The prognosis for patients multiple myeloma (MM) has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens that possess a high ...level of anti-tumor activity. In spite of this important progress, however, nearly all MM patients ultimately relapse, even those who experience a complete response to initial therapy. Management of relapsed MM thus represents a vital aspect of the overall care for patients with MM and a critical area of ongoing scientific and clinical research. This comprehensive manuscript from the International Myeloma Working Group provides detailed recommendations on management of relapsed disease, with sections dedicated to diagnostic evaluation, determinants of therapy, and general approach to patients with specific disease characteristics. In addition, the manuscript provides a summary of evidence from clinical trials that have significantly impacted the field, including those evaluating conventional dose therapies, as well as both autologous and allogeneic stem cell transplantation. Specific recommendations are offered for management of first and second relapse, relapsed and refractory disease, and both autologous and allogeneic transplant. Finally, perspective is provided regarding new agents and promising directions in management of relapsed MM.
Erythropoiesis-stimulating agents are used to treat anemia in patients with cancer. However, their safety and effectiveness is controversial. We did a systematic review of the clinical efficacy and ...harms of these agents in adults with anemia related to cancer or chemotherapy.
We conducted a systematic review of published and unpublished randomized controlled trials (RCTs) using accepted methods for literature searches, article selection, data extraction and quality assessment. We included RCTs involving anemic adults with cancer. We compared the use of erythropoiesis-stimulating agents with nonuse and assessed clinical outcomes (all-cause mortality, cardiovascular events and hypertension, health-related quality of life, blood transfusions and tumour response) and harms (serious adverse events) between groups.
We identified 52 trials (n = 12 006) that met our selection criteria. The pooled all-cause mortality during treatment was significantly higher in the group receiving erythropoiesis-stimulating therapy than in the control group (relative risk RR 1.15, 95% confidence interval CI 1.03 to 1.29). Compared with no treatment, use of erythropoiesis-stimulating agents led to clinically detectable improvements in disease-specific measures of quality of life. It also reduced the use of blood transfusions (RR 0.64, 95% CI 0.56 to 0.73). However, it led to an increased risk of thrombotic events (RR 1.69, 95% CI 1.27 to 2.24) and serious adverse events (RR 1.16, 95% CI 1.08 to 1.25).
Use of erythropoiesis-stimulating agents in patients with cancer-related anemia improved some disease-specific measures of quality of life and decreased the use of blood transfusions. However, it increased the risk of death and serious adverse events. Our findings suggest that such therapy not be used routinely as an alternative to blood transfusion in patients with anemia related to cancer.
The IALT, JBR.10, ANITA and Cancer and Leukemia Group B 9633 trials compared adjuvant chemotherapy with observation for patients with resected non-small-cell lung cancer (R-NSCLC). Data from the ...metastatic setting suggest high tumor class III beta-tubulin (TUBB3) expression is a determinant of insensitivity to tubulin-targeting agents (e.g. vinorelbine, paclitaxel). In 265 patients from JBR.10 (vinorelbine–cisplatin versus observation), high TUBB3 was an adverse prognostic factor and was associated (nonsignificantly) with ‘greater’ survival benefit from chemotherapy. We explored this further in additional patients from JBR.10 and the other three trials.
TUBB3 immunohistochemical staining was scored for 1149 patients on the four trials. The original JBR.10 cut-off scores were used to classify tumors as TUBB3 high or low. The prognostic and predictive value of TUBB3 on disease-free survival (DFS) and overall survival (OS) was assessed by Cox models stratified by trial and adjusted for clinical factors.
High TUBB3 expression was prognostic for OS hazard ratio (HR)=1.27 (1.07–1.51), P=0.008) and DFS HR=1.30 (1.11–1.53), P=0.001). TUBB3 was not predictive of a differential treatment effect interaction P=0.20 (OS), P=0.23 (DFS). Subset analysis (n=420) on vinorelbine–cisplatin gave similar results.
The prognostic effect of high TUBB3 expression in patients with R-NSCLC has been validated. We were unable to confirm a predictive effect for TUBB3.
In 2005, the first guidelines were published on the management of patients with multiple myeloma (MM). An expert panel reviewed the currently available literature as the basis for a set of revised ...and updated consensus guidelines for the diagnosis and management of patients with MM who are not eligible for autologous stem cell transplantation. Here we present recommendations on the diagnosis, treatment of newly diagnosed non-transplant-eligible patients and the management of complications occurring during induction therapy among these patients. These guidelines will aid the physician in daily clinical practice and will ensure optimal care for patients with MM.
Organisational culture has become a focus of much attention in industry in general and the nuclear industry in particular. In maintenance work, the research has addressed mainly human error issues or ...strategic decision making and optimisation. The present study utilises the CULTURE-questionnaire that is designed to measure the different cultural aspects of complex organisations. Functioning of the questionnaire and the results obtained in a case study at a maintenance organisation of a nuclear power plant are reported in this paper. The questionnaire consisted of four instruments: measures of values, psychological job characteristics, individual perceptions and organisational core task. Three of the instruments were factor analysed and 13 summated scales were formed. The core task instrument was used in a cluster analysis to separate the respondents into groups on the basis of their orientation towards the maintenance work. Differences between the work tasks, section, age and length of service were studied. Hierarchical position in the company influenced perceptions of values. Core task orientation influenced the perception and subjective feelings towards one's organisation. Several partially overlapping subcultures were thus identified. The implications of the different work orientations for effective maintenance are discussed.
The treatment of older persons with cancer is fraught by a delicate balance of targeting the disease while avoiding treatment‐related complications. “Personalized,” or “precision” medicine approaches ...can ease this problem through more efficacious and less toxic treatments. Multiple myeloma epitomizes the struggle to balance treatment options and their complications, for it is an incurable disease afflicting a predominantly aged population, and treatment is administered on a continuous schedule with little or no breaks. Over the last two decades, advances in drug development have improved outcomes for younger, fit patients, but older, frail patients have not realized the same benefit. This could be related to the benefits of three drug combinations, when frail patients can often tolerate only two drugs at a time. In myeloma, personalized approaches have lagged behind some other malignancies due to its genetic complexity and a paucity of abnormalities with associated targeted therapies. In contrast, the disease is managed with an array of drugs that target phenotypic characteristics common in malignant plasma cells. To address the unmet need for personalized medicine in myeloma, we developed a functional approach by profiling the sensitivity of patients’ myeloma to clinically available drugs. Through this, we observed that receiving at least two effective drugs portended better outcomes, leaving those patients who can only tolerate two drug regimens without room for error. We now describe a frail patient's case and their drug sensitivity profile to illustrate how personalized treatment could have led to an improved disease course. Personalized treatment could provide the greatest survival improvements to older adults with cancers, such as multiple myeloma, through avoiding undertreatment, limiting attrition through subsequent lines of therapy, reducing exposure to ineffective drugs and streamlining the management of relapses. Exploring these avenues is imperative to closing the gap of cancer‐related mortality in older and frail persons.
In comparison to the contemporary approach to multiple myeloma, personalized treatment has the potential to guide more efficient drug selection and disease targeting. Although three drug regimens have repeatedly proven superior in this disease, older adults often receive two drugs to minimize treatment‐related toxicities. Consequently, older adults are at risk to receive less effective treatment, contributing to their currently inferior outcomes. Here, we discuss Myeloma Drug Sensitivity Testing (My‐DST) as an approach to personalized treatment for Multiple Myeloma by distinguishing relative drug sensitivity (S) versus resistance (R) to the commonly used drugs for this malignancy. Through personalized therapy to optimize the ratio of effective drugs, older persons stand to derive the most benefit if we can minimize poor responses and side effects, simultaneously improving survival and quality of life (QOL) outcomes.
In any given week, media headlines publicize the benefits of a new “breakthrough” cancer drug, with patients and clinicians subsequently advocating for its use. ...
High-dose melphalan (HDM) is an essential component in the treatment of patients with multiple myeloma (MM). Few data are available regarding genetic polymorphisms associated with patient outcome or ...toxicity in this setting. To identify such polymorphisms, we performed a retrospective analysis, genotyping single nucleotide polymorphisms (SNPs) with the arrayed primer extension (APEX) technology in 169 patients having received HDM for MM. We analyzed 209 SNPs in 95 genes involved in drug metabolism, DNA repair, cell cycle and apoptosis. SNPs in ABCB1, CYP3A4 and TP53BP2 were associated with response to VAD induction therapy (P<0.01). SNPs in ALDH2, GSTT2 and BRCA1 were associated with response to HDM (P<0.01). Polymorphisms in CYP1A1, RAD51 and PARP were associated with disease progression whereas polymorphisms in ALDH2 and CYP1A1 were correlated with OS. Polymorphisms in BRCA1, CDKN1A and XRCC1 were associated with the occurrence of severe mucositis after HDM. These results suggest that SNPs of genes involved in drug metabolism or DNA repair could be used to distinguish MM patient subgroups with different toxicity/efficacy profiles.
► Safety indicators are tools for an effective safety management process. ► A theoretical framework for utilizing safety performance indicators is presented. ► The framework incorporates three types ...of indicators – outcome, monitor and drive. ► Drive indicators are utilized to direct activity in the organization. ► Monitor indicators provide a view on the dynamics of the organization.
An indicator can be considered any measure – quantitative or qualitative – that seeks to produce information on an issue of interest. Safety indicators can play a key role in providing information on organizational performance, motivating people to work on safety and increasing organizational potential for safety. We will describe the challenges of monitoring and driving system safety. Currently, the same lead indicators are used – explicitly or implicitly – for both purposes. The fact that the selection and use of safety performance indicators is always based on a certain understanding (a model) of the sociotechnical system and safety is often forgotten. We present a theoretical framework for utilizing safety performance indicators in safety–critical organizations that incorporates three types of safety performance indicators – outcome, monitor and drive indicators. We provide examples of each type of indicator and discuss the application of the framework in organizational safety management. We argue that outcome indicators are lag indicators since outcomes always follow something; they are the consequences arising from multiple other situational and contextual factors. Monitor and drive indicators are lead indicators. The main function of the drive indicators is to direct the sociotechnical activity in the organization by motivating certain safety-related activities. Monitor indicators provide a view on the dynamics of the organization: the practices, abilities, skills and motivation of the personnel – the organizational potential for safety. We conclude that organizations should better acknowledge the significance of monitor and drive indicators in safety management.
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