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BACKGROUND: Dynamic contrast-enhanced-MRI (DCE-MRI) is able to study bone marrow angiogenesis in patients with multiple myeloma (MM) and asymptomatic precursor diseases but its role in the management of MM has not yet been established. The aims of this prospective study was to compare DCE-MRI-based parameters between all monoclonal plasma cell disease stages in order to find out discriminatory parameters and to seek correlations with other diffusion-weighted MRI and positron emission tomography (PET)-based biomarkers in a hybrid simultaneous whole-body-2-[18F]fluorodeoxyglucose (FDG)-PET/MRI (WB-2-[18F]FDG-PET/MRI) imaging approach. METHODS: Patients with newly diagnosed Monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) or symptomatic MM according to international myeloma working group and underwent WB-2-[18F]FDG-PET/MRI imaging including bone marrow DCE sequences at the Nantes University Hospital were prospectively enrolled in this study before receiving treatment. RESULTS: One hundred and sixty-seven patients (N = 167, mean age: 64 years ± 11 [Standard deviation], 66 males) were considered for the analysis. DCE-MRI-based Peak Enhancement Intensity (PEI), Time to PEI (TPEI) and their maximum intensity time ratio (MITR: PEI/TPEI) values were significantly different between the different monoclonal plasma cell disease stages, PEI values increasing and TPEI values decreasing progressively along the spectrum of plasma cell disorders, from MGUS stage to symptomatic multiple myeloma. PEI values were significantly higher in patients with diffuse bone marrow involvement (either in PET or in MRI images) than in those without diffuse bone marrow involvement, unlike TPEI values. PEI and TPEI values were not significantly different between patients with or without focal bone lesions. CONCLUSION: Different DCE-MRI-based parameters (PEI, TPEI, MITR) could significantly differentiate all monoclonal plasma cell disease stages and complemented conventional MRI and PET-based biomarkers.

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Treatment with elotuzumab alone has no discernible antitumor effect and progress in chimeric antigen receptor T cells (CAR-T) therapy targeting CS1 is relatively slow. A retrospective analysis was performed on 236 patients with multiple myeloma (MM) and 30 patients with other plasma cell dyscrasias (PCDs). CS1 expression in NK cells, lymphocytes, and monoclonal plasma cells was assessed using multiparameter flow cytometry. Furthermore, new explorations were undertaken regarding the antitumor applications of elotuzumab. Patients with MM had significantly higher CS1 expression levels in plasma cells than other patients with PCDs, with no significant differences between lymphocytes and NK cells. In both patients with MM and other PCDs, CS1 expression was significantly higher in plasma cells than in NK cells and lymphocytes. Univariate and multivariate analyses revealed a significant correlation between CS1 expression in plasma (r = 0.60; P < 0.001) and NK (r = 0.79; P < 0.001) cells. Factors such as cytogenetic abnormalities, disease progression, and survival were not associated with CS1 expression in NK cells. Moreover, this study showed that elotuzumab strongly increases the cytotoxicity of NK cells against non-plasma and plasma tumor cells independent of their CS1 expression level. This underscores the potential of elotuzumab in combination with NK cells as an effective therapeutic strategy against a broad spectrum of tumor types.

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Gastrointestinal involvement in amyloidosis is reported in 3% of cases, mostly associated with multiple myeloma. An elderly man with chronic kidney disease presented to the hospital after a large melenic bowel movement. The patient was tachycardic and anemic to 3.8 g/dL on admission and was transfused blood. Endoscopy and colonoscopy were unremarkable. Subsequently, the patient had 2 more admissions for severe anemia requiring blood transfusion. Repeat esophagoduodenoscopy with capsule endoscopy were unremarkable. The patient was diagnosed with monoclonal gammopathy of undetermined significance by hemoglobin electrophoresis, and endoscopy biopsy revealed intestinal amyloidosis in a duodenal specimen. The patient's recurrent anemia was attributed to bleeding from gastrointestinal amyloidosis, in the absence of other identifiable sources of anemia, and was managed with intravenous iron infusions.

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Monoclonal Gammopathies of Renal Significance (MGRS) are a complex group of disorders characterized by the production of aberrant monoclonal proteins that interact with kidney structures, causing tissue damage. Unlike neoplastic forms, kidney damage in MGRS does not correlate with clone mass or circulating monoclonal protein levels, conferring unique pre-neoplastic or non-neoplastic properties to the responsible clones. This manuscript explores the heterogeneity of monoclonal proteins involved, varying from full immunoglobulins to free light chains (FLC), and how they result in a spectrum of kidney lesions with differing prognoses. We also elaborate on diagnostic challenges, emphasizing the indispensable role of kidney biopsy, including advanced techniques like laser microdissection and mass spectrometry (LMD/MS) for deposit characterization, particularly in ambiguous or complex cases. Clinical management and treatment considerations, including the necessity for clone identification, are also discussed.

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G protein-coupled estrogen receptor 1 (GPER1) activation is emerging as a promising therapeutic strategy against several cancer types. While GPER targeting has been widely studied in the context of solid tumors, its effect on hematological malignancies remains to be fully understood. Here, we show that GPER1 mRNA is down-regulated in plasma cells from overt multiple myeloma (MM) and plasma cell leukemia patients as compared to normal donors or pre-malignant conditions (monoclonal gammopathy of undetermined significance and smoldering MM); moreover, lower GPER1 expression associates with worse overall survival of MM patients. Using the clinically applicable GPER1-selective agonist G-1, we demonstrate that the pharmacological activation of GPER1 triggered in vitro anti-MM activity through apoptosis induction, also overcoming the protective effects exerted by bone marrow stromal cells. Noteworthy, G-1 treatment reduced in vivo MM growth in two distinct xenograft models, even bearing bortezomib-resistant MM cells. Mechanistically, G-1 upregulated the miR-29b oncosuppressive network, blunting an established miR-29b-Sp1 feedback loop operative in MM cells. Overall, this study highlights the druggability of GPER1 in MM, providing the first preclinical framework for further development of GPER1 agonists to treat this malignancy.

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The wave of coronavirus disease 2019 (COVID-19) with Omicron variant reached its first peak in Beijing, China in December 2022. We delineated characteristics and factors associated with adverse outcome of patients with plasma cell dyscrasias (PCDs) and COVID-19 during the first month of the wave. A total of 104 patients with a median age of 65 years were included in the study, with multiple myeloma (74%, n=77) and primary Immunoglobulin light chain amyloidosis (16.3%, n=17) being the two most common disease. Overall, severe or critical COVID-19 was developed in 18 (17.3%) patients, with a total all-cause mortality rate of 4.8% (n=5). The vaccination coverage was 41% and 48.1%, before and during the upsurge of Omicron, respectively, calling for the improvement of vaccination in PCD patients. Multivariable analysis revealed that age was the only independent risk factors (OR=1.14, 95% CI: 1.06-1.26, p = 0.002) associated with the development of severe or critical disease. Among patients with severe or critical group, low levels of albumin (HR=18.29; 95% CI: 1.82-183.44, p = 0.013) and high levels of lactic dehydrogenase (LDH) (HR=0.08; 95% CI: 0.01-0.65, p = 0.018) were associated with longer time to negative conversion of COVID-19.

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Amyloidosis is a plasma cell dyscrasia that leads to the excessive production and deposition of mutant protein fragments in various organs. Cardiac amyloidosis is often implicated in two main subtypes: transthyretin (ATTR) and light chain (AL). While both subtypes increase the risk of restrictive cardiomyopathy, cardiogenic shock, and arrhythmias, poorer outcomes are seen in those with cardiac infiltration secondary to AL amyloidosis. Prognosis depends on the timing of diagnosis and the extent of the disease burden prior to recognition and treatment. The following case report describes a young patient who was admitted to the intensive care unit (ICU) for concerns of decompensated heart failure of unknown etiology, later determined to be due to amyloidosis. We describe her clinical course prior to and during hospital admission, along with the proposed physiologic factors that may have contributed to her poor outcome.

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Solitary plasmacytomas (SPs) are tumors characterized by local monoclonal plasma cell proliferation, presenting without systemic manifestations. It mainly affects the axial skeleton, with calcaneal involvement being extremely rare. We report a case of a 48-year-old patient with a history of gunshot injury to his foot who presented with worsening heel pain and a calcaneal cyst. Biopsy revealed plasmacytoma, and subsequent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scan further supported the diagnosis of solitary plasmacytoma of the bone (SPB). Management included lesion excision, bone cement placement, and radiotherapy. However, due to recurrent osteomyelitis following cement placement, the patient eventually required total calcanectomy. SPB usually affects older adults, and developing the disease at a young age and in the calcaneus is exceedingly uncommon. Trauma is implicated as a possible inciting trigger in the pathogenesis of SPB without a clear association. This case highlights the importance of developing our current understanding of the clinical presentation and manifestations of SPB, beyond the conventional assumption that it only affects the axial skeleton of older individuals.

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Amyloid goiter is described as an accumulation of amyloid, an amorphous proteinaceous material, in the thyroid gland. The deposition of amyloid is relatively common in the thyroid gland. However, a significant clinical enlargement due to amyloid accumulation and fat deposition in the thyroid stroma resulting in diffuse goiter leading to compressive symptoms is a rare phenomenon. In this report, we describe a rare case of amyloid goiter with adipose metaplasia in a 38-year-old woman with a history of pulmonary tuberculosis who presented to the outpatient department with complaints of heartburn, abdominal discomfort, and hoarseness of voice. Incidentally patient had diffused multinodular neck swelling. Preliminary blood investigations were normal. The contrast-enhanced computed tomography neck showed multiple non-enhancing lesions and a diffusely enlarged thyroid gland, causing a mass effect on the oropharynx posteriorly and minimally on the trachea. Fine needle aspiration cytology thyroid revealed thyroiditis. The patient underwent a total thyroidectomy, and histopathological examination of the specimen showed an extracellular eosinophilic amorphous substance that was positive for Congo red and showed apple-green birefringence under polarized light, and large areas of adipose metaplasia were noted, and a diagnosis was made. The amyloid involvement can result from localized primary deposition or secondary to chronic inflammatory disease. The prevalence of amyloid goiter in developed countries is due to primary amyloidosis, and in developing countries is due to secondary amyloidosis. Patients with a history of pulmonary tuberculosis commonly present with renal amyloidosis as its complication. Patients with an enlarged thyroid gland and a history of chronic inflammatory conditions or plasma cell dyscrasias should be evaluated with extreme suspicion. The correlation of tuberculosis with the subsequent development of amyloid goiter highlights the need for research in this area.

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Recent insight in the genomic landscape of newly diagnosed multiple myeloma (NDMM) and its precursor conditions, monoclonal gammopathy of uncertain significance (MGUS), and smoldering myeloma have allowed the identification of patients with precursor conditions with a high risk of progression. These cases with "progressor" MGUS/SMM have a higher average mutation burden, have higher rates of mutations in specific genes such as MAPK, DNA repair, MYC, DIS3, and are enriched for specific mutational signatures when compared to non-progressors and are comparable to those found in NDMM. The highly preserved clonal heterogeneity seen upon progression of SMM, combined with the importance of these early variables, suggests that the identification of progressors based on these findings could complement and enhance the currently available clinical models based on tumor burden. Mechanisms leading to relapse/refractory multiple myeloma (RRMM) are of clinical interest given worse overall survival in this population. An Increased mutational burden is seen in patients with RRMM when compared to NDMM, however, there is evidence of branching evolution with many of these mutations being present at the subclonal level. Likewise, alterations in proteins associated with proteosome inhibitor and immunomodulatory drugs activity could partially explain clinical resistance to these agents. Evidence of chromosomal events leading to copy number changes is seen, with the presence of TP53 deletion, mutation, or a combination of both being present in many cases. Additional chromosomal events such as 1q gain and amplification may also interact and lead to resistance.

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Light chain (AL) amyloidosis is a plasma cell dyscrasia that results in an overproduction of immunoglobulins of the lambda or kappa light chains. These monoclonal ALs begin to form fibrils with each other and exert their toxic effect by depositing in different organs around the body. Disease presentation is indistinct, but it is ideal to diagnose this disorder before end-organ damage is caused. Once the diagnosis of AL amyloidosis is confirmed, the best treatment is autologous stem cell transplantation once a candidate is deemed fit for it; however, there are other chemotherapy agents whose patients can be administered until they undergo stem cell transplantation. In this case presentation and systematic review of AL amyloidosis, we discuss a patient who presented with septic shock and further workup leading to a diagnosis of advanced-stage amyloidosis. We also take a deeper look at AL amyloidosis providing a comprehensive review of the disease process and its treatment options.

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BACKGROUND: Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder. Plasma cell dyscrasias are a rare heterogeneous group of hematological disorders. The co-occurrence of CML and plasma cell dyscrasias in the same patient is an extremely rare incident and has been reported in several cases in the literature. CASE SUMMARY: In the present report, we described a rare case of the co-occurrence of CML and plasma cell dyscrasias in a 48-year-old man, and we discussed the reason why monoclonal gammopathy of undetermined significance progressed to smoldering multiple myeloma and eventually to multiple myeloma while being treated with dasatinib for CML. The tyrosine kinase inhibitor treatment and cytogenetic change may contribute to this phenomenon, and clonal hematopoiesis of indeterminate potential may lead to both CML and multiple myeloma cells in a patient. Future studies are warranted to further explain the hidden reasons. CONCLUSION: This case highlights that gene translocation may contribute to initiation and sustainability of clonal proliferation. Moreover, the treatment with tyrosine kinase inhibitor and cytogenetic change may contribute to progression from monoclonal gammopathy of undetermined significance to smoldering multiple myeloma and eventually to multiple myeloma.

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Monoclonal immunoglobin (M-protein) is a serum biomarker for the diagnosis of plasma cell dyscrasias. Despite limitation of analytical sensitivity and resolution, serum protein electrophoresis and immunofixation electrophoresis are still the front-line tests for the detection of M-proteins. Herein, we developed a MALDI-TOF Mass spectrometry-based method for the screening test of M-proteins in human serum. Based on the unique mass signature of different immunoglobin isotypes, M-Proteins could be rapidly identified and typed. The method demonstrated with high analytical performance and throughput, rapid and simple, which could be a new choice for the diagnosis of plasma cell dyscrasias.

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Nodular localized cutaneous amyloidosis is a rare form of cutaneous amyloidosis and is characterized by an extracellular deposition of insoluble amyloid fibrils which are either primarily cutaneous or a manifestation of an underlying systemic amyloidosis. Biopsy of the lesion is mandatory for the diagnosis, and histopathology shows diffuse amyloid deposits with plasmacytic infiltration. Apple-green birefringence characteristic of amyloidosis is observed when stained with Congo red and viewed under polarized light. Amyloid subtyping is done with laser microdissection followed by mass spectrometry. Majority of these lesions do not require any treatment but surgical excision, shave excision, laser therapy, and radiotherapy can be considered for symptomatic nodular localized primary cutaneous amyloidosis (NLPCA). We present a case of recurrent NLPCA in a 64-year-old woman who was treated with bortezomib and dexamethasone after failing several local therapies with excellent response.

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Multiple myeloma (MM) is the second most common hematological malignancy, arising from terminally differentiated B cells, namely plasma cells. miRNAs are small non-coding RNAs that participate in the post-transcriptional regulation of gene expression. In this study, we investigated the role of nine miRNAs in MM. CD138+ plasma cells were selected from bone marrow aspirates from MM and smoldering MM (sMM) patients. Total RNA was extracted and in vitro polyadenylated. Next, first-strand cDNA synthesis was performed using an oligo-dT-adapter primer. For the relative quantification of the investigated miRNAs, an in-house real-time quantitative PCR (qPCR) assay was developed. A functional in silico analysis of the miRNAs was also performed. miR-16-5p and miR-155-5p expression was significantly lower in the CD138+ plasma cells of MM patients than in those of sMM patients. Furthermore, lower levels of miR-15a-5p, miR-16-5p, and miR-222-3p were observed in the CD138+ plasma cells of MM patients with osteolytic bone lesions, compared to those without. miR-125b-5p was also overexpressed in the CD138+ plasma cells of MM patients with bone disease that presented with skeletal-related events (SREs). Furthermore, lower levels of miR-223-3p were associated with significantly worse overall survival in MM patients. In conclusion, we propose a miRNA signature with putative clinical utility in MM.

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Plasma cell dyscrasias (PCDs) are neoplastic diseases derived from plasma cells. Patients suffering from PCDs are at high risk of hypercoagulability and thrombosis. These conditions are associated with disease-related factors, patient-related factors, or the use of immunomodulatory drugs. As PCDs belong to neoplastic diseases, some other factors related to the cancer-associated hypercoagulability state in the course of PCDs are also considered. One of the weakest issues studied in PCDs is the procoagulant activity of neutrophil extracellular traps (NETs). NETs are web-like structures released from neutrophils in response to different stimuli. These structures are made of deoxyribonucleic acid (DNA) and bactericidal proteins, such as histones, myeloperoxidase, neutrophil elastase, and over 300 other proteins, which are primarily stored in neutrophil granules. NETs immobilize, inactivate the pathogens, and expose them to specialized cells of immune response. Despite their pivotal role in innate immunity, they contribute to the development and exacerbation of autoimmune diseases, trigger inflammatory response, or even facilitate the formation of cancer metastases. NETs were also found to induce activity of coagulation and are considered one of the most important factors inducing thrombosis. Here, we summarize how PCDs influence the release of NETs, and hypothesize whether NETs contribute to hypercoagulability in PCDs patients.

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In response to emerging discoveries, questions are mounting as to what factors are responsible for the progression of plasma cell dyscrasias and what determines responsiveness to treatment in individual patients. Recent findings have shown close interaction between the gut microbiota and multiple myeloma cells. For instance, that malignant cells shape the composition of the gut microbiota. We discuss the role of the gut microbiota in (i) the development and progression of plasma cell dyscrasias, and (ii) the response to treatment of multiple myeloma and highlight faecal microbiota transplantation as a procedure that could modify the risk of progression or sensitize refractory malignancy to immunotherapy.

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Extramedullary plasmacytoma (EMP) is a plasma cell disorder involving soft tissues in the absence of clonal bone marrow involvement or destructive bone lesions. When present in the gastrointestinal (GI) tract, and specifically the small intestine, it can cause a wide range of symptoms including GI bleeding, obstruction, and abdominal pain. The diagnosis is challenging, as it can hold an indolent course, and is infrequently encountered in clinical practice. Diagnosis requires biopsy of the involved organ, which can be obtained during surgery or endoscopy, and other workup to rule out systemic disease and bone marrow involvement. Treatment depends on the primary site of disease involvement and the presence of other features of systemic disease. We report a case of multiple small bowel plasmacytomas in a 51-year-old female who presented with small bowel obstruction. She eventually underwent surgical resection and is currently on chemotherapy awaiting stem cell transplant.

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BACKGROUND: Plasma cell dyscrasias (PCD) are characterized by an abnormal production of intact monoclonal immunoglobulins or parts such as heavy or light chains. In most cases, the monoclonal protein (also termed paraprotein) is produced by a clonal plasma cell population. The production of monoclonal proteins can result in deposits of various types and localization depending on the type, amount, and electrochemical properties of the paraprotein. One histopathologic presentation, albeit rare, are crystalline deposits. They can form in various organs and hence cause a wide spectrum of symptoms. CASE PRESENTATION: A 49-year-old man presented to the emergency department with eyestrain and foreign body sensation after overhead drilling. Examination of the eyes revealed crystalline deposits in the cornea of both eyes. After additional diagnostic testing, deposits were attributed to free light chains. Monoclonal gammopathy of undetermined significance (MGUS) was diagnosed according to serum electrophoresis and immunofixation. Four years later, new onset of proteinuria was detected. A percutaneous biopsy of the kidney showed severe light chain podocytopathy with secondary focal segmental glomerulosclerosis (FSGS) and light chain proximal tubulopathy (LCPT). In these lesions, crystalline deposits identical to the corneal deposits were found in ultrastructural and immunofluorescent analysis. The patient was diagnosed with monoclonal gammopathy of renal significance (MGRS), and a plasma cell directed therapy was initiated. CONCLUSIONS: PCD can present with a wide array of symptoms and are notoriously difficult to diagnose. Extrarenal manifestations such as crystalline deposits in the cornea are one possible manifestation. The case presented herein emphasizes the notion that extrarenal paraprotein deposits warrant a thorough search for the underlying clonal disease.

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