Selinexor for the treatment of patients with relapsed or refractory multiple myeloma.

OBJECTIVE: Multiple myeloma cells resist standard therapies due to overexpression of the transport protein, exportin 1. Selinexor is a novel drug that targets the Exportin 1 protein in these cells. DATA SOURCE: A comprehensive search was done, and data showing the efficacy and safety of selinexor in relapsed/refractory multiple myeloma was collected using PubMed, Google Scholar, and clincialtrials.gov. DATA SUMMARY: Results from the clinical trials STORM, BOSTON, and STOMP were included. Parts I and II of the STORM trial revealed a progression-free survival (PFS) of 4.7 and 3.7 months, a median duration of response of 6.2 and 4.4 months, and an overall survival of 7.3 and 8.4 months, respectively. BOSTON trial's SVd arm (selinexor, bortezomib, and dexamethasone) had a median follow-up period of 13.2 months and an mPFS of 13.93 months. The Vd arm (bortezomib and dexamethasone) had a median follow-up duration of 16.5 months and an mPFS of 9.46 months. The STOMP trial is still active and has limited data available. The SKd arm (selinexor, carfilzomib, and dexamethasone) reported an overall response rate of 66.7% in patients with triple refractory multiple myeloma, and 82% in patients with high-risk cytogenetics. The SPd arm (selinexor, pomalidomide, and dexamethasone) shows an overall response rate of 54.30% in pomalidomide naïve-nonrefractory, 35.70% in pomalidomide refractory and 60% in those dosed at RP2D. SRd arm (selinexor, lenalidomide, and dexamethasone) shows an overall response rate of 91.7% in lenalidomide naïve and 12.5% in lenalidomide refractory patients. SVd (selinexor, bortezomib, and dexamethasone) arm reported an overall response rate of 63% in all patients while the SDd arm (selinexor, daratumumab, and dexamethasone) showed an overall response rate of 73%. CONCLUSION: To improve the outcome of patients with relapsed/refractory multiple myeloma, it is critical to develop new therapies, assess potential therapeutic synergies, and overcome drug resistance by determining the efficacy of multiple myeloma therapies across multiple disease subgroups.

Immune Checkpoint Inhibitor-Associated Myocarditis: A Literature Review.

Recently in the field of oncology, immune checkpoint inhibitors (ICI) are being increasingly utilized both in clinical trials and in clinical practice. It is a form of biological therapy that targets tumors by activating the immune system, which in turn eliminates proliferating cancer cells. These have numerous immune-related adverse events (irAEs), one of which is myocarditis, which has high rates of mortality. This article was a narrative review of myocarditis related to ICI use.  Studies from the PubMed, Cochrane, and American Society of Clinical Oncology (ASCO) databases were used in writing this review. The databases were searched for original publications for adverse effects related to ICI use and myocarditis specifically. There are numerous published instances of cancer immunotherapy causing myocarditis. ICI therapy has numerous benefits, as it upregulates the immune system to target cancer cells, utilizing the body's own defense mechanisms to target proliferating cells. Myocarditis is a serious side effect, however. Therefore, on balance, these monotherapies are worth using. While this literature review primarily identifies cross-reaction as the main mechanism of myocarditis, there are other possible mechanisms. One proposed mechanism involves a shared antigen between the myocardial tissue and the tumor. This mechanism is called molecular mimicry, where the monoclonal antibody attacks both the myocardial tissue and the tumor cell. Management of ICI-induced myocarditis has not been studied by randomized controlled trials or prospective studies, but based on previous case reports and case series it is mostly treated with steroids initially. An ICI rechallenge after temporary discontinuation appears conceivable in many cases, especially given its therapeutic effects, but only limited data are available on the safety of a rechallenge after an irAE. The lack of RCTs regarding rechallenge with an ICI after irAE, more so specifically about myocarditis, along with the overall results and the complexity involved in such cases once again emphasize the need to make decisions on an individual basis by a multidisciplinary expert working group. At the same time, the focus should also be on publishing more data as the need will grow along with the indications for ICI therapies.

Use of venetoclax in t(11;14) positive relapsed/refractory multiple myeloma: A systematic review.

BACKGROUND: The plasma cell malignancy, multiple myeloma (MM), remains incurable despite advanced treatment protocols. Overexpression of Bcl-2 (an anti-apoptotic protein), in MM harboring the translocation (11;14), contributes to resistance to prior therapy. Venetoclax, a selective oral inhibitor of BCL-2 is a novel agent that shows promise as a therapeutic agent. AIMS: The objective of this systematic review is to address how the use of venetoclax, alone or as a combination regimen, contributed to the treatment of patients with t(11:14) positive relapsed/refractory multiple myeloma (RRMM). DATA SOURCES: This systematic review was conducted in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was done on 5th June 2022. A literature search was conducted on PubMed and Scopus, 145 articles were screened and 10 studies were included. Risk of bias assessment was performed using the Methodological Index for Non-Randomized Studies (MINORS) criteria. DATA SUMMARY: Across the studies reviewed, a total of 311 patients were identified with t(11;14) positive RRMM. The overall response rate achieved ranged between 33% and 95.5%. Furthermore, the use of venetoclax has exhibited a favorable adverse effect profile. Side effects included hematological side effects, nausea, vomiting, and diarrhea. CONCLUSION: Venetoclax demonstrates promising results. When given with drugs like dexamethasone, daratumumab and carfilzomib, a synergistic effect is seen in treating translocation (11:14) positive relapsed/refractory MM. The use of venetoclax in clinical practice can potentially improve outcomes and quality of life in RRMM patients, and future research should continue to explore this promising treatment option.

Pembrolizumab-Induced Myasthenia Gravis: A Case Report and Review of the Literature.

Myasthenia gravis (MG) is one of the most common neuromuscular adverse effects of immune checkpoint inhibitors (ICIs) and can result in significant morbidity and mortality when it affects the bulbar and respiratory muscles. Diagnosing immune-related MG (irMG) is challenging due to its nonspecific presentation and high negativity rate for MG antibody markers. Patients, primary care providers, and emergency care providers should be educated about MG as a potential adverse effect of ICIs for timely diagnosis and intervention.

Treatment of eculizumab refractory paroxysmal nocturnal hemoglobinuria: A systematic review about current treatment options and future direction.

Objectives: C5 inhibitors such as eculizumab and ravulizumab are the first-line treatment in the management of paroxysmal nocturnal hemoglobinuria (PNH). However, some patients develop novel symptoms as part of their treatment with eculizumab, and the disease is termed as eculizumab refractory PNH. The aim of this study was to conduct a systematic review on the available treatment modalities for the management of eculizumab refractory PNH. Methods: Two authors independently searched two databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of 70 studies were obtained: 4 out 70 studies were found to meet the inclusion criteria. Results: Four studies were found to meet the inclusion criteria of our study. Two studies were published in 2021 and two studies were published in 2020. All four studies were multicenter clinical trials. Two studies were phase III clinical trials, one study was a phase II clinical trial, and one study was a phase I clinical trial. Two studies were about pegcetacoplan, one was about danicopan, and one was about iptacopan. Conclusion: Based upon the findings of our systematic review, we recommend an individualized treatment plan based on the mechanism of eculizumab refractoriness and the mechanism of PNH breakthrough. This recommendation is subject to the available resources and clinical expertise available at different hospitals. More studies using study designs such as randomized controlled trials comparing multiple drugs should be performed to accurately assess the different medications and aid in designing guidelines of the management of eculizumab refractory PNH. Level of evidence: Level I.

A systematic review on the available treatment modalities for Bacillus Calmette-Guérin-unresponsive carcinoma in situ and tumors in patients who are ineligible for or decline radical cystectomy.

Introduction: Globally, urothelial bladder carcinoma is a disease which carries a poor prognosis. There are various treatment modalities for urothelial bladder carcinoma with intravesical Bacillus Calmette-Guérin immunotherapy being the most efficacious intravesical therapy and the treatment of choice for patients with carcinoma in situ. A number of chemotherapeutic drugs are also available for the management of Ta/T1 tumors such as mitomycin C and epirubicin. However, relapse and progression is quite common. The optimal management of patients with Bacillus Calmette-Guérin-unresponsive disease remains to be a challenge. The purpose of this study was to conduct a systematic review on the treatment modalities available for the management of Bacillus Calmette-Guérin-unresponsive carcinoma in situ and urothelial bladder carcinoma in patients who are ineligible or decline radical cystectomy. Methods: Two authors independently searched three databases on the treatment modalities available for the management of Bacillus Calmette-Guérin-unresponsive carcinoma in situ and Bacillus Calmette-Guérin-unresponsive urothelial bladder carcinoma. Results: The systematic search resulted in 15 studies. We recommend the use of intravesical CG0070 adenovirus or hyperthermic intravesical chemotherapy mitomycin C in patients with carcinoma in situ only disease. In patients with carcinoma in situ ± Ta/T1 disease, we recommend the use of intravesical radiofrequency-induced chemohyperthermia or electromotive drug administration of mitomycin C. In patients who have Ta/T1 disease, we recommend the use of either hyperthermic intravesical chemotherapy epirubicin or electromotive drug administration mitomycin C followed by chemohyperthermia mitomycin C. If any of these second line therapies fail, an alternative regimen would be a combination of gemcitabine, cabazitaxel, and cisplatin. Conclusion: This recommendation is subject to the available resources and clinical expertise available in different hospitals. More studies using study designs such as randomized controlled trials comparing multiple drugs with larger sample sizes and regular follow-up intervals should be performed to accurately assess the different medications and aid in designing guidelines to guide the management of Bacillus Calmette-Guérin-unresponsive non-muscle invasive intravesical bladder cancer.

Narrative review: mesenchymal-epithelial transition inhibitors-meeting their target.

Genetic alterations in mesenchymal-epithelial transition (MET) are commonly found in solid tumors, especially in non-small cell lung cancer (NSCLC). However, agents targeting MET have not progressed until recently. Advancements in our understanding of the role of various MET aberrations in carcinogenesis have allowed MET-directed therapy to find its way to clinic use. Of all MET alterations, MET exon 14 skipping (METex14 skip+ or MET ∆ 14 ), stands out as a true oncogenic driver. Recently, MET tyrosine kinase inhibitors (TKI) targeting METex14 skipping were able to demonstrate significant improvement in clinical outcomes including response rate and progression free survival. Of these, capmatinib was granted accelerated approval by the FDA in May 2020 for patients with advanced NSCLC harboring METex14 skip alterations. Tepotinib, another TKI, has shown significant activity in a phase II trial and received breakthrough therapy designation from the FDA in September 2019. MET amplification (METAmp ) and overexpression are usually a late phenomenon in tumorigenesis and aggravate malignant properties of transformed cells. Capmatinib and savolitinib have shown activity in patients with NSCLC with high levels of METAmp . Several other agents are being developed and under evaluation in clinical trials involving multiple tumor types. In addition to TKIs, MET overexpression is also an appealing target for development of antibody conjugated chemotherapy. Understanding the mechanisms of resistance to MET TKIs and alterations in anti-tumor immunity through MET inhibition are clinically relevant areas that need further exploration.

Acute Myeloid Sarcoma: An Unusual Cause of Diarrhea.

A 62-year-old man with a past medical history of hypothyroidism was admitted for diarrhea and abdominal pain for three weeks. Initial workup for diarrhea was negative. His condition deteriorated after hospitalization. He underwent sigmoidoscopy which showed rectosigmoid mucosal ulceration. Pathology showed leukemic cells infiltration of the mucosa. The patient underwent bone marrow biopsy which confirmed the diagnosis of acute myeloid leukemia (AML). He received induction chemotherapy and his symptoms improved.

Efficacy and Adverse Events in Metastatic Melanoma Patients Treated with Combination BRAF Plus MEK Inhibitors Versus BRAF Inhibitors: A Systematic Review.

We reviewed the literature to assess the efficacy and risk of constitutional, cardiac, gastrointestinal, and dermatological toxicities of combined BRAF plus MEK inhibitors versus BRAF inhibitors alone in patients with metastatic melanoma with BRAF mutations. Searches were conducted in PubMed, Cochrane Database of Systematic Reviews, Google scholar, ASCO, Scopus, and EMBASE for reports published from January 2010 through March 2019. Efficacy, including progression-free survival (PFS) and overall survival (OS) rates, were assessed by hazard ratio (HR); objective response rates (ORR) were assessed by odds ratio (OR). The randomized clinical trials (RCTs) with comparison to vemurafenib monotherapy were included to determine constitutional, gastrointestinal, cardiac, and dermatological toxicities using PRISMA statistical analysis with relative risk (RR) for equal comparison to avoid inclusion bias. Five RTCs comprising 2307 patients were included to assess efficacy, while three of the five RCTs comprising 1776 patients were included to assess adverse events. BRAF plus MEK inhibitor combination therapy demonstrated overall better efficacy compared to BRAF inhibitor monotherapy. Combination therapies appear to have favorable dermatologic side effect profiles, similar constitutional and cardiac profiles, and slightly worse gastrointestinal profiles compares to monotherapy regimens.