in maintenance. The clinical responses and adverse events were recorded after CAR-T infusion and Selinexor administration. In vitro analysis of the influence of Selinexor on CAR-T cell function was performed using myeloma cell lines.. After infusion, both patients achieved stringent complete remission (sCR), and were maintained in sCR at data-cutoff, with survival over 13 and 10 months, respectively. Neither immune effector cell-associated neurotoxicity syndrome nor over grade 2 cytokine release syndrome was observed. Meanwhile, the patients showed good tolerance to the combination. In addition, we demonstrated that low dose of Selinexor could upregulate the expression of BCMA on plasma cell lines and subsequently enhance the function of CAR-T cell in vitro.. The combination of Selinexor and CT103A exerts preliminary synergistic effect, and can be developed as a promising strategy for relapsed/refractory extramedullary myeloma.

Topics: Antibodies; B-Cell Maturation Antigen; Humans; Immunotherapy, Adoptive; Multiple Myeloma; Plasma Cells; Receptors, Chimeric Antigen

RAS/RAF/MEK/ERK pathway inhibitors exhibit significant anti-tumor effects against various tumor types, including multiple myeloma (MM), and they are predicted to play a pivotal role in precision medicine. The XPO1 inhibitor KPT-330 has also exhibited promising efficacy in combination with other novel drugs in treating relapsed/refractory MM (RRMM). In this study, we explored the anti-tumor effects of a combination of the pan-RAF inhibitor TAK-580 and KPT-330. Importantly, TAK-580 enhanced KPT-330-induced cytotoxicity and apoptosis in human myeloma cell lines and primary myeloma cells from RRMM patients. Moreover, TAK-580 and KPT-330 synergistically inhibited nuclear phospho-FOXO3a and enhanced cytoplasmic phospho-FOXO3a in MM cells, leading to cytoplasmic enhanced Bim expression and finally apoptosis. This indicates that TAK-580 enhances KPT-330-induced cytotoxicity and apoptosis primarily via the FOXO3a-Bim axis. In addition, TAK-580 enhanced the cytotoxicity of KPT-330 against MM cells even in the presence of IGF-1. Taken together, our results demonstrate that a combination of pan-RAF inhibitor and XPO1 inhibitor is a potential therapeutic option in treating MM.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Drug Synergism; Heterocyclic Compounds, 3-Ring; Humans; Hydrazines; Multiple Myeloma; Triazoles; Tumor Cells, Cultured

Topics: Administration, Oral; ADP-ribosyl Cyclase 1; Antibodies, Monoclonal, Humanized; Clinical Trials, Phase II as Topic; Drug Resistance, Neoplasm; Europe; Humans; Hydrazines; Immunomodulating Agents; Membrane Glycoproteins; Multiple Myeloma; Proteasome Inhibitors; Recurrence; Triazoles

Selinexor is a first in class selective inhibitor of nuclear export (SINE), blocks exportin 1 (XPO1), a protein transporter, that among other actions, shuttles cargo proteins such as tumor suppressor proteins (TSPs), the glucocorticoid receptor (GR), and oncoprotein messenger RNAs (mRNAs) across the nuclear membrane to cytoplasm. By blocking XPO1, selinexor facilitates nuclear preservation and activation of TSPs, and prevents mRNA translation of the oncoproteins leading to induction of apoptosis. The therapeutic value of selinexor in combination with dexamethasone has been successfully demonstrated in treating relapsed and/or refractory myeloma (RRMM), leading to the Food and Drug Administration (FDA) approval of selinexor in combination with dexamethasone in 2019 for the treatment of adult patients with RRMM who received at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, at least 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody (mAb) - a pentarefractory myeloma. More recently, selinexor in combination with bortezomib and dexamethasone was approved by the FDA in December 2020, based on the BOSTON study among RRMM patients who had received at least one prior line of therapy. With more available safety and efficacy data supporting the increased interval between dosing of selinexor (and lesser cumulative weekly dosing) and schedule, contrary to the originally approved dose of 160 mg per week, the supportive care guidelines needed to be revisited. The current manuscript summarizes the supportive care solutions with weekly dosing of selinexor and identifies the ideal potential patient for selinexor treatment.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Consensus; Dexamethasone; Humans; Hydrazines; Multiple Myeloma; Triazoles

The treatment of relapse or refractory multiple myeloma (RRMM) is still a big challenge in clinic. Recently, several clinical trials indicated that the XPO1 inhibitor, selinexor could significantly improve the remission rate in MM patients. However, the heterogeneous genetic background greatly influenced the efficiency of selinexor among MM. Here, we tried to characterized the biomarkers associated with selinexor sensitivity by analyzing gene expression data in MM patients. We found the cytogenetic background of selinexor sensitive MM patients was not limited to specific cytogenetic subtypes. In addition, by weighted gene co-expression network analysis (WGCNA), we obtained 10 key genes which showed a strong correlation with the selinexor sensitivity in MM patients. Notably, ABCC4 (MRP4) was the only gene which was both differentially expressed and proved to be clinical prognostic valuable (both for event-free survival and overall survival) in MM patients. We further validated the heterogenous expression of ABCC4 in MM cell lines and its value as a novel indicator for selinexor sensitivity. Moreover, immune infiltration analysis showed that ABCC4 expression had a significantly positive correlation with NK infiltration as well as immunotherapy target TIM-3 (HAVCR2) expression. Collectively, our findings indicated that ABCC4 might be a predictive biomarker of selinexor sensitivity in MM patients, which could be enhanced if combined with immunotherapy drugs such as TIM-3 inhibitor.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Drug Resistance, Neoplasm; Hepatitis A Virus Cellular Receptor 2; Humans; Hydrazines; Karyopherins; Multidrug Resistance-Associated Proteins; Multiple Myeloma; Neoplasm Recurrence, Local; Receptors, Cytoplasmic and Nuclear; Triazoles

BACKGROUND Approximately 10% to 15% of patients with multiple myeloma (MM) are diagnosed with high-risk disease and have poor prognosis. Clinical trial data supports the combined use of selinexor, bortezomib, and dexamethasone (XVd) for treatment of patients with MM who have received at least 1 prior therapy. Information on the efficacy of XVd and of subsequent allogeneic stem cell transplantation (SCT) in heavily pretreated patients with high-risk MM is limited. CASE REPORT We present a case of a 58-year-old woman with high-risk MM (revised International Staging System Stage III; serum ß₂-microglobulin; 8.0 mg/L; and presence of del[17p]) who had received 8 prior treatment lines, and whose disease was refractory to ixazomib, bortezomib, and all immunomodulatory agents. Before initiating XVd (once weekly 1.3 mg/m² bortezomib subcutaneously, 80 mg selinexor per os, and 40 mg dexamethasone per os), the patient had severely hypoplastic bone marrow and was transfusion dependent. After 1 cycle of XVd, she achieved a partial response, and after 4 cycles, a very good partial response (VGPR). No adverse reactions to selinexor were observed. Because of the VGPR, a haploidentical transplant was planned. At posttransplant week 4, the patient had become transfusion independent. She remained relapse-free for 13 months after initiating XVd. Maintenance treatment with lenalidomide was initiated, and following receipt of donor lymphocyte infusions due to loss of donor chimerism, the patient's light chain levels improved. CONCLUSIONS This report presents the cytogenetics and management of a heavily pretreated patient with high-risk MM treated with SVd followed by SCT.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Female; Hematopoietic Stem Cell Transplantation; Humans; Hydrazines; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Triazoles

Selinexor is the first selective inhibitor of nuclear export to be approved for the treatment of relapsed or refractory multiple myeloma (MM). Currently, there are no known genomic biomarkers or assays to help select MM patients at higher likelihood of response to selinexor. Here, we aimed to characterize the transcriptomic correlates of response to selinexor-based therapy.. We performed RNA sequencing on CD138+ cells from the bone marrow of 100 patients with MM who participated in the BOSTON study, followed by differential gene expression and pathway analysis. Using the differentially expressed genes, we used cox proportional hazard models to identify a gene signature predictive of response to selinexor, followed by validation in external cohorts.. The three-gene signature predicts response to selinexor-based therapy in patients with MM in the BOSTON cohort. Then, we validated this gene signature in 64 patients from the STORM cohort of triple-class refractory MM and additionally in an external cohort of 35 patients treated in a real-world setting outside of clinical trials. We found that the signature tracks with both depth and duration of response, and it also validates in a different tumor type using a cohort of pretreatment tumors from patients with recurrent glioblastoma. Furthermore, the genes involved in the signature, WNT10A, DUSP1, and ETV7, reveal a potential mechanism through upregulated interferon-mediated apoptotic signaling that may prime tumors to respond to selinexor-based therapy.. In this study, we present a present a novel, three-gene expression signature that predicts selinexor response in MM. This signature has important clinical relevance as it could identify patients with cancer who are most likely to benefit from treatment with selinexor-based therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Hydrazines; Multiple Myeloma; Neoplasm Recurrence, Local; Triazoles

BACKGROUND Numerous treatment options are available for patients with multiple myeloma (MM). Because of the course of the disease, most patients will experience serial relapse or the MM will become refractory to most of these treatments, leaving patients with few or no treatment options over time. Selinexor, a treatment with a novel mechanism of action, is an oral selective inhibitor of nuclear export (SINE) compound that blocks exportin 1, the major nuclear exporter of tumor suppressor proteins. CASE REPORT In this case series, we report on treatment with the weekly oral administration of selinexor combined with bortezomib and dexamethasone (XVd) in 3 patients from Argentina who were heavily treated (5-7 prior therapies) for MM that relapsed or was refractory to each previous treatment. Two patients had the high-risk cytogenetic abnormality del(17p). All 3 patients experienced efficacy with XVd reaching a best response of partial response or very good partial response. These responses were consistent with those of patients from the BOSTON study who were treated with XVd but were less heavily pretreated (1-3 prior therapies) and had a shorter median time since diagnosis of MM (7 years vs 3.7 years). The 3 patients experienced adverse events (AEs) that included nausea, thrombocytopenia, asthenia, and fatigue, which were similar to the most commonly reported AEs associated with selinexor treatment. CONCLUSIONS With its oral administration, novel mechanism of action, and responses in heavily pretreated patients, selinexor may help to address an important clinical need in the treatment of patients with relapsed/refractory MM.

Topics: Antineoplastic Combined Chemotherapy Protocols; Argentina; Dexamethasone; Humans; Hydrazines; Multiple Myeloma; Neoplasm Recurrence, Local; Triazoles

Single-agent belantamab mafodotin (belamaf; BLENREP) demonstrated deep and durable responses in patients with relapsed/refractory multiple myeloma and ≥ 3 prior lines of therapy, including an immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody (DREAMM-2; NCT03525678).. At the time of this study, STORM Part 2, NCT02336815 (selinexor plus low-dose dexamethasone; sel + dex) was systematically identified as the only feasible comparator to the DREAMM-2 cohort. Matching-adjusted indirect comparisons (MAIC) evaluated efficacy and safety of belamaf (2.5 mg/kg; n = 97) versus sel + dex (80 mg + 20 mg, respectively; n = 123). Populations were weighted for clinically validated effect modifiers and prognostic factors. Outcomes included overall survival (OS), progression-free survival (PFS), duration of response (DoR), overall response rate (ORR), time to response (TTR), and safety. The relative efficacy of belamaf versus standard of care (SoC) on OS was estimated by a Bucher indirect treatment comparison using the MAIC-adjusted hazard ratios (HR) for OS of belamaf (DREAMM-2) versus sel + dex (STORM Part 2) and a HR adjusted for refractoriness to carfilzomib and high-risk cytogenetics of sel + dex (STORM) versus SoC (MAMMOTH).. Belamaf demonstrated improved OS (HR 0.53; 95% confidence interval 0.34, 0.83; p = 0.005) and DoR (0.41; 0.21, 0.83; p = 0.013) versus sel + dex. There were no statistically significant differences in ORR, TTR, and PFS. Belamaf had a favorable safety profile for most evaluable hematologic (any-grade, Grade 3-4) and non-hematologic (any-grade) adverse events versus sel + dex. Significantly improved OS was observed with belamaf versus SoC (0.29; 0.16, 0.54; p < 0.001).. Single-agent belamaf represents a new treatment option for triple-class refractory patients with RRMM.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Humans; Hydrazines; Multiple Myeloma; Neoplasm Recurrence, Local; Standard of Care; Triazoles

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Female; Humans; Hydrazines; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Triazoles

Elderly and frail patients with multiple myeloma (MM) are more vulnerable to the toxicity of combination therapies, often resulting in treatment modifications and suboptimal outcomes. The phase 3 BOSTON study showed that once-weekly selinexor and bortezomib with low-dose dexamethasone (XVd) improved PFS and ORR compared with standard twice-weekly bortezomib and moderate-dose dexamethasone (Vd) in patients with previously treated MM. This is a retrospective subgroup analysis of the multicenter, prospective, randomized BOSTON trial. Post hoc analyses were performed to compare XVd versus Vd safety and efficacy according to age and frailty status (<65 and ≥65 years, nonfrail and frail). Patients ≥65 years with XVd had higher ORR (OR 1.77, p = .024), ≥VGPR (OR, 1.68, p = .027), PFS (HR 0.55, p = .002), and improved OS (HR 0.63, p = .030), compared with Vd. In frail patients, XVd was associated with a trend towards better PFS (HR 0.69, p = .08) and OS (HR 0.62, p = .062). Significant improvements were also observed in patients <65 (ORR and TTNT) and nonfrail patients (PFS, ORR, ≥VGPR, and TTNT). Patients treated with XVd had a lower incidence of grade ≥ 2 peripheral neuropathy in ≥65 year-old (22% vs. 37%; p = .0060) and frail patients (15% vs. 44%; p = .0002). Grade ≥3 TEAEs were not observed more often in older compared to younger patients, nor in frail compared to nonfrail patients. XVd is safe and effective in patients <65 and ≥65 and in nonfrail and frail patients with previously treated MM.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Clinical Trials, Phase III as Topic; Dexamethasone; Drug Administration Schedule; Female; Frailty; Gastrointestinal Diseases; Hematologic Diseases; Humans; Hydrazines; Kaplan-Meier Estimate; Male; Middle Aged; Multicenter Studies as Topic; Multiple Myeloma; Peripheral Nervous System Diseases; Progression-Free Survival; Randomized Controlled Trials as Topic; Retrospective Studies; Severity of Illness Index; Triazoles

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Female; Humans; Hydrazines; Male; Multiple Myeloma; Triazoles

Topics: Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Hematopoietic Stem Cell Transplantation; Humans; Hydrazines; Male; Multiple Myeloma; Neoplasm Recurrence, Local; Oligopeptides; Transplantation, Homologous; Treatment Outcome; Triazoles

Idecabtagene vicleucel (ide-cel, bb2121), a chimeric antigen receptor (CAR) T cell therapy, has been investigated in patients with relapsed and refractory multiple myeloma (RRMM) who have received an immunomodulatory drug, proteasome inhibitor, and anti-CD38 antibody in the single-arm phase 2 KarMMa clinical trial. Two therapies with distinct mechanisms of action - selinexor plus dexamethasone (Sd) and belantamab mafodotin (BM) - are currently approved in the United States for heavily pretreated patients, including those who are triple-class refractory. To compare ide-cel versus Sd and ide-cel versus BM, matching-adjusted indirect comparisons were performed. Ide-cel extended progression-free survival (PFS) and overall survival (OS) versus both Sd and BM (hazard ratio (HR); 95% confidence interval (CI)). PFS: ide-cel versus Sd, 0.46; 0.28-0.75; ide-cel versus BM, 0.45; 0.27-0.77. OS: ide-cel versus Sd, 0.23; 0.13-0.42; ide-cel versus BM, 0.35; 0.14-0.87. These results suggest ide-cel offers clinically meaningful improvements over currently approved regimens for patients with heavily pretreated RRMM.

Topics: Antibodies, Monoclonal, Humanized; Dexamethasone; Humans; Hydrazines; Multiple Myeloma; Triazoles; United States

Topics: Bortezomib; Boston; Control Groups; Dexamethasone; Humans; Hydrazines; Multiple Myeloma; Triazoles

The BOSTON trial showed that use of once-weekly selinexor, bortezomib, and dexamethasone (SVd) prolonged progression-free survival compared to twice-weekly bortezomib and dexamethasone (Vd) in patients with relapsed or refractory (R/R) multiple myeloma (MM). In this study, we constructed a Markov model to assess the cost-effectiveness of SVd versus Vd in R/R MM. We calculated the incremental cost-effectiveness ratio (ICER) of each treatment strategy from a US payer perspective, using a lifetime horizon and a willingness-to-pay threshold of $150,000 per quality-adjusted life-year (QALY). Use of SVd was associated with an incremental cost of $170,002 compared to Vd alone ($1,015,120 vs. $845,118, respectively), an incremental effectiveness of 0.35 QALYs (3.43 vs. 3.08 QALYs, respectively), and an ICER of $487,361/QALY. These data suggest that use of once-weekly SVd for R/R M/M is unlikely to be cost-effective compared to twice-weekly Vd.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Cost-Benefit Analysis; Dexamethasone; Humans; Hydrazines; Multiple Myeloma; Neoplasm Recurrence, Local; Quality-Adjusted Life Years; Triazoles

Nearly all patients with multiple myeloma undergo multiple rounds of therapy. The phase III BOSTON trial of once-weekly selinexor and once-weekly bortezomib with dexamethasone (XVd) vs twice-weekly bortezomib and dexamethasone (Vd) is the basis for this cost-effectiveness analysis in previously treated multiple myeloma from a US commercial payer perspective over a lifetime horizon.. A partitioned survival model enabled use of direct overall survival and progression-free survival curves from BOSTON to generate four health states for XVd and Vd: progression-free survival on treatment, progression-free survival off treatment, post-progression, and mortality. Using a 1-week cycle length, benefits and costs were discounted at 3.0% annually. Additional comparators were included in an exploratory analysis that compared XVd against seven additional regimens (six triplets, one doublet).. After considering costs, utility, progression, and survival, the base-case incremental cost-effectiveness ratio of XVd vs Vd was $475,430/quality-adjusted life-year (QALY). The 50% cost-effectiveness probability midpoint was near $470,000/QALY, based on a probabilistic sensitivity analysis. The robustness of the analysis was supported by additional scenario assessment and deterministic and probabilistic sensitivity analyses, which generally demonstrated little variance, with greatest sensitivity to variations in discount rates and utility values. In an exploratory analysis against external comparators, XVd showed a higher QALY gain with a lower cost (i.e., dominance) compared with lenalidomide/dexamethasone (Rd), pomalidomide/bortezomib/dexamethasone (PVd), and carfilzomib/pomalidomide/dexamethasone (KPd).. Addition of XVd to the previously treated multiple myeloma treatment landscape provides a novel oral treatment option, which, when compared to Vd in the base-case analysis resulted in an incremental cost-effectiveness ratio of $475,430/QALY. Exploratory analyses comparing against external comparators suggest that XVd was dominant vs Rd, PVd, and KPd.. Patients with multiple myeloma often relapse and require multiple treatments to extend survival while maintaining quality of life. Many of the standard treatment regimens include twice-weekly bortezomib, which is associated with potentially severe peripheral neuropathy. The novel triplet regimen of once-weekly selinexor and once-weekly bortezomib with dexamethasone (XVd) improves cancer response and progression-free survival while decreasing the rate of peripheral neuropathy. This study used economic modeling to calculate the cost of the triplet XVd regimen per life-year gained and per quality-adjusted life-year gained. XVd had a lower cost with a higher quality-adjusted life-year benefit compared with lenalidomide/dexamethasone, pomalidomide/bortezomib/dexamethasone, and carfilzomib/pomalidomide/dexamethasone in previously treated multiple myeloma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Boston; Cost-Benefit Analysis; Dexamethasone; Humans; Hydrazines; Multiple Myeloma; Neoplasm Recurrence, Local; Triazoles

Topics: Acute Kidney Injury; Humans; Hydrazines; Multiple Myeloma; Triazoles; Tumor Lysis Syndrome

Supportive care improves outcomes in many cancers. In the pivotal STORM study selinexor, a first-in-class, oral, selective exportin 1 inhibitor, and low-dose dexamethasone proved to be an effective treatment for patients with triple-class refractory myeloma. We conducted a post-hoc analysis to test the hypothesis that increased utilization of supportive care measures in a sub-cohort of the STORM study prolonged treatment duration with- and improved efficacy of- selinexor.. The STORM protocol included specific recommendations for dose modifications and supportive care to mitigate selinexor most common adverse events (AEs) including nausea, fatigue, and thrombocytopenia. The Tisch Cancer Center at Mount Sinai School of Medicine (MSSM) incorporated additional supportive care strategies within the framework of the STORM protocol.. Of 123 patients enrolled in STORM, 28 were enrolled at MSSM. The overall response rate was 26.2% in the overall STORM population and 53.6% in the MSSM cohort. Moreover, duration of response, progression free survival, and overall survival were longer in the MSSM cohort. AEs and dose modification events were similar in the 2 groups. The MSSM cohort had more dose reductions (67.9% vs. 50.5%), and higher use of multiple antiemetic agents (71.4% vs. 50.1%) and romiplostim (32.1% vs. 6.3%), but less discontinuations due to treatment-related AEs (3.6% vs. 25.3%).. These results suggests that in addition to more frequent dose reductions, prompter and more aggressive supportive care may have contributed to the low discontinuation rate, longer duration therapy, and greater efficacy rates observed in the MSSM cohort. (ClinicalTrials.gov NCT02336815).

Topics: Humans; Hydrazines; Multiple Myeloma; Treatment Outcome; Triazoles

Topics: Active Transport, Cell Nucleus; Antineoplastic Combined Chemotherapy Protocols; Humans; Hydrazines; Multiple Myeloma; Triazoles

Topics: Advisory Committees; Drug Approval; Humans; Hydrazines; Multiple Myeloma; Triazoles; United States; United States Food and Drug Administration

Topics: Humans; Hydrazines; Multiple Myeloma; Quality of Life; Survival Analysis; Triazoles

Selinexor is an oral, small molecule inhibitor of the nuclear export protein exportin 1 with demonstrated activity in hematologic and solid malignancies. Side effects associated with selinexor include nausea, vomiting, fatigue, diarrhea, decreased appetite, weight loss, thrombocytopenia, neutropenia, and hyponatremia. We reviewed 437 patients with multiple myeloma treated with selinexor and assessed the kinetics of adverse events and impact of supportive care measures. Selinexor reduced both platelets and neutrophils over the first cycle of treatment and reached a nadir between 28 and 42 days. Platelet transfusions and thrombopoietin receptor agonists were effective at treating thrombocytopenia, and granulocyte colony stimulating factors were effective at resolving neutropenia. The onset of gastrointestinal side effects (nausea, vomiting, and diarrhea) was most common during the first 1-2 weeks of treatment. Nausea could be mitigated with 5-HT3 antagonists and either neurokinin 1 receptor antagonists, olanzapine, or cannbainoids. Loperamide and bismuth subsalicylate ameliorated diarrhea. The primary constitutional side effects of fatigue and decreased appetite could be managed with methylphenidate, megestrol, cannabinoids or olanzapine, respectively. Hyponatremia was highly responsive to sodium replacement. Selinexor has well-established adverse effects that mainly occur within the first 8 weeks of treatment, are reversible, and respond to supportive care.

Topics: Aged; Antineoplastic Agents; Appetite; Clinical Trials as Topic; Diarrhea; Fatigue; Female; Humans; Hydrazines; Hyponatremia; Male; Middle Aged; Multiple Myeloma; Nausea; Thrombocytopenia; Triazoles

Topics: Adult; Aged; Cell- and Tissue-Based Therapy; Female; Humans; Hydrazines; Male; Middle Aged; Multiple Myeloma; Receptors, Chimeric Antigen; Triazoles

Seventy-six FDA-approved oncology drugs and emerging therapeutics were evaluated in 25 multiple myeloma (MM) and 15 non-Hodgkin's lymphoma cell lines and in 113 primary MM samples. Ex vivo drug sensitivities were mined for associations with clinical phenotype, cytogenetic, genetic mutation, and transcriptional profiles. In primary MM samples, proteasome inhibitors, dinaciclib, selinexor, venetoclax, auranofin, and histone deacetylating agents had the broadest cytotoxicity. Of interest, newly diagnosed patient samples were globally less sensitive especially to bromodomain inhibitors, inhibitors of receptor tyrosine kinases or non-receptor kinases, and DNA synthesis inhibitors. Clustering demonstrated six broad groupings of drug sensitivity linked with genomic biomarkers and clinical outcomes. For example, our findings mimic clinical observations of increased venetoclax responsiveness in t(11;14) patients but also identify an increased sensitivity profile in untreated patients, standard genetic risk, low plasma cell S-Phase, and in the absence of Gain(1q) and t(4;14). In contrast, increased ex vivo responsiveness to selinexor was associated with biomarkers of poor prognosis and later relapse patients. This "direct to drug" screening resource, paired with functional genomics, has the potential to successfully direct appropriate individualized therapeutic approaches in MM and to enrich clinical trials for likely responders.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Hydrazines; Multiple Myeloma; Precision Medicine; Sulfonamides; Triazoles; Tumor Cells, Cultured

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Humans; Hydrazines; Middle Aged; Multiple Myeloma; Triazoles

High-dose chemotherapy with melphalan followed by autologous transplantation is a first-line treatment for multiple myeloma. Here, we present preclinical evidence that this treatment may be significantly improved by the addition of exportin 1 inhibitors (XPO1i). The XPO1i selinexor, eltanexor, and KOS-2464 sensitized human multiple myeloma cells to melphalan. Human 8226 and U266 multiple myeloma cell lines and melphalan-resistant cell lines (8226-LR5 and U266-LR6) were highly sensitized to melphalan by XPO1i. Multiple myeloma cells from newly diagnosed and relapsed/refractory multiple myeloma patients were also sensitized by XPO1i to melphalan. In NOD/SCIDγ mice challenged with either parental 8226 or U266 multiple myeloma and melphalan-resistant multiple myeloma tumors, XPO1i/melphalan combination treatments demonstrated stronger synergistic antitumor effects than single-agent melphalan with minimal toxicity. Synergistic cell death resulted from increased XPO1i/melphalan-induced DNA damage in a dose-dependent manner and decreased DNA repair. In addition, repair of melphalan-induced DNA damage was inhibited by selinexor, which decreased melphalan-induced monoubiquitination of FANCD2 in multiple myeloma cells. Knockdown of FANCD2 was found to replicate the effect of selinexor when used with melphalan, increasing DNA damage (γH2AX) by inhibiting DNA repair. Thus, combination therapies that include selinexor or eltanexor with melphalan may have the potential to improve treatment outcomes of multiple myeloma in melphalan-resistant and newly diagnosed patients. The combination of selinexor and melphalan is currently being investigated in the context of high-dose chemotherapy and autologous transplant (NCT02780609). SIGNIFICANCE: Inhibition of exportin 1 with selinexor synergistically sensitizes human multiple myeloma to melphalan by inhibiting Fanconi anemia pathway-mediated DNA repair.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; DNA Damage; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Exportin 1 Protein; Fanconi Anemia Complementation Group D2 Protein; Humans; Hydrazines; Karyopherins; Melphalan; Mice, Inbred NOD; Multiple Myeloma; Nestin; Receptors, Cytoplasmic and Nuclear; Triazoles; Ubiquitination; Xenograft Model Antitumor Assays

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase I as Topic; Dexamethasone; Humans; Hydrazines; Multicenter Studies as Topic; Multiple Myeloma; Retreatment; Triazoles

Topics: Dexamethasone; Humans; Hydrazines; Multiple Myeloma; Triazoles

Topics: Dexamethasone; Humans; Hydrazines; Multiple Myeloma; Triazoles

Topics: Dexamethasone; Humans; Hydrazines; Multiple Myeloma; Triazoles

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Dexamethasone; Humans; Hydrazines; Multiple Myeloma; Treatment Outcome; Triazoles

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Clinical Trials, Phase I as Topic; Humans; Hydrazines; Multiple Myeloma; Randomized Controlled Trials as Topic; Treatment Outcome; Triazoles

Exportin1 (XPO1; also known as chromosome maintenance region 1, or CRM1) controls nucleo-cytoplasmic transport of most tumor suppressors and is overexpressed in many cancers, including multiple myeloma, functionally impairing tumor suppressive function via target mislocalization. Selective inhibitor of nuclear export (SINE) compounds block XPO1-mediated nuclear escape by disrupting cargo protein binding, leading to retention of tumor suppressors, induction of cancer cell death, and sensitization to other drugs. Combined treatment with the clinical stage SINE compound selinexor and the irreversible proteasome inhibitor (PI) carfilzomib induced synergistic cell death of myeloma cell lines and primary plasma cells derived from relapsing/refractory myeloma patients and completely impaired the growth of myeloma cell line-derived tumors in mice. Investigating the details of SINE/PI-induced cell death revealed (i) reduced Bcl-2 expression and cleavage and inactivation of Akt, two prosurvival regulators of apoptosis and autophagy; (ii) intracellular membrane-associated aggregation of active caspases, which depended on caspase-10 protease activity; and (iii) novel association of caspase-10 and autophagy-associated proteins p62 and LC3 II, which may prime activation of the caspase cascade. Overall, our findings provide novel mechanistic rationale behind the potent cell death induced by combining selinexor with carfilzomib and support their use in the treatment of relapsed/refractory myeloma and potentially other cancers.

Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagy; Caspase 10; Caspase 8; Cell Line, Tumor; Disease Models, Animal; Drug Synergism; Enzyme Activation; Humans; Hydrazines; Intracellular Space; Mice; Multiple Myeloma; Oligopeptides; Proteasome Inhibitors; Triazoles; Xenograft Model Antitumor Assays

Acquired proteasome-inhibitor (PI) resistance is a major obstacle in the treatment of multiple myeloma (MM). We investigated whether the clinical XPO1-inhibitor selinexor, when combined with bortezomib or carfilzomib, could overcome acquired resistance in MM. PI-resistant myeloma cell lines both in vitro and in vivo and refractory myeloma patient biopsies were treated with selinexor/bortezomib or carfilzomib and assayed for apoptosis. Mechanistic studies included NFκB pathway protein expression assays, immunofluorescence microscopy, ImageStream flow-cytometry, and proximity-ligation assays. IκBα knockdown and NFκB activity were measured in selinexor/bortezomib-treated MM cells. We found that selinexor restored sensitivity of PI-resistant MM to bortezomib and carfilzomib. Selinexor/bortezomib treatment inhibited PI-resistant MM tumor growth and increased survival in mice. Myeloma cells from PI-refractory MM patients were sensitized by selinexor to bortezomib and carfilzomib without affecting non-myeloma cells. Immunofluorescence microscopy, Western blot, and ImageStream analyses of MM cells showed increases in total and nuclear IκBα by selinexor/bortezomib. Proximity ligation found increased IκBα-NFκB complexes in treated MM cells. IκBα knockdown abrogated selinexor/bortezomib-induced cytotoxicity in MM cells. Selinexor/bortezomib treatment decreased NFκB transcriptional activity. Selinexor, when used with bortezomib or carfilzomib, has the potential to overcome PI drug resistance in MM. Sensitization may be due to inactivation of the NFκB pathway by IκBα.

Topics: Active Transport, Cell Nucleus; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bortezomib; Cell Line, Tumor; Cell Nucleus; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Exportin 1 Protein; Female; Gene Expression Regulation, Neoplastic; Humans; Hydrazines; Karyopherins; Mice, Inbred NOD; Mice, SCID; Multiple Myeloma; NF-kappa B; NF-KappaB Inhibitor alpha; Oligopeptides; Proteasome Endopeptidase Complex; Protein Stability; Proteolysis; Receptors, Cytoplasmic and Nuclear; RNA Interference; Time Factors; Transcription, Genetic; Transfection; Triazoles; Xenograft Model Antitumor Assays