Recommendations for the effective use of T-cell-redirecting therapies: a Canadian consensus statement.

Background: T-cell-redirecting therapies, such as bispecific antibodies and chimeric antigen receptor T-cells, exploit the cytotoxic capabilities of the immune system to destroy cells expressing specific surface antigens, including malignant cells. These therapies have demonstrated unprecedented rates, depth, and duration of responses in relapsed and refractory multiple myeloma. However, there are significant challenges in implementing these therapies into practice, which require multidisciplinary and multicenter coordination and significant healthcare resources to effectively manage these patients.

Selective PET imaging of CXCR4 using the AlF-labeled antagonist LY2510924.

Background: [Ga]PentixaFor detects C-X-C chemokine receptor type 4 (CXCR4) overexpression in various malignancies, such as multiple myeloma and non-Hodgkin lymphomas, as well as in endocrine and inflammatory disorders. This study aimed to develop an AlF-labeled radiotracer derived from LY2510924 for CXCR4-targeted imaging, leveraging the physical and logistical advantages of fluorine-18.

Methods: We designed a CXCR4-specific radioprobe, [F]AlF-NOTA-SC, based on LY2510924 by incorporating a triglutamate linker and NOTA chelator to enable AlF-labeling.

The global multiple myeloma incidence and mortality burden in 2022 and predictions for 2045.

Background: Multiple myeloma (MM) is an important haematological malignancy in older adults, with a relatively poor prognosis. We aimed to present the current global patterns of incidence and mortality from MM, and predict new cases and deaths by 2045.

Methods: Estimated numbers of MM cases and deaths and age-standardized (World) incidence and mortality rates per 100,000 people were obtained from the GLOBOCAN 2022 database covering 185 countries.

CancerHubs: a systematic data mining and elaboration approach for identifying novel cancer-related protein interaction hubs.

Conventional approaches to predict protein involvement in cancer often rely on defining either aberrant mutations at the single-gene level or correlating/anti-correlating transcript levels with patient survival. These approaches are typically conducted independently and focus on one protein at a time, overlooking nucleotide substitutions outside of coding regions or mutational co-occurrences in genes within the same interaction network. Here, we present CancerHubs, a method that integrates unbiased mutational data, clinical outcome predictions and interactomics to define novel cancer-related protein hubs.

Secondary Malignancies After Autologous Stem Cell Transplantations in Patients With Malignant Lymphoma and Multiple Myeloma.

Background: Secondary malignancies are potential complications after high-dose therapy and autologous stem cell transplantation (ASCT). Information on the detailed course of such events is scarce, yet may be essential to minimize the impact of these sequelae.

Patients And Methods: We regularly monitored 877 patients for up to 31 years after ASCT in our outpatient department.

Treatment adherence and effectiveness in patients treated with carfilzomib-based therapy combinations for relapsed/refractory multiple myeloma in Germany: interim results from the non-interventional CARO study.

Therapy adherence can significantly influence the outcome of cancer patients. The prospective, non-interventional CARO study (NCT02970747) investigated adherence, effectiveness, and safety of carfilzomib in patients with relapsed/refractory multiple myeloma (RRMM) in the German real-world setting. In total, 359 patients were included at 69 sites.

Pseudokinase TRIB3 stabilizes SSRP1 via USP10-mediated deubiquitination to promote multiple myeloma progression.

Multiple myeloma (MM), the world's second most common hematologic malignancy, poses considerable clinical challenges due to its aggressive progression and resistance to therapy. Addressing these challenges requires a detailed understanding of the mechanisms driving MM initiation, progression, and therapeutic resistance. This study identifies the pseudokinase tribble homolog 3 (TRIB3) as a high-risk factor that promotes MM malignancy in vitro and in vivo.

Bone marrow stromal cells protect myeloma cells from ferroptosis through GPX4 deSUMOylation.

Bone marrow stromal cells (BMSCs) are vital for preventing chemotherapy induced apoptosis of multiple myeloma (MM), but roles and machinery in other forms of cell death have not been well elucidated. Here, using an in vitro BMSC-MM interacting model, we observed BMSCs protected MM cells from labile iron pool (LIP) and reactive oxygen species (ROS) triggered ferroptosis by elevating glutathione peroxidase 4 (GPX4). Mechanistically, direct interaction with BMSCs upregulated the expression of SUMO-specific protease 3 (SENP3) in MM cells through CD40/CD40L signaling pathway, and SENP3 de-conjugated SUMO2 at lysine 75 residue to stabilize GPX4 protein, thereby consuming ROS to obviate ferroptosis in MM cells from the Vk∗MYC mouse model, as well as in CD138B220 cells separated from the Cd40l;Prx1 mice (CD40-CKO) and Sumo2 knock out (SUMO2-KO) mice.

Efficacy and Safety of Daratumumab in Intermediate/High-risk Smoldering Multiple Myeloma: Final Analysis of CENTAURUS.

Early intervention of smoldering multiple myeloma (SMM) may delay progression to multiple myeloma. Here, we present the final analysis of the phase 2 CENTAURUS study (NCT02316106). In total, 123 patients with intermediate/high-risk SMM were randomized to intravenous daratumumab 16 mg/kg following a Long intense (n = 41), Intermediate (n = 41), or Short intense (n = 41) dosing schedule.

Tumor burden quantified by Soluble B-Cell Maturation Antigen and Metabolic Tumor Volume determine myeloma CAR-T outcomes.

Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a breakthrough treatment for relapsed and refractory multiple myeloma (RRMM). However, these products are complex to deliver and alternative options are now available. Identifying biomarkers that can predict therapeutic outcomes is crucial for optimizing patient selection.

ADAR1-regulated cytoplasmic dsRNA-sensing pathway is a novel mechanism of lenalidomide resistance in multiple myeloma.

Immunomodulatory agents (IMiDs) are a major class of drugs for treating multiple myeloma (MM); however, acquired resistance to IMiDs remains a significant clinical challenge. While alterations in cereblon (CRBN) and its pathway are known to contribute to IMiD resistance, they account for only 20-30% of cases, and the underlying mechanisms in the majority of the resistance cases remain unclear. Here, we identified ADAR1 as a novel driver of lenalidomide resistance in MM.

Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma.

Background: Daratumumab, an anti-CD38 monoclonal antibody, has been approved for the treatment of multiple myeloma. Data are needed regarding the use of daratumumab for high-risk smoldering multiple myeloma, a precursor disease of active multiple myeloma for which no treatments have been approved.

Methods: In this phase 3 trial, we randomly assigned patients with high-risk smoldering multiple myeloma to receive either subcutaneous daratumumab monotherapy or active monitoring.

Isatuximab, Lenalidomide, Bortezomib, and Dexamethasone Induction Therapy for Transplant-Eligible Newly Diagnosed Multiple Myeloma: Final Part 1 Analysis of the GMMG-HD7 Trial.

Previously, addition of isatuximab (Isa) to standard-of-care lenalidomide-bortezomib-dexamethasone (RVd) in transplant-eligible patients with newly diagnosed multiple myeloma in the GMMG-HD7 trial (ClinicalTrials.gov identifier: NCT03617731) resulted in a significant increase of minimal residual disease negativity (MRD-) rates after induction therapy. A total of 662 patients were randomly assigned to receive induction therapy with Isa-RVd (n = 331) or RVd (n = 329), followed by single or tandem autologous stem-cell transplant and second random assignment to maintenance with lenalidomide alone or Isa-lenalidomide.

Pharmacokinetics of Zilurgisertib With and Without Food from Single and Multiple Ascending Dose Phase 1 Studies in Healthy Adults.

Background And Objectives: The oral, potent, and highly selective activin receptor-like kinase 2 (ALK2) inhibitor zilurgisertib (INCB000928) is in development as a treatment for fibrodysplasia ossificans progressiva (FOP), and for anemia due to myelofibrosis, myelodysplastic syndromes, and multiple myeloma. Saliva is an attractive alternative to blood for drug monitoring and pharmacokinetic analysis, as it is non-invasive to retrieve. This is beneficial for patients, such as those with FOP, for whom blood draws can be challenging due to soft tissue damage susceptibility that can cause progressive heterotopic ossification, and for whom tourniquet time and blood draws must be minimized.

Idecabtagene vicleucel (ide-cel) for the treatment of triple-class exposed relapsed and refractory multiple myeloma.

Introduction: Modern anti-myeloma therapies have broken new ground in the treatment of the disease, and the incorporation of ide-cel in the treatment landscape represents one of the major scientific and clinical advances.

Areas Covered: Ide-cel was the first cell-based gene therapy approved for the treatment of triple-class exposed relapsed/refractory myeloma patients, showing impressive results, and demonstrating superiority over standard regimens in terms of efficacy, potential treatment-free intervals, and improved quality of life in heavily pretreated patients and in high-risk disease. This review summarizes the state-of-the-art of the most recent updates deriving from the use of ide-cel within ongoing, or upcoming, clinical trials, and from real-life experiences.

Can you Diagnose Immune Thrombocytopenia in Myeloma? A Case of Thrombocytopenia in a Patient with Multiple Myeloma.

Unlabelled: Multiple myeloma (MM) is the second most common haematological malignancy, the diagnosis of which has doubled in recent years. Immune thrombocytopenia consists of isolated thrombocytopenia secondary to antibody mediated peripheral platelet destruction. In most cases, there is no identifiable cause (primary immune thrombocytopenia).

A role for diet and gut microbiota metabolites in autologous hematopoietic cell transplant recipients.

Introduction: The gut microbiome has an established role in allogeneic hematopoietic cell transplantation (allo-HCT), but not in an auto-HCT setting. We have hypothesized that fecal short-chain fatty acids (SCFA) and urinary 3-indoxyl sulfate (3-IS), which are metabolites derived from the action of the gut microbiome on dietary fiber, play a role in auto-HCT outcomes.

Methods: This was a single-center prospective study involving auto-HCT recipients.

A Discount on the Cost of Cancer: India's Homegrown CAR-T Cell Therapy.

Chimeric antigen receptor T cell (CAR-T) therapy has revolutionized the treatment of blood cancer. By improving survival outcomes for patients with B-cell malignancies, which hitherto have been unparalleled by conventional chemotherapy, CAR-T therapy is a beacon of hope for many patients with cancer. However, harvesting, modifying, and reintroducing T cells is costly, which means that not every patient with cancer who needs CAR-T therapy has the financial capacity to receive it.

Financial conflicts among physician speakers at the April 12, 2024 Oncology Drug Advisory Meeting: Who decided that MRD can be a novel regulatory endpoint in myeloma?

Background: In April 2024, the Oncology Drug Advisory Committee (ODAC) voted to approve minimal residual disease (MRD) as a new regulatory endpoint for multiple myeloma (MM) despite its poor trial-level surrogacy. This is expected to result in faster MM drug approvals, a potential boon for the pharmaceutical companies that make them. This study investigates the prevalence of financial conflicts of interest (FCOIs) with these companies among United States (US)-based physician speakers at the meeting.

Chemotherapeutic potential of radotinib against blood and solid tumors: A beacon of hope in drug repurposing.

Tyrosine kinase inhibitors (TKIs) represent a pivotal class of targeted therapies in oncology, with multiple generations developed to address diverse molecular targets. Imatinib is the first TKI developed to target the BCR-ABL1 chimeric protein, which is the key driver oncogene implicated in Philadelphia chromosome-positive chronic myeloid leukemia (CML). Several second-generation tyrosine kinase inhibitors (2GTKIs), such as nilotinib, dasatinib, bosutinib, and radotinib (RTB), followed the groundbreaking introduction of imatinib.

Canagliflozin differentially modulates carfilzomib-induced endoplasmic reticulum stress in multiple myeloma and endothelial cells.

Carfilzomib (CFZ), a second-generation proteasome inhibitor, is a key treatment for multiple myeloma (MM), but its use is associated with significant cardiovascular adverse events (CVAEs), including heart failure and hypertension. Endothelial dysfunction is believed to contribute to these CVAEs. Building on our previous findings that CFZ induces endothelial toxicity and that canagliflozin protects against CFZ-induced endothelial apoptosis, this study aimed to evaluate CFZ-induced endoplasmic reticulum (ER) stress and autophagy in endothelial and MM cells, as well as the impact of canagliflozin on these processes and its impact on the anticancer effects of CFZ in MM cells.

B-Lymphoblastic Leukemia with BCR::ABL1-like Features After Long-term Lenalidomide Therapy.

Lenalidomide, a derivative of thalidomide, is a type of immunomodulatory drug (IMiD) that has been standard therapy for multiple myeloma (MM) and other hematologic malignancies for almost two decades. The success of these drugs in MM has contributed to increased survival of patients and, as a result, patients are at risk for a secondary primary malignancy (SPM), some of which occur as a result of treatment for MM. MM patients have an increased risk for acute myeloid leukemia (AML) and Kaposi sarcoma.