Lactate accumulation promotes immunosuppression and fibrotic transformation of bone marrow microenvironment in myelofibrosis.

Background: Clonal myeloproliferation and fibrotic transformation of the bone marrow (BM) are the pathogenetic events most commonly occurring in myelofibrosis (MF). There is great evidence indicating that tumor microenvironment is characterized by high lactate levels, acting not only as an energetic source, but also as a signaling molecule.

Methods: To test the involvement of lactate in MF milieu transformation, we measured its levels in MF patients' sera, eventually finding a massive accumulation of this metabolite, which we showed to promote the expansion of immunosuppressive subsets.

Emergencies in Hematology: Why, When and How I Treat?

Hematological emergencies are critical medical conditions that require immediate attention due to their rapid progression and life-threatening nature. As various examples, hypercalcemia, often associated with cancers such as multiple myeloma, can lead to severe neurological and cardiac dysfunction. Hyperleukocytosis, common in acute myeloid leukemias, increases the risk of leukostasis and multiorgan failure.

Enhanced Antitumor Activity by the Combination of Dasatinib and Selinexor in Chronic Myeloid Leukemia.

Background: Chronic myeloid leukemia is a hematological malignancy characterized by the abnormal proliferation of leukemic cells. Despite significant progress with tyrosine kinase inhibitors, such as Dasatinib, resistance remains a challenge. The aim of the present study was to investigate the potential of Selinexor, an Exportin-1 inhibitor, to improve TKI effectiveness on CML.

Multiple Myeloma in 2023 Ways: From Trials to Real Life.

Multiple myeloma is a chronic hematologic malignancy that obstinately tends to relapse. Basic research has made giant strides in better characterizing the molecular mechanisms of the disease. The results have led to the manufacturing of new, revolutionary drugs which have been widely tested in clinical trials.

Efficacy and safety of tixagevimab-cilgavimab versus SARS-CoV-2 breakthrough infection in the hematological conditions.

Background: Managing SARS-CoV-2 infection in frail and immunosuppressed patients still represents an open challenge, but, starting from the phase 3 PROVENT study, prophylaxis with tixagevimab-cilgavimab has improved the approach in this category of patients, guaranteeing a better outcome and inferior mortality. Real-life data in a heterogeneous cohort are few.

Methods: The aim of this study is to evaluate the benefit of prophylaxis with tixagevimab-cilgavimab in a cohort of 202 patients affected by different hematological diseases (lymphoproliferative, myeloproliferative, autoimmune, patients recently receiving a bone marrow transplant), active (with ongoing treatment), or in watch-and-wait strategy, followed in our center, during a median follow-up of 249 (45-325) days.

Lenalidomide plus Dexamethasone Combination as First-Line Oral Therapy of Multiple Myeloma Patients: A Unicentric Real-Life Study.

Based on the results obtained in clinical trials, the use of the combination of lenalidomide and dexamethasone (Len/Dex) has become a potential therapeutic choice for newly diagnosed multiple myeloma (NDMM) ineligible for autologous stem cell transplantation. This study evaluated 89 frail NDMM patients treated with first-line oral association. At the last follow-up, 34 out of 89 patients (38.

Multicentric Castleman Disease and Concurrent Hematological Disorders: The Occurrence of Plasmacytoma and the Hypotheses Arising from Literature Review.

The concomitant presence of Castleman disease (CD) with other hematological pathology is an event described in the literature with increasing frequency, able to modify the diagnostic and curative approach in such patients. Very few studies in the literature describe the association of CD with concomitant neoplastic diseases; the most frequent are Kaposi's sarcomas (especially in HIV and human herpes virus-8-positive patients) and lymphoproliferative disorders, such as lymphomas. Instead, since the association with plasma cell diseases such as multiple myeloma and plasmacytoma is infrequent, there is a lack of literature.

Clinical outcome of SARS-CoV-2 infections occurring in multiple myeloma patients after vaccination and prophylaxis with tixagevimab/cilgavimab.

Introduction: Patients with multiple myeloma (MM) frequently reported immune impairment with an increased risk for infection-related mortality. We aimed to evaluate the immune response in MM patients vaccinated for SARS-CoV-2 during active treatment.

Methods: We enrolled 158 patients affected by active MM or smoldering MM (SMM) and 40 healthy subjects.

Lactate trafficking inhibition restores sensitivity to proteasome inhibitors and orchestrates immuno-microenvironment in multiple myeloma.

Metabolic changes of malignant plasma cells (PCs) and adaptation to tumour microenvironment represent one of the hallmarks of multiple myeloma (MM). We previously showed that MM mesenchymal stromal cells are more glycolytic and produce more lactate than healthy counterpart. Hence, we aimed to explore the impact of high lactate concentration on metabolism of tumour PCs and its impact on the efficacy of proteasome inhibitors (PIs).

Reduced Absolute Count of Monocytes in Patients Carrying Hematological Neoplasms and SARS-CoV2 Infection.

Background: Clinical course of COVID-19 depends on several patient-specific risk factors, including immune function, that is largely compromised in cancer patients.

Methods: We prospectively evaluated 120 adult consecutive patients (including 34 cases of COVID-19 breakthrough after two full doses of BNT162b2 vaccine) with underlying hematological malignancies and a SARS-CoV-2 infection, in terms of patient's clinical outcome.

Results: Among fully vaccinated patients the achievement of viral clearance by day 14 was more frequent than in unvaccinated patients.

CXCL12/CXCR4 axis supports mitochondrial trafficking in tumor myeloma microenvironment.

Mesenchymal stromal cells (MSCs) within the protective microenvironment of multiple myeloma (MM) promote tumor growth, confer chemoresistance and support metabolic needs of plasma cells (PCs) even transferring mitochondria. In this scenario, heterocellular communication and dysregulation of critical signaling axes are among the major contributors to progression and treatment failure. Here, we report that myeloma MSCs have decreased reliance on mitochondrial metabolism as compared to healthy MSCs and increased tendency to deliver mitochondria to MM cells, suggesting that this intercellular exchange between PCs and stromal cells can be consider part of MSC pro-tumorigenic phenotype.

Belantamab Mafodotin and Relapsed/Refractory Multiple Myeloma: This Is Not Game Over.

Although the therapeutic landscape for multiple myeloma (MM) has expanded, the disease always tends to relapse. In an attempt to obtain deep and durable responses, each relapse requires the use of a new strategy. In recent years, new treatment options have emerged, even for heavily treated patients.

Lenalidomide and Pomalidomide Improve Function and Induce FcγRI/CD64 in Multiple Myeloma Neutrophils.

Myeloid dysfunction is an emerging hallmark of microenvironment changes occurring in multiple myeloma (MM). Our previous work showed that FcγRI/CD64 overexpression in neutrophils of newly diagnosed MM patients is associated to inferior outcomes, reduced oxidative bursts and phagocytosis, with an increased risk of bacterial infections. Pomalidomide is a novel immune-modulatory drug approved for relapsed/refractory patients (RRMM), with drug-related neutropenia as major limitation to treatment.

Daratumumab as Single Agent in Relapsed/Refractory Myeloma Patients: A Retrospective Real-Life Survey.

Background: The anti-CD38 monoclonal antibody daratumumab is approved as a single agent for the treatment of patients with relapsed/refractory multiple myeloma (RRMM) who received at least three prior lines of therapy, including proteasome inhibitor and immunomodulatory agent. A retrospective multicentric study was designed to evaluate feasibility, tolerability, and efficacy of daratumumab in monotherapy in RRMM.

Methods: This study included 44 consecutive RRMM patients that underwent daratumumab monotherapy after a median number of four prior therapies (range 2-9).

Younger patients with Waldenström Macroglobulinemia exhibit low risk profile and excellent outcomes in the era of immunotherapy and targeted therapies.

We analyzed 160 young Waldenström Macroglobulinemia (WM) patients with a median age of 49 years (range 23-55 years), diagnosed between January 2000 and January 2019 in 14 Italian centers. At diagnosis, 70% of patients were asymptomatic. With a median follow-up of 5.

Plasticity of High-Density Neutrophils in Multiple Myeloma is Associated with Increased Autophagy Via STAT3.

In both monoclonal gammopathy of uncertain significance (MGUS) and multiple myeloma (MM) patients, immune functions are variably impaired, and there is a high risk of bacterial infections. Neutrophils are the most abundant circulating leukocytes and constitute the first line of host defense. Since little is known about the contribution of autophagy in the neutrophil function of MGUS and MM patients, we investigated the basal autophagy flux in freshly sorted neutrophils of patients and tested the plastic response of healthy neutrophils to soluble factors of MM.

Serum free light chains and multiple myeloma: Is it time to extend their application?

In nonsecretory, oligo-secretory, and light chain multiple myeloma patients, serial sFLC evaluation could precede biochemical and clinical disease progression, even in extramedullary relapse, thus initiating early treatment with novel anti-MM agents.

Clinical Benefit of Long-Term Disease Control with Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients.

Background: We retrospectively analysed relapsed/refractory MM (RRMM) patients treated with pomalidomide and dexamethasone (PomaD) either in real life, or previously enrolled in an interventional (STRATUS, MM-010) or currently enrolled in an observational study (MM-015) to provide further insights on safety and tolerability and clinical efficacy.

Methods: Between July 2013 and July 2018, 76 RRMM patients (including 33 double refractory MM) received pomalidomide 4 mg daily given orally on days 1-21 of each 28-day cycle, and dexamethasone 40 mg weekly (≤75 years) or 20 mg weekly for patients aged > 75 years. In nine patients a third agent was added to increase the response: Cyclophosphamide (in two fit patients) or clarithromycin (in seven frail patients).

A rare case of multiple myeloma with intracranial extramedullary relapse: One or more myeloma clones?

In a minority of relapsed myeloma, patient's disease may spread into extramedullary sites, associated with high degrees of heterogeneity. The breadth of myeloma therapeutic armamentarium allows clinicians to manage its heterogeneous presentation, including intracranial relapses, with fair success resulting in a significant prolongation of survival.

Feasibility, Tolerability and Efficacy of Carfilzomib in Combination with Lenalidomide and Dexamethasone in Relapsed Refractory Myeloma Patients: A Retrospective Real-Life Survey of the Sicilian Myeloma Network.

The ASPIRE (NCT01080391) phase 3 trial showed the efficacy of carfilzomib, lenalidomide and dexamethasone (KRd) triplet for relapse and refractory multiple myeloma (RRMM). However, little is known about safety and efficacy of KRd outside a clinical trial context. Herein we report real life results of KRd given to 130 RRMM patients from 12 Sicilian Centers.

Imatinib increases cytotoxicity of melphalan and their combination allows an efficient killing of chronic myeloid leukemia cells.

BCR/ABL positive cells are known to be resistant to DNA damage induced by chemotherapy while they are sensitive to imatinib (IM), a tyrosine kinase inhibitor (TKI). To evaluate whether this drug can increase the activity of cytotoxic drugs on BCR/ABL positive cells, we measured the toxicity of cytosine arabinoside (ARA-C), hydroxyurea (HU) and melphalan (MEL), after a pretreatment of 24 h with IM on K562 cell line. The highest cytotoxic effect was seen when the TKI was followed by MEL; our results indicate that inhibition of BCR/ABL activity by IM increased the cytotoxicity of MEL by favoring the DNA damage induced by this drug and by shortening the time for DNA repair at the G2/M checkpoint.