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

Lenalidomide Maintenance with or without Prednisone in Newly Diagnosed Myeloma Patients: A Pooled Analysis

We conducted a pooled analysis of two phase III trials, RV-MM-EMN-441 and EMN01, to compare maintenance with lenalidomide-prednisone vs. lenalidomide in newly diagnosed transplant-eligible and -ineligible myeloma patients. Primary endpoints were progression-free survival, progression-free survival 2 and overall survival with both regimens. A secondary aim was to evaluate the impact of duration of maintenance on overall survival and on outcome after relapse. A total of 625 patients (lenalidomide-prednisone arm, n = 315; lenalidomide arm, n = 310) were analyzed. The median follow-up was 58 months. Median progression-free survival (25 vs. 19 months; p = 0.08), progression-free survival 2 (56 vs. 49 months; p = 0.9) and overall survival (73 months vs. NR; p = 0.08) were not significantly different between the two arms. Toxicity profiles of lenalidomide-prednisone and lenalidomide were similar, with the exception of neutropenia that was higher in the lenalidomide arm (grade ≥ 3: 9% vs. 19%, p < 0.001), without an increase in the rate of infections. Overall survival (median NR vs. 49 months, p < 0.001), progression-free survival from relapse (median 35 vs. 24 months, p = 0.004) and overall survival from relapse (median not reached vs. 41 months, p = 0.002) were significantly longer in patients continuing maintenance for ≥2 years. We showed that the addition of prednisone at 25 or 50 mg every other day (eod) to lenalidomide maintenance did not induce any significant advantage

Randomized phase III study (ADMYRE) of plitidepsin in combination with dexamethasone vs. dexamethasone alone in patients with relapsed/refractory multiple myeloma

The randomized phase III ADMYRE trial evaluated plitidepsin plus dexamethasone (DXM) versus DXM alone in patients with relapsed/refractory multiple myeloma after at least three but not more than six prior regimens, including at least bortezomib and lenalidomide or thalidomide. Patients were randomly assigned (2:1) to receive plitidepsin 5 mg/m2 on D1 and D15 plus DXM 40 mg on D1, D8, D15, and D22 (arm A, n = 171) or DXM 40 mg on D1, D8, D15, and D22 (arm B, n = 84) q4wk. The primary endpoint was progression-free survival (PFS). Median PFS without disease progression (PD) confirmation (IRC assessment) was 2.6 months (arm A) and 1.7 months (arm B) (HR = 0.650; p = 0.0054). Median PFS with PD confirmation (investigator’s assessment) was 3.8 months (arm A) and 1.9 months (arm B) (HR = 0.611; p = 0.0040). Median overall survival (OS, intention-to-treat analysis) was 11.6 months (arm A) and 8.9 months (arm B) (HR = 0.797; p = 0.1261). OS improvement favoring arm A was found when discounting a crossover effect (37 patients crossed over from arm B to arm A) (two-stage method; HR = 0.622; p = 0.0015). The most common grade 3/4 treatment-related adverse events (% of patients arm A/arm B) were fatigue (10.8%/1.2%), myalgia (5.4%/0%), and nausea (3.6%/1.2%), being usually transient and reversible. The safety profile does not overlap with the toxicity observed with other agents used in multiple myeloma. In conclusion, efficacy data, the reassuring safety profile, and the novel mechanism of action of plitidepsin suggest that this combination can be an alternative option in patients with relapsed/refractory multiple myeloma after at least three prior therapy lines

Prevention and management of adverse events of novel agents in multiple myeloma: A consensus of the European Myeloma Network

During the last few years, several new drugs have been introduced for treatment of patients with multiple myeloma, which have significantly improved the treatment outcome. All of these novel substances differ at least in part in their mode of action from similar drugs of the same drug class, or are representatives of new drug classes, and as such present with very specific side effect profiles. In this review, we summarize these adverse events, provide information on their prevention, and give practical guidance for monitoring of patients and for management of adverse events

A note on the first order logic of complete BL chains

In [10] it is claimed that the set of predicate tautologies of all complete BL-chains and the set of all standard tautologies (i.e., the set of predicate formulas valid in all standard BL-algebras) coincide. As noticed in [11], this claim is wrong. In this paper we show that a complete BL-chain B satisfies all standard BL-tautologies iff for any transfinite sequence (a(i) : i is an element of I) of elements of B, the condition Lambda(i is an element of I) (a(i)(2)) = (Lambda(i is an element of I) a(i))(2) holds in B

Knowledge-Driven versus data-driven logics

International audienceThe starting point of this work is the gap between two distinct traditions in information engineering: knowledge representation and data-driven modelling. The first tradition emphasizes logic as a tool for representing beliefs held by an agent. The second tradition claims that the main source of knowledge is made of observed data, and generally does not use logic as a modelling tool. However, the emergence of fuzzy logic has blurred the boundaries between these two traditions by putting forward fuzzy rules as a Janus-faced tool that may represent knowledge, as well as approximate non-linear functions representing data. This paper lays bare logical foundations of data-driven reasoning whereby a set of formulas is understood as a set of observed facts rather than a set of beliefs. Several representation frameworks are considered from this point of view: classical logic, possibility theory, belief functions, epistemic logic, fuzzy rule-based systems. Mamdani's fuzzy rules are recovered as belonging to the data-driven view. In possibility theory a third set-function, different from possibility and necessity plays a key role in the data-driven view, and corresponds to a particular modality in epistemic logic. A bi-modal logic system is presented which handles both beliefs and observations, and for which a completeness theorem is given. Lastly, our results may shed new light in deontic logic and allow for a distinction between explicit and implicit permission that standard deontic modal logics do not often emphasize

Durability and Sustainability of Concrete Structures (DSCS-2018)

Modern construction is unthinkable without concrete, the world production and consumption of which is about 10 billion m3 per year. Given the steady growth of the world’s population by 2050, it is expected to double this volume, which will undoubtedly be significantly affected on energy consumption and increase global CO2 emissions. Concrete is perhaps the most universal building material since the beginning and development of civilization. It is sufficient to recall the Great Wall of China, the palaces and temples of Ancient India, the pyramids of Ancient Egypt, the unique buildings of Romans, made with the use of lime-pozzolanic binders. Universality of concrete is defined by simplicity and convenience of its production, rather low cost, structural integrity and homogeneity, durability and a long service life under various aggressive environments. However, the concrete image is sometimes not favorable. It is associated with greater labor intensity of construction works and dismantlement, massive structures, a large impact on the environment in connection with the s consumption of not renewable natural resources. The same perception is greatly facilitated by the fact that, according to Gigaton Throwdown Initiative, “the cement industry is responsible for about 5 to 7% of total CO2 emissions, or 2.1 Gt per year.” Indeed, when producing cement clinker about 0.9 t CO2 / t clinker are produced. Taking into account the annual increase in the production and use of Portland-based cement (more than 4.1 million tons per year) that is the main binder used in the production of concrete, this fact poses a significant threat to humanity as a whole. According to the Intergovernmental Panel on Climate Change (IPCC), actions are necessary to reduce carbon dioxide emissions because in about 30 years CO2 concentrations is expected to reach 450 ppm – a dangerous point above which irreversible climate change will occur on our planet. Since concrete will remain the main building material in the future, it is expected that if new ways and mechanisms to reduce the environmental burden by at least 50% will be not found, it is not possible to maintain the existing level of impact. This problem is so deep and serious that there is hardly a single way to solve it. There is a need for an integrated approach, several complementary activities that provide some synergy. Until recently, the main efforts were aimed at improving technological processes and reducing the consumption of clinker through the production of blended cements, as well as the creation of new types of binders. Active search for alternative binders has led to the development of sulfoaluminate-based cements; alkali-activated materials and geopolymers (slag, fly ash, metakaolin, etc.), efficient and fairly water-resistant magnesia cements; phosphate cements (ammonium phosphate, silicate phosphate, magnesium phosphate etc.), cements with calcium halogen-aluminate and the so called low water demand binders. With the advent of high-performance concretes and new technologies, the possibility of a radical increase of the cement factor in conventional concrete due to the use of high performance superplasticizers and other chemical admixtures, dramatically reducing the water consumption of the concrete mixture; active mineral additives such as micro silica, metakaolin, fly ash, finely ground granulated slag, etc., as well as a variety of inert fillers that can improve the functionality of concrete mixtures, such as fine limestone. Strictly speaking, “pozzolanic effect” and “filler effect” are easily combined and provide a certain synergy. The potential for reducing cement consumption in concrete production is still undervalued. This is due to certain fears of decreasing the corrosion resistance of concrete and durability of reinforced concrete structures, since the great bulk of the existing standards is prescriptive and sets the minimum cement content in concrete under specific operating conditions. Reinforced concrete structures of buildings and constructions, as a rule, initially, shall have the design strength and sufficiently long service life because their construction often requires a significant investment. The durability of these structures, however, is determined by different ageing processes and the influence of external actions, so their life will be limited. As a result, many structures need to be repaired or even replaced in fairly short time periods, resulting in additional costs and environmental impacts. Therefore, there is a need to improve the design principles of structures taking into account the parameters of durability and thus achieving a sufficiently long service life. Development of the concept of design of structures based on their life cycle, “environmental design”, including a holistic approach that optimizes material and energy resources in the context of operating costs, allow us to completely revise our ideas about structural concrete construction. It should be noted that many recent developments in the field of life cycle analysis (LCA) are aimed at expanding and deepening traditional approaches and creating a more complete description of the processes with the analysis of sustainable development (LCSA) to cover not only the problems associated mainly with the product (product level), but also complex problems related to the construction sector of the economy (at the sector level) or even the general economic level (economy level). The approach to “environmental design” is based on such models and methods of design, which takes into account a set of factors of their impact on the environment, based on the concept of “full life cycle” or models of accounting for total energy consumption and integrated CO2 emission. All of this could become a basis for the solution of the global problem – to contain the growing burden on the environment, providing a 50% reduction in CO2 emissions and energy consumption in the construction industry. Hence a special sharpness P. K. Mehta’s phrase acquires: “...the future of the cement and concrete industry will largely depend on our ability to link their growth for sustainable development...” The above-mentioned acute and urgent problems form the basis of the agenda of the Second edition of International Workshop on “Durability and Sustainability of Concrete Structures – DSCS-2018,” held in Moscow on 6 – 7 June 2018 under the auspices of the American Concrete Institute, the International Federation on structural concrete and the International Union of experts and laboratories in the field of building materials, systems and structures. The selected papers of this major forum, which brought together more than 150 experts from almost 40 countries of the world, are collected in this ACI SP