Hematogenous extramedullary relapse in multiple myeloma - a multicenter retrospective study in 127 patients.

The current study assesses the characteristics and outcomes of multiple myeloma (MM) patients, treated with novel agents for hematogenous extramedullary (HEMM) relapse. Consecutive patients diagnosed with HEMM between 2010-2018 were included. Patients' characteristics at diagnosis and at HEMM presentation, response to treatment, survival and factors predicting survival were recorded and analyzed. A group of 127 patients, all diagnosed with HEMM by imaging (87.3%) and/or biopsy (79%), were included. Of those, 44% were initially diagnosed with ISS3, 57% presented with plasmacytomas, and 30% had high-risk cytogenetics. Median time to HEMM was 32 months. In multivariate analysis, ISS3 and bone plasmacytoma predicted shorter time to HEMM (P = .005 and P = .008, respectively). Upfront autograft was associated with longer time to HEMM (P = .002). At HEMM, 32% of patients had no BM plasmacytosis, 20% had non-secretory disease and 43% had light-chain disease. Multiple HEMM sites were reported in 52% of patients, mostly involving soft tissue, skin (29%), and pleura/lung (25%). First treatment for HEMM included proteasome inhibitors (50%), immunomodulatory drugs (IMiDs) (39%), monoclonal antibodies (10%), and chemotherapy (53%). Overall response rate (ORR) was 57%. IMiDs were associated with higher ORR (HR 2.2, 95% CI 1.02-4.7, P = .04). Median survival from HEMM was 6 months (CI 95% 4.8-7.2). Failure to achieve ≥VGPR was the only significant factor for worse OS in multivariate analyses (HR = 9.87, CI 95% 2.35 - 39, P = .001). In conclusion, HEMM occurs within 3 years of initial myeloma diagnosis and is associated with dismal outcome. The IMiDs might provide a higher response rate, and achievement of ≥VGPR predicts longer survival.

Circulating Tumour DNA Analysis for Tumour Genome Characterisation and Monitoring Disease Burden in Extramedullary Multiple Myeloma.

Mutational characterisation in extramedullary multiple myeloma (EM-MM) patients is challenging due to inaccessible EM plasmacytomas, unsafe nature of multiple biopsies and the spatial and temporal genomic heterogeneity apparent in MM (Graphical abstract). Conventional monitoring of disease burden is through serum markers and PET-CT, however these modalities are sometimes inadequate (serum markers), not performed in a timely manner (PET-CT) and uninformative for identifying mutations driving disease progression. DNA released into the blood by tumour cells (ctDNA) contains the predominant clones derived from the multiple disease foci. Blood-derived ctDNA can, therefore, provide a holistic illustration of the major drivers of disease progression. In this report, the utility of ctDNA, as an adjunct to currently available modalities in EM-MM, is presented for a patient with EM and oligosecretory (OS) disease. Whole exome sequencing of contemporaneously acquired tumour tissue and matched ctDNA samples revealed the presence of spatial and temporal genetic heterogeneity and the identification of pathways associated with drug resistance. Longitudinal monitoring of plasma samples revealed that ctDNA can be utilised to define the dynamic clonal evolution co-existent with disease progression and as an adjunct non-invasive marker of tumour burden.

A retrospective study of correlation of morphologic patterns, MIB1 proliferation index, and survival analysis in 134 cases of plasmacytoma.

Plasmacytoma classified into solitary plasmacytoma of bone (SPB) and extramedullary plasmacytoma (EMP) is characterized by infiltrate of plasma cells of diverse maturity and by their monoclonal immunoglobulin products. Both SPB and EMP represent different groups of neoplasm in terms of location, tumor progression, and overall survival rate. There is a need for features that indicate likelihood of myeloma in patients with plasmacytoma without other manifestations. This study was an attempt to study the morphologic patterns of plasmacytoma (SPB and EMP), MIB1 proliferation index, and correlation of these with clinicopathologic features and survival of the patients. The study group comprised of 134 cases of plasmacytoma (88 SPB and 46 EMP) over duration of 8 years and were graded as per Bartl's histologic grading system. Commonest site was vertebral body in SPB (36%) and upper aerodigestive tract in EMP (48%). On serum electrophoresis, overall M band was detected in 41% cases. Both SPB and EMP on histology revealed similar morphologic features. MIB1 proliferation index ranged from less than 1% to 80%. It was slightly higher in EMP in comparison with SPB (P value = .002). Seventy percent of cases, which progressed to multiple myeloma (MM) showed MIB1 labeling index more than 10%; however, it was not statistically significant in predicting the disease progression. With the median follow-up of 19 months (range, 1-99 months), 10 SPB had disease progression of which 7 converted to MM, and 3 developed EMP, with a median interval of 21 months (range, 8-75 months) for the development of MM and 3 months (range, 3-9 months) for the progression to EMP. Five-year survival for EMP varied by site, with poorest survival in brain/central nervous system EMP as compared with EMP at other sites. To conclude, grade and MIB1 proliferation index help in predicting aggressive course in plasmacytoma.

Radiotherapy for solitary plasmacytoma of bone and soft tissue: outcomes and prognostic factors.

We investigated treatment outcomes of radiotherapy for solitary plasmacytoma (SP) and prognostic factors affecting survival. Between 1996 and 2010, a total of 38 patients were treated with radiotherapy for histologically proven plasmacytoma without evidence of multiple myeloma. Among these, 16 and 22 patients had SP originating from extramedullary soft tissue (EMP) and bone, respectively. Thirteen patients received adjuvant chemotherapy, and three patients underwent surgery prior to radiotherapy. At a median follow-up of 50 months (range, 8-142), radiotherapy demonstrated excellent local control (5- and 10-year local control rates, 81%). However, the 10-year multiple myeloma-free survival (MMFS) was 54% and the 10-year overall survival (OS) rates was 35%. Solitary bone plasmacytoma (SBP) more frequently progressed to multiple myeloma (MM) than EMP (10-year MMFS, 0% vs. 71%, p = 0.02). Radiotherapy with doses ≥40 Gy demonstrated better local control (10-year LC, 100% vs. 60%, p = 0.04) in SBP. In the multivariate analysis, elevated ß2-microglobulin was a significantly unfavorable prognostic factor affecting OS (p = 0.03). In conclusion, radiotherapy effectively treated SP without significant toxicity. However, progression to MM presents a challenging problem. Novel therapeutics are needed for patients with unfavorable prognostic factors.

[Plasmacytoid urothelial carcinoma of the bladder with prostate cancer: report of two cases]. / Variante plasmacytoïde de carcinome urothélial vésical et cancer prostatique : à propos de deux cas.

Plasmacytoid urothelial carcinoma (PUC) is a rare variant of urothelial carcinoma with aggressive clinicopathological behaviours. We experienced two cases of PUC of urinary bladder. Both cases were advanced cancer with extravesical invasion and lymph node metastases. They also had coexisting prostatic carcinoma, one was preoperatively diagnosed and the other was incidentally discovered after surgery. As these cases were the first report of PUC simultaneously associated with prostatic carcinoma, clinicopathological features and the treatment options were discussed.

[18F-FDG PET-CT in a case of solitary plasmacytoma of the soft palate]. / Tomografía por emisión de positrones con ¹8F-fluorodeoxy-glucosa en un caso de plasmocitoma solitario de paladar blando.

Solitary plasmacytoma is an uncommon tumor of plasma cells that can appear in the head and neck. It must be differentiated from multiple myeloma because of its initial presentation. A case of solitary plasmacytoma on the palate is presented. Furthermore, role of ¹8F-fluorodeoxyglucose Positron Emission Tomography (¹8F-FDG-PET) in its initial staging is analyzed.

How We Manage Patients with Plasmacytomas.

PURPOSE OF REVIEW: To discuss the diagnostic approach, treatment options, and future considerations in the management of plasmacytomas, either solitary or in the context of overt multiple myeloma (MM). RECENT FINDINGS: Advanced imaging techniques such as whole-body magnetic resonance imaging and positron emission tomography/computerized tomography are essential for the diagnostic workup of solitary plasmacytomas (SP) to rule out the presence of other disease foci. The role of flow cytometry and clonal plasma cell detection is currently under study together with other prognostic factors for the identification of patients with SP at high risk of progression to overt MM. Solitary plasmacytomas are treated effectively with local radiotherapy whereas systemic therapy is required at relapse. Clonal plasma cells that accumulate at extramedullary sites have distinct biological characteristics. Patients with MM and soft tissue involvement have poor outcomes and should be treated as ultra-high risk. A revised definition of SP that distinguishes between true solitary clonal PC accumulations and SP with minimal bone marrow involvement should be considered to guide an appropriate therapeutic and follow-up approach. Future studies should be conducted to determine optimum treatment approaches for patients with MM and paraskeletal or extramedullary disease.

Circulating tumor cells in murine myeloma.

BALB/c mice bearing subcutaneous ADJ-PC5 myelomas had hematologic findings suggestive of a preleukemic syndrome: thrombocytopenia, anemia, leukocytosis, and megakaryocytic hyperplasia. Six BALB/c myelomas were successfully transplanted sc by fragments or cell suspensions of spleens from mice bearing a subcutaneous tumor, though typical myeloma cells were difficult to visualize by light microscopy in these spleens. The fidelity of transmission of the ADJ-PC5 myeloma by this procedure was shown by the retention of idiotypic specificity of the immunoglobulin produced by the tumor in a radioimmunoassay. The tumorigenic cell that homed to the spleen was apparent as early as 8 days after sc transplantation of the myeloma. The spleens of tumor-bearing mice, however, could destroy or suppress the expansion or growth of a limited number of cells that had migrated to the spleens. Tumorigenic cells present in the peripheral circulation constituted 2-3% of the leukocytes. These cells, however, had reduced levels of the murine myeloma viral and cell-associated antigens, were difficult to detect by an indirect immunofluorescence assay, and did not rapidly divide in this environment, as indicated by the very low number of cells detected by autoradiography.

Factor XIII deficiency in BALB/c mice with plasmacytoma.

These studies examined the fate of Factor XIII (fibrin-stabilizing factor) in mice with plasmacytoma (MOPC-300, MOPC-384, MOPC-467, and J-558). Plasma Factor XIII levels in these mice decreased progressively with tumor expansion. No plasma inhibitors of Factor XIII activity could be detected. Factor XIII was found on plasmacytoma cell membranes and in the cytoplasm of the malignant cells by immunofluorescence. The inverse relationship between tumor load and plasma Factor XIII levels suggested that the fibrin-stabilizing factor was absorbed by the malignant cells.

Serum-free light-chain analysis in diagnosis and management of multiple myeloma and related conditions.

The introduction of the serum-free light-chain (S-FLC) assay has been a breakthrough in the diagnosis and management of plasma cell dyscrasias, particularly monoclonal light-chain diseases. The first method, proposed in 2001, quantifies serum-free light-chains using polyclonal antibodies. More recently, assays based on monoclonal antibodies have entered into clinical practice. S-FLC measurement plays a central role in the screening for multiple myeloma and related conditions, in association with electrophoretic techniques. Analysis of S-FLC is essential in assessing the risk of progression of precursor diseases to overt plasma cell dyscrasias. It is also useful for risk stratification in solitary plasmacytoma and AL amyloidosis. The S-FLC measurement is part of the new diagnostic criteria for multiple myeloma, and provides a marker to follow changes in clonal substructure over time. Finally, the evaluation of S-FLC is fundamental for assessing the response to treatment in monoclonal light chain diseases.

[Soluble syndecan-1 levels in different plasma cell dyscrasias]. / Szolúbilis syndecan-1-(CD 138)-koncentráció plazmasejt-dyscrasiákban.

INTRODUCTION: Syndecans are a family of cell surface proteoglycans. In the bone marrow of multiple myeloma patients syndecan-1 is expressed only on the surface of malignant plasma cells. The aim of the study was to determine the soluble syndecan-1 levels in different plasma cell dyscrasias. METHODS: The serum concentration of soluble syndecan-1 was measured using human syndecan-1 enzyme-linked immunosorbent assay kit. RESULTS: Patients with multiple myeloma showed a significantly higher median serum syndecan-1 level than patients with plasmocytoma or monoclonal gammopathy of undetermined significance. Statistically significant differences were also observed among Salmon-Durie subgroups of 50 patients suffering from multiple myeloma. In addition to these findings a statistical correlation with other independent prognostic factors such as serum beta2-microglobulin level, monoclonal immunoglobulin concentration, and bone marrow plasma cell count could also be noted. A significant decrease in median serum syndecan level was observed in patients who responded to chemotherapy, whereas no change in the median syndecan-1 level could be observed in nonresponders. CONCLUSION: These findings confirm the observation that high serum soluble syndecan-1 level is associated with a more advanced disease stage and is a strong independent indicator of poor prognosis. A diminished serum syndecan-1 reading as a result of chemotherapy may be a good indicator of favorable response to antitumor treatment.

Solitary extramedullary plasmocytoma of the thyroid: a case report and histological approach to plasma cells infiltrate in the thyroid gland.

BACKGROUND: Solitary extramedullary plasmacytoma (SEP) is a rare malignant neoplasm arising from plasma cells. SEP mostly occurs in the upper respiratory tract. Thyroid gland is rarely affected (<78 cases). METHODS/RESULTS: We describe the case of a 78-year-old woman presenting a rapidly enlarging palpable thyroid mass. Neck computed tomography scan showed enlargement of both thyroid lobes. Laboratory tests were normal, including serum protein level with no monoclonal gamma globulin peak. Cytology was suspicious for lymphoma. Biopsy showed an infiltrating neoplasm composed of atypical tumor cells with abundant cytoplasm and eccentric nuclei. These revealed diffuse immunoreactivity for CD138 and predominant staining for immunoglobulin kappa light chains. Clinical workup for multiple myeloma was negative. CONCLUSIONS: SEP should be considered in the differential diagnosis of a rapidly enlarging thyroid nodule and be distinguished from involvement of thyroid in multiple myeloma, mucosa-associated lymphoid tissue lymphoma, plasma cell granuloma and medullary carcinoma. Clinical correlation and immunohistochemistry are crucial in avoiding pitfalls.

The Crow-Fukase syndrome: a study of 102 cases in Japan.

Clinical manifestations of 102 cases with the Crow- Fukase syndrome (the syndrome of polyneuropathy, anasarca, skin changes, endocrinopathy, dysglobulinemia, and organomegaly), with or without myeloma, were reviewed. Fifty-six cases with myeloma consisted of 31 with osteosclerotic, 17 with mixed osteosclerotic and osteolytic, and 8 with osteolytic. Forty-six cases without myeloma consisted of 2 with extramedullary plasmacytoma, 33 with M protein alone, and 11 with polyclonal protein alone. There was no significant difference in incidence of the major clinical manifestations between the two groups with and without myeloma. They had a common characteristic histologic finding of the lymph node resembling that of Castleman's disease.

Solitary bone plasmacytoma: outcome and prognostic factors following radiotherapy.

PURPOSE: To clarify the natural history of solitary plasmacytoma of bone (SBP) after radiation treatment. METHODS AND MATERIALS: Between 1965-1996, we identified 57 previously untreated patients with a SBP. A serum myeloma protein was present in 33 patients (58%) and Bence Jones proteinuria was present in an additional eight patients (14%). The median radiotherapy dose was 50 Gy (range, 30-70 Gy). Overall survival, cause-specific survival, and freedom from progression to multiple myeloma were calculated actuarially. RESULTS: Local control was achieved in 55 of 57 patients (96%). For those 29 patients (51%) who subsequently developed multiple myeloma, the median time to progression was 1.8 years. There was a direct correlation between persistence of abnormal protein following radiotherapy and the likelihood of developing multiple myeloma. Among 11 patients with disappearance of myeloma protein, only two developed multiple myeloma after 4 and 12 years, in contrast to progression in 57% of patients with a persistent protein peak and 63 % of those with nonsecretory disease (p = 0.02). Among 23 patients with thoracolumbar spine disease, 7 of 8 patients staged with plain radiographs alone developed multiple myeloma in comparison with 1 of 7 patients who also had magnetic resonance imaging (MRI) (p = 0.08). For all patients, the median survival from radiotherapy was 11.0 years. The median cause-specific survival of patients with disappearance of myeloma protein was significantly longer than that of the remaining patients (p = 0.004). CONCLUSION: Results supported the importance of precise staging that includes MRI of the spine for optimum patient selection and the application of definitive radiotherapy. Those patients with myeloma protein that disappears following radiotherapy represent a category with a high likelihood of cure.

Coexisting primary early gastric plasmacytoma and sarcoidosis with hypercalcaemia.

We report on a 61-year-old woman with coexisting early stage primary gastric plasmacytoma and sarcoidosis with hypercalcaemia. Laboratory data on admission showed hypercalcaemia, with 12.8 mg/dl, parathyroid hormone-related peptide (PTHrP) 1.2 pmol/l, C-PTHrP 69.5 pmol/l, and 1,25-dihydroxyvitamin D3 46.7 pg/ml. Neoplastic plasma cells proliferated in the propria mucosa of the stomach, showed a monoclonal immunoglobulin of cytoplasmic IgA (lambda light chain) and were positive for leucocyte common antigen and epithelial membrane antigen on paraffin section prepared from a stomach biopsy specimen. Russel bodies were present, as were crystals. Abundant sarcoid granulomas were observed in many of the regional lymph nodes around the stomach and in the dermis of a skin nodule. The patient underwent subtotal gastrectomy with administration of antimyeloma chemotherapy. We suggest that the hypercalcaemia in this patient was due to PTHrP production by neoplastic plasma cells.

Determination of IL6, IL1, and IL4 in the plasma of patients with multiple myeloma.

Interleukin 6 (IL6) plasma levels were measured in 63 patients with multiple myeloma and 8 individuals with benign monoclonal gammopathy. 15 of these 71 samples showed by an enzyme linked immunosorbent assay (ELISA) detectable levels that ranged from 5 to 107 pg of IL6/ml. The IL6 levels of patients with multiple myeloma did not differ significantly from those of normal individuals (N = 25, range 5-27 pg IL6/ml) (Student's t-test, p = 0.295). The samples were negative for IL4; 3 were found positive for IL1 beta. A correlation between IL6, IL4 and IL1 beta levels and disease status was not observed for this group of patients.

Nodal plasmacytoma with significant paraproteinaemia.

We present a case of primary nodal plasmacytoma in an elderly Chinese woman that was associated with significant paraproteinaemia and paraproteinuria. Clinical and laboratory features of the patient satisfied Durie's criteria for the diagnosis of multiple myeloma. The present case was unusual in two aspects. Firstly, there was no evidence of clonal plasma cell proliferation elsewhere in the body after extensive radiological investigations, repeated bone marrow examinations, and polymerase chain reaction for immunoglobulin gene rearrangement study. Secondly, the clinical behaviour was indolent despite the large amount of paraprotein production, and showed satisfactory disease control with local radiotherapy. The differential diagnoses of plasmacytosis in the lymph node are also discussed.