Background: Multiple myeloma (MM) is a heterogeneous plasma cell malignancy with non-specific symptoms and disease heterogeneity at clinical and biological levels. This non-specific set of symptoms, including bone pain, anemia, renal failure, hypercalcemia, and neuropathy, can mislead diagnosis as chronic or benign conditions, resulting in a delay in diagnosis. Timely identification is paramount to prevent organ damage and reduce morbidity. Methods: In this review, we present an overview of recent literature concerning the factors leading to the delayed diagnosis of MM and the impact of delayed diagnosis. This includes factors relevant to physicians and systems, diagnostic processes, primary healthcare services, and laboratory and imaging data access and interpretation. Other emerging technologies to diagnose NCIs include AI-based decision support systems and biomarker-focused strategies. Findings: Delayed diagnosis can lead to presentation at advanced disease stages associated with life-threatening complications and shorter progression-free survival. Patients are often seen by many physicians before they are referred to hematology. Understanding of clinical red flags for MM in primary care is inadequate. Our findings indicate that limited access to diagnostic tests, inconsistent follow-up of MGUS/SMM patients, and a lack of interdepartmental coordination delay the diagnostic process. Conclusions: Multimodal tools for early diagnosis of MM. Educational campaigns to raise awareness of the disease, algorithms dedicated to routine care and novel technologies, including AI and big data analytics, and new biomarkers may serve this purpose, as well as genomic approaches to the premalignant MGUS stage.

Background: Multiple myeloma (MM) is a heterogenous plasma cell malignancy with non-specific symptoms and disease heterogeneity at clinical and biological levels. This non-specific set of symptoms, including bone pain, anemia, renal failure, hypercalcemia, and neuropathy can mislead diagnosis as chronic or benign conditions, resulting in a delay in diagnosis. Timely identification is paramount to prevent organ damage and reduce morbidity. Methods: In this review, we present an overview of recent literature concerning the factors leading to delayed diagnosis of MM and the impact of delayed diagnosis. This includes factors relevant to physicians and systems, diagnostic processes, primary healthcare services, and laboratory and imaging data access and interpretation. Other emerging technologies to diagnose NCIs include AI-based decision support systems and biomarker-focused strategies. Findings: Delayed diagnosis can lead to presentation at advanced disease stages associated with life-threatening complications and shorter progression-free survival. Patients are often seen by many physicians before they are referred to hematology. Understanding of clinical red flags for MM in primary care is inadequate. Our findings indicate that limited access to diagnostic tests and inconsistent follow-up of MGUS/SMM patients, as well as lack of interdepartmental coordination, delay the diagnostic process. Conclusion: Multimodal tools for early diagnosis of MM. Educational campaigns to raise awareness of the disease, algorithms dedicated to routine care, and novel technologies including AI and big data analytics, and new biomarkers may serve this purpose, as well as genomic approaches to the premalignant MGUS stage.

Background: Mediastinal gray zone lymphoma (MGZL) is a rare B-cell lymphoma characterized by overlapping clinicopathologic and molecular features of primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (CHL). Under current WHO-HEMA5 and International Consensus Classification (ICC) frameworks, MGZL is restricted to EBV-negative lymphomas arising in the mediastinum. Methods: This review summarizes current evidence on epidemiology, clinical presentation, pathology, molecular characteristics, diagnostic challenges, and therapeutic approaches to MGZL, with data derived from retrospective series, limited prospective cohorts, and recent molecular studies. Results: MGZL predominantly affects young adults and commonly presents with bulky mediastinal disease. Diagnosis is challenging due to transitional morphology, pleomorphic Reed–Sternberg-like cells, and variable expression of B-cell and activation markers. Molecular studies demonstrate shared alterations with PMBL and CHL, including 9p24.1 (JAK2/PD-L1/PD-L2) gains, while additional reported features such as HOXA5 hypomethylation and MYC copy number gains support its biological distinctiveness, although evidence remains limited. Frontline treatment commonly involves intensive chemoimmunotherapy regimens such as DA-EPOCH-R; however, outcomes remain inferior to PMBL and CHL, with 5-year overall survival rates of approximately 40–60%. Relapsed or refractory disease frequently requires salvage chemotherapy and autologous stem cell transplantation. Immune-based therapies, including brentuximab vedotin and PD-1 inhibitors, have shown promising activity, particularly in combination. Conclusions: MGZL remains a diagnostically challenging and therapeutically complex lymphoma with inferior outcomes compared with related mediastinal lymphomas. Advances in molecular profiling and immunotherapy offer promising avenues toward more personalized treatment; however, prospective clinical trials and international collaboration are urgently needed to establish evidence-based management strategies for this rare entity.

Background and Aim: Exportin 1 (XPO1) is the principal nuclear export receptor for numerous tumor-suppressor proteins, regulatory factors, and selected oncogenic mRNAs and has emerged as a therapeutically relevant vulnerability in multiple myeloma (MM). Selinexor, a first-in-class oral selective inhibitor of nuclear export (SINE), targets XPO1 and has demonstrated antimyeloma activity both as a doublet and in combination with established therapeutic agents. This review summarizes the biological rationale and molecular mechanisms of XPO1 inhibition, clinical evidence supporting selinexor-based therapy, mechanisms of resistance and potential predictive biomarkers, and practical considerations regarding toxicity management. Materials and Methods: A narrative review of the published literature on XPO1 biology and selinexor in MM was performed, with emphasis on preclinical mechanistic studies, prospective clinical trials, and studies addressing resistance, biomarkers, pharmacology, and treatment-related toxicity. Particular attention was given to pivotal and clinically relevant studies evaluating selinexor-based regimens, including Selinexor Treatment of Refractory Myeloma (STORM), BOSTON, and combination cohorts from the STOMP program, together with recent translational studies expanding the molecular framework of XPO1 inhibition. Results: XPO1 inhibition exerts pleiotropic antimyeloma effects through nuclear retention and reactivation of tumor-suppressor proteins, suppression of NF-κB-dependent signaling and oncogenic mRNA translation, enhancement of glucocorticoid signaling, and disruption of cellular protein homeostasis. More recent findings implicate treatment-induced XPO1 degradation through ubiquitin-regulatory mechanisms and suppression of lipid biosynthesis through the Lipin1–SREBP axis. Clinically, selinexor demonstrated activity in heavily pretreated triple-class refractory MM and subsequently showed improved efficacy when incorporated into once-weekly combination regimens, particularly with bortezomib and dexamethasone. Additional combinations with carfilzomib, pomalidomide, lenalidomide, and daratumumab have demonstrated clinically meaningful activity in selected relapsed/refractory multiple myeloma (RRMM) populations. Candidate determinants of response and resistance include XPO1 Cys528 alterations, hnRNPU, USP7-dependent regulation of XPO1 stability, and Lipin1–SREBP signaling, although none is currently prospectively validated for patient selection. Treatment-related cytopenias, gastrointestinal toxicity, fatigue, and hyponatremia remain important but can frequently be addressed through proactive supportive care and dose optimization. Conclusion: XPO1 inhibition represents a mechanistically distinct therapeutic strategy in MM, and selinexor has established clinical activity across multiple relapsed/refractory settings. Increasing use of lower-dose, once-weekly combination strategies has improved its therapeutic feasibility, while emerging insights into XPO1 degradation, metabolic regulation, and molecular determinants of response are broadening the biological framework of this drug class. Prospective biomarker validation and optimization of treatment sequencing will be important for defining the future role of XPO1-directed therapy in the evolving MM treatment landscape.

Background: Mediastinal gray zone lymphoma (MGZL) is a rare B-cell lymphoma which shares clinicopathologic and molecular features between primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (CHL). Although included as provisional disease entity back in 2008 WHO classification after initial description in 1998, the concept of MGZL has since evolved, with latest WHO-HEMA5 and ICC limiting the entity to EBV-negative mediastinal lesion. Methods: This review summarizes the historical evolution, epidemiology, clinicopathologic characteristics, immunophenotypic and genetic features, diagnostic challenges, and therapeutic strategies for MGZL. Data from retrospective series, prospective cohorts, and recent molecular studies are synthesized to provide a comprehensive perspective. Results: MGZL generally affects young adults, especially males, and presents with bulky mediastinal disease. Transitional morphology, pleomorphic Reed–Sternberg–like cells, and variable B-cell and activation markers make its diagnosis challenging. Molecular studies have shown that they share changes with PMBL and CHL such as 9p24. 1 (JAK2/PD-L1/PD-L2); however, specific alterations, including HOXA5 hypomethylation and MYC gains, argue for its designation as a separate entity. Therapeutically, DA-EPOCH-R is one of the most effective regimens, but prognosis is still worse than PMBL or CHL, 5-year OS ~40–60%. Salvage chemotherapy and autologous transplantation are frequently necessary for relapsed/refractory disease. Novel therapies, especially brentuximab vedotin and PD-1 inhibitors, appear to be effective, especially in combination. Conclusion: MGZL continues to be a diagnostically challenging, and therapeutically complex lymphoma with an inferior prognosis compared to related entities. Advancements in molecular profiling and immunotherapy suggest the promise of personalized therapy. Yet, prospective clinical trials and international cooperation are urgently needed to develop guidelines for therapy of this rare lymphoma.