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Phase 1/2 trial of ixazomib, cyclophosphamide and dexamethasone in patients with previously untreated symptomatic multiple myeloma.

Ixazomib is the first oral proteasome inhibitor to enter the clinic. Given the efficacy of bortezomib in combination with cyclophosphamide and dexamethasone, we studied the combination of ixazomib, cyclophosphamide and dexamethasone (ICd) in newly diagnosed multiple myeloma (NDMM) and patients with measurable disease, irrespective of transplant eligibility, were enrolled. The phase 1 was to determine the maximum tolerated dose (MTD) of cyclophosphamide in the combination. Patients received ixazomib 4 mg (days 1, 8, 15), dexamethasone 40 mg (days 1, 8, 15, 22), and cyclophosphamide 300 or 400 m

LncRNA NEAT1 restrains the malignant biological characteristics of acute myeloid leukemia via regulating CTCF/CXCR2 axis.

Acute myeloid leukemia (AML) is notorious in the field of hematology for its poor efficacy, frustrating prognosis, and it is prone to refractory or relapsed conditions. Previous studies in our team have shown that some Long noncoding RNAs (lncRNAs) and chemokine receptors play key regulatory roles in AML. The findings of this study demonstrated that the expression of NEAT1 was atypically low in both clinical AML specimens and AML cell lines. Overexpression of NEAT1 was capable of attenuating the malignant biological characteristics of AML cells, including inhibiting the malignant proliferation

Role of Stem Cell Transplantation in Multiple Myeloma.

Autologous stem cell transplantation (auto-SCT) has been the standard of care in eligible newly diagnosed multiple myeloma (MM) patients. Outcomes of patients with MM have improved significantly due to the advent of several novel drugs. Upfront use of these drugs in induction therapy has significantly increased the rate and depth of responses that have translated into longer remission and survival. This has now raised a debate regarding the role and relevance of auto-SCT in the management of myeloma. However, clinical trials have confirmed the utility of auto-SCT even in the era of novel drugs

Novel Approaches Outside the Setting of Immunotherapy for the Treatment of Multiple Myeloma: The Case of Melflufen, Venetoclax, and Selinexor.

Although the survival rate of patients with multiple myeloma has significantly improved in the last years thanks to the introduction of various classes of new drugs, such as proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies, the vast majority of these subjects relapse with a more aggressive disease due to the acquisition of further genetic alterations that may cause resistance to current salvage therapies. The treatment of these often "triple" (or even more) refractory patients remains challenging, and alternative approaches are required to overcome the onset of that re

Evolving role of neurokinin 1-receptor antagonists for chemotherapy-induced nausea and vomiting.

To examine pharmacologic and clinical characteristics of neurokinin 1 (NK1)-receptor antagonists (RAs) for preventing chemotherapy-induced nausea and vomiting (CINV) following highly or moderately emetogenic chemotherapy, a literature search was performed for clinical studies in patients at risk of CINV with any approved NK1 RAs in the title or abstract: aprepitant (capsules or oral suspension), HTX019 (intravenous [IV] aprepitant), fosaprepitant (IV aprepitant prodrug), rolapitant (tablets or IV), and fixed-dose tablets combining netupitant or fosnetupi-tant (IV netupitant prodrug) with the 5

Unc-51 like kinase 3 (ULK3) contributes to autophagy and cell survival in multiple myeloma.

Despite effective therapies such as proteasome inhibitors, multiple myeloma (MM) patients relapse with refractory disease. Analysis of RNA sequencing data from CD138 + MM patient cells (n = 813) across disease stages identifies an autophagy gene signature. Particularly elevated ULK3 expression is strongly associated with disease progression. Functional studies reveal that ULK3 supports MM cell survival via the ULK-ATG13-FIP200 complex. We generate small-molecule kinase inhibitors (SG3-014/MA9-060) exhibiting nanomolar potency against ULK3, with binding confirmed by co-crystallization. While ex

Integrating MBMA and QSP to Identify Key Covariates and Predict Treatment Outcomes in Relapsed/Refractory Multiple Myeloma.

This study demonstrates the application of a model based meta analysis (MBMA) framework to characterize the safety and efficacy profiles of therapies in relapsed and refractory multiple myeloma (RRMM). Published clinical trial data were analyzed to evaluate the incidence of Grade ≥ 3 neutropenia and overall response rate (ORR), providing a quantitative foundation for model-informed drug development. The final model incorporated trial- and treatment-level covariates and was evaluated using visual predictive checks and predictive simulations. Results revealed increased neutropenia risk associate

Response-adapted lenalidomide-dexamethasone (LenDex) intensification after CyBorD induction for transplant-eligible multiple myeloma: the PIANO study.

PURPOSE: Combination therapy with novel agents is the standard initial treatment for transplant-eligible patients with newly diagnosed multiple myeloma. However, the benefit of additional induction therapy for insufficient response remains unclear. This multicenter prospective study investigated response-adapted intensification with lenalidomide and dexamethasone (LenDex) after cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in patients who did not achieve a very good partial response (VGPR) or better, followed by autologous stem cell transplantation (ASCT) and lenalidomide maintenanc

Multimodal imaging diagnosis of multiple myeloma with renal involvement: a case report.

BackgroundExtramedullary renal involvement secondary to multiple myeloma (MM) is extremely rare and prone to preoperative misdiagnosis. Its clinical and imaging manifestations have not been systematically summarized, leading to frequent preoperative misdiagnosis. To summarize the multimodal imaging characteristics and clinical diagnostic value of MM with renal involvement through a typical case report, so as to improve the understanding and early recognition rate of this disease.Case presentationA 67-year-old male patient with left lumbodorsal pain was examined by multimodal imaging. Ultrasoun

Dynamic Prediction of Survival Outcomes in Multiple Myeloma.

Background: Multiple myeloma (MM) remains an incurable plasma cell malignancy characterized by marked clinical heterogeneity. Existing prognostic frameworks, including the International Staging System (ISS) and FISH-defined cytogenetic risk, are anchored at diagnosis and do not capture the evolutionary dynamics of disease or treatment response, leaving an unmet need for risk models that retain prognostic validity longitudinally. Methods: Using transcriptomic data from 762 CD138-selected MM plasma cells from newly diagnosed patient samples in the MMRF CoMMpass study (NCT01454297), we computed s

Efficacy and safety of isatuximab subcutaneous plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma: results of the Phase 2 study IZALCO.

In the Phase 2 IZALCO study, we evaluated efficacy, patient preference, safety and pharmacokinetics for isatuximab administered SC by an innovative on-body injector (OBI) or manual injection, plus carfilzomib-dexamethasone (Kd) in relapsed/refractory multiple myeloma (RRMM) patients. In Part 1, isatuximab SC was injected manually (cycles 1-6). In Part 2, patients were randomized to isatuximab SC by manual injection (cycles 1-3) followed by OBI administration (cycles 4-6) or to isatuximab OBI (cycles 1-3) followed by manual injection (cycles 4-6). From cycle 7, all patients could choose either

Infection events in patients with newly diagnosed multiple myeloma with anti-CD38 monoclonal antibody-based first line regimens: A multicentric Italian experience.

Multiple myeloma (MM) is a malignancy characterized by the clonal proliferation of plasma cells. It accounts for approximately 1% of all cancers and is the second most common hematologic malignancy after lymphoma. Infections represent a major cause of morbidity and mortality in patients with newly diagnosed multiple myeloma (NDMM), contributing to approximately 45% of early deaths, particularly in elderly individuals and during the initial months of therapy. Current treatment options for MM, including anti-CD38 monoclonal antibodies (CD38 mAbs), proteasome inhibitors, immunomodulatory drugs (s

Validation of a data-driven multicomponent T2 analysis for quantifying myelin content in the cuprizone mouse model of multiple sclerosis.

BACKGROUND: Myelin quantification is essential for understanding a wide range of neurodegenerative pathologies. Voxel-wise multicomponent T2 (mcT2) analysis is the common approach for this purpose, yet no gold standard technique exist that can overcome the ambiguity of fitting several T2 components to a single-voxel signal. This challenge is further exacerbated in preclinical scan settings due to the addition of spurious diffusion encoding, resulting from the use of imaging gradients that are at least an order of magnitude larger than on typical clinical scanners. PURPOSE: Assess the utility

At-Home Care Program for Acute Myeloid Leukemia Induction Phase in Patients Treated with Venetoclax-Based Low-Intensity Regimens.

Background: Even though venetoclax in combination with azacitidine (VenAza) is considered a low-intensity regimen, its patients present a high incidence of cytopenia and infections during the first courses, making the initial management a challenging phase. Methods: This difficulty in our center led to the establishment of an At-Home (AH) program for ramp-up and follow-up patients during the VenAza combination induction phase focused on therapy administration, patient and caregiver education, and management of adverse events (AEs). A total of 70 patients with newly diagnosed acute myeloid leuk

Newly Diagnosed Multiple Myeloma Patients with Skeletal-Related Events and Abnormal MRI Pattern Have Poor Survival Outcomes: A Prospective Study on 370 Patients.

Contemporary information is sparse on the frequency of skeletal-related events (SREs) in multiple myeloma (MM) patients at a population-based level in the era of novel agents. In this context, we conducted this single-center, prospective, observational study to determine the incidence of SREs among newly diagnosed MMs (NDMM) and to explore the possible correlations with disease characteristics, imaging finding, and patient prognosis. A total of 370 patients with available baseline MRIs were included. Among them, 208 (56%) presented with at least one SRE at diagnosis. Fractures were the most co

Role of Venetoclax in the Treatment of Relapsed and Refractory Multiple Myeloma.

Biomarker-driven targeted therapies have been an area of exploration for innovative therapeutic options in oncology. B-cell lymphoma-2 (BCL-2) protein is an anti-apoptotic protein expressed on the clonal plasma cells in patients with multiple myeloma (MM). MM subsets with t (11;14) have overexpression of BCL-2 and can benefit from venetoclax (VEN) when used either alone or in combination with other chemotherapeutic agents with an overall response rate (ORR) ranging from 40% to 100%. The most commonly reported grade ≥ 3 adverse effects include cytopenias and gastrointestinal side effects. This

Frontline treatment patterns and attrition rates by subsequent lines of therapy in patients with newly diagnosed multiple myeloma.

BackgroundFor patients with multiple myeloma (MM), each additional line of therapy (LOT) is associated with lower response rates, shorter treatment duration and treatment-free intervals, and increased rates of toxicities and comorbidities. Here, we examine frontline treatment patterns, and attrition rates by LOT among newly diagnosed MM (NDMM) patients in the United States who were eligible or ineligible for autologous stem cell transplant (ASCT).MethodsData were identified from three US patient-level databases collectively covering the period January 2000 to September 2018. Patients had an in

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… Vd and Rd were the most common standard-of-care (SoC) frontline treatments for patients who did not receive ASCT; the use of Rd as frontline therapy in this setting is consistent with current guidelines [ 13 ], although the use of triplets is increasing, and use of Vd is consistent with another real-world …

Восстановление ТРНС последнего универсального общего пастора (Общества) на пути к восстановлению системы перевода Древних.

Реконструирование ансестральной последовательности (АСР) было использовано для изучения эволюции переводческой системы путем определения последовательности tRNA в "Last Archaeal Common Ancestor" (LACA), "Last Bacterial Common Ancestor" (LBCA) и "Last Universal Common Ansancestor" (LUCA), которые в наших предыдущих исследованиях назывались "Общество". Составное филогенетическое дерево, взятое из реконструированных последовательности ТРНА, выявило топологию, отличную от ранее выведенных аминоачил-тРНА синтетазы (АРС). Такая непоследовательность может отражать изменения в структурных особенностях

Classification of Dystonia.

Dystonia is a hyperkinetic movement disorder characterized by abnormal movement or posture caused by excessive muscle contraction. Because of its wide clinical spectrum, dystonia is often underdiagnosed or misdiagnosed. In clinical practice, dystonia could often present in association with other movement disorders. An accurate physical examination is essential to describe the correct phenomenology. To help clinicians reaching the proper diagnosis, several classifications of dystonia have been proposed. The current classification consists of axis I, clinical characteristics, and axis II, etiolo

Current Status and Perspectives of Allogeneic Hematopoietic Stem Cell Transplantation in Elderly Patients with Acute Myeloid Leukemia.

As in younger patients, allogeneic stem cell transplantation (alloHSCT) offers the best chance for durable remission in older patients (≥60 years) with acute myeloid leukemia (AML). However, defining the best treatment strategy (and in particular, whether or not to proceed to alloHSCT) for elderly patients with AML remains a difficult decision for the hematologist, since potential toxicity of conditioning regimens, risks of graft-versus-host disease, impaired immune reconstitution and the need for prolonged immunosuppression may be of major concern in these vulnerable patients with complex nee