Targeting the MARCH5-MFN2 axis to enhance mitochondrial fusion and sensitize multiple myeloma cells to venetoclax.

Background: Accumulating evidence suggests that mitochondrial fission and fusion events are imbalanced in cancer due to defective activity of their key regulators. In this study, we investigated the functional role of the E3 ubiquitin ligase Membrane-Associated Ring-CH-Type Finger 5 (MARCH5) in regulating cell growth, metabolic reprogramming and drug resistance in multiple myeloma (MM) through the negative regulation of the mitochondrial fusion driver mitofusin 2 (MFN2).

Methods: Cell viability and apoptosis were evaluated in MM cell lines or in co-culture with stromal cells using the CellTiter-Glo® Cell Viability Assay and Annexin V/7-AAD staining, respectively.

Vaccination in Multiple Myeloma: Challenges and Strategies.

Background: Multiple myeloma (MM) is a hematological malignancy characterized by profound immunosuppression resulting from both disease-related mechanisms and treatment-induced immune dysfunction. This compromised immune status markedly increases susceptibility to infections, a leading cause of morbidity and mortality in MM patients. While vaccination represents a cornerstone of infection prevention, standard immunization strategies often yield suboptimal responses in this population.

Integration of [F]FDG-PET radiomics with liquid biopsy improves outcome prediction in newly diagnosed diffuse large B-cell lymphoma.

Early identification of relapsing/refractory diffuse large B-cell lymphoma (DLBCL) represents an unmet clinical need. A real-life cohort of newly diagnosed DLBCL (n = 120) treated with R-CHOP was investigated. Using the standardized uptake value (SUV) threshold of 4.

Correction: Sgherza et al. Efficacy and Safety of Isatuximab, Carfilzomib, and Dexamethasone (IsaKd) in Multiple Myeloma Patients at the First Relapse After Autologous Stem Cell Transplantation and Lenalidomide Maintenance: Results from the Multicenter, Real-Life AENEID Study. 2025, , 595.

In the original publication [...

Rethinking the feasibility and safety of venetoclax-obinutuzumab in chronic lymphocytic leukemia: non-traditional factors may play a role in clinical practice.

The concept of fitness for novel agents in chronic lymphocytic leukemia (CLL) remains debated. Comorbidities and treatment-related logistics are increasingly recognized as key factors in treatment feasibility. Venetoclax-obinutuzumab (VO) has demonstrated efficacy in both fit and unfit patients in clinical trials, yet real-world data remain limited.

Richter transformation in diffuse large B-cell lymphoma in patients with chronic lymphocytic leukemia receiving ibrutinib: risk factors and outcomes.

This study aimed to define the incidence and risk factors for diffuse large B cell lymphoma variant of RT (DLBCL-RT) in 976 patients with CLL who received ibrutinib therapy. DLBCL-RT was recorded in 83 (8.5%) patients, with a 7-year 15.

Elexacaftor/tezacaftor/ivacaftor (ETI) therapy modifies the expression of interferon beta and inflammatory genes in the airways of adult patients with cystic fibrosis: a pilot study.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies have revolutionized the treatment of cystic fibrosis (CF) by targeting the underlying protein defect. Investigating how elexacaftor/tezacaftor/ivacaftor (ETI) therapy affects interferon (IFN) signalling and inflammatory cytokine production in CF airway epithelial cells may clarify its role in alleviating the dysregulated innate immune response. Clinical efficacy was evaluated in 26 modulator-naive CF patients with at least one F508del mutation before and after 3 and 6 months of ETI treatment.

Maintenance therapy after ASCT in newly diagnosed multiple myeloma patients: single agent combination drugs.

Introduction: Maintenance therapy plays a crucial role in prolonging progression-free survival and overall survival in multiple myeloma. Lenalidomide remains the gold standard, as demonstrated in phase 3 trials, consistently showing superior survival compared to observation or placebo. However, both established and novel agents - such as thalidomide and pomalidomide, proteasome inhibitors (PIs), monoclonal antibodies (moAbs), and bispecific antibodies - have been investigated as alternatives to assess their efficacy and safety.

Treatment-Free Remission in Chronic Myeloid Leukemia: Revisiting the "W" Questions.

Chronic myeloid leukemia (CML) has undergone a transformation from a fatal disease to a chronic, manageable condition with the advent of tyrosine kinase inhibitors (TKIs), particularly imatinib. This shift has significantly improved survival rates, and for some patients, achieving deep molecular response (DMR) has made treatment-free remission (TFR) a feasible goal. However, the ability to sustain TFR remains a challenge, primarily due to the persistence of leukemia stem cells (LSCs), which are inherently resistant to TKIs and contribute to relapse after treatment cessation.

Measurement of Immunoglobulin Intraclonal diversification refines the clinical impact of IGHV mutational status in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) cells may bear mutations in IGHV genes, the 2%-cutoff allowing to discriminate two subsets, unmutated (U)- or mutated (M)-CLL, with different clinical course. IGHV genes may also incorporate additional ongoing mutations, a phenomenon known as intraclonal diversification (ID). Here, through an original bioinformatic workflow for NGS data, we used the inverse Simpson Index (iSI) as diversity measure among IGHV sequences to dichotomize cases with different ID levels into ID (iSI ≥ 1.

Unraveling Obesity and Multiple Myeloma: Insights from Epidemiology and Molecular Mechanisms.

Purpose Of Review: The global incidence of obesity has risen dramatically in recent decades, with consequent detrimental health effects. Extensive studies have demonstrated that obesity significantly affects the risk, prognosis, and progression of various cancers, including multiple myeloma (MM). As an established modifiable risk factor for both MM and its precursor stages -monoclonal gammopathy of unknown significance (MGUS) and smoldering MM (SMM)- the association between obesity and disease onset has become a compelling area of research.

TP53-Mutated Acute Myeloid Leukemia: Unanswered Questions.

TP53-mutated acute myeloid leukemia (AML) remains one of the most treatment-resistant hematologic malignancies, with poor overall survival despite advancements in therapeutic strategies. The loss of functional p53 compromises DNA repair, apoptosis, and genomic stability, rendering both conventional and novel therapies largely ineffective. This review evaluates the efficacy of various treatment approaches, including intensive chemotherapy (IC), hypomethylating agents (HMAs), venetoclax-based regimens, and immune checkpoint inhibitors.

Mitochondrial fission factor drives an actionable metabolic vulnerability in multiple myeloma.

Proliferating multiple myeloma (MM) cells in the bone marrow fluctuate across various metabolic states to resist cancer treatments. Herein, we investigate how mitochondrial dynamics, which controls mitochondrial fitness via coordinated fission and fusion events, shapes MM cell metabolism impacting growth, survival and drug sensitivity. We identify MFF (Mitochondrial Fission Factor), a pivotal driver of mitochondrial fragmentation, as being highly expressed in MM plasma cells bearing cytogenetic abnormalities predicting poor clinical outcome.

Lenalidomide maintenance after bortezomib, thalidomide and dexamethasone (VTD) induction and autologous stem cell transplantation: an Italian real-life study of 602 patients.

Not available.

Efficacy and Safety of Isatuximab, Carfilzomib, and Dexamethasone (IsaKd) in Multiple Myeloma Patients at the First Relapse After Autologous Stem Cell Transplantation and Lenalidomide Maintenance: Results from the Multicenter, Real-Life AENEID Study.

: In the randomized, phase-3 IKEMA trial, the triplet isatuximab, carfilzomib, and dexamethasone (IsaKd) demonstrated superior clinical benefit compared to those of carfilzomib and dexamethasone alone in patients with relapsed/refractory multiple myeloma after 1-3 prior treatments. : Our real-world, AENEID study aimed to evaluate the efficacy and safety of IsaKd in patients who relapsed after frontline lenalidomide treatment, poorly represented in the IKEMA trial. Specifically, in the present multicenter analysis, we enrolled eighty-two patients who received, between April 2022 and September 2024 and outside of clinical trials, at least one cycle of IsaKd as a second-line treatment at the first relapse after induction therapy, autologous stem cell transplantation (ASCT), and lenalidomide maintenance.

Venetoclax-based regimens in octogenarian patients with CLL: efficacy, safety, and comparison to BTKi in a multicenter cohort.

Octogenarians represent a significant fraction of patients with chronic lymphocytic leukemia (CLL) but, despite the prevalence of the disease in this age group, limited data are available on the safety and efficacy of novel drugs in this subgroup. We conducted a multicenter retrospective study enrolling 120 octogenarian patients who received venetoclax (Ven) regimens in any line. Regarding efficacy, we found Ven to perform similarly to what is reported in younger patients with CLL, with an overall response rate of 91%, a complete response rate of 44%, and median progression-free survival of 44 months.

Rilzabrutinib for the Treatment of Immune Thrombocytopenia.

Advancements in the understanding of ITP pathogenesis have led to significant improvements in disease management through the use of both traditional immunosuppressive strategies and novel targeted therapies. However, a subset of patients remains refractory to treatment or achieves only transient benefits, underscoring the need for alternative therapeutic approaches. Bruton's tyrosine kinase (BTK) inhibitors have emerged as a promising strategy for autoimmune cytopenias, including ITP, due to their ability to modulate key immune pathways.

Prognostic Significance of +1q Alterations in Relapsed/Refractory Multiple Myeloma Treated With Daratumumab-, Elotuzumab-, and Carfilzomib-Based Triplet Regimens: A Multicenter Real-World Analysis of 635 Patients.

Relapsed/refractory multiple myeloma (RRMM) research on the impact of +1q abnormalities in real-world settings is limited. This study evaluated the prognostic and predictive significance of 1q gain [gain(1q)] and amplification [ampl(1q)] in 635 RRMM patients treated with daratumumab-, elotuzumab-, and carfilzomib-based triplet regimens. Patients with +1q abnormalities had lower deep response rates [≥ CR: 9.

Frailty predicts treatment-related toxicity and discontinuation in older adults with chronic lymphocytic leukemia treated with BTK and BCL-2 inhibitors: Findings from a prospective single-center cohort study.

Introduction: Chronic lymphocytic leukemia (CLL) particularly impacts older adults with multiple comorbidities. The advent of targeted therapies has improved outcomes, but challenges related to treatment adherence and drug interactions persist. Assessment of frailty is recommended to tailor treatment, though its application in clinical settings is often limited due to its complexity.

Therapeutic Strategies for Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia in Adult Patients: Optimizing the Use of Monoclonal Antibodies.

The treatment landscape for relapsed or refractory acute lymphoblastic leukemia (RR ALL) has evolved significantly with the introduction of monoclonal antibodies such as blinatumomab and inotuzumab ozogamicin. These agents have demonstrated remarkable efficacy, achieving high response rates and minimal residual disease (MRD) negativity. However, the optimal selection, sequencing, and integration of monoclonal antibodies and other modalities like standard chemotherapy or chimeric antigen receptor T-cell therapy remain areas of active investigation.

Relapsed/Refractory Follicular Lymphoma: Current Advances and Emerging Perspectives.

Follicular lymphoma (FL) is a prevalent indolent non-Hodgkin lymphoma (NHL) characterized by a relapsing course and eventual refractoriness to therapy. Despite advancements in treatment, FL remains incurable, necessitating ongoing research into novel therapeutic strategies. This review provides a comprehensive overview of current standard treatments for relapsed or refractory (R/R) FL, including chemoimmunotherapy and stem cell transplantation, and delves into emerging therapies such as chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies.

Avatrombopag for the Treatment of Immune Thrombocytopenia.

Avatrombopag, a second-generation thrombopoietin receptor agonist (TPO-RA), represents a significant advancement in the treatment of chronic immune thrombocytopenic purpura (cITP) and a potential therapeutic option for other thrombocytopenic disorders. Approved in both the USA and Europe, avatrombopag offers a convenient oral dosing regimen, initiated at 20 mg daily with food, to achieve and maintain platelet counts ≥ 50 × 10/L. Its favorable safety profile, characterized by minimal hepatic toxicity and the absence of dietary restrictions, distinguishes it from older TPO-RAs such as eltrombopag and romiplostim.

Efficacy and Prognostic Indicators of Isatuximab, Pomalidomide, and Dexamethasone (IsaPd) in Daratumumab-Refractory Multiple Myeloma Patients: A Multicenter Real-World Study.

This multicenter real-world analysis evaluated the efficacy of isatuximab, pomalidomide, and dexamethasone (IsaPd) in 51 patients with multiple myeloma (MM) who were refractory to daratumumab (Dara-R). The majority were under 70 years old (60.8%), predominantly female (56.

Refining High-Risk Multiple Myeloma: Advancements in Genomic, Clinical, and Prognostic Criteria.

Multiple myeloma (MM) is a heterogeneous disease, with MM patients experiencing different clinical outcomes depending on the disease's biological features. Novel insights into the molecular mechanisms of MM have led to the introduction of sophisticated drugs, which dramatically improved patient treatment and survival. To date, young patients with newly diagnosed MM could experience a median overall survival (OS) of 10 years.