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Sporadic late-onset nemaline myopathy (SLONM) associated with monoclonal protein (MP) is a rare disease with an aggressive, and often fatal course. Whether SLONM + MP represents a malignancy or dysimmune disease remains unclear. Currently, two main approaches are used to treat SLONM + MP: nonchemotherapy-based treatment (immunosuppression, intravenous immunoglobulins, plasmapheresis and plasma exchange) or chemotherapy with or without autologous stem cell transplantation. Due to the rare occurrence of the disease, the best treatment modality is unknown. We analyzed treatment and outcomes in a large cohort of 53 patients with SLONM + MP: four our own patients and 49 cases from published literature. Neurological improvement in the nonchemotherapy group (N = 25) was observed in 52% of patients: 8% reached marked improvement, 8% moderate response, 36% mild response; none reached complete remission (CR). In the chemotherapy group (N = 28), neurological improvement was seen in 86% of patients: 46% reached CR, 25% marked response, 11% moderate response and 4% mild response. The best neurological improvement correlated with deep hematological remission. Mean time to best response in the chemotherapy group was 8 months versus 21 months in the nonchemotherapy group (P < .001). Overall survival was higher in patients in the chemotherapy group. A chemotherapy approach should be the preferred treatment for patients with SLOMN + MP with the goal to reach complete hematologic remission. Based on the clinical, morphological peculiarities, aggressive disease course and superior clinical benefits of chemotherapy over nonchemotherapy, SLONM + MP should be considered as a hematological malignancy with the presence of MP of clinical rather than undetermined significance.

Pyoderma gangrenosum (PG) is a rare, inflammatory dermatologic condition characterized by painful cutaneous ulcerations. Herein, we describe the third documented case of PG arising in an elective plastic surgery patient who had undergone an otherwise uncomplicated facelift. We describe the course of her diagnosis and management of PG, which involved her face and neck and then progressed to her lower extremities. Although the etiology remains unknown, PG often arises in a host with another autoimmune disease. In the case described, the patient was diagnosed with an immunoglobulin A gammopathy shortly after she developed PG. Following the case report, the pathogenesis, diagnosis, and treatment strategy of PG is briefly reviewed. Level of Evidence: 5

Amyloidosis refers to a group of diseases in which tissues and organs accumulate amyloid — a protein with an abnormal structure, which leads to impairment of their function. There are systemic forms of amyloidosis, involving the internal organs and skin, and cutaneous ones, where the disease process affects only the skin. Here, we present a case of a seventy-year-old woman diagnosed with primary cutaneous amyloidosis.

Light-chain deposition disease (LCDD) is a rare paraproteinaemia characterized by the deposition of monoclonal immunoglobulins with a non-fibrillar structure and hence Congo red negative deposits. Kidney disease is the more frequent manifestation, but other organs may also be involved. A 70-year-old man with hypertension and mild chronic renal failure showed a hepatomegaly without splenomegaly. His renal and liver test rapidly got worse. A serum electrophoresis and immunofixation isolated monoclonal kappa light-chain gammopathy, with serum free kappa light chain excess. The bone marrow biopsy showed the presence of interstitial infiltration of plasma cells like multiple myeloma type at initial phase. Periumbilical fat biopsy was negative. Echocardiography demonstrated an infiltrative cardiac disease. The biopsies of the duodenum small intestine mucosa showed flaps with eosinophil material (Masson’s staining) with atrophic crypts and chronic inflammation at chorion level. Amyloid substance was negative. There was a strong positivity for light chains kappa compatible with LCDD. A liver biopsy confirmed this finding. Therapy with dexamethasone and bortezomib improved clinical state and hepatic and renal laboratory tests. Chemotherapy based on novel anti-myeloma agents should be rapidly considered in LCDD patients with severe organ involvement.

Background English bulldogs disproportionally develop an expansion of small B-cells, which has been interpreted as B-cell chronic lymphocytic leukemia (BCLL). However, clonality testing in these cases has often not been supportive of neoplasia. Hypothesis English bulldogs have a syndrome of nonneoplastic B-cell expansion. Animals Eighty-four English bulldogs with small-sized CD21+ B-cell lymphocytosis in the blood as determined by flow cytometry. Methods This is a retrospective study. We characterized this syndrome by assessing B-cell clonality, clinical presentation, flow cytometric features, and immunoglobulin gammopathy patterns. We identified 84 cases with CD21+ lymphocytosis among 195 English bulldogs with blood samples submitted to the Colorado State University-Clinical Immunology laboratory for immunophenotyping between 2010 and 2019. Flow cytometry features were compared to normal B-cells and BCLL cases. PCR for antigen receptor rearrangements (PARR) by multiple immunoglobulin primers was performed to assess B-cell clonality. A subset of cases with gammopathy were examined by protein electrophoresis, immunofixation, and immunoglobulin subclass ELISA quantification. Results Seventy percent (58/83) of cases had polyclonal or restricted polyclonal immunoglobulin gene rearrangements, suggesting nonmalignant B-cell expansion. The median age of all dogs in the study was 6.8 years and 74% were male. The median (range) lymphocyte count was 22 400/μL (2000-384 400/μL) and B-cells had low expression of class II MHC and CD25. Splenomegaly or splenic masses were detected in 57% (26/46) of cases and lymphadenopathy in 11% (7/61). Seventy-one percent (52/73) of cases had hyperglobulinemia and 77% (23/30) with globulin characterization had IgA ± IgM polyclonal or restricted polyclonal gammopathy patterns. Conclusions and clinical importance Polyclonal B-cell lymphocytosis in English bulldogs is characterized by low B-cell class II MHC and CD25 expression, splenomegaly and hyperglobulinemia consisting of increased IgA ± IgM. We hypothesize that this syndrome has a genetic basis.

Waldenstrom macroglobulinemia is a lymphoplasmacytic lymphoma with bone marrow involvement and a monoclonal IgM gammopathy. Infiltration of the skin by neoplastic cells is very rare, and it can be difficult to distinguish from marginal zone lymphoma. The MYD88 L265P mutation is strongly associated with Waldenstrom macroglobulinemia, and it may be helpful in differentiating the two disorders, although the presence of this mutation is not specific, and other factors must be considered when making the final diagnosis. We present a diagnostically challenging case of cutaneous Waldenstrom macroglobulinemia in which the MYD88 L265P mutation was identified in the skin but not in the bone marrow, due to a low tumor burden.

Background The clinical, histologic, and immunopathologic features of IgA pemphigus have not been studied on a large scale. Objective To synthesize existing data on the epidemiologic, clinical, histologic, and immunologic features of IgA pemphigus. Methods We performed a systematic review using MEDLINE, Embase, and Web of Science databases. Case reports and series of patients with IgA pemphigus were included. Results A total of 119 eligible studies, comprising 137 patients with IgA pemphigus with a mean age of 51.5 ± 21.0 years, were included. Most patients presented with vesicles (80.8%), pustules (75.0%), and circinate plaques (63.6%). Pruritus was present in 65.6% of reported patients. Intercellular deposition of IgA was noted in almost all patients (97.0%), and the remaining 3.0% of patients had IgA positivity on indirect immunofluorescence or enzyme-linked immunosorbent assay confirming the diagnosis. IgA circulating intercellular antibodies were detected in only 66.7% patients. IgA gammopathy and ulcerative colitis were associated with IgA pemphigus in 9.5% and 6.6% patients, respectively. Oral dapsone and corticosteroids were the mostly commonly used treatments. Limitations Results are mainly based on case reports and small case series. Conclusions The diagnosis of IgA pemphigus may be considered in patients presenting with vesiculopustular eruption and circinate plaques with truncal and extremity involvement.

A 13-year-old spayed female American Cocker Spaniel was presented for evaluation of a cough and weight loss. Physical exam revealed generalized lymphadenopathy. The patient was diagnosed with marginal zone lymphoma (MZL) on histopathology of an extirpated lymph node. This report demonstrates an unusual case of a pleomorphic neoplastic population documented on cytologic evaluation that had moncytoid features and peripheral blood involvement; a previously undocumented IgG1 monoclonal gammopathy was also an interesting feature of this canine MZL. The patient did not undergo chemotherapy for lymphoma and was euthanized over 4 years after the initial presentation.

Monoclonal gammopathy of renal significance (MGRS) encompasses a group of disorders in which a monoclonal immunoglobulin (M-protein) secreted by a B-cell or plasma cell clone causes renal disease. Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a form of MGRS where M-protein is deposited in the glomerulus. Although evidence is limited, the current consensus is that therapy for PGNMID should be directed against the underlying clone. However, it is conceivable that there is heterogeneity in the renal prognosis of PGNMID and that not all patients have need for clone-directed therapy. Here, we report two cases of PGNMID with IgM-kappa gammopathy. In one case of a 53-year-old woman the glomerulonephritis resolved without clone-directed therapy. In the other case of a 34-year-old woman clone-directed therapy was discontinued due to adverse effects. Although no hematological response was achieved, the PGNMID resolved. In both cases there are no signs of a recurrent glomerulonephritis in over 3 years of follow-up. Here, we review the literature and suggest that some PGNMID patients have a favorable renal prognosis in whom clone-directed therapy can be withheld or postponed. Further research is warranted to yield predictors to identify these patients and to better understand the disease course of PGNMID.

PURPOSE: Lymphoproliferative disease in common variable immunodeficiency disease (CVID) is heterogeneous in pathogenesis and ranges from non-malignant lymphoid hyperplasia to lymphoma. METHODS: The United States Immunodeficiency Network (USIDNET) patient registry was queried for lymphoproliferative diseases reported in CVID patients. Diagnoses included as possible manifestations of lymphoproliferation included lymphadenopathy, lymphoid hyperplasia, lymphocytic inflammation, lymphocytosis, and gammopathy. RESULTS: Among 1091 CVID patients, lymphoproliferative conditions were reported in 17.2% (N = 188). These conditions included lymphadenopathy (N = 192, 12.3%), lymphoid hyperplasia or lymphocytic inflammation (N = 50, 4.6%), lymphocytosis (N = 3, 0.3%), and gammopathies (N = 3, 0.3%). Of the 188 patients with lymphoproliferative conditions, 15 (8%) also had a diagnosis of lymphoma, while the remaining 173 (92%) did not. Nine (4.8%) had a diagnosis of non-lymphomatous malignancy including basal cell carcinoma (N = 3, 1.6%), thyroid carcinoma (N = 2, 1.1%), gynecologic cancer (N = 2, 1.1%), testicular cancer (N = 1), and vocal cord carcinoma (N = 1). CVID patients with lymphoma were older than patients with lymphoproliferative disease who did not have a diagnosis of lymphoma at the time of analysis (median age 49 vs. 35 years, p = 0.005). CVID patients with lymphoproliferative disease had 2.5 times higher odds of having chronic lung disease compared with those with lymphoma (OR = 0.4, p = 0.049). There were no significant differences in the frequency of autoimmune, gastrointestinal, hepatic, or granulomatous disease between these populations. CONCLUSIONS: While CVID patients are at increased risk for lymphoma, lymphoproliferation may be observed in the absence of a concurrent hematologic or solid tumor malignancy.

Waldenstrom's macroglobulinemia (WM) is a rare and slowly progressive disorder, a variant of lymphoplasmacytic lymphoma, which needs therapy only when patient becomes symptomatic. WM presents usually with constitutional symptoms, organomegaly, cytopenias, and hyperviscosity syndrome. This neoplasm is composed of small lymphocytes, plasmacytoid lymphocytes, and plasma cells that typically involve the bone marrow, and it is associated with an immunoglobulin M (IgM) gammopathy. Here we report the case a 60-year-old male with WM who initially presented with anemia and fatigue. The patient had no lymphadenopathy or any organomegaly. The diagnosis of WM was made after morphological and immunohistochemical examination of bone marrow of the patient along with an elevated serum IgM level. The patient responded well to plasmapheresis and chemotherapy. This case is unusual because the patient lacked the common clinical features of WM. A thorough clinical and hematological work up including serum electrophoresis, bone marrow study, and immunohistochemistry helps in distinguishing WM from other lymphomas and plasma cell dyscrasias.

Tremors have been well-described in association with monoclonal gammopathy. We report a case of a patient with asymmetric hands tremor who responded well to levodopa-carbidopa treatment. Further workup showed an underlying gammopathy. To our knowledge, this is one of the rarest case reports of successful treatment of gammopathy-related tremors with levodopa-carbidopa. The patient was a 75-year-old male who presented to the neurology clinic for a one-year history of worsening tremors in bilateral upper extremities. A review of systems was only remarkable for mild numbness and tingling in his feet. His neurological examination was remarkable for asymmetric right more than left (R > L) resting and kinetic tremor in both upper extremities associated with mild rigidity and bradykinesia in right upper extremity and decreased bilateral ankle jerks. With the primary diagnosis of Parkinson’s disease, he was started on levodopa-carbidopa and a neuropathy workup was requested. His follow-up visit after three months was remarkable for significant improvement of his tremors with carbidopa-levodopa. However, his blood work was consistent with a significant increase in lambda light chain levels and the presence of an M spike in serum protein electrophoresis. Based on the presentation and clinical workup, he was finally found to have both multiple myeloma and ​Waldenstrom’s macroglobulinemia. Underlying malignancy was treated with chemotherapy and immunotherapy. Levodopa-carbidopa was discontinued after three months of chemotherapy and his tremor did not recur in one year of follow-up. Gammopathy is one of the well-known causes of tremors in the adult population. It can cause both resting and kinetic tremors in the upper extremities. It is supposed that peripheral neuropathy associated with gammopathy is the main underlying cause of tremors in these groups of patients. However, central causes are also suggested. In this case, we are led to conclude that our patient’s tremor was centrally mediated since it responded well to dopamine replacement therapy. However, further study is needed to elucidate the role of dopamine depletion in the pathogenesis of tremors associated with gammopathies.

Background Cardiac light chain amyloidosis (AL-CA) patients often die within three months of starting chemotherapy. Chemotherapy for non-immunoglobulin M gammopathy with AL-CA frequently includes bortezomib (Bor), cyclophosphamide (Cy), and dexamethasone (D). We previously reported that NT-ProBNP levels can double within 24h of dexamethasone administration, suggesting a deleterious impact on cardiac function. In this study, we evaluate the role of dexamethasone in early cardiovascular mortality during treatment. Methods and findings We retrospectively assessed 100 de novo cardiac AL patients (62% male, mean age 68 years) treated at our institute between 2009 and 2018 following three chemotherapy regimens: CyBorDComb (all initiated on day 1; 34 patients), DCyBorSeq (D, day 1; Cy, day 8; Bor, day 15; 17 patients), and CyBorDSeq (Cy, day 1; Bor, day 8; D, day 15; 49 patients). The primary endpoint was cardiovascular mortality and cardiac transplantation at days 22 and 455. At day 22, mortality was 20.6% with CyBorDComb, 23.5% with DCyBorSeq, and 0% with CyBorDSeq (p = 0.003). At day 455, mortality was not significantly different between regimens (p = 0.195). Acute toxicity of dexamethasone was evaluated on myocardial function using a rat model of isolated perfused heart. Administration of dexamethasone induced a decrease in left ventricular myocardium contractility and relaxation (p Conclusion Delaying dexamethasone during the first chemotherapy cycle reduces the number of early deaths without extending survival. It is clear that dexamethasone is beneficial in the long-term treatment of patients with AL-CA. However, the initial introduction of dexamethasone during treatment is critical, but may be associated with early cardiac deaths in severe CA. Thus, it is important to consider the dosage and timing of dexamethasone introduction on a patient-severity basis. The impact of dexamethasone in the treatment of AL-CA needs further investigation.

We present an update on a 63 year old gentleman with a six year history of necrobiotic xanthogranuloma (NXG) on a background of hepatitis C.1 Additional investigations revealed trace oligoclonal gammopathy with IgG kappa and lambda. To chronicle his treatment, he presented after unsuccessful treatment with nbUVB (burns), hydroxychloroquine (ineffective) and acitretin (life-threatening side effects). In May 2014, there was mild subjective improvements with monthly 2g/kg intravenous immunoglobulin (IVIG) (over 5 days) for 4 months. In February 2015, 100mg of thalidomide daily for two months did not help.

Background: Brucellosis, a major health problem in developing countries, is a multisystem infection with a broad spectrum of clinical manifestations. Hematological complications, ranging from an intravascular coagulopathy to mild homeostasis disorders (such as gammopathy), have been reported in brucella infection. These signs and symptoms may lead to misdiagnosis of brucellosis with other hematological diseases. Case: A 65-year-old male whose occupation was shepherding was referred to our hospital as a known case of multiple myeloma with continuous fever, muscle weakness, and night sweating after taking 2 courses of chemotherapy. The laboratory diagnosis of multiple myeloma had been based on the observation of a high percent of plasma cells in the bone marrow aspiration. At follow- up, the result of patient's fever workup, with 2 sets of blood cultures, was positive for Brucella melitensis. Isolated brucella was confirmed as B. melitensis by 16S rRNA sequencing. Brucellosis serologic test was performed by agglutination test and positive results were obtained. The patient was discharged with the cessation of fever and general improvement after the end of the parental treatment phase of brucella bacteremia. Conclusions: Brucella infection may cause a severe disease, mimicking a primary hematological disease, which could complicate the correct diagnosis. In brucellosis cases, due to the wide range of symptoms, in addition to cultivation and serological methods, molecular methods should also be used to prevent inappropriate diagnosis and additional costs.

Background. Cutis laxa is a rare dermatosis that is inherited or acquired and clinically features loose, wrinkled, and redundant skin with decreased elasticity. This heterogeneous connective tissue disorder may be localized or generalized, with or without internal manifestations. Generalized cutis laxa often has a cephalocaudal progression and is attributed to inflammatory cutaneous eruptions, medications, and infections. Cutis laxa is also associated with several other conditions including rheumatoid arthritis, systemic lupus erythematosus, and plasma-cell dyscrasias.Case Presentation. We report an unusual case of a 35-year-old male with progression of generalized acquired cutis laxa and vasculitis that occurred over a period of one year. No cutaneous inflammatory eruption preceded or accompanied his decreased skin elasticity, and a biopsy of the skin showed elastolysis. His cutaneous manifestation led to systemic evaluation and an eventual diagnosis of smoldering multiple myeloma accompanied by aortitis and anemia. His myeloma and vasculitis were successfully treated with cyclophosphamide, bortezomib, and dexamethasone and high-dose prednisone, respectively, with no improvement to his cutis laxa.Conclusions. The presence of monoclonal gammopathy is strongly associated with several dermatological entities such as acquired cutis laxa. We propose a new term for the dermatological manifestations caused by paraproteinemia: monoclonal gammopathy of dermatological significance, or MGODS, and stress the evaluation of an underlying gammopathy in the setting of certain dermatologic conditions, including scleromyxedema and amyloidosis. We present a case of a newly acquired cutis laxa secondary to plasma-cell dyscrasias that exemplifies MGODS, alongside a brief literature review, and underscore the clinical relevance of monoclonal gammopathies of dermatological significance.

Cryoglobulins are immunoglobulins that undergo reversible precipitation at cold temperatures. Monoclonal type-I cryoglobulinaemia is the least frequent and is associated to hematological diseases such as multiple myeloma, Waldenström’s macroglobulinaemia, chronic lymphocytic leukaemia and lymphoma. We describe the case of a 60-year-old female patient, who suffered from burning pain in her feet for ten months before her admission. The patient presented intermittent distal cyanosis that progressed to digital ischaemia. She also reported paresthesia in her hands, difficulty in writing, and a 26-kg-weight loss. At the physical examination, it was identified livedo reticularis, palpable purpura, and painful ecchymotic lesions in her calves and feet. Moreover, peripheral pulses were palpable and symmetrical. It was observed an atrophy of the right first dorsal interosseous and both extensor digitorum brevis, as well as a distal bilateral apalesthesia and allodynia. Both Achilles reflexes were absent. Laboratory tests revealed anemia, high erythrosedimentation rate and C-reactive protein. Serum protein electrophoresis showed a monoclonal IgG-Kappa gammopathy. The results also evidenced the presence of Bence-Jones proteinuria. The bone marrow biopsy revealed less than 10% of plasma cells, and skin biopsy informed leukocytoclastic vasculitis. The patient was treated with high-dose intravenous steroids and cyclophosphamide. The treatment showed that the skin lesions had improved, pain disappeared and motor deficit stopped its progression.

Recent research has dramatically advanced our understanding of the genetic basis of multiple myeloma (MM). MM displays enormous inter- and intratumoral heterogeneity, and underlies a clonal evolutionary process driven and shaped by diverse factors such as clonal competition, tumor microenvironment, host immunity, and therapy. Two main cytogenetic groups are distinguished: MM with recurrent translocations involving the immunoglobulin heavy chain locus and MM with hyperdiploidy involving the odd chromosomes. The disease virtually always starts with a preneoplastic prodromal phase-monoclonal gammopathy of undetermined significance-that variably progresses to symptomatic MM within a few months or many years. Tumor heterogeneity and its evolution in space and time have important consequences for the clinical management and outcome of MM patients. At diagnosis, spatial intratumoral heterogeneity poses a challenge for classification and risk stratification. During maintenance therapy, clonal evolution may complicate disease monitoring and promote drug resistance. Upon progression or transformation, identifying the dominant disease-driving neoplastic clones and elucidating their properties are key to tailor personalized therapy. In this review, we discuss tumor heterogeneity and clonal evolution in MM, integrating pathological, radiological, molecular genetics, and clinical data. Current and prospective classification schemes and prognostic parameters, incorporating new genetic and proteomic discoveries and advances in imaging, are highlighted. In addition, the roles of the tumor microenvironment, host immunity, and resistance mutations, and their effects on therapy, are discussed. An improved understanding of high-risk disease, tumor heterogeneity, and clonal evolution will guide future therapies and may ultimately lead towards a cure for MM.

A 72-year-old man presented with a 6-month history of systemic edema. Hyperpigmentation, hemangioma, pleural effusion, IgG-kappa-type monoclonal protein, high vascular endothelial growth factor values, renal failure, and nerve conduction study abnormalities were also present. Multiparameter flow cytometry (MFC) showed 0.2% neoplastic plasma cells (CD38-, CD56-, and kappa-positive; CD19-, CD27-, and lambda-negative) in the bone marrow leading to POEMS syndrome. Cases involving kappa-type POEMS syndrome are extremely rare. A kidney biopsy revealed membranous proliferative glomerulonephritis-like changes in our case. Lenalidomide-dexamethasone therapy improved the renal function. Detection of neoplastic plasma cells by MFC was useful for the accurate diagnosis and treatment evaluation.

A 5-y-old female Golden Retriever was presented with a 2-wk history of hyporexia, vomiting, diarrhea, lethargy, weight loss, polyuria, and polydipsia. Clinical examination and ultrasonography revealed multiple organ enlargement with gallbladder and kidney nodules suggestive of disseminated neoplasia. Hematologic and biochemical analyses revealed pancytopenia, hypercalcemia, and monoclonal IgA gammopathy suspicious for a plasma cell neoplasm. Bone marrow and blood smear examination revealed neoplastic atypical cells highly suggestive of lymphoid origin. Autopsy confirmed the presence of homogeneous white masses and multifocal pale infiltrates in the spleen, kidney, small intestine, gallbladder, and urinary tract. Histologic features were consistent with a multicentric atypical plasma cell tumor. Tumor cells were negative for CD204, IBA-1, E-cadherin, CD3, CD5, CD79a, CD20, and PAX5, and positive for MUM1, consistent with plasma cell origin. The presence of > 20% of circulating blastic plasma cells was consistent with primary plasma cell leukemia with plasmablastic morphology, a disease rarely described in veterinary medicine.

We report here a case of primitive plasma cell leukemia with immunoglobulin (Ig) E. IgE myeloma is an exceptional variant of multiple myeloma, with a very poor prognosis. Its biological diagnosis requires specific analyzes in order to detect IgE gammopathy. Plasma cell leukemia (PCL) is also a very rare and very severe form of multiple myeloma. There are two variants: primitive PCL (pPCL) occurring de novo and secondary PCL (sPCL), evolution of a preexisting myeloma. Its diagnosis is essentially biological since it is defined by a blood plasmocytosis greater than 2 G/L or 20% of the leucocytes.

Waldenstrom Macroglobulinemia (WM) is a rare disorder with approximately 1200 new cases diagnosed in the United States every year [1]. It is characterized by a monoclonal IgM gammopathy in the bloo...

MYD88 mutation has been reported in various lymphomas, specifically in lymphoplasmacytic lymphoma. Yet, the mutation has not been reported in primary follicular lymphoma. Here, we present a 62-year-old male with follicular lymphoma who had an MYD88 L265P somatic mutation and monoclonal IgM gammopathy. He received four cycles of R-CHOP immunochemotherapy. Interim PET/CT evaluation indicated a state of stable disease (SD). Neither did serum IgM remarkably drop. He was then given a bortezomib-contained regimen which significantly reduced the level of serum IgM. To the best of our knowledge, this is the first report of follicular lymphoma with monoclonal IgM and MYD88 L265P mutation. The present case indicated bortezomib may benefit these patients.

A 4-year-old female neutered albino domestic ferret (Mustela putorius furo) was referred for acute progressive nonambulatory paraparesis. Physical examination was unremarkable, while neurological examination revealed nonambulatory paraparesis, decreased postural reactions on both pelvic limbs, upper-motor-neuron bladder and thoracolumbar pain. Prereferral hematology and biochemistry were almost normal, while whole body computed tomography revealed a left-sided T13 cranial articular process fracture and material of uncertain nature inside the spinal canal with secondary compressive myelopathy. On magnetic resonance imaging, the lesion was extradural. Decompressive surgery was performed and the surgically excised abnormal tissue was sent for histological investigations, which confirmed a plasma cell neoplasia clinically compatible with solitary osseous plasmacytoma. Prednisolone was started for a total of 5 months; at 10-month follow-up, the ferret was comfortable and ambulatory with only residual left pelvic limb monoparesis. Surgical treatment should be considered in solitary vertebral plasmacytomas, as it seems to be successful giving a long survival time to the patient. This is the first report to describe the magnetic resonance imaging findings and successful surgical treatment for a vertebral solitary osseous plasmacytoma in a ferret with focal osteolysis in the absence of systemic disease and gammopathy.

Although it is unquestionable that monoclonal gammopathy causes occlusive nonvasculitic vasculopathy,1 it is not clear yet, if it can cause immunoglobulin-mediated leukocytoclastic vasculitis (LcV) and how vigorously both conditions should be treated in monoclonal gammopathy of unclear significance (MGUS). In the recent nomenclature of cutaneous vasculitides (addendum to the CHCC2012),2 vasculitis in MGUS is mentioned as a possible, so-far unproven entity. Previous case reports did not sufficiently or explicitly distinguish it from occlusive vasculopathy. Adding to this dilemma is a lack of consensus with oncologists if or when chemotherapies are justified in MGUS with a paraprotein-associated disease. We provide evidence by means of 2 cases of MGUS that monoclonal gammopathy can cause primary immunoglobulin-mediated LcV and that its oncologic treatment abolishes it.

In humans, misdiagnoses of monoclonal gammopathy after use of therapeutic monoclonal antibodies has been documented. This triggers concerns for similar misdiagnoses in animals treated with monoclonal antibodies. The aim of this study was to evaluate if lokivetmab interferes with serum protein electrophoresis and immunofixation electrophoresis in dogs.Residual sera from 25 client-owned, healthy blood donor dogs from 2 veterinary hospitals in Germany were used. The residual sera were analysed with serum protein electrophoresis and immunofixation electrophoresis before and after being spiked with lokivetmab at a concentration of 10 µg/ml (corresponding to the mean peak serum concentration after a subcutaneous injection of 2 mg/kg lokivetmab).No monoclonal gammopathy was observed on serum protein electrophoresis and all proteins had a normal distribution pattern without any pathologic bands on immunofixation electrophoresis. The absolute γ-globulin values of spiked samples, however, were significantly higher than in the native sera although they remained within the reference interval. No other globulin fractions were significantly different.This study suggests that lokivetmab at a dose of 2 mg/kg is not detected as a monoclonal peak on serum protein electrophoresis or immunofixation electrophoresis, and thus is unlikely to lead to a misdiagnosis of other diseases that are characterised by monoclonal gammopathies.ZIEL: Beim Menschen wurden Fehldiagnosen einer monoklonalen Gammopathie nach Verwendung therapeutischer monoklonaler Antikörper dokumentiert. Dies löst Bedenken hinsichtlich ähnlicher Fehldiagnosen bei Tieren aus, die mit monoklonalen Antikörpern behandelt wurden. Ziel dieser Studie war zu evaluieren, ob Lokivetmab mit der Serumproteinelektrophorese und der Immunfixationselektrophorese bei Hunden interferiert.Zur Untersuchung gelangten übrig gebliebene Serumproben von 25 privat gehaltenen, gesunden Blutspenderhunden aus 2 Tierkliniken in Deutschland. Die Serumproben wurden vor und nach der Mischung mit Lokivetmab in einer Konzentration von 10 µg/ml mittels Serumproteinelektrophorese und Immunfixationselektrophorese analysiert. Die gewählte Konzentration entspricht der mittleren maximalen Serumkonzentration nach einer subkutanen Injektion von 2 mg/kg Lokivetmab.Bei der Serumproteinelektrophorese zeigte sich keine monoklonale Gammopathie und bei der Immunfixationselektrophorese wiesen alle Proteine ein normales Verteilungsmuster ohne pathologische Banden auf. Die absoluten γ-Gammaglobulin-Werte der aufgestockten Proben waren jedoch signifikant höher als die der nativen Seren, blieben jedoch im Referenzintervall. Die anderen Globulinfraktionen differierten nicht signifikant.Die Ergebnisse legen nahe, dass Lokivetmab in einer Dosis von 2 mg/kg nicht als monoklonaler Peak bei der Serumprotein- oder Immunfixationselektrophorese erkannt wird und daher wahrscheinlich nicht zu einem fälschlichen Verdacht einer mit einer monoklonalen Gammopathie einhergehenden Erkrankung führt.

Subcorneal pustular dermatosis (SPD), also known as Sneddon-Wilkinson disease, is a skin condition for which treatments are poorly codified. Anti-tumor necrosis factor alpha (TNFα) efficacy has been reported in multidrug-resistant SPD, as in our two cases. In the first case, an 83-year-old woman was monitored for SPD, associated with monoclonal IgA gammopathy. After multiple-line treatment failure, infliximab (5mg/kg) led to clinical improvement, noted few days following the first injection, and with complete remission at one month. At 12 months, the patient relapsed and concomitant serum anti-TNFα antibodies were found. A switch to adalimumab led to complete remission in three months with a follow-up of six months. In the second case, a 62-year-old woman was monitored for SPD associated with monoclonal IgA gammopathy recalcitrant to different lines of treatment. Treatment with adalimumab (40mg every two weeks) in combination with dapsone led to significant improvement after two injections. Five months later, she relapsed. It was then decided to reduce the interval between injections to once a week. Rapid improvement was achieved in one month allowing resumption of the original frequency of the injection without relapse after 20 months of follow-up. In conclusion, our cases confirm the previously reported efficacy of anti-TNFα in resistant SPD. They also highlight a risk of secondary loss of efficacy, reinforced by the literature data. Substitution of another TNFα blocker or shortening of interval between injections provided a renewal in response to treatment.

Plasmacytoma a neoplastic proliferation of plasma cells is one of the forms of plasma cell dyscrasia that may manifest as multiple myeloma, primary amyloidosis, or monoclonal gammopathy of unknown significance. Factors such as viral pathogenesis and irritation from inhaled irritants have been noted. Genetic factors may also play a role; however, no specific loci for the origin of this disease have been identified. Plasmacytoma mainly affects people in the 5th to 6th decade of their lives. Diagnostic criteria for SP (published by the International Myeloma Working Group, IMWG) indicate that the lesion must be solitary in nature without clinical, radiographical or biochemical evidence of systemic MM. Recent guidelines recommend MRI or PET/CT evaluation, in addition to standard x-ray skeletal survey, to exclude multifocal disease [1].

Background and Aims Monoclonal gammopathy of renal significance (MGRS) refers to any plasma cell or B cell clonal lymphoproliferation that has at least one kidney lesion related to the monoclonal immunoglobulin productions plus, the underlying clone is not responsible for tumour complications. Plus, does not meet any haematological criteria for specific treatment. Although considered a non-malignant or smouldering hematologic condition, its effects on the kidney are not benign since it frequently evolves to end-stage renal disease. There has been some reluctance in treating these patients but increasing evidence has shown that renal outcomes are closely associated with the haematological response to chemotherapy. We aimed to evaluate the incidence of MGRS in the North of Portugal and to assess patients’ characteristics, treatment and follow-up. Method We have, retrospectively, collected information of all patients with a biopsy proven MGRS diagnosis, from four Portuguese centers. Demographic, clinical, laboratorial data and treatment were analysed. Follow-up was made until dialysis start, death of until December 2020. Survival curves were analysed according to the treatment performed, the histological diagnosis, the type of chains, the estimated glomerular filtration rate (eGFR) and proteinuria at the time of diagnosis. Baseline characteristics were reported as mean ± standard deviation (SD) and median (min-max) for continuous variables or as number (percentage) for categorical variables. Survival curves were analysed using Kaplan–Meier method. Statistical calculations were performed using SPSS. Results Our study included 36 patients, with a mean age of 69 ± 11 years old and 52,8% were males. At baseline, the median value of serum creatinine (sCr) was 1,2 (0,4-6,3) mg/dL, which represented a mean eGFR of 55,4 ± 30,4 ml/min/1,73 m2 according to the CKD-EPI formula. The nephrotic syndrome was the most common (72%) renal presentation. The median proteinuria value was 8,0 (0,5-28) g per day and the mean albumin value was 2,7 ± 0,8 g/dL. The mean value of monoclonal protein was 5,5 ± 4,8 g/L with 62,5% of the patients having an abnormal serum free light chain ratio. Table 1 describes the type of gammopathy found, being the IgG/Kappa the most observed. The immunoglobulin light chain amyloidosis (AL amyloidosis) and the monoclonal immunoglobulin deposition disease (MIDD), mainly light chain deposition disease (LCDD) were the most frequent histological diagnosis (Table 2). Monoclonal gammopathy of undetermined significance (MGUS) was the most frequent haematological diagnosis (Table 3). Treatment was done in 75% of the cases and bortemozib-based regimens were the most used. Three patients (8,3%) received a bone marrow auto transplant. Approximately 40% of the patients had complete haematological and renal response. Treatment regimens and haematological and renal responses are summarized in Table 4 and 5. Survival curves (Figures 1–2) were significantly higher in younger patients (p=0,039) and both renal and global survival were better (p=0,023) in MIDD compared to AL amyloidosis. No statistically significant differences were detected when analysing according to treatment, type of chain, eGFR, proteinuria and serum albumin at admission. Conclusion The incidence of MGRS is probably underestimated and its treatment is yet far to be universal. In our series, 25% of the patients weren’t proposed to any treatment. MGRS approach requires a multidisciplinary team composed by Nephrologists, Pathologists, Onco-Haematologists and a Bone Marrow Transplantation department. Since not all hospitals meet these conditions, referral centers of greater expertise are required for a prompt diagnosis and to provide the most adequate treatment. We hope that in a near future more centres join this project and that this represents the first step towards the creation of a Portuguese group dedicated to the study and treatment of MGRS.

Proliferation and apoptosis of neoplastic cells are prognostic biomarkers in plasma cell neoplasms (PCNs). The prognostic capacity of proliferation to apoptosis ratio (Ratio-PA) in the era of immunomodulatory treatments is re-evaluated in 316 gammopathy of undetermined significance (MGUS), 57 smoldering multiple myeloma (SMM), and 266 multiple myeloma (MM) patients. Ratio-PA of 0.77 ± 0.12, 1.94 ± 0.52, and 11.2 ± 0.7 (p &lt, 0.0001) were observed in MGUS, SMM, and MM patients. Ten-year overall survival (10y-OS) rates for patients with low/high Ratio-PA were 93.5%/77.3% p &lt, 0.0001) for MGUS, 82.5%/64.7% (p &lt, 0.05) for SMM, and 62.3%/47.0% (p &lt, 0.05) for MM. For patients with low, intermediate, and high risk, 10y-OS for low/high Ratio-PA were 95.5%/72.9% (p &lt, 0.0001), 74.2%/50.4% (p &lt, 0.0001), and 35.3%/20.0% (p = 0.836), respectively. Ratio-PA was an independent prognostic factor for OS (HR = 2.119, p &lt, 0.0001, Harrell-C-statistic = 0.7440 ± 0.0194) when co-analyzed with sex, age, and standard risk. In patients with Ratio-PAhigh, only first-line therapy with VRd/VTd, but not PAD/VCD, coupled with ASCT was associated with high 10y-OS (82.7%). Tumor cell Ratio-PA estimated at diagnosis offers a prognostic biomarker that complements standard risk stratification and helps to guide the clinical management of pre-malignant and symptomatic PCNs. Every effort should be made to provide first-line therapies including VTd or VRd associated with ASCT to patients with Ratio-PAhigh at higher risk of progression and death.

IntroductionMonoclonal antibodies (mAb) targeting plasma cells are malignant gammopathy designed and approved therapies. In recent years, these antibodies have also been increasingly introduced for non-malignant conditions such as autoimmune-mediated diseases. The Anti-Phospholipid Syndrome (APS) is an immune-mediated disorder in which autoantibodies against phospholipid associated proteins could elicit the activation of the coagulation cascade in specific situations. Therefore, the mainstream treatment for APS patients is the use of anticoagulant therapy. However, there are refractory patients who would benefit from targeting the antibodies rather than their effects. Rituximab, a B-cell depleting mAb, and intravenous immunoglobulins (IVIG) have been used in APS patients without showing a clear beneficial effect or a significant drop in anti-phospholipid antibody (aPL) levels.Clinical caseWe present our first APS case treated with daratumumab, an anti-CD38 mAb, in a 21-year-old patient with APS who presented with recurrent venous thromboembolic events despite adequate anticoagulant therapy. She tested positive for lupus anticoagulant, anti-cardiolipin IgG, anti-beta-2-glycoprotein-I IgG and anti-phosphatidylserine/prothrombin IgG and IgM. She was administered one dose weekly of daratumumab for 4 weeks. The treatment showed an adequate safety profile and was well tolerated. The patient was discharged after undergoing a clinically significant improvement. After the therapy, her levels of positive aPL declined significantly and most continued to decrease during the next three months. The patient experienced a new thrombotic episode two years after the therapy associated with poor adherence to antithrombotic therapy.ConclusionsThe treatment with daratumumab showed an adequate safety profile, was well tolerated and led to a significant clinical improvement. Levels of aPL lowered on therapy and the next three months and then rose again during follow-up. Further investigation is needed to better elucidate the role and optimal timing and doses of daratumumab in treatment of refractory APS.

Monoclonal gammopathy of undetermined significance (MGUS) may be associated with pathologies with severe neuromuscular manifestations such as sporadic late‐onset nemaline myopathy (SLONM). We describe a difficult to diagnose case of SLNOM with marked clinical improvement after achieving gammopathy complete hematologic response.

Introduction: Gaucher disease (GD), although pan-ethnic and rare (common in Ashkenazi Jews), is of great importance to hematologists both for diagnosis and management. The need for increased awareness of GD is that delayed diagnosis may lead to preventable irreversible complications (mainly skeletal) or unnecessary invasive procedures (e.g. bone marrow biopsy), and the birth of another affected sibling due to lack of genetic consulting.Areas covered: The review outlines the common hematological manifestations of GD, including splenomegaly, thrombocytopenia, and anemia. Other hematological manifestations such as coagulation abnormalities, platelet dysfunction, gammopathy, and other hematological malignancies associated with GD are also discussed. Current and future treatment modalities are delineated, including enzyme replacement and substrate reduction therapy, pharmacological chaperon, and gene therapy. A literature search was conducted to identify original research articles relevant to hematology manifestations and GD published before November 2020.Expert opinion: Patients with GD should be ideally followed and treated in a center of excellence where the GD expert benefits from experienced consultants in relevant disciplines. Due to the availability of several very expensive treatment options, it is important to have an unbiased expert who can select the most suitable management for the individual patients (including withholding prescription in asymptomatic patients).

Daratumumab is a monoclonal antibody directed against the transmembrane glycoprotein CD38 expressed on plasma cells and lymphoplasmocytes, with a proven efficacy in multiple myeloma. Here we show its clinical efficacy in a patient with cold agglutinin disease (CAD) relapsed after multiple lines of therapy. CAD is caused by cold reactive autoantibodies that induce complement mediated hemolysis and peripheral circulatory symptoms. The disease is also characterized by the presence of monoclonal IgM gammopathy and of a lymphoid bone marrow infiltration that benefits from B-cell targeting therapies (i.e., rituximab) but also from plasma cell directed therapies, such as proteasome inhibitors. In the patient described, we also show that daratumumab therapy influenced the dynamics of several immunoregulatory cytokine levels (IL-6, IL-10, IL-17, IFN-γ, TNF-α, TGF-β) indicating an immunomodulatory effect of the drug beyond plasma cell depletion. In addition, we provide a literature review on the use of daratumumab in autoimmune conditions, including multi-treated and refractory patients with autoimmune hemolytic anemia (both CAD and warm forms), Evans syndrome (association of autoimmune hemolytic anemia and immune thrombocytopenia) and non-hematologic autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis.

An unusual clonal gammopathy was reported in COVID-19 patient but whether this anomaly is related or not to the disease has not yet been clarified. To this aim, we selected a cohort of 35 COVID-19 patients swab positive and investigated serological levels of IL-6, immune response to major viral antigens and electrophoretic profile. Elevated levels of IL-6 were accompanied by a significative humoral response to viral Spike protein, revealing an altered electrophoretic profile in the gamma region. We can conclude that elevated levels of IL-6 triggers humoral response inducing a transient plasma cell dyscrasia in severe COVID-19 patients.

We report a 73-year-old male with no relevant past medical history who presented with nephrotic syndrome and jaundice. Subsequent studies revealed immunoglobulinM (IgM) monoclonal gammopathy. Kidney biopsy revealed monoclonal Ig deposition disease and amyloidosis. Bone marrow biopsy demonstrated

The detection of monoclonal immunoglobulins is a key element in the diagnosis of monoclonal gammopathy. In clinical practice, screening and measurement of monoclonal proteins are commonly performed using capillary zone electrophoresis (CZE). Some exogenous substances, such as iodinated contrast agents, absorb incident UV light at the same wavelengths as the peptide bonds and may therefore interfere with the detection of proteins in CZE. We herein use the description of a case to illustrate that iodinated contrast agents can mask the presence of monoclonal immunoglobulins in CZE and we discuss the strategy needed to confirm this interference. Performing immunofixation, immunosubtraction, or a second CZE at a distance from the first blood sample is not only necessary to confirm the presence of an iodinated contrast media interference but also to ensure the absence of monoclonal proteins.

Background Waldenstrom macroglobulinemia (WM) is a rare chronic B-cell lymphoma. Familial clustering of WM has been observed over the years. However, little is known about the contribution of inherited genetic variants to familial WM cases. Methods The authors performed whole exome sequencing (WES) of germline DNA samples from twins, one diagnosed with WM and the other diagnosed with immunoglobulin M monoclonal gammopathy of undetermined significance, and their healthy siblings. Bioinformatics analysis of public biological databases was used to identify the most relevant familial WM candidate from WES. Transcript expression and protein levels of the familial WM candidate were evaluated in the WM patient and 2 unaffected members of the kindred. Results Among the 10 shared candidate mutations in the twins, the authors identified a novel heterozygous germline mutation in four and a half LIM domains protein 2 (FHL2; c.G226A, p.V76M) as a familial WM-associated mutation. FHL2 appeared to be connected with reported signaling pathways and disease-driving genes such as IL6 and HCK in WM. In addition, the authors found reduced FHL2 messenger RNA and protein expression in peripheral blood samples from the patient with WM in comparison with the healthy siblings. Conclusions Taken together, these findings indicate that an FHL2g226a mutation may play an important role in familial WM, and they provide new screening possibilities for familial cases. Lay summary Familial clustering in Waldenstrom macroglobulinemia (WM) has been observed over the years. The authors performed whole exome sequencing of germline DNA samples from twins, one diagnosed with WM and the other diagnosed with immunoglobulin M monoclonal gammopathy of undetermined significance, and their healthy siblings. Among the 10 shared candidate mutations in the twins, a novel heterozygous germline mutation in four and a half LIM domains protein 2 (FHL2; c.G226A, p.V76M) was identified as the most relevant familial WM candidate through bioinformatics analysis of a public database. Also, messenger RNA and protein expression of FHL2 was significantly lower in peripheral blood mononuclear cells of the WM patient in comparison with the healthy siblings, and this suggested that the function of FHL2 was impaired when mutated.

Scleredema is a connective tissue disorder that presents as diffuse induration of skin, most often involving the upper body. Scleredema can be associated with prior infection, monoclonal gammopathy, and diabetes mellitus. Pyoderma gangrenosum is a neutrophilic dermatosis that presents as an ulcer with violaceous borders. Pyoderma gangrenosum can be idiopathic or associated with various conditions. A 66-year-old man with a 20-year history of scleredema diabeticorum presented with idiopathic pyoderma gangrenosum in the affected area of scleredema on his neck. His pyoderma gangrenosum resolved after treatment with topical and intralesional corticosteroids. Diseases associated with scleredema, pyoderma gangrenosum or both are reviewed.

CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M [IgM] paraprotein, cold agglutinins, and disialosyl antibodies) is a rare syndrome characterized by chronic neuropathy with sensory ataxia, ocular, and/or bulbar motor weakness in the presence of a monoclonal IgM reacting against gangliosides containing disialosyl epitopes. Data regarding associated hematologic malignancies and effective therapies in CANOMAD are scarce. We conducted a French multicenter retrospective study that included 45 patients with serum IgM antibodies reacting against disialosyl epitopes in the context of evocating neurologic symptoms. The main clinical features were sensitive symptoms (ataxia, paresthesia, hypoesthesia; n = 45, 100%), motor weakness (n = 18, 40%), ophthalmoplegia (n = 20, 45%), and bulbar symptoms (n = 6, 13%). Forty-five percent of the cohort had moderate to severe disability (modified Rankin score, 3-5). Cold agglutinins were identified in 15 (34%) patients. Electrophysiologic studies showed a demyelinating or axonal pattern in, respectively, 60% and 27% of cases. All patients had serum monoclonal IgM gammopathy (median, 2.6 g/L; range, 0.1-40 g/L). Overt hematologic malignancies were diagnosed in 16 patients (36%), with the most frequent being Waldenström macroglobulinemia (n = 9, 20%). Forty-one patients (91%) required treatment of CANOMAD. Intravenous immunoglobulins (IVIg) and rituximab-based regimens were the most effective therapies with, respectively, 53% and 52% of partial or better clinical responses. Corticosteroids and immunosuppressive drugs were largely ineffective. Although more studies are warranted to better define the optimal therapeutic sequence, IVIg should be proposed as the standard of care for first-line treatment and rituximab-based regimens for second-line treatment. These compiled data argue for CANOMAD to be included in neurologic monoclonal gammopathy of clinical significance.