Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma

Presented as an oral presentation at the 2011 Annual Meeting of the American Society of Hematology, San Diego, CA, December 10-13, 2011.-- et al.[Purpose]: This final analysis of the phase III VISTA trial (Velcade As Initial Standard Therapy in Multiple Myeloma: Assessment With Melphalan and Prednisone) was conducted to determine whether the overall survival (OS) benefit with bortezomib-melphalan-prednisone (VMP) versus melphalanprednisone (MP) in patients with myeloma who were ineligible for transplantation was maintained after 5 years of follow-up and to explore the risk of second primary malignancies. [Patients and Methods]: In all, 682 patients received up to nine 6-week cycles of VMP or MP and were then observed every 12 weeks or less. Data on second primary malignancies were collected by individual patient inquiries at all sites from 655 patients. [Results]: After median follow-up of 60.1 months (range, 0 to 74 months), there was a 31% reduced risk of death with VMP versus MP (hazard ratio [HR], 0.695; P < .001; median OS 56.4 v 43.1 months). OS benefit with VMP was seen across prespecified patient subgroups (age ≥ 75 years, stage III myeloma, creatinine clearance < 60 mL/min). Sixty-three percent of VMP patients and 73% of MP patients had received subsequent therapy. Time to next therapy (median, 30.7 v 20.5 months; HR, 0.557; P < .001) was longer with VMP than with MP. Among patients who received subsequent therapies, survival from start of subsequent therapy was similar following VMP (median, 28.1 months) or MP (median, 26.8 months; HR, 0.914). Following VMP/MP, incidence proportions of hematologic malignancies (1%/1%) and solid tumors (5%/3%) and exposure-adjusted incidence rates (0.017/0.013 per patient-year) were similar and were consistent with background rates. [Conclusion]: VMP resulted in a significant reduction in risk of death versus MP that was maintained after 5 years' follow-up and despite substantial use of novel-agent-based salvage therapies. There is no emerging safety signal for second primary malignancies following VMP.Supported by Millennium Pharmaceuticals, Janssen Research & Development, and Janssen Global Services.Peer Reviewe

Expert panel consensus statement on the optimal use of pomalidomide in relapsed and refractory multiple myeloma

This work is licensed under a Creative Commons Attribution 3.0 Unported License.-- et al.In this report, a panel of European myeloma experts discuss the role of pomalidomide in the treatment of relapsed and refractory multiple myeloma (RRMM). Based on the available evidence, the combination of pomalidomide and low-dose dexamethasone is a well-tolerated and effective treatment option for patients with RRMM who have exhausted treatment with lenalidomide and bortezomib. The optimal starting dose of pomalidomide is 4 mg given on days 1-21 of each 28-day cycle, whereas dexamethasone is administered at a dose of 40 mg weekly (reduced to 20 mg for patients aged >75 years). The treatment should continue until evidence of disease progression or unacceptable toxicity. Dose-modification schemes have been established for patients who develop neutropenia, thrombocytopaenia and other grade 3-4 adverse events during pomalidomide therapy. Guidance on the prevention and management of infections and venous thromboembolism is provided, based on the available clinical evidence and the experience of panel members. The use of pomalidomide in special populations, such as patients with advanced age, renal impairment or unfavourable cytogenetic features, is also discussed.Editorial support was funded by Celgene.Peer Reviewe

Hydrogeological effects on terrestrial gravity measurements

For the 20 last years, terrestrial and satellite gravity measurements have reached such a precision that they allow for identification of the signatures from water storage fluctuations. In particular, hydrogeological effects induce significant time-correlated signature in the gravity time series. Gravity response to rainfall is a complex function of the local geologic and climatic conditions, e.g., rock porosity, vegetation, evaporation, and runoff rates. The gravity signal combines contributions from many geophysical processes, source separation being a major challenge. At the local scale and short-term, the associated gravimetric signatures often exceed the tectonic and GIA effects, and monitoring gravity changes is a source of information on local groundwater mass balance, and contributes to model calibrations. Some aquifer main characteristics can then be inferred by combining continuous gravity, geophysical and hydrogeological measurements. In Membach, Belgium, a superconducting gravimeter has monitored gravity continuously for more than 24 years. This long time series, together with 300 repeated absolute gravity measurements and environmental monitoring, has provided valuable information on the instrumental, metrological, hydrogeological and geophysical points of view. This has allowed separating the signal sources and monitoring partial saturation dynamics in the unsaturated zone, convective precipitation and evapotranspiration at a scale of up to 1 km², for signals smaller than 1 nm/s², equivalent to 2.5 mm of water. Based on this experience, another superconducting gravimeter was installed in 2014 in the karst zone of Rochefort, Belgium. In a karst area, where the vadose zone is usually thicker than in other contexts, combining gravity measurements at the surface and inside accessible caves is a way to separate the contribution from the unsaturated zone lying between the two instruments, from the saturated zone underneath the cave, and the common mode effects from the atmosphere or other regional processes. Those experiments contribute to the assessment of the terrestrial hydrological cycle, which is a major challenge of the geosciences associated with key societal issues: availability of freshwater, mitigation of flood hazards, or measurement of evapotranspiration

Detecting hydrological connectivity using causal inference from time series: synthetic and real karstic case studies

We investigate the potential of causal inference methods (CIMs) to reveal hydrological connections from time series. Four CIMs are selected from two criteria, linear or nonlinear and bivariate or multivariate. A priori, multivariate, and nonlinear CIMs are best suited for revealing hydrological connections because they fit nonlinear processes and deal with confounding factors such as rainfall, evapotranspiration, or seasonality. The four methods are applied to a synthetic case and a real karstic case study. The synthetic experiment confirms our expectation: unlike the other methods, the multivariate nonlinear framework has a low false-positive rate and allows for ruling out a connection between two disconnected reservoirs forced with similar effective precipitation. However, for the real case study, the multivariate nonlinear method was unstable because of the uneven distribution of missing values affecting the final sample size for the multivariate analyses, forcing us to cope with the results' robustness. Nevertheless, if we recommend a nonlinear multivariate framework to reveal actual hydrological connections, all CIMs bring valuable insights into the system's dynamics, making them a cost-effective and recommendable comparative tool for exploring data. Still, causal inference remains attached to subjective choices, operational constraints, and hypotheses challenging to test. As a result, the robustness of the conclusions that the CIMs can draw always deserves caution, especially with real, imperfect, and limited data. Therefore, alongside research perspectives, we encourage a flexible, informed, and limit-aware use of CIMs without omitting any other approach that aims at the causal understanding of a system

Factors associated with the continuum of care of HIV infected patients in Belgium

BREACHinfo:eu-repo/semantics/nonPublishe

Novel risk stratification algorithm for estimating the risk of death in patients with relapsed multiple myeloma: external validation in a retrospective chart review.

OBJECTIVES AND DESIGN: A novel risk stratification algorithm estimating risk of death in patients with relapsed multiple myeloma starting second-line treatment was recently developed using multivariable Cox regression of data from a Czech registry. It uses 16 parameters routinely collected in medical practice to stratify patients into four distinct risk groups in terms of survival expectation. To provide insight into generalisability of the risk stratification algorithm, the study aimed to validate the risk stratification algorithm using real-world data from specifically designed retrospective chart audits from three European countries. PARTICIPANTS AND SETTING: Physicians collected data from 998 patients (France, 386; Germany, 344; UK, 268) and applied the risk stratification algorithm. METHODS: The performance of the Cox regression model for predicting risk of death was assessed by Nagelkerke's R2, goodness of fit and the C-index. The risk stratification algorithm's ability to discriminate overall survival across four risk groups was evaluated using Kaplan-Meier curves and HRs. RESULTS: Consistent with the Czech registry, the stratification performance of the risk stratification algorithm demonstrated clear differentiation in risk of death between the four groups. As risk groups increased, risk of death doubled. The C-index was 0.715 (95% CI 0.690 to 0.734). CONCLUSIONS: Validation of the novel risk stratification algorithm in an independent 'real-world' dataset demonstrated that it stratifies patients in four subgroups according to survival expectation

Pomalidomide plus low-dose dexamethasone in patients with relapsed/refractory multiple myeloma and moderate renal impairment: a pooled analysis of three clinical trials

Renal impairment (RI) is a major comorbidity in patients with multiple myeloma (MM). Here we present the pooled safety and efficacy analysis of three clinical trials (MM-002, MM-003, and MM-010) of pomalidomide + low-dose dexamethasone (POM + LoDEX) in patients with moderate RI (creatinine clearance [CrCl] ≥ 30 to <60 mL/min) and without RI (≥ 60 mL/min). Trial protocols were approved by the institutional review board of each site involved. Patients with RI were older than patients without RI, although other baseline characteristics were similar. The dosing and safety profile of POM + LoDEX was similar across RI subgroups. Median overall response rate, progression-free survival, time to progression, and duration of response were not significantly different between RI subgroups. However, patients with vs. without RI had significantly shorter median overall survival (10.5 vs. 14.0 months, respectively; p = .004). This analysis demonstrates that POM + LoDEX is a safe and effective treatment for patients with moderate RI. The trials were registered at ClinicalTrials.gov as NCT00833833 (MM-002), NCT01311687 (MM-003), and NCT01712789 (MM-010) and at EudraCT as 2010-019820-30 (MM-003) and 2012-001888-78 (MM-010)

Hydrogeological effects on terrestrial gravity measurements

For the 20 last years, terrestrial and satellite gravity measurements have reached such a precision that they allow for identification of the signatures from water storage fluctuations. In particular, hydrogeological effects induce significant time-correlated signature in the gravity time series. Gravity response to rainfall is a complex function of the local geologic and climatic conditions, e.g., rock porosity, vegetation, evaporation, and runoff rates. The gravity signal combines contributions from many geophysical processes, source separation being a major challenge. At the local scale and short-term, the associated gravimetric signatures often exceed the tectonic and GIA effects, and monitoring gravity changes is a source of information on local groundwater mass balance, and contributes to model calibrations. Some aquifer main characteristics can then be inferred by combining continuous gravity, geophysical and hydrogeological measurements. In Membach, Belgium, a superconducting gravimeter has monitored gravity continuously for more than 24 years. This long time series, together with 300 repeated absolute gravity measurements and environmental monitoring, has provided valuable information on the instrumental, metrological, hydrogeological and geophysical points of view. This has allowed separating the signal sources and monitoring partial saturation dynamics in the unsaturated zone, convective precipitation and evapotranspiration at a scale of up to 1 km², for signals smaller than 1 nm/s², equivalent to 2.5 mm of water. Based on this experience, another superconducting gravimeter was installed in 2014 in the karst zone of Rochefort, Belgium. In a karst area, where the vadose zone is usually thicker than in other contexts, combining gravity measurements at the surface and inside accessible caves is a way to separate the contribution from the unsaturated zone lying between the two instruments, from the saturated zone underneath the cave, and the common mode effects from the atmosphere or other regional processes. Those experiments contribute to the assessment of the terrestrial hydrological cycle, which is a major challenge of the geosciences associated with key societal issues: availability of freshwater, mitigation of flood hazards, or measurement of evapotranspiration

Patient Preferences for Multiple Myeloma Treatments : A Multinational Qualitative Study

Background: Investigational and marketed drugs for the treatment of multiple myeloma (MM) are associated with a range of characteristics and uncertainties regarding long term side-effects and efficacy. This raises questions about what matters most to patients living with this disease. This study aimed to understand which characteristics MM patients find most important, and hence should be included as attributes and levels in a subsequent quantitative preference survey among MM patients. Methods: This qualitative study involved: (i) a scoping literature review, (ii) discussions with MM patients (n = 24) in Belgium, Finland, Romania, and Spain using Nominal Group Technique, (iii) a qualitative thematic analysis including multi-stakeholder discussions. Results: MM patients voiced significant expectations and hopes that treatments would extend their lives and reduce their cancer signs and symptoms. Participants however raised concerns about life-threatening side-effects that could cause permanent organ damage. Bone fractures and debilitating neuropathic effects (such as chronic tingling sensations) were highlighted as major issues reducing patients' independence and mobility. Patients discussed the negative impact of the following symptoms and side-effects on their daily activities: thinking problems, increased susceptibility to infections, reduced energy, pain, emotional problems, and vision problems. MM patients were concerned with uncertainties regarding the durability of positive treatment outcomes, and the cause, severity, and duration of their symptoms and side-effects. Patients feared short-term positive treatment responses complicated by permanent, severe side-effects and symptoms. Conclusions: This study gained an in-depth understanding of the treatment and disease-related characteristics and types of attribute levels (severity, duration) that are most important to MM patients. Results from this study argue in favor of MM drug development and individual treatment decision-making that focuses not only on extending patients' lives but also on addressing those symptoms and side-effects that significantly impact MM patients' quality of life. This study underscores a need for transparent communication toward MM patients about MM treatment outcomes and uncertainties regarding their long-term efficacy and safety. Finally, this study may help drug developers and decision-makers understand which treatment outcomes and uncertainties are most important to MM patients and therefore should be incorporated in MM drug development, evaluation, and clinical practice.Peer reviewe

Chimeric antigen receptor T-cell therapy for multiple myeloma: a consensus statement from The European Myeloma Network

Adoptive cellular therapy using chimeric antigen receptor T-cell (CART) therapy is currently being evaluated in patients with relapsed / refractory multiple myeloma (MM). The majority of CAR-T cell programs now being tested in clinical trials are targeting B-cell maturation antigen. Several recent phase I / II trials show promising preliminary results in patients with MM progressing on proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies targeting CD38. CAR-T cell therapy is a potentially life-threatening strategy that can only be administered in experienced centers. For the moment, CAR-T cell therapy for MM is still experimental, but once this strateg