Network Meta-Analysis of Once Weekly Selinexor-Bortezomib-Dexamethasone in Previously Treated Multiple Myeloma.

Background: Despite the availability of new treatments, multiple myeloma (MM) is an incurable cancer with nearly all patients relapsing and undergoing multiple lines of treatment. Performing head-to-head comparisons of all treatment options is not feasible. Thus, network meta-analyses play an important role in allowing health-care decision makers to compare the effectiveness of treatment options. Objectives: A Bayesian network meta-analysis (NMA) was developed from studies identified from a systematic literature review (SLR) to evaluate the efficacy of once weekly oral selinexor with once weekly bortezomib and low-dose dexamethasone (XVd) relative to other therapies in previously treated MM. Methods: Ovid was systematically searched for phase 2-3 randomized clinical trials (RCTs) in MM that assessed progression-free survival (PFS), overall survival (OS) and overall response rates (ORR). Two population subsets were assessed: second-line patients (2L) and third-line or greater patients (3L+). Base case results compared all regimens against twice weekly bortezomib and dexamethasone (Vd) as the anchored comparator regimen. Results: Forty-seven RCTs met inclusion. For 2L PFS, OS and ORR, XVd had, on average, out of all iterations, the 6th (out of 21), 4th (out of 15), and 5th (out of 20) best result, respectively, versus Vd. For 3L+ PFS, OS and ORR, XVd had the 12th (out of 24), 11th (out of 22), and 8th (out of 25) best result, respectively, versus Vd. There was no statistically significant difference between XVd and other top-ranking therapies for PFS, OS, and ORR in either 2L and 3L+ except for daratumumab/bortezomib/dexamethasone [DVd], which was favorable versus XVd (2L PFS only). Discussion: Results for XVd were more favorable in 2L, having a higher probability of being a top 5 regimen, compared with 3L+ therapies based on the reported clinical trial results. However, in typical clinical practice, most triplet regimens have been modified using weekly bortezomib dosing, raising questions about the actual efficacy of these regimens versus the reported results using twice weekly bortezomib dosing. Conclusions: The addition of XVd, which was designed with once weekly bortezomib dosing, to the treatment landscape for previously treated MM provides a regimen that may potentially be noninferior to the other top 5 regimens in both 2L and 3L+ settings and is associated with less peripheral neuropathy.

Cost Effectiveness of Triplet Selinexor-Bortezomib-Dexamethasone (XVd) in Previously Treated Multiple Myeloma (MM) Based on Results from the Phase III BOSTON Trial.

BACKGROUND AND OBJECTIVE: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.

US Budget Impact Model for Selinexor, Bortezomib, and Dexamethasone for the Treatment of Previously Treated Multiple Myeloma.

PURPOSE: To estimate the budget impact of selinexor, bortezomib, and dexamethasone (XVd) in patients with previously treated multiple myeloma (MM) from the perspective of a private third-party payer and Medicare in the US. METHODS: The introduction of XVd as an option for patients with previously treated MM compared to no introduction of XVd was considered from a private third-party US payer (with 1,000,000 members) and a Medicare perspective in one-year increments for 3 years. Total annual treatment costs were calculated as the sum of drug costs, costs of treating serious treatment emergent adverse events (grade ≥3), ongoing best supportive care costs, and mortality costs. RESULTS: The absolute budget impact (Millions, USD) of including XVd from a private third-party payer plan perspective was $0.06, $0.07, $0.08 and $0.22 for years 1, 2, 3, and overall, respectively. The relative budget impact of including XVd was 0.33%, 0.40%, 0.43%, and 0.38% for years 1, 2, 3, and overall, respectively. This translated to a per member per month (PMPM) budget impact of $0.005, $0.006, $0.007, and $0.006 (USD), for years 1, 2, 3, and overall, respectively. From a Medicare perspective, the absolute budget impact (Millions, USD) of including XVd was $29.68, $36.62, $39.42 and $105.72 for years 1, 2, 3, and overall, respectively. The relative budget impact of including XVd was 0.33%, 0.40%, 0.43%, and 0.38% percent for years 1, 2, 3, and overall, respectively. This translated to a PMPM budget impact of $0.041, $0.051, $0.054, and $0.049 (USD), for years 1, 2, 3, and overall, respectively. Sensitivity analyses showed general consistency with the base-case findings. CONCLUSION: Understanding the potential budget impact of new therapies in MM is vital for payers to manage spending and assess treatment value. The introduction of XVd presents a manageable budget impact for a third-party US payer and Medicare.

Health-related quality of life and pain with selinexor in patients with advanced dedifferentiated liposarcoma.

Objective: Compare health-related quality of life (HRQoL) of selinexor versus placebo in patients with dedifferentiated liposarcoma. Materials & methods: HRQoL was assessed at baseline and day 1 of each cycle using the European Organization for Research and Treatment of Cancer 30-item core quality of life questionnaire. Results were reported from baseline to day 169 (where exposure to treatment was maximized while maintaining adequate sample size). Results: Pain scores worsened for placebo versus selinexor across all postbaseline visits, although differences in HRQoL at some visits were not significant. Other domains did not exhibit significant differences between arms; however, scores in both arms deteriorated over time. Conclusion: Patients treated with selinexor reported lower rates and slower worsening of pain compared with patients who received placebo.

Lay abstract The goal of this study was to compare the health-related quality of life (HRQoL) of patients with advanced unresectable dedifferentiated liposarcoma treated with selinexor compared with those treated with placebo. HRQoL was measured prior to treatment initiation and at the first day of each cycle of their treatment using the European Organization for Research and Treatment of Cancer 30-item core quality of life questionnaire. Pain scores worsened for placebo compared with selinexor across all visits after treatment, but differences at some visits were not significant. Other domains did not exhibit significant differences between arms; however, scores in both arms worsened over time reflecting the progressive disease burden in this patient population. As pain is one of the most devastating symptoms associated with advanced and progressing cancers, the significant reduction in pain in the selinexor arm, according to patient perception, represent a relevant added value of this drug in dedifferentiated liposarcoma.

An integrated genomic approach to the assessment and treatment of acute myeloid leukemia.

Traditionally, new scientific advances have been applied quickly to the leukemias based on the ease with which relatively pure samples of malignant cells can be obtained. Currently, our arsenal of approaches used to characterize an individual's acute myeloid leukemia (AML) combines hematopathologic evaluation, flow cytometry, cytogenetic analysis, and molecular studies focused on a few key genes. The advent of high-throughput methods capable of full-genome evaluation presents new options for a revolutionary change in the way we diagnose, characterize, and treat AML. Next-generation DNA sequencing techniques allow full sequencing of a cancer genome or transcriptome, with the hope that this will be affordable for routine clinical care within the decade. Microarray-based testing will define gene and miRNA expression, DNA methylation patterns, chromosomal imbalances, and predisposition to disease and chemosensitivity. The vision for the future entails an integrated and automated approach to these analyses, bringing the possibility of formulating an individualized treatment plan within days of a patient's initial presentation. With these expectations comes the hope that such an approach will lead to decreased toxicities and prolonged survival for patients.

Green tea catechins inhibit angiogenesis through suppression of STAT3 activation.

Previous studies indicate that green tea extract may inhibit breast cancer progression by blocking angiogenesis, although the molecular mechanisms are not well defined. We demonstrate that administration of Polyphenon E (Poly E), a standardized green tea extract, inhibited MDA-MB231 breast cancer and human dermal microvascular endothelial (HMVEC) cell migration and the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase 9 (MMP9). In addition, Poly E inhibited VEGF-induced neovascularization in vivo. We also demonstrate that Poly E blocked signal transducers and activators of transcription (STAT) signaling by suppressing interferon-gamma (IFN-gamma)-induced gene transcription via IFN-gamma-activating sequence (GAS) elements and downstream STAT3 activation by inhibiting STAT1 and STAT3 dimerization in MDA-MB231 cells. Transient expression of constitutively active STAT3 significantly reduced the inhibitory effect of Poly E on cell migration and VEGF and MMP9 expression. Taken together, these observations indicate that green tea extract inhibits angiogenesis partly through the disruption of STAT3-mediated transcription of genes, including VEGF.

Unlabeled uses of intravenous immune globulin.

PURPOSE: The unlabeled uses of intravenous immune globulin (IVIG) were reviewed. SUMMARY: A literature review was conducted to identify studies examining the unlabeled uses of IVIG. A review of 138 clinical trial abstracts identified 10 trials examining 2 labeled uses (635 patients) and 128 trials examining 61 different off-label uses (6781 patients). The most common off-label indications included multiple sclerosis, graft-versus-host disease in transplant patients, prevention of antiphospholipid syndrome in miscarriage, Guillain-Barré syndrome, and progression of human immunodeficiency virus after delivery. The studies appeared to support many of the acceptable off-label uses cited by various guideline groups. A total of 276 case reports were identified, with 268 reports representing 156 different off-label uses (362 patients). Seven meta-analyses were identified, evaluating recurrent miscarriage, in vitro fertilization failure, infection in preterm infants, multiple sclerosis, immune thrombocytopenic purpura, and pemphigoid. With the exception of recurrent miscarriage and infection in preterm infants, the off-label use of IVIG for these indications was associated with positive outcomes. An examination of IVIG guidelines by specialty society, payer, and other review organizations revealed that the biomedical evidence supporting off-label uses is being interpreted in different ways. Health care institutions are strongly urged to approve and closely monitor specific uses of IVIG to reserve dwindling supplies for the "best-evidence" uses. Clinicians should be aware of the limits of knowledge in many off-label uses and exercise restraint in prescribing for unproven indications. CONCLUSION: A literature review identified more than 150 unlabeled uses of IVIG. The evidence for these uses is being interpreted in different ways by various reviewing organizations.

Inhibition of mammary tumorigenesis in the C3(1)/SV40 mouse model by green tea.

Previous studies show inhibitory effects of green tea in chemically induced mammary tumors or human tumor explants, but not in spontaneous tumor models that are more representative of human breast cancer. The C3(1)/SV40 mouse model is particularly suited for breast cancer prevention studies because it produces spontaneous ductal adenocarcinomas and a predictable time course for mammary tumorigenesis through a multistage progression similar to that occurring in humans. We therefore used this model to test the chemoprotective effects of green tea. Administration of 0.5% Polyphenon E (Poly E) (a standardized preparation of green tea extract) in drinking water delayed tumor onset and suppressed tumor growth by 40%, compared to tap water-fed animals, with no adverse side effects. Histological analysis of mammary glands showed that green tea slowed the progression of ductal lesions to advanced mammary intraepithelial neoplasias and suppressed tumor invasiveness. Green tea inhibited the proliferation of ductal epithelial cells and tumors and, overall, disrupted post-pubertal ductal growth. Immunohistochemical analyses also demonstrated that green tea inhibited angiogenesis through a decrease in both ductal epithelial and stromal VEGF expression and a decrease in intratumoral microvascular density. Our data strongly support the potential use of green tea as a breast cancer chemopreventive agent.

Recruitment of histone deacetylase 4 to the N-terminal region of estrogen receptor alpha.

Transcriptional activation of estrogen receptor alpha (ERalpha) is regulated by the ligand-dependent activation function 2 and the constitutively active N-terminal activation function 1. To identify ERalpha N-terminal-specific coregulators, we screened a breast cDNA library by T7 phage display and isolated histone deacetylase 4 (HDAC4). HDAC4 interacts with the ERalpha N terminus both in vitro and in vivo. Presence of the ERalpha DNA binding domain and hinge region reduce HDAC4 recruitment whereas full-length ERalpha enhances recruitment. HDAC4 interaction is selective for the ERalpha and not ERbeta N terminus and occurs in the nucleus. We demonstrate in vivo that HDAC4 is recruited by the N terminus to the promoter of an endogenous estrogen responsive gene. HDAC4 suppresses transcriptional activation of ERalpha by estrogen and selective ER modulators (SERMs) such as tamoxifen in a cell type-dependent manner. Consistently, silencing of HDAC4 promotes the agonist effect of SERMs (tamoxifen and raloxifene) in a cell type-specific manner. These findings indicate a role for HDAC4 in regulating ERalpha activity as a novel N-terminal coregulator and uncover a mechanism by which certain cell types regulate SERM behavior.

Potent ligand-independent estrogen receptor activation by 3,3'-diindolylmethane is mediated by cross talk between the protein kinase A and mitogen-activated protein kinase signaling pathways.

We investigated the mechanism of ligand-independent activation of the estrogen receptor (ER) by 3,3'-diindolylmethane (DIM), a promising anticancer agent derived from vegetables of the Brassica genus, in Ishikawa and HEC-1B human endometrial cancer cells. DIM stimulated the activity of an ER-responsive reporter by over 40-fold, equivalent to the maximum induction produced by estradiol (E2), whereas cotreatment of cells with the ER antagonist, ICI-182,780 (ICI), abolished the stimulatory effect of DIM. DIM also induced the expressions of the endogenous genes, TGF-alpha, alkaline phosphatase, and progesterone receptor similar to levels induced by E2. Induction of gene expression by DIM was inhibited by the protein synthesis inhibitor, cycloheximide. In addition, cotreatment of cells with the protein kinase A (PKA) inhibitor, H89, or the MAPK inhibitor, PD98059, reduced DIM activation of the ER by 75% and 50%, respectively. Simultaneous treatment of cells with both inhibitors completely abolished the effect of DIM. DIM stimulated MAPK activity and induced phosphorylation of the endogenous PKA target, cAMP response element binding protein (CREB), in a PKA-dependent manner. Expression of MCREB, a nonphosphorylatable CREB mutant, partially abolished activation of the ER by DIM. These results demonstrate that DIM is a mechanistically novel activator of the ER that requires PKA-dependent phosphorylation of CREB.