New proteasome inhibitors in the treatment of multiple myeloma

Abstract The treatment of patients with relapsed and/or refractory multiple myeloma has improved considerably in the last 15 years, after the introduction of proteasome inhibitors and immunomodulatory drugs. The first clinical trials with new proteasome inhibitors have produced exciting results, particularly those comparing triplet regimens with standard doublet regimens, with a gain in progression-free survival accompanied by an acceptable safety profile and either similar or better health-related quality of life. New proteasome inhibitors hold the potential to fill unmet needs in multiple myeloma management regarding improvement of clinical outcomes, including delayed progression of disease in high-risk patients. This review summarizes the main pharmacological properties and clinical outcomes of these agents, and discusses their potential to change the whole multiple myeloma therapeutic landscape.

New proteasome inhibitors in the treatment of multiple myeloma.

The treatment of patients with relapsed and/or refractory multiple myeloma has improved considerably in the last 15 years, after the introduction of proteasome inhibitors and immunomodulatory drugs. The first clinical trials with new proteasome inhibitors have produced exciting results, particularly those comparing triplet regimens with standard doublet regimens, with a gain in progression-free survival accompanied by an acceptable safety profile and either similar or better health-related quality of life. New proteasome inhibitors hold the potential to fill unmet needs in multiple myeloma management regarding improvement of clinical outcomes, including delayed progression of disease in high-risk patients. This review summarizes the main pharmacological properties and clinical outcomes of these agents, and discusses their potential to change the whole multiple myeloma therapeutic landscape.

Respira project: Humanistic and economic burden of asthma in Brazil.

OBJECTIVE: To determine the association of asthma on health-related quality of life (QoL), productivity, and use of healthcare resources among adults in Brazil. METHODS: Data were analyzed from the 2015 Brazil National Health and Wellness Survey, a cross-sectional survey with 12,000 adult respondents. Asthma and control groups were compared with respect to health-related QoL, asthma control, work productivity, and adherence. Generalized linear models were developed to compare asthma-related associations controlling for potential confounding factors. RESULTS: Among respondents, 4.1% (n = 494) reported an asthma diagnosis; those without asthma symptoms were used as the control group (n = 11,487). Regarding asthma control, 51.2% of patients had uncontrolled asthma, 36.4% partially controlled asthma, and 12.3% were fully controlled. Short-acting ß2 agonists were the most commonly used class of drugs (38.5%). Approximately 32.4% of asthma patients were considered fully adherent to their treatment. In multivariable analyses, asthma patients presented lower health-related QoL and had more frequent visits with medical healthcare providers (6.1 versus 4.2) emergency room visits (1.0 versus 0.5), and more hospitalizations (0.4 versus 0.2), than control respondents six months prior to the study (p < 0.05). Rates of absenteeism and presenteeism varied between 11.5% and 7.4% (p < 0.05) and 30.4% and 20.9% (p < 0.001) between asthma patients and controls, respectively. CONCLUSIONS: Asthma had a negative association on health-related QoL, work productivity, and use of healthcare resources. Excessive use of short-acting ß2 agonists and poor treatment adherence reflect poor asthma control and suggest the need to implement new strategies for asthma treatment in Brazil.

Optimisation of a quantitative polymerase chain reaction-based strategy for the detection and quantification of human herpesvirus 6 DNA in patients undergoing allogeneic haematopoietic stem cell transplantation.

Human herpesvirus 6 (HHV-6) may cause severe complications after haematopoietic stem cell transplantation (HSCT). Monitoring this virus and providing precise, rapid and early diagnosis of related clinical diseases, constitute essential measures to improve outcomes. A prospective survey on the incidence and clinical features of HHV-6 infections after HSCT has not yet been conducted in Brazilian patients and the impact of this infection on HSCT outcome remains unclear. A rapid test based on real-time quantitative polymerase chain reaction (qPCR) has been optimised to screen and quantify clinical samples for HHV-6. The detection step was based on reaction with TaqMan® hydrolysis probes. A set of previously described primers and probes have been tested to evaluate efficiency, sensitivity and reproducibility. The target efficiency range was 91.4% with linearity ranging from 10-106 copies/reaction and a limit of detection of five copies/reaction or 250 copies/mL of plasma. The qPCR assay developed in the present study was simple, rapid and sensitive, allowing the detection of a wide range of HHV-6 loads. In conclusion, this test may be useful as a practical tool to help elucidate the clinical relevance of HHV-6 infection and reactivation in different scenarios and to determine the need for surveillance.

Optimisation of a quantitative polymerase chain reaction-based strategy for the detection and quantification of human herpesvirus 6 DNA in patients undergoing allogeneic haematopoietic stem cell transplantation

Human herpesvirus 6 (HHV-6) may cause severe complications after haematopoietic stem cell transplantation (HSCT). Monitoring this virus and providing precise, rapid and early diagnosis of related clinical diseases, constitute essential measures to improve outcomes. A prospective survey on the incidence and clinical features of HHV-6 infections after HSCT has not yet been conducted in Brazilian patients and the impact of this infection on HSCT outcome remains unclear. A rapid test based on real-time quantitative polymerase chain reaction (qPCR) has been optimised to screen and quantify clinical samples for HHV-6. The detection step was based on reaction with TaqMan® hydrolysis probes. A set of previously described primers and probes have been tested to evaluate efficiency, sensitivity and reproducibility. The target efficiency range was 91.4% with linearity ranging from 10-106 copies/reaction and a limit of detection of five copies/reaction or 250 copies/mL of plasma. The qPCR assay developed in the present study was simple, rapid and sensitive, allowing the detection of a wide range of HHV-6 loads. In conclusion, this test may be useful as a practical tool to help elucidate the clinical relevance of HHV-6 infection and reactivation in different scenarios and to determine the need for surveillance.

FLT3 mutation and AML/ETO in a case of Myelodysplastic syndrome in transformation corroborates the two hit model of leukemogenesis.

The aim of this report is to present a case of Myelodysplastic syndrome (MDS) who presented, during AML transformation, a step-wise genetic progression that corroborates the two hit model of leukemogenesis. A RCDM-RS (WHO)/RARS (FAB) patient with normal karyotype at diagnosis, evolved into AML after six months of follow up. At transformation, AML/ETO fusion was detected, although marrow blast cells were not increased until 21 days later, when FLT3-ITD was also demonstrated pointing out that the overgrowth of the FLT3/ITD clone was concomitant with the outburst of marrow blasts. These findings corroborates the two hit model of leukemogenesis in which one class of mutations (Class I) (FLT3/ITD) confers a proliferative or survival advantage to cells, and a second class of mutations (Class II) (AML/ETO) interferes with hematopoietic differentiation.