Explore the vast range of titles available.

Certain clinical features predict progression from smoldering to overt multiple myeloma. Patients with high-risk features who were treated with lenalidomide and dexamethasone were less likely to have disease progression and had a higher rate of survival than untreated patients. Smoldering multiple myeloma is a plasma-cell proliferative disorder characterized by a monoclonal component of at least 3 g per deciliter, a level of plasma-cell infiltration into bone marrow of at least 10%, or both features. 1 Currently, patients with smoldering myeloma are not treated until symptomatic disease develops. 2 In the past, few drugs were effective against myeloma, and the available treatments, mainly alkylating agents, led to concerns about long-term toxicity. Attempts at early intervention with alkylating agents, 3 – 5 bisphosphonates, 6 – 8 antagonists of the receptor of interleukin-1β, 9 or thalidomide 10 – 13 failed to show a significant benefit. Although the risk of progression to . . .

In this phase 1–2 study involving patients with relapsed or refractory myeloma, a bispecific antibody (teclistamab) that mediates T-cell activation and subsequent lysis of myeloma cells expressing B-cell maturation antigen induced responses in 63% of the patients, including a complete response in nearly 40%.

Recent advances in the treatment of multiple myeloma have increased the need for accurate diagnosis of the disease. The detection of bone and bone marrow lesions is crucial in the investigation of multiple myeloma and often dictates the decision to start treatment. Furthermore, detection of minimal residual disease is important for prognosis determination and treatment planning, and it has underscored an unmet need for sensitive imaging methods that accurately assess patient response to multiple myeloma treatment. Low-dose whole-body CT has increased sensitivity compared with conventional skeletal survey in the detection of bone disease, which can reveal information leading to changes in therapy and disease management that could prevent or delay the onset of clinically significant morbidity and mortality as a result of skeletal-related events. Given the multiple options available for the detection of bone and bone marrow lesions, ranging from conventional skeletal survey to whole-body CT, PET/CT, and MRI, the International Myeloma Working Group decided to establish guidelines on optimal use of imaging methods at different disease stages. These recommendations on imaging within and outside of clinical trials will help standardise imaging for monoclonal plasma cell disorders worldwide to allow the comparison of results and the unification of treatment approaches for multiple myeloma.

Introduction of the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide has substantially improved outcomes for patients with multiple myeloma. As a result, these drugs have become cornerstones of current antimyeloma treatment regimens. However, after several years of clinical experience it has become apparent that peripheral neuropathy is the most common and potentially disabling non-haematological side-effect associated with thalidomide and bortezomib. Maximising treatment benefit while preserving quality of life therefore requires a careful balance between achieving optimum activity and minimising toxicity, including neuropathy, to further enhance efficacy. In this review, we discuss all aspects of drug-induced peripheral neuropathy in myeloma, with a particular focus on thalidomide and bortezomib.

Multiple myeloma (MM) is an incurable disease, whose clinical heterogeneity makes its management challenging, highlighting the need for biological features to guide improved therapies. Deregulation of specific long non-coding RNAs (lncRNAs) has been shown in MM, nevertheless, the complete lncRNA transcriptome has not yet been elucidated. In this work, we identified 40,511 novel lncRNAs in MM samples. lncRNAs accounted for 82% of the MM transcriptome and were more heterogeneously expressed than coding genes. A total of 10,351 overexpressed and 9,535 downregulated lncRNAs were identified in MM patients when compared with normal bone-marrow plasma cells. Transcriptional dynamics study of lncRNAs in the context of normal B-cell maturation revealed 989 lncRNAs with exclusive expression in MM, among which 89 showed de novo epigenomic activation. Knockdown studies on one of these lncRNAs, SMILO (specific myeloma intergenic long non-coding RNA), resulted in reduced proliferation and induction of apoptosis of MM cells, and activation of the interferon pathway. We also showed that the expression of lncRNAs, together with clinical and genetic risk alterations, stratified MM patients into several progression-free survival and overall survival groups. In summary, our global analysis of the lncRNAs transcriptome reveals the presence of specific lncRNAs associated with the biological and clinical behavior of the disease.

Patients with newly diagnosed multiple myeloma who were ineligible for treatment with high-dose chemotherapy plus hematopoietic stem-cell transplantation were randomly assigned to receive either melphalan and prednisone alone or melphalan and prednisone plus bortezomib. The time to disease progression (the primary outcome) was longer in the bortezomib group. The combination of bortezomib, melphalan, and prednisone appears to be effective as initial treatment in patients with multiple myeloma who cannot withstand high-dose therapy. The combination of bortezomib, melphalan, and prednisone appears to be effective as initial treatment in patients with multiple myeloma who cannot withstand high-dose therapy. Therapy with melphalan plus prednisone, which has been the standard of care for patients with newly diagnosed multiple myeloma for more than 40 years, 1 , 2 is associated with a median survival of 29 to 37 months. 3 – 6 During the past decade, high-dose therapy with hematopoietic stem-cell transplantation has become the preferred treatment for patients under the age of 65 years, 7 – 9 but older patients and patients with clinically significant coexisting illnesses usually do not tolerate this treatment. Since the median age at diagnosis of myeloma is approximately 70 years, 10 more than half the patients with newly diagnosed myeloma may not . . .

Background: Graft-versus-host disease (GvHD) remains the major obstacle to successful allogeneic hematopoietic stem cell transplantation, despite of the immunosuppressive regimens administered to control T cell alloreactivity. PI3K/AKT/mTOR pathway is crucial in T cell activation and function and, therefore, represents an attractive therapeutic target to prevent GvHD development. Recently, numerous PI3K inhibitors have been developed for cancer therapy. However, few studies have explored their immunosuppressive effect. Methods: The effects of a selective PI3K inhibitor (BKM120) and a dual PI3K/mTOR inhibitor (BEZ235) on human T cell proliferation, expression of activation-related molecules, and phosphorylation of PI3K/AKT/mTOR pathway proteins were analyzed. Besides, the ability of BEZ235 to prevent GvHD development in mice was evaluated. Results: Simultaneous inhibition of PI3K and mTOR was efficient at lower concentrations than PI3K specific targeting. Importantly, BEZ235 prevented naïve T cell activation and induced tolerance of alloreactive T cells, while maintaining an adequate response against cytomegalovirus, more efficiently than BKM120. Finally, BEZ235 treatment significantly improved the survival and decreased the GvHD development in mice. Conclusions: These results support the use of PI3K inhibitors to control T cell responses and show the potential utility of the dual PI3K/mTOR inhibitor BEZ235 in GvHD prophylaxis.

Climate has a strong influence on fire activity, varying across time and space. We analyzed the relationships between fire-weather conditions during the main fire season and antecedent water-balance conditions and fires in two Mediterranean-type regions with contrasted management histories: five southern countries of the European Union (EUMED)(all fires); the Pacific western coast of the USA (California and Oregon, PWUSA)(national forest fires). Total number of fires (≥1 ha), number of large fires (≥100 ha) and area burned were related to mean seasonal fire weather index (FWI), number of days over the 90th percentile of the FWI, and to the standardized precipitation-evapotranspiration index (SPEI) from the preceding 3 (spring) or 8 (autumn through spring) months. Calculations were made at three spatial aggregations in each area, and models related first-difference (year-to-year change) of fires and FWI climate variables to minimize autocorrelation. An increase in mean seasonal FWI resulted in increases in the three fire variables across spatial scales in both regions. SPEI contributed little to explain fires, with few exceptions. Negative water-balance (dry) conditions from autumn through spring (SPEI8) were generally more important than positive conditions (moist) in spring (SPEI3), both of which contributed positively to fires. The R2 of the models generally improved with increasing area of aggregation. For total number of fires and area burned, the R2 of the models tended to decrease with increasing mean seasonal FWI. Thus, fires were more susceptible to change with climate variability in areas with less amenable conditions for fires (lower FWI) than in areas with higher mean FWI values. The relationships were similar in both regions, albeit weaker in PWUSA, probably due to the wider latitudinal gradient covered in PWUSA than in EUMED. The large variance explained by some of the models indicates that large-scale seasonal forecast could help anticipating fire activity in the investigated areas.

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.

The landscape of multiple myeloma (MM) has changed considerably in the past two decades regarding new treatments, insight into disease biology and innovation in the techniques available to assess measurable residual disease (MRD) as the most accurate method to evaluate treatment efficacy. The sensitivity and standardization achieved by these techniques together with unprecedented rates of complete remission (CR) induced by new regimens, raised enormous interest in MRD as a surrogate biomarker of patients’ outcome and endpoint in clinical trials. By contrast, there is reluctance and general lack of consensus on how to use MRD outside clinical trials. Here, we discuss critical aspects related with the implementation of MRD in clinical practice.