Search Results (101)

Background and Objectives: Extramedullary plasmacytoma (EMP) is a rare monoclonal B-cell neoplasm that typically affects the head and neck region, with a predilection for the sinonasal tract. Clinical presentation is often nonspecific, leading to delayed diagnosis. This study aims to improve our understanding of sinonasal EMP by reviewing the recent literature and presenting a case series from our clinical experience. Materials and Methods: A systematic review of published cases of sinonasal EMP from 2000 to 2023 was conducted using the PubMed database, yielding 28 eligible cases. Additionally, we retrospectively analyzed three patients diagnosed and treated at our institutions. Inclusion criteria included histologically and immunohistochemically confirmed EMP without evidence of systemic multiple myeloma. Data on demographics, tumor location, symptoms, treatment, and outcomes were collected and analyzed descriptively. Results: Sinonasal EMP most commonly presented with unilateral nasal obstruction and epistaxis. Tumors were primarily located in the nasal cavity and paranasal sinuses, often extending beyond a single anatomical site. In the literature cohort, the most frequent treatment was combined surgery and radiotherapy (35.71%), followed by radiotherapy alone (17.86%). Recurrence was reported in 10.71% of cases, and 7.14% of patients died due to disease progression. All three patients in our case series underwent surgical excision; two received postoperative radiotherapy. No recurrences or progression to multiple myeloma were observed during follow-up (12–24 months). Conclusions: Sinonasal EMP is a rare but radiosensitive tumor with a favorable prognosis when treated with surgery and/or radiotherapy. Early diagnosis, histopathological confirmation, and exclusion of systemic disease are essential. Multidisciplinary management and long-term follow-up are critical due to the risk of recurrence and transformation into multiple myeloma. Full article

Multiple myeloma (MM) is an incurable malignancy characterized by the proliferation of abnormal plasma cells within the bone marrow, followed by potential dissemination to extramedullary sites. The bone marrow barrier (BMB) plays a pivotal role in plasma cell homing and disease progression. Bone marrow endothelial cells (BMECs) and bone marrow stromal cells (BMSCs), through their interactions with MM cells, secrete adhesion molecules, angiogenic cytokines, anti-apoptotic factors, and growth-promoting signals that support MM cell survival and proliferation. This review examines the components of the BMB and the major pathways involved in MM pathogenesis. Targeting the interactions between MM cells and the BMB may offer novel therapeutic opportunities. Full article

Introduction: Acute Myeloid Leukemia (AML) is a hematologic malignancy characterized by the clonal expansion of myeloid progenitors. While it primarily affects the bone marrow, extramedullary relapse occurs in 3–5% of cases, and it is linked to poor prognosis. Central nervous system (CNS) involvement presents diagnostic challenges due to nonspecific symptoms. CNS manifestations include leptomeningeal dissemination, nerve infiltration, parenchymal lesions, and myeloid sarcoma, occurring at any disease stage and frequently asymptomatic. Methods: A 62-year-old man with a recent history of AML in remission presented with diplopia and aching paresthesias in the left periorbital region spreading to the left frontal area. The diagnostic workup included neurological and hematological evaluation, lumbar puncture, brain CT, brain magnetic resonance imaging (MRI) with contrast, and dermatological evaluation with skin biopsy due to the appearance of nodular skin lesions on the abdomen and thorax. Results: Neurological evaluation showed hypoesthesia in the left mandibular region, consistent with left trigeminal nerve involvement, extending to the periorbital and frontal areas, and impaired adduction of the left eye with divergent strabismus in the primary position due to left oculomotor nerve palsy. Brain MRI showed an equivocal thickening of the left oculomotor nerve without enhancement. Cerebrospinal fluid (CSF) analysis initially showed elevated protein (47 mg/dL) with negative cytology; a repeat lumbar puncture one week later detected leukemic cells. Skin biopsy revealed cutaneous AML localization. A diagnosis of AML relapse with CNS and cutaneous localization was made. Salvage therapy with FLAG-IDA-VEN (fludarabine, cytarabine, idarubicin, venetoclax) and intrathecal methotrexate, cytarabine, and dexamethasone was started. Subsequent lumbar punctures were negative for leukemic cells. Due to high-risk status and extramedullary disease, the patient underwent allogeneic hematopoietic stem cell transplantation. Post-transplant aplasia was complicated by septic shock; the patient succumbed to an invasive fungal infection. Conclusions: This case illustrates the diagnostic complexity and poor prognosis of extramedullary AML relapse involving the CNS. Early recognition of neurological signs, including cranial nerve dysfunction, is crucial for timely diagnosis and management. Although initial investigations were negative, further analyses—including repeated CSF examinations and skin biopsy—led to the identification of leukemic involvement. Although neuroleukemiosis cannot be confirmed without nerve biopsy, the combination of clinical presentation, neuroimaging, and CSF data strongly supports the diagnosis of extramedullary relapse of AML. Multidisciplinary evaluation remains essential for detecting extramedullary relapse. Despite treatment achieving CSF clearance, the prognosis remains unfavorable, underscoring the need for vigilant clinical suspicion in hematologic patients presenting with neurological symptoms. Full article

Hepatosplenomegaly can occur in extrahepatic diseases such as Philadelphia-negative chronic myeloproliferative neoplasms (MPNs), which may involve the liver and vasculature. In myelofibrosis, extramedullary hematopoiesis can be present in the liver, even within hepatic sinusoids. Liver biopsies in MPN patients have shown platelet aggregates obstructing these sinusoids. Both liver and spleen stiffness are significantly higher in myelofibrosis, correlating with the severity of bone marrow fibrosis. Spleen stiffness is also elevated in myelofibrosis and polycythemia Vera compared to essential thrombocythemia. MPNs are a leading cause of splanchnic vein thrombosis in the absence of cirrhosis or local malignancy, especially in the presence of the JAK2V617F mutation. This mutation promotes thrombosis through endothelial dysfunction and inflammation. It is found in endothelial cells, where it enhances leukocyte adhesion and upregulates thrombogenic and inflammatory genes. Hepatic sinusoidal microthromboses in MPNs may contribute to portal hypertension and liver dysfunction. MPN therapies can also affect liver function. While hepatocytolysis has been reported, agents such as Hydroxycarbamide and Ruxolitinib exhibit antifibrotic hepatic effects in experimental models. Overall, MPNs are linked to chronic inflammation, increased thrombotic risk—particularly splanchnic thrombosis—and atherogenesis. Full article

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults but is rare in Asia. Extramedullary and extranodal manifestations in CLL are generally uncommon, and muscle involvement is extremely rare. A 70-year-old male with CLL presented with bilateral plantar pain, predominantly on the left side. Anemia and reduced platelet count prompted ibrutinib treatment. MRI revealed high-signal areas in the muscles, suggesting inflammation. Anemia and thrombocytopenia improved, but the pain persisted for 8 months. Histopathological findings confirmed CLL infiltration of the muscles. Radiotherapy alleviated the pain, and the patient remains under observation. Careful caution was needed because (1) MRI findings suggested an inflammatory lesion, broadening differential diagnosis, and (2) CLL may coexist with inflammatory diseases. Histopathological examination is essential for correct diagnosis and treatment. Full article

Background: 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. Methods: 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. Results: After a median follow-up time of 12.9 months (range, 1–77), the overall response rate, at least a very good partial response rate, and median progression-free survival time were 79.3%, 56.1%, and 24.4 months, respectively. This slightly lower performance compared to that in the IKEMA study may be attributed to the well-known poor prognostic impact of lenalidomide refractoriness (len-R), developed by all our patients during maintenance therapy, and to a higher proportion of patients with extramedullary disease present in our series, which was identified as the only factor significantly affecting the PFS in multivariable analysis. The median overall survival was not reached, as in the pivotal trial, while the 1-year survival probability was 85.1%. Regarding the safety profile, our findings were consistent with those of the IKEMA trial, with no new safety signals reported. Conclusions: These real-world data support the use of IsaKd as a valuable option for len-R MM patients relapsing after the first-line therapy, including ASCT and lenalidomide maintenance. Full article

Background/Objectives: In recent years, efforts by the scientific community to elucidate the underlying mechanisms of clonal expansion and selection within tumors have led to the theory of “tumor ecosystems”, implicating, among other factors, the role of the microenvironment in therapy resistance and tumor progression. In this context, the contribution of the microenvironment in the development of multiple myeloma (MM) is being investigated, imparting great emphasis on continuous clonal evolution. This process gives rise to aggressive clones with the potential to spread to extramedullary sites, rendering any treatment strategy practically ineffective. This systematic review aimed to gather knowledge about the immune microenvironment (IME) of extramedullary plasma cell myeloma and the differences in immune synthesis between medullary and extramedullary disease (EMD). Methods: A search strategy according to PRISMA guidelines was conducted in seven databases, and six articles meeting the inclusion criteria were encompassed in the study. Results: Results obtained from molecular analysis as well as flow cytometry and immunofluorescence indicated profound genetic instability at EMD sites along with spatial and temporal heterogeneity of the IME, implying a possible correlation between them. Both genetic and microenvironment variability were notably greater in EMD compared to medullary disease. The establishment of an immunosuppressive microenvironment was the rule, with exhausted CD8+ and natural killer (NK) cells, M2 macrophages, and inactivated dendritic cells found co-localized with neoplastic plasma cells, whereas cytotoxic CD8+ cells, M1 macrophages, and active dendritic cells congregated in tumor-free areas. Post-therapy alterations in the immune milieu were also noted and were concerned mostly the percentages of Tregs and MDSCs. Conclusions: The recognition of the microenvironment-myeloma cell interplay is essential for designing specific therapeutic strategies and ameliorating disease prognosis. Full article

Multiple myeloma is biologically and clinically a complex and heterogeneous disease which develops late in life, with the median age at the time of initial diagnosis being 66 years. In 1975, Durie and Salmon developed the first broadly adopted staging system in multiple myeloma, and in the ensuing decades, the risk stratification tools have improved and now incorporate different parameters to better predict the prognosis and to guide the treatment decisions. The International Staging System (ISS) was initially developed in 2005, revised in 2015 (R-ISS), and again in 2022 (R2-ISS). Tremendous progress has been achieved in multiple myeloma therapy over the past 25 years with the approval of immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies, resulting in a major paradigm shift. The dysfunction of the innate and adaptive immune system, especially in the T cell repertoire, represents a hallmark of multiple myeloma evolution over time, supporting the need for additional therapeutic approaches to activate the host’s immune system and to overcome the immunosuppressive tumor microenvironment. Novel T cell-directed therapies include chimeric antigen receptor (CAR) T cell therapies and bispecific antibodies that leverage the immune system’s T cells to recognize and attack the tumor cells. Second-generation anti-BCMA CAR T cell therapies and bispecific antibodies that bind the tumor antigen BCMA or GPRC5D onto myeloma cells and CD3 on the T cell’s surface are currently available for the treatment of relapsed/refractory multiple myeloma. Despite impressive results obtained with currently approved treatments, multiple myeloma remains incurable, and almost all patients eventually relapse. Moreover, patients with extramedullary disease and plasma cell leukemia represent an unmet medical need that require additional strategies to improve the outcome. In this review, we provide an overview of the evolution of risk stratification and the treatment of multiple myeloma. Full article

Background: Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of plasma cells, with extramedullary myeloma (EMM) being an aggressive form involving malignant infiltration beyond the bone marrow. Copper metabolism is essential for tumor proliferation and metastasis, with copper metabolism MURR1 domain (COMMD) proteins regulating these processes and maintaining copper homeostasis. Dysregulated copper homeostasis contributes to cancer progression, including MM, with elevated copper levels linked to disease aggressiveness and poor prognosis. This study investigates the role of the COMMD3 in mediating MM cell progression, particularly its influence on copper metabolism. Methods: Comprehensive bioinformatics analyses were conducted on bone marrow and extramedullary samples to determine the expression of COMMD3, which was validated through in vitro and in vivo functional assays. The MM cell lines RPMI8226 and MM1S underwent lentiviral transfection for COMMD3 overexpression and knockdown. RNA sequencing was conducted on COMMD3 knockdown cells to identify differentially expressed genes. Functional assays measured cell proliferation, migration, apoptosis, and copper metabolism, with a non-obese diabetic severe combined immune-deficiency gamma (NSG) mouse xenograft model providing in vivo validation. Results: Elevated COMMD3 expression was correlated with extramedullary myeloma and poor prognosis in MM patients. COMMD3 promoted MM cell proliferation and migration, modulating intracellular copper levels, likely through the ATOX1-ATP7A-LOX copper-metabolism-related pathway. High ATOX1 expression was correlated with worse outcomes, and ATOX1 inhibition abolished COMMD3’s effects. Conclusions: This study highlights the pivotal role of COMMD3 in MM progression, particularly via the ATOX1-ATP7A-LOX axis. These findings provide insights into EMM mechanisms and position COMMD3 as a potential therapeutic target. Future research is needed to validate these findings in larger clinical cohorts and to unravel the precise molecular interactions between COMMD3 and copper metabolism proteins. Full article

Pleural thickening can be the result of inflammation or infection but can also have a neoplastic origin. Depending on the clinical context, a pleural lesion or mass is often initially suspected of malignancy. Benign pleural tumors are rare, and their appearance on ultrasound (US) is also described less frequently than pleural metastases or malignancies. There are few descriptions of contrast-enhanced Ultrasound (CEUS) in particular. This review introduces the basics of transthoracic ultrasound (TUS) of the pleura and CEUS of the pleura and lung. CEUS is recommended for pulmonary applications in the EFSUMB guidelines in non-hepatic applications. This article provides an overview of the characteristics of benign pleural thickening, tumor-like lesions, and benign pleural tumors on transthoracic B-mode US with color Doppler imaging (CDI) and CEUS. In detail, characteristics in TUS and CEUS are described for infectious/inflammatory pleural thickening (empyema, tuberculous pleuritis, hemothorax, fibrothorax), pleural thickening in various systemic diseases, in tumor-like conditions (plaques, splenosis, endometriosis, mesothelial cysts, lymphangiomatosis) and benign tumors (lipoma, benign SFT, schwannoma, solitary extramedullary/extraosseous plasmacytoma). The descriptions are illustrated by corresponding US and CEUS images. Full article

Background/Objectives: Idecabtagene vicleucel (ide-cel), an anti-B-cell maturation chimeric antigen receptor T-cell therapy, represents an unprecedented treatment option for relapsed/refractory multiple myeloma (R/R MM). Nevertheless, given its limitations, including the risk of adverse effects and unclear durability of efficacy, there remains a need to report the real-world clinical outcomes of ide-cel therapy in patients with R/R MM, as well as explore host predictive factors for therapy. Methods: We performed a single-center retrospective analysis of 25 adult patients with R/R MM who received ide-cel between 2021 and 2023 at the University of California San Diego Health. Data on baseline characteristics, efficacy, safety, and post-relapse outcomes were collected. Treatment responses were assessed using the International Myeloma Working Group criteria while survival analyses were conducted using the Kaplan–Meier and Cox proportional hazards methods. Results: The median age was 65. Twelve patients (48%) were male. Patients received a median of six lines of prior therapy with four patients (16%) receiving prior BCMA-targeted therapy. Six patients (24%) had high-risk cytogenetics while ten patients (40%) had extramedullary disease. The incidence of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome incidence was 92% and 12%, respectively. All grade infection occurred in 11 patients (44%). Cytomegalovirus (CMV) reactivation occurred in 9 of 19 patients (47%) who were CMV IgG positive prior to CAR T-cell therapy. The objective response rate (ORR) was 84%; stringent complete response was seen in 14 patients (56%). After a median follow-up of 13 months, median progression-free survival (PFS) was 13.9 months (95% CI: 9.21 months—not reached [NR]); median overall survival (OS) was not reached (95% CI: 19.5 months—NR). Among the 11 patients (44%) who progressed after ide-cel therapy, median OS2 was 13.7 months; especially poor outcomes (median OS2 of 1.74 months) were observed in four patients who did not respond to ide-cel. Six of these eleven patients remained alive at time of data cutoff. Univariate and multivariate analysis revealed no significant predictors of ORR, PFS, or OS. Conclusions: Overall, ide-cel had comparable efficacy and safety to the KarMMa-1 trial and other reported real-world experiences. Full article

Background/Objectives: Developing high-performance artificial intelligence (AI) models for rare diseases is challenging owing to limited data availability. This study aimed to evaluate whether a novel three-class annotation method for preparing training data could enhance AI model performance in detecting osteosarcoma on plain radiographs compared to conventional single-class annotation. Methods: We developed two annotation methods for the same dataset of 468 osteosarcoma X-rays and 378 normal radiographs: a conventional single-class annotation (1C model) and a novel three-class annotation method (3C model) that separately labeled intramedullary, cortical, and extramedullary tumor components. Both models used identical U-Net-based architectures, differing only in their annotation approaches. Performance was evaluated using an independent validation dataset. Results: Although both models achieved high diagnostic accuracy (AUC: 0.99 vs. 0.98), the 3C model demonstrated superior operational characteristics. At a standardized cutoff value of 0.2, the 3C model maintained balanced performance (sensitivity: 93.28%, specificity: 92.21%), whereas the 1C model showed compromised specificity (83.58%) despite high sensitivity (98.88%). Notably, at the 25th percentile threshold, both models showed identical false-negative rates despite significantly different cutoff values (3C: 0.661 vs. 1C: 0.985), indicating the ability of the 3C model to maintain diagnostic accuracy at substantially lower thresholds. Conclusions: This study demonstrated that anatomically informed three-class annotation can enhance AI model performance for rare disease detection without requiring additional training data. The improved stability at lower thresholds suggests that thoughtful annotation strategies can optimize the AI model training, particularly in contexts where training data are limited. Full article

Multiple myeloma (MM) is the second most prevalent hematologic malignancy, particularly affecting the elderly. The disease often begins with a premalignant phase known as monoclonal gammopathy of undetermined significance (MGUS), solitary plasmacytoma (SP) and smoldering multiple myeloma (SMM). Multiple imaging modalities are employed throughout the disease continuum to assess bone lesions, prevent complications, detect intra- and extramedullary disease, and evaluate the risk of neurological complications. The implementation of advanced imaging analysis techniques, including artificial intelligence (AI) and radiomics, holds great promise for enhancing our understanding of MM. The integration of advanced image analysis techniques which extract features from magnetic resonance imaging (MRI), computed tomography (CT), or positron emission tomography (PET) images has the potential to enhance the diagnostic accuracy for MM. This innovative approach may lead to the identification of imaging biomarkers that can predict disease prognosis and treatment outcomes. Further research and standardized evaluations are needed to define the role of radiomics in everyday clinical practice for patients with MM. Full article

Myeloid sarcoma (MS), an extramedullary form of acute myeloid leukemia (AML) is a rare tumor mass of myeloid blasts. It can disseminate to any one or multiple anatomical sites, with (synchronous MS) or without (isolated MS) bone marrow (BM) involvement. The aim of this review is to describe the most recent advances in MS regarding diagnosis, molecular background, various clinical manifestations from several organs, and treatment approaches. Due to the lack of prospective, randomized clinical trials, therapeutic decisions are a challenge for the clinician. In the era of novel targeted AML treatments, a critical analysis of how to decide the best option for individual patients, also covering the possible central nervous system (CNS) prophylaxis is provided. For the majority of the patients, AML induction chemotherapy, followed by hematopoietic stem cell transplantation (HSCT) is generally recommended. This paper discusses the role of radiotherapy, the treatment of refractory and relapsed disease, along with the therapeutic approach of difficult-to-treat patients, due to specific problems related to different anatomical sites of MS. Full article

Extramedullary myeloma with pulmonary and pleural involvement is rare and can present in different ways. Here we present two cases of extramedullary pulmonary disease in relapsed/refractory multiple myeloma. Background: Multiple myeloma remains an incurable disease with unmet need for new treatments for high-risk disease such as extramedullary plasmacytoma. Relapses can occur at different stages due to the heterogeneity of the disease. While relapsed/refractory disease can be challenging to treat, progression can also lead to extramedullary disease which indicates an aggressive form with poor outcomes. Pulmonary extramedullary disease can present in various ways, such as a lung mass, parenchymal infiltrates, pleural mass, or pleural effusion. Objective: Our case series highlights two different presentations of pulmonary extramedullary disease and a review of the treatment of relapsed/refractory myeloma. Our patients highlight the progression of their multiple myeloma due to the aggressive nature of their extramedullary disease. Their cases emphasize the importance of new targeted treatments to treat extramedullary disease and penta-refractory disease as there is no currently accepted standard regimen for this difficult to treat condition. Full article