Immunotherapeutic approaches have remarkably changed the treatment paradigm for multiple myeloma, and encouraging patient responses have warranted further investigation into mAbs, adoptive T-cell therapy, vaccines, and combination therapy.
Despite advances in treatment for multiple myeloma, the majority of patients ultimately develop relapsed disease marked by immune evasion and resistance to standard therapy. Immunotherapy has emerged as a powerful tool for tumor-directed cytotoxicity with the unique potential to induce immune memory to reduce the risk of relapse. Understanding the specific mechanisms of immune dysregulation and dysfunction in advanced myeloma is critical to the development of further therapies that produce a durable response. Adoptive cellular therapy, most strikingly CAR T cell therapy, has demonstrated dramatic responses in the setting of refractory disease. Understanding the factors that contribute to immune evasion and the mechanisms of response and resistance to therapy will be critical to developing the next generation of adoptive cellular therapies, informing novel combination therapy, and determining the optimal time to incorporate immune therapy in the treatment of myeloma.
Heart failure is a major source of morbidity and mortality, driven, in part, by maladaptive sympathetic hyperactivity in response to poor cardiac output. Current therapies target β-adrenergic and angiotensin II G proteincoupled receptors to reduce adverse cardiac remodeling and improve clinical outcomes; however, there is a pressing need for new therapeutic approaches to preserve cardiac function. β-arrestin is a multifunctional protein which has come under analysis in recent years as a key player in G protein-coupled receptor signal transduction and a potential therapeutic target in heart failure. β-arrestin attenuates β-adrenergic and angiotensin II receptor signaling to limit the deleterious response to excessive sympathetic stimulation while simultaneously transactivating cardioprotective signaling cascades that preserve cardiac structure and function in response to injury. β-arrestin signaling may provide unique advantages compared to classic heart failure treatment approaches, but a number of challenges currently limit clinical applications. In this review, we discuss the role and functions of β-arrestin and the current attempts to develop G protein-coupled receptor agonists biased towards β-arrestin activation. Furthermore, we examine the functional diversity of cardiac β-arrestin isotypes to explore key considerations in the promise of β-arrestin as a pharmacotherapeutic target in heart failure.
Carfilzomib and dexamethasone (Kd) has significant activity in relapsed and refractory multiple myeloma. Kd has not previously been evaluated in newly diagnosed multiple myeloma (NDMM). We report a single-arm phase 2 study of 72 patients with NDMM to evaluate the efficacy and tolerability of Kd induction.Carfilzomib was administered in two dosing cohorts with dosing of 20/45 mg/m 2 in the first 25 patients and 20/56 mg/m 2 in the subsequent 47 patients. Carfilzomib was administered on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle, dexamethasone 20 mg was administered orally on days 1, 2, 8,9,15,16, 22 and 23. Treatment was continued to maximum response, progression of disease, or regimen intolerability. Endpoints included overall response rate (ORR), regimen toxicity and impact of carfilzomib on CD34+ stem cell collection yield. Sixty-five pts achieved at least a partial response (PR) for an ORR of 90%. The maximum response achieved was complete response or better in 5 (7%), very good partial response (VGPR) in 42 (58%), PR in 18 (25%) and stable disease in 7 pts (10%). Toxicities were predominantly low grade with 547 grade 1/2 adverse events and 44 grade ≥3 events. The rate of grade ≥3 cardiovascular adverse events was 11.1% with eight observed events. The activity of Kd described represents the highest rate of overall response and ≥VGPR for any 2-agent combination in NDMM reported to date. Kd demonstrated a safety profile consistent with previously reported carfilzomib studies.
Patients with urothelial carcinoma (UC) tend to be older and frailer with a large number of chronic medical conditions. This is particularly pronounced in those with locally advanced or metastatic UC. Prior to 2016, treatment options in advanced urothelial carcinoma (aUC) were limited to chemotherapy, and as a result, a large number of patients were not receiving diseasedirected therapy. Over the last six years, multiple alternative modalities including immune checkpoint inhibitors, enfortumab vedotin, sacituzumab govitecan and erdafitinib have been introduced. They are being used clinically in older and frail patients, but their efficacy and safety profiles remain underexplored in these populations. Based upon available evidence, age does not appear to impact the efficacy and tolerance of immune checkpoint inhibitors if patients are fit enough to receive therapy. There is still not enough evidence to draw specific conclusions regarding the use of enfortumab vedotin, sacituzumab govitecan and erdafitinib in older and frail patients. Regardless, in all older patients with aUC, it is critical to evaluate for frailty through geriatric screening tools and comprehensive assessments. Combining these evaluations with consideration of an individual patient's goals should be the foundation upon which therapeutic decisions are made in this population of patients. Key Points Age is not an independent predictor of safety or efficacy in the management of aUC, but instead, should serve as a signal to providers to assess for frailty, which can have a significant impact on outcomes. In older and frailer patients with advanced urothelial carcinoma, immune checkpoint inhibitors appear to be a well-tolerated treatment modality in the first and second line settings. At present, there is not enough data to comment definitively on the efficacy and safety of enfortumab vedotin, sacituzumab govitecan and erdafitinib in older and frail patients.2 Setting the Stage: The Introduction of ICIs, Enfortumab Vedotin, Sacituzumab Govitecan and Erdafitinib Since the 1980's, cisplatin has been the primary agent in aUC. It is the foundation upon which multiple combination regimens have been developed including methotrexate, vinblastine, adriamycin and cisplatin (MVAC) as well as gemcitabine plus cisplatin (GC) [13]. Ultimately, a head-to-head phase III trial of GC versus MVAC demonstrated similar overall response rate, progression free survival (PFS) and overall survival (OS), but given less adverse effects associated with GC, it has been the preferred first-line (1L) regimen in cisplatin-eligible patients [14][15]. Prior to 2016, the preferred therapy in cisplatin-ineligible patients was carboplatin and gemcitabine. Carboplatin-based regimens are inferior to cisplatin-based regimens with worse objective and complete responses, but they are better tolerated in frailer patients [16][17]. In those deemed platinum-ineligible, non-platinum-based regimens centered on the use of gemcitabine, but even still, as much as 23.8% -48.4% of patients were n...
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