Impact of prior lenalidomide or proteasome inhibitor exposure on the effectiveness of ixazomib–lenalidomide–dexamethasone for relapsed/refractory multiple myeloma: A pooled analysis from the INSURE study

Objectives: To characterize the impact of prior exposure and refractoriness to lenalidomide or proteasome inhibitors (PIs) on the effectiveness and safety of ixazomib–lenalidomide–dexamethasone (IRd) in relapsed/refractory multiple myeloma (RRMM). Methods: INSURE is a pooled analysis of adult RRMM patients who had received IRd in ≥2 line of therapy from three studies: INSIGHT MM, UVEA‐IXA, and REMIX. Results: Overall, 391/100/68 were lenalidomide‐naïve/−exposed/−refractory and 37/411/110 were PI‐naïve/−exposed/−refractory. Median duration of therapy (DOT) was 15.3/15.6/4.7 months and median progression‐free survival (PFS) was 21.6/25.8/5.6 months in lenalidomide‐naïve/exposed/refractory patients. Median DOT and PFS in PI‐naïve/exposed/refractory patients were 20.4/15.2/6.9 months and not reached/19.8/11.4 months, respectively. The proportion of lenalidomide‐naïve/exposed/refractory patients in INSIGHT and UVEA‐IXA who discontinued a study drug due to adverse events (AEs) was ixazomib, 31.6/28.2/28.0% and 18.6/6.7/10.5%; lenalidomide, 21.9/28.2/16.0% and 16.1/6.7/10.5%; dexamethasone, 18.4/20.5/16.0% and 10.6/0/10.5%, respectively. The proportion of PI‐naïve/exposed/refractory patients in INSIGHT and UVEA‐IXA who discontinued a study drug due to AEs was: ixazomib, 44.4/28.8/27.8% and 22.2/16.7/15.7%; lenalidomide, 33.3/22.0/19.4% and 16.7/15.9/11.8%; dexamethasone, 33.3/17.4/16.7% and 16.7/9.5/7.8%, respectively. REMIX AE discontinuation rates were unavailable. Conclusion: IRd appeared to be effective in RRMM patients in routine clinical practice regardless of prior lenalidomide or PI exposure, with better outcomes seen in lenalidomide‐ and/or PI‐nonrefractory versus refractory patients

Integrated analysis of randomized controlled trials evaluating bortezomib + lenalidomide + dexamethasone or bortezomib + thalidomide + dexamethasone induction in transplant-eligible newly diagnosed multiple myeloma

ObjectiveProviding the most efficacious frontline treatment for newly diagnosed multiple myeloma (NDMM) is critical for patient outcomes. No direct comparisons have been made between bortezomib + lenalidomide + dexamethasone (VRD) and bortezomib + thalidomide + dexamethasone (VTD) induction regimens in transplant-eligible NDMM.MethodsAn integrated analysis was performed using patient data from four trials meeting prespecified eligibility criteria: two using VRD (PETHEMA GEM2012 and IFM 2009) and two using VTD (PETHEMA GEM2005 and IFM 2013-04).ResultsThe primary endpoint was met, with VRD demonstrating a noninferior rate of at least very good partial response (>= VGPR) after induction vs VTD. GEM comparison demonstrated improvement in the >= VGPR rate after induction for VRD vs VTD (66.3% vs 51.2%; P = .00281) that increased after transplant (74.4% vs 53.5%). Undetectable minimal residual disease rates post induction (46.7% vs 34.9%) and post transplant (62.4% vs 47.3%) support the benefit of VRD vs VTD. Treatment-emergent adverse events leading to study and/or treatment discontinuation were less frequent with VRD (3%, GEM2012; 6%, IFM 2009) vs VTD (11%, IFM 2013-04).ConclusionThese results supported the benefit of VRD over VTD for induction in transplant-eligible patients with NDMM. The trials included are registered with ClinicalTrials.gov (NCT01916252, NCT01191060, NCT00461747, and NCT01971658)

Vulnerability to high risk sexual behaviour (HRSB) following exposure to war trauma as seen in post-conflict communities in eastern uganda: a qualitative study

<p>Abstract</p> <p>Background</p> <p>Much of the literature on the relationship between conflict-related trauma and high risk sexual behaviour (HRSB) often focuses on refugees and not mass in-country displaced people due to armed conflicts. There is paucity of research about contexts underlying HRSB and HIV/AIDS in conflict and post-conflict communities in Uganda. Understanding factors that underpin vulnerability to HRSB in post-conflict communities is vital in designing HIV/AIDS prevention interventions. We explored the socio-cultural factors, social interactions, socio-cultural practices, social norms and social network structures that underlie war trauma and vulnerability to HRSB in a post-conflict population.</p> <p>Methods</p> <p>We did a cross-sectional qualitative study of 3 sub-counties in <it>Katakwi </it>district and 1 in <it>Amuria </it>in Uganda between March and May 2009. We collected data using 8 FGDs, 32 key informant interviews and 16 in-depth interviews. We tape-recorded and transcribed the data. We followed thematic analysis principles to manage, analyse and interpret the data. We constantly identified and compared themes and sub-themes in the dataset as we read the transcripts. We used illuminating verbatim quotations to illustrate major findings.</p> <p>Results</p> <p>The commonly identified HRSB behaviours include; transactional sex, sexual predation, multiple partners, early marriages and forced marriages. Breakdown of the social structure due to conflict had resulted in economic destruction and a perceived soaring of vulnerable people whose propensity to HRSB is high. Dishonour of sexual sanctity through transactional sex and practices like incest mirrored the consequence of exposure to conflict. HRSB was associated with concentration of people in camps where idleness and unemployment were the norm. Reports of girls and women who had been victims of rape and defilement by men with guns were common. Many people were known to have started to display persistent worries, hopelessness, and suicidal ideas and to abuse alcohol.</p> <p>Conclusions</p> <p>The study demonstrated that conflicts disrupt the socio-cultural set up of communities and destroy sources of people's livelihood. Post-conflict socio-economic reconstruction needs to encompass programmes that restructure people's morals and values through counselling. HIV/AIDS prevention programming in post-conflict communities should deal with socio-cultural disruptions that emerged during conflicts. Some of the disruptions if not dealt with, could become normalized yet they are predisposing factors to HRSB. Socio-economic vulnerability as a consequence of conflict seemed to be associated with HRSB through alterations in sexual morality. To pursue safer sexual health choices, people in post-conflict communities need life skills.</p

Social autopsy: INDEPTH Network experiences of utility, process, practices, and challenges in investigating causes and contributors to mortality

<p>Abstract</p> <p>Background</p> <p>Effective implementation of child survival interventions depends on improved understanding of cultural, social, and health system factors affecting utilization of health care. Never the less, no standardized instrument exists for collecting and interpreting information on how to avert death and improve the implementation of child survival interventions.</p> <p>Objective</p> <p>To describe the methodology, development, and first results of a standard social autopsy tool for the collection of information to understand common barriers to health care, risky behaviors, and missed opportunities for health intervention in deceased children under 5 years old.</p> <p>Methods</p> <p>Under the INDEPTH Network, a social autopsy working group was formed to reach consensus around a standard social autopsy tool for neonatal and child death. The details around 434 child deaths in Iganga/Mayuge Health and Demographic Surveillance Site (HDSS) in Uganda and 40 child deaths in Dodowa HDSS in Ghana were investigated over 12 to 18 months. Interviews with the caretakers of these children elicited information on what happened before death, including signs and symptoms, contact with health services, details on treatments, and details of doctors. These social autopsies were used to assess the contributions of delays in care seeking and case management to the childhood deaths.</p> <p>Results</p> <p>At least one severe symptom had been recognized prior to death in 96% of the children in Iganga/Mayuge HDSS and in 70% in Dodowa HDSS, yet 32% and 80% of children were first treated at home, respectively. Twenty percent of children in Iganga/Mayuge HDSS and 13% of children in Dodowa HDSS were never taken for care outside the home. In both countries most went to private providers. In Iganga/Mayuge HDSS the main delays were caused by inadequate case management by the health provider, while in Dodowa HDSS the main delays were in the home.</p> <p>Conclusion</p> <p>While delay at home was a main obstacle to prompt and appropriate treatment in Dodowa HDSS, there were severe challenges to prompt and adequate case management in the health system in both study sites in Ghana and Uganda. Meanwhile, caretaker awareness of danger signs needs to improve in both countries to promote early care seeking and to reduce the number of children needing referral. Social autopsy methods can improve this understanding, which can assist health planners to prioritize scarce resources appropriately.</p

Daratumumab plus lenalidomide and dexamethasone for untreated myeloma

This is an accepted manuscript of an article published by Massachusetts Medical Society in New England Journal of Medicine on 30/05/2019, available online: https://doi.org/10.1056/NEJMoa1817249 The accepted version of the publication may differ from the final published version.Copyright © 2019 Massachusetts Medical Society. Lenalidomide plus dexamethasone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. We sought to determine whether the addition of daratumumab would significantly reduce the risk of disease progression or death in this population. METHODS We randomly assigned 737 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation to receive daratumumab plus lenalidomide and dexamethasone (daratumumab group) or lenalidomide and dexamethasone alone (control group). Treatment was to continue until the occurrence of disease progression or unacceptable side effects. The primary end point was progression-free survival. RESULTS At a median follow-up of 28.0 months, disease progression or death had occurred in 240 patients (97 of 368 patients [26.4%] in the daratumumab group and 143 of 369 patients [38.8%] in the control group). The estimated percentage of patients who were alive without disease progression at 30 months was 70.6% (95% confidence interval [CI], 65.0 to 75.4) in the daratumumab group and 55.6% (95% CI, 49.5 to 61.3) in the control group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.43 to 0.73; P<0.001). The percentage of patients with a complete response or better was 47.6% in the daratumumab group and 24.9% in the control group (P<0.001). A total of 24.2% of the patients in the daratumumab group, as compared with 7.3% of the patients in the control group, had results below the threshold for minimal residual disease (1 tumor cell per 105 white cells) (P<0.001). The most common adverse events of grade 3 or 4 were neutropenia (50.0% in the daratumumab group vs. 35.3% in the control group), anemia (11.8% vs. 19.7%), lymphopenia (15.1% vs. 10.7%), and pneumonia (13.7% vs. 7.9%).Published versio

Exome sequencing identifies germline variants in DIS3 in familial multiple myeloma

[Excerpt] Multiple myeloma (MM) is the third most common hematological malignancy, after Non-Hodgkin Lymphoma and Leukemia. MM is generally preceded by Monoclonal Gammopathy of Undetermined Significance (MGUS) [1], and epidemiological studies have identified older age, male gender, family history, and MGUS as risk factors for developing MM [2]. The somatic mutational landscape of sporadic MM has been increasingly investigated, aiming to identify recurrent genetic events involved in myelomagenesis. Whole exome and whole genome sequencing studies have shown that MM is a genetically heterogeneous disease that evolves through accumulation of both clonal and subclonal driver mutations [3] and identified recurrently somatically mutated genes, including KRAS, NRAS, FAM46C, TP53, DIS3, BRAF, TRAF3, CYLD, RB1 and PRDM1 [3,4,5]. Despite the fact that family-based studies have provided data consistent with an inherited genetic susceptibility to MM compatible with Mendelian transmission [6], the molecular basis of inherited MM predisposition is only partly understood. Genome-Wide Association (GWAS) studies have identified and validated 23 loci significantly associated with an increased risk of developing MM that explain ~16% of heritability [7] and only a subset of familial cases are thought to have a polygenic background [8]. Recent studies have identified rare germline variants predisposing to MM in KDM1A [9], ARID1A and USP45 [10], and the implementation of next-generation sequencing technology will allow the characterization of more such rare variants. [...]French National Cancer Institute (INCA) and the Fondation Française pour la Recherche contre le Myélome et les Gammapathies (FFMRG), the Intergroupe Francophone du Myélome (IFM), NCI R01 NCI CA167824 and a generous donation from Matthew Bell. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award number S10OD018522. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank the Association des Malades du Myélome Multiple (AF3M) for their continued support and participation. Where authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organizatio

Myélome multiple et bisphosphonates (étude descriptive comparant l'utilisation du zolédronate et du pamidronate aux différentes recommandations)

CAEN-BU Médecine pharmacie (141182102) / SudocLYON1-BU Santé (693882101) / SudocSudocFranceF