Plasmacytoma Research Articles

Calcium-Based Imaging of the Spine at Dual-Layer CT and Evaluation of Vertebral Fractures in Multiple Myeloma.

To evaluate the prediction of vertebral fractures in plasma cell dyscrasias using dual-layer CT (DLCT) with quantitative assessment of conventional CT image data (CI), calcium suppressed image data (CaSupp), and calculation of virtual calcium-only (VCa) image data. Patients (n = 81) with the diagnosis of a plasma cell dyscrasia and whole-body DLCT at the time of diagnosis and follow-up were retrospectively enrolled. CI, CaSupp25, and CaSupp100 were quantitatively analyzed using regions of interest in the lumbar vertebral bodies and fractured vertebral bodies on baseline or follow-up imaging. VCa were calculated by subtraction (CaSupp100-CaSupp25), delineating bone only. Logistic regression analyses were performed to assess the possibility of imminent spine fractures. In 24 patients, new vertebral fractures were observed in the follow-up imaging. The possibility of new vertebral fractures was significant for baseline assessment of CT numbers in CI, CaSupp25, and VCa (p = 0.01, respectively), with a higher risk for new fractures in the case of lower CT numbers in CI (Odds ratio = [0.969; 0.994]) and VCa (Odds ratio = [0.978; 0.995]) and in the case of higher CT numbers in CaSupp 25 (Odds ratio 1.015 [1.006; 1.026]). Direct model comparisons implied that CT numbers in CaSupp 25 and VCa might show better fracture prediction than those in CI (R2 = 0.18 both vs. 0.15; AICc = 91.95, 91.79 vs. 93.62), suggesting cut-off values for CI at 103 HU (sensitivity: 54.2%; specificity: 82.5; AUC: 0.69), for VCa at 129 HU (sensitivity: 41.7%; specificity: 94.7; AUC: 0.72). Quantitative assessment with CaSupp and calculation of VCa is feasible to predict the vertebral fracture risk in MM patients. DLCT may prove useful in detecting imminent fractures.

Unleashing the Impact of Exosomes Derived from Human Placental Mesenchymal Stem Cells (hPMSCs) on U-266 Myeloma Cell Line.

Multiple myeloma (MM) is a malignancy of plasma cells, terminally differentiated B cells, with complications like hypercalcemia, renal failure, anemia, and bone disease, which are also known as CRAB criteria. MM develops from monoclonal gammopathy of unknown significance (MGUS), a pre-malignant plasma cell dyscrasia. Over some time, MGUS has the potential to progress into smoldering multiple myeloma (SMM), which can evolve into MM. MM rarely progresses into plasma cell leukemia (PCL), a condition in which malignant plasma cells no longer stay in the bone marrow niche and circulate in the peripheral blood. In MM, various soluble factors play important roles, andinterleukin-6 has different vital roles. Interleukin-6, an inflammatory cytokine, has significant roles in the growth, survival, angiogenesis, metastasis, and apoptosis resistance in MM. Interleukin-6 is produced and secreted by both autocrine from myeloma cells and paracrine from bone marrow stromal cells. To tackle MM, various therapeutic approaches were applied over many years, and according to the results, most patients withMM can respond well to first-line treatment. However, the majority of patients may relapse as conventional treatment may not be curative. So, there is an urgent need for novel cell-based and cell-free therapeutic strategies, such as mesenchymal stem cell-based therapies and their products to offer new therapeutic strategies for MM. Materials and Methods: In the present study, we investigated the impacts of exosomes derived from human placental mesenchymal stem cells (hPMSCs) on apoptosis and interleukin-6 expression in a myeloma cell line, U-266, for the first time. hPMSCs were isolated from the human placenta and cultured in a DMEM medium. After characterizing the cells and acknowledging their identity, they underwent several passages and their supernatant was collected to harvest exosomes. The exosomes were isolated by ultracentrifugation and characterized by DLS and TEM, and their concentration was measured by BCA protein assay. U266 cells were treated with different concentrations of exosomes and then MTT and annexin/propidium iodide flow cytometry tests were performed to evaluate cell viability. Afterward, a real-time PCR test was performed to evaluate interleukin-6 gene expression. Results: According to our findings, treatment of U-266 cells with hPMSCS-derived exosomes led to the preservation of myeloma cells without changes in their cell cycle. Surprisingly, treatments did not hinder the expression of interleukin-6 in the myeloma cells. Conclusion: In MM patients, interleukin-6 pl ays different roles, and it is a desirable target to design new therapeutic strategies. To evaluate the effects of new therapeutic strategies, we designed and performed our study to estimate the effects of cell-free therapeutic strategy. In the present study, the impacts of hPMSCS-derived exosomes on the viability of MM cells and interleukin-6 gene expression were evaluated. The results showed that hPMSCS-derived exosomes resulted in the perseverance of myeloma cells without changes in the cell cycle. Furthermore, the interleukin-6 gene expression level showed no significant change.

Interference with PLA2G16 promotes cell cycle arrest and apoptosis and inhibits the reprogramming of glucose metabolism in multiple myeloma cells by modulating the Hippo/YAP signaling pathway.

Multiple myeloma, which is a clonal plasma cell tumor, derives from a postmitotic lymphoid B-cell lineage and remains untreatable. Group XVI phospholipase A2 (PLA2G16) can either be a tumor suppressor or an oncogene in different types of cancer. This study was intended to explore the role of PLA2G16 in multiple myeloma and to reveal the reaction mechanism. The mRNA and protein expressions of PLA2G16 in human bone marrow stromal cell line HS-5 and multiple myeloma cells were assessed using reverse transcription-quantitative PCR and western blot. The transfection efficacy of sh-PLA2G16 and oe-YAP was examined using reverse transcription-quantitative PCR and western blot. Through cell counting kit-8 assay and 5-ethynyl-2'- deoxyuridine staining, multiple myeloma cell viability and proliferation were detected. Flow cytometry was used to measure cell apoptosis and cell cycle distribution. Oxygen consumption rate, the activities of mitochondrial respiratory chain complexes I-V, and the activity of caspase-3 were estimated with Seahorse XF24 analyzer, oxidative phosphorylation activity assay kit, and caspase-3 assay kit, respectively. Lactate production and glucose consumption were evaluated usingcorresponding assay kits. Western blot was employed to meaure proteins associated with cell cycle, glycolysis, pentose phosphate pathway as well as Hippo/YAP signaling pathway. In this study, PLA2G16 expression was greatly increased in multiple myeloma cells and PLA2G16 silence inhibited cell proliferation, promoted cell apoptosis, facilitated cell cycle arrest, and suppressed the reprogramming of glucose metabolism in multiple myeloma. It was also identified that PLA2G16 depletion inhibited the Hippo/YAP signaling pathway. Further experiments revealed that the overexpression of YAP partially reversed the inhibitory effects of PLA2G16 silence on multiple myeloma cell malignant development and the reprogramming of glucose metabolism. Collectively, PLA2G16 silence impeded multiple myeloma progression and inhibited glucose metabolism reprogramming by blocking the Hippo/YAP signaling pathway.

Tumor detection by analysis of both symmetric- and hemi-methylation of plasma cell-free DNA

Aberrant DNA methylation patterns have been used for cancer detection. However, DNA hemi-methylation, present at about 10% CpG dinucleotides, has been less well studied. Here we show that a majority of differentially hemi-methylated regions (DHMRs) in liver tumor DNA or plasma cells free (cf) DNA do not overlap with differentially methylated regions (DMRs) of the same samples, indicating that DHMRs could serve as independent biomarkers. Furthermore, we analyzed the cfDNA methylomes of 215 samples from individuals with liver or brain cancer and individuals without cancer (controls), and trained machine learning models using DMRs, DHMRs or both. The models incorporated with both DMRs and DHMRs show a superior performance compared to models trained with DMRs or DHMRs, with AUROC being 0.978, 0.990, and 0.983 in distinguishing control, liver and brain cancer, respectively, in a validation cohort. This study supports the potential of utilizing both DMRs and DHMRs for multi-cancer detection.

Salivary gland amyloidosis: Proteomic identification and clinicopathologic characterization of 57 cases

Salivary gland amyloidosis is an uncommon diagnosis. Most studies have focused on minor salivary gland biopsies as a surrogate site for diagnosing systemic amyloidosis, while only few studies have investigated major salivary gland amyloidosis. We retrospectively identified 57 major and minor salivary gland amyloidosis cases typed using a proteomics-based method between 2010 and 2022. Frequency of amyloid types, clinicopathologic features, and distribution patterns of amyloid deposits were assessed. The indication for salivary gland biopsy/resection (known in 34 cases) included suspected amyloidosis (N = 14; 41.2%), lesion/mass (N = 12; 35.3%), swelling/enlargement (N = 5; 14.7%), and rule out Sjogren syndrome (N = 3; 8.8%). Concurrent pathology was reported in 16 cases, and included chronic sialadenitis (N = 11), extranodal marginal zone lymphoma (N = 3), plasma cell neoplasm (N = 1), and pleomorphic adenoma (N = 1). We identified 3 types of amyloidosis: immunoglobulin light chain/AL (N = 47; 82.5%); immunoglobulin heavy chain/AH (N = 1; 1.8%), and transthyretin/ATTR (N = 9; 15.8%). The patterns of amyloid deposits (assessed in 35 cases) included: 1) Perivascular and/or periductal distribution (N = 18; 51.4%); 2) Mass formation (N = 9; 25.7%); 3) Stromal micronodule formation (N = 7; 20.0%); and 4) Diffuse interstitial involvement (N = 1; 2.9%). We also identified one case of AL amyloidosis localized to the major salivary gland, where only 6 other cases with adequate staging workup to exclude systemic amyloidosis were previously reported. In conclusion, salivary gland amyloidosis is an uncommon diagnosis but may be underrecognized due to low index of suspicion. Most cases of salivary gland amyloidosis are AL type, but a minority are ATTR. Therefore, proteomics-based typing remains essential for treatment and prognosis.

Renal Transplant Outcomes in Plasma Cell Dyscrasias and AL Amyloidosis after Treatment with Daratumumab.

Background: The morbidity and mortality from AL amyloidosis has significantly improved with the development of novel treatments. Daratumumab is a highly effective treatment for AL amyloidosis, but end-stage kidney disease is a common complication of this condition. Kidney transplantation is the ideal form of renal replacement therapy but has historically been contraindicated in this group of patients. Methods: Given the improved survival and better treatments of both conditions, we argue that it is time to reconsider transplanting these patients. Results: We report our experience of transplanting four patients with AL amyloidosis who had achieved stable remission through treatment with daratumumab. Conclusions: We highlight the key challenges involved and discuss important clinical issues for patients receiving daratumumab, particularly the difficulties with interpreting the crossmatch in light of daratumumab and immunoglobulin therapy interference. We also discuss the complexities involved in balancing the risks of infection, relapse, rejection, and immunosuppression in such patients.

Enhanced stabilisation and reduced fibril forming potential of an amyloidogenic light chain using a variable heavy domain to mimic the homodimer complex.

Light chain amyloidosis (AL), is classified as a plasma cell dyscrasia, whereby a mutant plasma cell multiplies uncontrollably and secretes enormous amounts of immunoglobulin-free light chain (FLC) fragments. These FLCs undergo a process of misfolding and aggregation into amyloid fibrils, that can cause irreversible system-wide damage. Current treatments that focus on depleting the underlying plasma cell clone are often poorly tolerated, particularly in patients with severe cardiac involvement, meaning patient prognosis is poor. An alternative treatment approach currently being explored is the inhibition of FLC aggregation by stabilisation of the native conformer. Here, we aimed to identify and characterise antibody fragments that target FLC domains and promote their stabilisation. Using phage-display screening methods, we identified a variable heavy (VH) domain, termed VH1, targeted towards the FLC. Using differential scanning fluorimetry and surface plasmon resonance, VH1 was characterised to bind and kinetically stabilise an amyloidogenic FLC, whereby a > 5.5 °C increase in thermal stability was noted. This improved stability corresponded to the inhibition of fibril formation, where 10 : 1 LC : VH1 concentration reduced aggregation to baseline levels. X-ray crystallographic structures of the LC : VH1 complex at atomic resolution revealed binding in a 1 : 1 ratio, mimicking the dimeric antigen binding sites of the native immunoglobulin molecule and the native LC homodimer.

Current Status on Management of Primary Plasma Cell Leukemia.

Plasma Cell Leukemia (PCL) is a very rare and highly aggressive form of plasma cell dyscrasia. This review seeks to evaluate the outcomes of PCL in the context of combination novel agent therapy and stem cell transplant (SCT) protocols. The diagnostic criteria for PCL have now evolved to include patients with 5% circulating PC. While management remains challenging, the incorporation of novel agent-based induction regimen has significantly improved early mortality and reduced attrition of patients proceeding to SCT. In recent prospective clinical trials, patients with PCL demonstrated an overall response rates of 69% to 86%, with progression-free and overall survival ranging from 13.8 to 15.5months and 24.8 to 36.3months, respectively. B-cell lymphoma 2 (BCL2) inhibitors, such as venetoclax present a targeted intervention opportunity for patients with PCL with t(11;14). Dedicated clinical trials tailored to PCL are crucial, integrating newer therapies in the frontline setting to further optimize responses and enhance overall outcomes.

Radiotherapy for Solitary Bony or Extramedullary Plasmacytoma.

This study aimed to determine the oncological outcomes associated with curative radiotherapy for solitary bony or extramedullary plasmacytomas by drawing on clinical data from a single tertiary center. This study aimed to provide a comprehensive understanding of the efficacy of radiotherapeutic interventions and delineate the patterns of disease recurrence. Eleven consecutive patients diagnosed with solitary bony or extramedullary plasmacytomas and treated between May 2007 and November 2023 were retrospectively screened. Different radiotherapy doses and fractionations were employed, and statistical analyses were performed to assess overall survival (OS) and disease-free survival (DFS). Among the 11 patients (9 males and 2 females), primary tumors were located within the bone in seven patients, whereas extramedullary tumors were observed in four patients. The median prescribed radiation dose was 46 Gy. The 5-year OS and DFS were 83.3% and 28.9%, respectively. Progression to multiple myeloma occurred in four patients with primary bony plasmacytoma. Local control rate was 88.9%, and one patient experienced distant metastasis after 32 months. Bony plasmacytoma has a high tendency of leading to multiple myeloma rather than extramedullary plasmacytoma (5-year progression to multiple myeloma-free survival rate, 20.8% vs. 100%, p=0.08). Radiotherapy is effective for solitary plasmacytomas with favorable local control and high objective response rates. A comparison with the existing literature supports the role of radiotherapy in the management of these conditions. The differences in outcomes between bony and extramedullary plasmacytomas emphasize the need for personalized treatment approaches.

Transthyretin Amyloid Cardiomyopathy – Setting the Diagnosis Step by Step

Introduction: Transthyretin amyloid cardiomyopathy (ATTR-CM) can be diagnosed in the absen-ce of histology with typical echocardiographic fi ndings and skeletal scintigraphy showing grade 2 or 3 myocardial tracer uptake, when clonal plasma cell dyscrasia is excluded. Aim: To present a patient diagnosed with ATTR-CM, who was hospitalized with clinical signs of congestive heart failure. Case Report: An 84-year-old man was hospitalized with clinical signs of heart failure. Echocardiography showed concentric left ventricular hypertrophy (LVH) with reduced systolic function, along with impaired LV global longitudinal strain (GLS) with apical sparing (-9.9%). Serum and urine protein electrophoresis with immunofi xation were obtained and were negative for plasma cell dyscrasia. Bone scintigraphy showed similar radiotracer uptake in the myocar-dium and ribs (Perugini grade 2). The diagnosis of ATTR-CM was confi rmed. Conclusion: ATTR-CM is an underdiagnosed condition and should be suspected in patients with heart failure and unexplained LVH.

Bone Marrow Aspiration and Biopsy Findings in Patients with Hematological Disorders in a Tertiary Care Center from Eastern Nepal: An Institutional Experience

Background: Bone marrow study is an important study which is performed when the peripheral blood examination and other laboratory tests and clinical signs and symptoms are suggestive and sometimes inconclusive of both hematological neoplastic and non-neoplastic conditions. The aim of this study was to study about the indications of bone marrow to assess the diagnostic value and comparison of microscopic findings with immunophenotyping and molecular studies. Methods: A total of 102cases were analyzed retrospectively and prospectively from January 2022 to October 2023. All the bone marrow aspiration and trephine biopsy received at the laboratory during this period were included in the study and other cases were analyzed form medical record of the department. Results: Among the 102 cases, mean age of the patient was 48 years and majority were male patients. The age range was between 17-80 years. The male: female ratio was 1.25:1. Weakness was most common presenting complain. Acute leukemia was the most frequent diagnosis (24.5%) followed by myeloproliferative neoplasm (7.8%), primary aplastic anemia (6.9%), myelodysplastic syndrome (5.8%), megaloblastic anemia (4.9%) and plasma cell dyscrasia (3.9%), CLPD (2.9%), ITP (1.9%). Reactive marrow constituted 3.9% and few of the rare diagnosis included hypereosinophilia with PDGFRA mutation, Leishmaniasis etc. Conclusions: The study concludes the bone marrow aspirate and biopsy examination is still the gold standard technique for screening and definite diagnosis of hematological conditions. Immunophenotyping and molecular studies are important for treatment purpose and in case of cytomorphological dilemma.

Light-Chain Deposition Diseases of the CNS: Review of Pathogenesis, Imaging Features, and Radiographic Mimics.

Light-chain deposition disease (LCDD) is a rare CNS disorder characterized by the extracellular accumulation of monoclonal immunoglobulin light chains in various organs. LCDD typically arises secondary to an underlying plasma cell dyscrasia, such as monoclonal gammopathy of undetermined significance or multiple myeloma. However, rare cases can occur in the absence of a demonstrable plasma cell disorder. The kidneys, liver, lungs, and heart are the most affected organs. Intracerebral LCDD, particularly without an underlying plasma cell neoplasm, represents an exceedingly uncommon entity with limited documented cases in the literature. This review article explores the pathogenesis, histopathologic features, and characteristic neuroimaging findings of intracerebral LCDD. We emphasize the diverse imaging presentations of this disease, which can closely resemble other neurologic pathologies. Recognizing these potential mimics is crucial for avoiding misdiagnosis, especially in the absence of a known underlying plasma cell disorder. This article aims to provide a comprehensive overview from a neuroradiologic perspective, facilitating the recognition and differentiation of this challenging entity.

The association between statin use and non-Hodgkin lymphoma; a systematic review and meta-analysis

Introduction: Statins reduce the cancer risk; however, non-Hodgkin lymphoma (NHL) evidence remains controversial. Therefore, we aimed to evaluate the relationship between statin consumption and NHL risk using a systematic review and meta-analysis. Materials and Methods: In this systematic review and meta-analysis, international databases, including Scopus, PubMed, Web of Science, Cochrane, and Google Scholar search engines, were searched without a time limit up to September 21, 2023. Data analysis was performed using STATA 14 software, and the significance level was considered P<0.05. Results: The results of combining 13 studies (9 case-control studies and 4 cohort studies) with a total sample size of 1142 740 subjects showed that statin consumption could reduce NHL risk by 22% (RR: 0.78; 95% CI: 0.69, 0.88). Statin consumption in cohort studies reduced NHL risk by 14% (RR: 0.86; 95% CI: 0.77, 0.95), but in case-control studies, it reduced NHL risk by 26% (RR: 0.74; 95% CI: 0.62, 0.90). Furthermore, statin consumption reduced diffuse large B-cell lymphoma risk by 24% (RR: 0.76; 95% CI: 0.67, 0.87) and marginal zone risk by 26% (RR: 0.74; 95% CI: 0.59, 0.93). However, it did not affect reducing the risk of chronic lymphocytic leukemia/small lymphocytic lymphoma (RR: 0.94; 95% CI: 0.85, 1.05), follicular (RR: 0.96; 95% CI: 0.83, 1.10), plasma cell neoplasms (RR: 0.97; 95% CI: 0.70, 1.33), T cell lymphoma (RR: 0.81; 95% CI: 0.55, 1.19) and B cell lymphoma (RR: 0.94; 95% CI: 0.44, 2.01). Conclusion: Statin consumption significantly reduced the risk of NHL, diffuse large B-cell lymphoma, and marginal zone but did not affect other NHL types. Registration: This study has been compiled based on the PRISMA checklist, and its protocol was registered on the PROSPERO (CRD42023469126) and Research Registry (UIN: reviewregistry1732) website.

Application and pitfalls of immunophenotyping in challenging plasma cell neoplasms: A case series

Multiple myeloma (MM) is an incurable malignant plasma cell neoplasm, representing the second most common hematopoietic cancer. As plasma cell neoplasms are clonal and often secrete a monoclonal protein (M-spike), laboratory diagnosis is usually straightforward, especially when ancillary studies such as immunohistochemistry, flow cytometry, and protein electrophoresis are available in addition to microscopic examination. Despite the repertoire of diagnostic tools, rare cases pose diagnostic dilemmas, especially when reagent antibodies do not react as expected, extent of disease is patchy, or when disease occurs in unique age groups. In this retrospective study, we report a series of challenging diagnostic cases, discussing aberrant findings and comparing them to more classic counterparts. Twelve cases collected during routine clinical sign-out were reanalyzed and include examples of MGUS, classic multiple myeloma, t(11; 14) rearranged myeloma, minimal residual disease, AA and AL amyloidosis, truncated light chain, non-secretory and non-producer myeloma, biphenotypic myeloma, oligoclonal expansion after bone marrow transplant, and plasma cell leukemia in a young adult. This cohort showcases the diversity of atypical presentations of plasma cell neoplasms, and we highlight standardized approaches to workup to avoid diagnostic pitfalls.

Monoclonal gammopathy of clinical signifi cance with osteosclerotic lesions - a case report and a literature review.

Multiple myeloma is a common plasma cell neoplasia usually accompanied by the formation of osteolytic foci, whereas osteosclerotic myeloma is a very rare form of plasma cell dyscrasia. When osteosclerotic myeloma is detected, osteosclerotic foci are usually part of the POEMS syndrome. Osteosclerotic myeloma without other manifestations of the POEMS syndrome is an unusual finding. In a 46-year-old woman, osteosclerotic changes of the temporoparietal region caused soft tissue induration over this lesion, which initiated further investigation. Imaging studies subsequently showed multiple osteosclerotic foci in the skull. Examination of blood proteins revealed 8 g/L of IgG-lambda monoclonal immunoglobulin, subclass IgG1. In search of the cause of the osteosclerotic changes, FDG-PET/CT was performed, which revealed no FDG accumulation, i.e., no other tumor (breast or stomach cancer). Low-dose CT showed irregular bone structure, but not significant osteolytic or osteosclerotic foci. To map the extent of osteosclerotic changes, NaF-PET/CT imagination followed, which revealed multiple spots with high fluoride accumulation. A parietal bone biopsy showed osteosclerosis with minor clonal plasma cell infiltration. Trepanobioptic bone marrow sampling revealed an infiltration of bone marrow with atypical plasma cells in 8%. Flow-cytometric examination of bone marrow showed 0,37% of plasma cells, however predominantly (91%) clonal with lambda expression. MRI of the brain identified asymptomatic meningeal thickening. There was no evidence of POEMS syndrome in the patient; thus, we concluded the diagnosis as monoclonal gammopathy of clinical significance with osteosclerosis which was previously termed osteosclerotic multiple myeloma. Monoclonal gammopathy of clinical significance (MGCS) with osteosclerotic skeletal changes, documented on CT and multiple foci with intensive osteoneogenesis, documented on NaF-PET/CT without evidence of POEMS syndrome, is an extremely rare form of plasma cell dyscrasia. This publication documents the unique clinical manifestations of IgG-lambda type plasma cell proliferation without signs of POEMS syndrome and the role of NaF-PET/CT imaging. Classification of this disease as MGSC with osteosclerotic manifestations is more consistent with the indolent nature of the disease with a significantly better prognosis, compared with multiple myeloma.

Diagnosis and Treatment of Autoimmune Acquired Coagulation Factor Deficiencies: An Evidence-Based Review of Japanese Practice.

Among the acquired coagulation factor deficiencies, autoimmune coagulation factor deficiencies (AiCFD) are rare and result from autoantibody production against coagulation factors. In Japan, a nationwide survey on AiCFD has been conducted since 2009. Autoimmune factor XIII, factor VIII, von Willebrand factor, factor V, and factor X deficiencies (AiF13D, AiF8D, AiVWFD, AiF5D, and AiF10D, respectively) have been enacted as "designated intractable disease-282." The incidence of AiF8D, AiF13D, and AiF5D was 1.83, 0.044, and 0.038 per million people/year, respectively, whereas that of AiVWFD and AiF10D was not calculable owing to the small number of patients. AiF13D and AiF8D were often idiopathic, whereas AiVWFD was often associated with plasma cell neoplasms. Epistaxis was a characteristic symptom of AiVWFD, intramuscular bleeding was frequent in AiF13D and AiF8D, and subcutaneous bleeding (purpura) was frequent in AiF13D and AiF10D, although none were specific to any one disease. Differential diagnosis cannot be made based on bleeding symptoms alone; therefore, rapid and accurate testing is mandatory. Definitive diagnosis of AiCFD necessitates identifying the presence of coagulation factor "inhibitors" and/or "autoantibodies." Therefore, these tests should be performed upon unexplained severe acquired coagulation factor deficiencies. The mainstay of treatment for AiCFD was hemostatic therapy and autoantibody eradication therapy, which included the replacement of coagulation factors or "bypass" agents and administration of immunosuppressants. The rate of hemorrhagic death was high in AiF13D (13%), followed by AiF5D (7%) and Ai10D (5%); therefore, early diagnosis and optimal treatment are essential for AiCFDs. Given the unknown long-term prognosis, "intractable disease platform registries" have begun to accumulate in Japan.

POEMS syndrome with undetectable M-protein: a case report and literature review

BackgroundPolyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare plasma cell (PC) neoplasm with associated paraneoplastic syndrome. According to the current diagnostic criteria, peripheral polyneuropathy and monoclonal PC proliferative disorder represent two mandatory criteria.Case presentationWe report a 54-year-old male with peripheral neuropathy of bilateral lower limbs, sclerotic bone lesions, elevated vascular endothelial growth factor (VEGF) levels, splenomegaly, extravascular volume overload, endocrinopathy, and skin hemangiomas. Of note, serum and urine protein electrophoresis (PEP) and immunofixation electrophoresis (IFE) of this patient indicated undetectable M-protein and the normal ratio of free light chains κ and λ (FLC-R (κ/λ)). No monoclonal PCs were found in bone marrow examinations or biopsy of diseased bones. However, his clinical manifestations matched most of the diagnostic criteria. After excluding other diseases that are easily confused with POEMS syndrome, the diagnosis of variant POEMS syndrome with undetectable M-protein was proposed. The patient obtained clinically significant improvement and elevated VEGF returned to normal after 6 months of treatment with lenalidomide plus dexamethasone.ConclusionsMonoclonal PC dyscrasia (M-protein) while being a mandatory criterion for POEMS syndrome is undetectable in a considerable amount of patients that otherwise demonstrate typical symptoms. Here, we reported a case of variant POEMS syndrome with featured clinical manifestations, elevated VEGF levels, and good response to therapies targeting PCs but no evidence of M-protein. Therefore, negative results in M-protein and monoclonal PCs aren’t enough to reject the diagnosis of POEMS syndrome. It is imperative to recognize the variant form of POEMS syndrome.

Inference of genomic lesions from single-cell RNA-seq in myeloma improves functional intraclonal and interclonal analysis

AbstractSmoldering multiple myeloma (SMM) is an asymptomatic plasma cell (PC) neoplasm that may evolve with variable frequency into multiple myeloma (MM). SMM is initiated by chromosomal translocations involving the immunoglobulin heavy-chain locus or by hyperdiploidy and evolves through acquisition of additional genetic lesions. In this scenario, we aimed at establishing a reliable analysis pipeline to infer genomic lesions from transcriptomic analysis, by combining single-cell RNA sequencing (scRNA-seq) with B-cell receptor sequencing and copy number abnormality (CNA) analysis to identify clonal PCs at the genetic level along their specific transcriptional landscape. We profiled 20 465 bone marrow PCs derived from 5 patients with SMM/MM and unbiasedly identified clonal and polyclonal PCs. Hyperdiploidy, t(11;14), and t(6;14) were identified at the scRNA level by analysis of chimeric reads. Subclone functional analysis was improved by combining transcriptome with CNA analysis. As examples, we illustrate the different functional properties of a light-chain escape subclone in SMM and of different B-cell and PC subclones in a patient affected by Wäldenstrom macroglobulinemia and SMM. Overall, our data provide a proof of principle for inference of clinically relevant genotypic data from scRNA-seq, which in turn will refine functional annotation of the clonal architecture of PC dyscrasias.

Allogeneic stem cell transplantation in multiple myeloma: is there still a place?

The introduction of novel agents dramatically improved response and outcomes of multiple myeloma (MM) and led to a sharp decline in the use of allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Thus, recent guidelines do not recommend anymore allo-HSCT as consolidation in the first-line treatment of newly diagnosed MM, even in high-risk patients. In a relapsed/refractory setting, allo-HSCT is not routinely recommended but should only be performed within clinical trials in young and high-risk patients. Nonetheless, allo-HSCT still represents a potential curative approach that has been used for decades in the treatment of MM and plasma cell neoplasms with favorable results and may still represent a treatment option for carefully selected patients. Despite that promising results were obtained with CAR T-cell therapies and bispecific antibodies in triple- and penta-exposed/refractory MM, these patients will inevitably relapse. To date, less is known about outcomes of allo-HSCT in patients exposed to novel immunotherapeutic drugs. Therefore, allo-HSCT could represent a reasonable treatment choice for younger and high-risk patients who have relapsed after CAR T-cell therapies and bispecific antibodies as well as an alternative for patients not eligible to these treatments and in those countries where immunotherapies are not yet available. In the choice of conditioning, reduced intensity conditioning regimens are currently recommended for the lower toxicity and mortality. Moreover, the use of alternative donors, particularly haploidentical, has progressively increased in last years with results comparable to full matched donors. Finally, post-transplantation maintenance strategies are encouraged whenever feasible.

Extramedullary Intracranial Plasmacytomas: A Systematic Review of Literature.

Extramedullary plasmacytoma (EMP) is an uncommon disorder characterized by the development of abnormal plasma cell tumors outside the bone marrow. These tumors are typically observed in various locations, including the upper respiratory tract, gastrointestinal tract, and other soft tissues. Among the less explored manifestations of EMP is intracranial EMP, which remains poorly understood due to the limited literature available on the subject. The objective was to comprehend the population characteristics, localization, type, treatment, and outcomes of intracranial EMP. A systematic review of the literature for EMPs was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The strategy "extramedullary plasmacytoma AND multiple myeloma" was used for the search. The search terms were queried using PubMed, Embase, Scopus, Cochrane, and Web of Science databases. We included only those studies that presented clinical studies with patients diagnosed with intracranial plasmacytomas. In this study, a total of 84 patients from 25 studies were analyzed. The average age of diagnosis was 57.25 years, with a slightly higher proportion of females (57%) compared to male patients (43%). The most common locations of intracranial plasmacytomas were the clivus (29.7%), frontal lobe (18.9%), parietal lobe (8.1%), occipital lobe (6.7%), temporal lobe (6.7%), and sphenoid (4%). Chordoma and meningioma were the most common differential diagnoses encountered during clinical investigations. Treatment modalities included radiotherapy (RT), chemotherapy (QT), surgical resection (SR), and conservative approaches. The most frequent treatment combinations were SR + RT (19%) and RT only (17.8%). Mortality was reported in 48% of the cases, with complete resolution observed in 10 cases and partial resolution in 3 cases. The average follow-up duration was 37.5 months. The clivus is the most frequently reported site of extramedullary intracranial plasmacytoma (EMIP) occurrence, representing 29.7% of cases. Chordomas were commonly observed alongside EMIPs and emerged as the primary differential diagnosis. RT was the predominant treatment modality, with SR considered when feasible. RT alone demonstrated the highest effectiveness in managing EMIPs (30%), while QT as a sole intervention showed lower efficacy. However, a combination of dexamethasone, lenalidomide, and targeted RT displayed promising results, offering improved tumor response and increased safety.