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16. Cabezas-Wallscheid N, Eichwald V, de Graaf J, et al. Instruction of haematopoietic lineage choices, evolution of transcriptional land- scapes and cancer stem cell hierarchies derived from an AML1-ETO
mouse model. EMBO Mol Med. 2013;5(12):1804-1820.
17. Rhoades KL, Hetherington CJ, Harakawa N, et al. Analysis of the role of AML1-ETO in leukemogenesis, using an inducible transgenic
mouse model. Blood. 2000;96(6):2108-2115.
18. Yuan Y, Zhou L, Miyamoto T, et al. AML1-ETO expression is direct-
ly involved in the development of acute myeloid leukemia in the presence of additional mutations. Proc Natl Acad Sci U S A. 2001;98(18):10398-10403.
19. Christen F, Hoyer K, Yoshida K, et al. Genomic landscape and clonal evolution of acute myeloid leukemia with t(8;21): an international study on 331 patients. Blood. 2019;133(10):1140-1151.
20. Kuchenbauer F, Schnittger S, Look T, et al. Identification of additional cytogenetic and molecular genetic abnormalities in acute myeloid leukaemia with t(8;21)/AML1-ETO. Br J Haematol. 2006;134(6):616-619.
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Carfilzomib combination treatment as first-line therapy in multiple myeloma: where do we go from the Carthadex (KTd)-trial update?
Monika Engelhardt,1,2 Kwee Yong,3 Sara Bringhen4 and Ralph Wäsch1,2
1Hematology and Oncology, Faculty of Medicine, University of Freiburg, Freiburg, Germany; 2Comprehensive Cancer Center Freiburg (CCCF), Freiburg, Germany; 3University College London, London, UK and 4UNITO Dipartimento di Oncologia, University of Turin, Turin, Italy
E-mail: MONIKA ENGELHARDT - monika.engelhardt@uniklinik-freiburg.de doi:10.3324/haematol.2019.228684
The prognosis and treatment of multiple myeloma (MM) patients have substantially changed in the last decade due to a better understanding of the disease and the introduction of novel agents (NA) with new mechanisms of action against malignant plasma cells.1–3 In parallel with the improved understanding of myeloma biology, the field has witnessed a flood of NA, including immunomodulatory drugs (IMiD: thalidomide, lenalidomide, pomalidomide); proteasome inhibitors (PI: bortezomib, carfilzomib, ixazomib), monoclonal anti- bodies (mAb: daratumumab, elotuzumab),4 and histone deacetylase inhibitors, which have substantially improved progression-free survival (PFS) and overall sur- vival (OS). Other NA in clinical trials (selinexor, veneto- clax, novel immunotherapeutics, iberdomide, and others) are being intensively tested, and specifically immunotherapeutics beyond mAb, such as bispecific T- cell engager (BITE) molecules and chimeric antigen recep- tor (CAR)-T cells will expand anti-myeloma therapy options.1–4 Concomitantly, the application of tools that reliably assess “frailty” of patients is also helping with decision making, given that many patients with MM are elderly and often have significant comorbidities.5–10 Sustained disease response is crucial in fit and in frail patients, since disease response can significantly improve quality of life and may reduce MM-induced comorbidity. Optimizing tolerability for timely treatment delivery has also proved beneficial.11 However, this may prove chal- lenging with triplet or quadruplet regimens that are being developed for continued therapy, where adverse events (AE) may lead to treatment interruptions and discontinu- ation.
After the introduction of the first PI bortezomib (Btz/V), second- and third-generation PI were developed, with the aim of providing therapy that would be poten- tially more efficacious and less toxic, including an improved polyneuropathy (PNP) side effect profile. Carfilzomib (Cfz/K) is a second-in-class, epoxyketone- based, irreversibly binding PI, which is approved in com- bination with dexamethasone (Kd) or lenalidomide and dexamethasone (KRd) for the treatment of relapsed/refractory MM (RRMM) patients.12,13 The ENDEAVOR study compared Kd versus Btz plus dexam- ethasone (Vd) and reported a longer PFS and OS, with lower risk of painful PNP with Kd.13 The ASPIRE study demonstrated the superiority of KRd over Rd, with unprecedented PFS benefit, as well as OS benefit in RRMM.14 These studies have established the place of Cfz in treating RRMM.
Dyspnea, hypertension and cardiac toxicities stand out as clinically relevant side effects, and a widening experi- ence of these has led to published guidance for the use of Cfz, as well as a re-appraisal of the baseline cardiovascu- lar morbidity present in this patient group.15 Such guid- ance provides a helpful description of expected events, as well as suggestions for subsequent monitoring, detection and management.16,17 The analysis of cardiovascular adverse events (CVAE) in Cfz-treated patients revealed that, in those with CVAE, 91% had uncontrolled hyper- tension, with acute coronary syndrome or cardiac arrhythmias each present in 4.5%. Subjects with CVAE also had significantly higher blood pressure, left ventricu- lar mass, and pulse wave velocity at baseline evaluation, compared to those without. Baseline uncontrolled blood
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