POEMS Syndrome- An Overview

The purpose of this review is to provide the latest information on POEMS syndrome. The authors conducted a literature search of available sources describing the issue of POEMS syndrome with special focus on syndrome and made a comparison and evaluation of relevant findings. The results of this review indicate that POEMS syndrome is associated with a group of disorders known as monoclonal gammopathies or plasma cell dyscrasias. These disorders are characterized the uncontrolled growth of a single clone (monoclonal) of plasma cells, which results in the abnormal accumulation of M-proteins (also known as immunoglobulin) in the blood which has a significant impact on the quality of life of both the patients and his/her family. Diagnoses are often delayed because the syndrome is rare and can be mistaken for other neurologic disorders, most commonly chronic inflammatory demyelinating polyradiculoneuropathy. Therefore, early and proper diagnosis and treatment are necessary in order to reduce or even eliminate both symptoms and social burden of the patient.

A Rare Cause of Acquired Factor X Deficiency in an 87-Year-Old Female

Factor X deficiency is a rare coagulopathy that can be inherited or acquired. Acquired factor X deficiency has been associated with plasma cell dyscrasias, amyloids, and use of vitamin K antagonists. Of plasma cell dyscrasias, most cases in the literature have been associated with multiple myeloma with or without concomitant AL amyloidosis. Here, we present a rare case of acquired isolated factor X deficiency in an elderly patient with immunoglobulin A (Ig A) monoclonal gammopathy of undetermined significance (MGUS). Herein, we highlight a rare cause of acquired factor X deficiency, and we hope to contribute to the growing literature of plasma cell dyscrasias associated with factor X deficiency.

Neutrophil Extracellular Traps (NETs) and Hypercoagulability in Plasma Cell Dyscrasias—Is This Phenomenon Worthy of Exploration?

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.

A Novel B Cell Antigen Designated Lambda Myeloma Antigen (LMA) Has Been Identified Using Two Fully Human Monoclonal Antibodies (Mabs) That Bind to Similar Epitopes on Plasma Cells from Patients with Plasma Cell Dyscrasias

Introduction: The novel kappa (κ) myeloma antigen (KMA) has been described and a specific monoclonal antibody KappaMab (formerly MDX-1097) developed which is currently in a Phase IIb clinical trial. In this study 2 human LambdaMabs (10B3 and 7F11) were shown to specifically bind to a conformational epitope in the lambda (λ) light chain constant region when it is held in non-covalent association with lipids in the cell membrane (LMA). The 10B3 Mab binds to all λ isotypes and 7F11 binds to isotypes 2 and 3; neither antibody binds κ light chain or immunoglobulin (Igλ or Igκ). Methods: To detect LMA on λ+ myeloma cell lines and on λ-restricted patient bone marrow (BM) samples, 7F11 and 10B3 Fab'2 fragments were conjugated to APC and R-PE and used to stain the λ myeloma cell lines LP-1, RPMI8226 and OPM-2 followed by flow cytometry analysis. KappaMab Fab'2 (KMA Fab'2) and the κ myeloma cell line JJN3 were used as a negative control and to identify KMA on κ-restricted patient BM samples. Patient BM samples (κ=43 and λ=22) included Monoclonal Gammopathy of Undetermined Significance (MGUS), untreated and treated multiple myeloma (MM) patients, AL amyloidosis, plasmacytoma and Waldenstroms macroglobulinemia (WM). Multiparametric FCM immunophenotyping was performed with the 10B3 Fab'2 fragments and CD38, CD138, CD269 (BCMA), CD319 (SLAM F7), CD56 and CD45 Mabs. Plasma cells (PCs) were identified by the co-expression of CD38 and CD138, then CD138+/CD38+ gated cells were analyzed for 10B3 or KMA, CD269, CD319, and CD56. KMA and LMA Fab'2 fragments were used as negative controls for each other. The antigen density of KMA or LMA versus BCMA on PCs in 55 samples was assessed using Quantibrite beads. Immunohistochemistry (ICH) tissue cross-reactivity studies using validated automated methods on tissue with whole antibody 7F11-biotin and 10B3-FITC were performed on MM cell lines, λ myeloma lung tissue (plasmacytoma) and a panel of 38 normal human tissues. Serial sections from snap frozen blocks were used to retain the conformational epitope and then stained with the λ Mabs and visualised by light microscopy. Results: The conjugated 10B3 Fab'2 fragment bound to LMA-expressing cell lines LP-1, RPMI8226 and OPM-2 (isotypes 1-3) and 7F11 bound to RPMI8226 and OPM-2, (isotypes 2-3); neither bound JJN3. KMA Fab'2 did not bind to λ myeloma cell lines but bound JJN3. Expression profiles for patient BM samples (Table 1) showed KMA was expressed on PCs from untreated (N=9/17; 53%) and treated (N=8/11; 73%) MM samples, whereas BCMA expression was 88% (N=15/17) and 82% (N=9/11) respectively. BM PCs from all 3 plasmacytoma cases and 1 WM case were positive for both KMA and BCMA. BM PCs from MGUS cases were all positive for BCMA and positive for KMA in half the cases studied. The expression of KMA and CD56 was highest on PCs from treated MM patient samples. Antigen density for KMA and BCMA was similar in the untreated patients. In treated patients KMA density was higher than BCMA, other samples had lower antigen density of both KMA and BCMA. LMA (Table 2) and BCMA were expressed on 50% and 90% of untreated MM samples and all LMA+ samples co-expressed BCMA but only 1 co-expressed CD56. All treated λMM samples expressed BCMA and 60% expressed LMA. LMA was positive on PCs from the 3 amyloidosis samples, BCMA was expressed weakly in only 1 of these whereas CD56 was always co-expressed with LMA. MGUS and WM samples did not express LMA. Similar to KMA, the antigen density of LMA and BCMA was equivalent in untreated patients but in treated patients LMA density was higher than BCMA. All 3 amyloidosis samples were λ isotype. IHC results showed that 10B3 and 7F11 bound to myeloma cell lines and 10B3 bound to PCs in λ plasmacytoma sections. Both Mabs bound occasional PCs or dendritic cells in the GI tract mucosa, tonsil and various secondary lymphoid organs. No off-target binding of 10B3 and 7F11 was observed and both antibodies bound occasional PCs in secondary lymphoid tissue. Conclusion: These studies used mostly myeloma samples and a small number of other plasma cell dyscrasias. Nevertheless expression of KMA and LMA was identified on PCs across the spectrum of disease. Within the treated patient cohort the antigen density of KMA or LMA was higher than that of BCMA and implies there is an enrichment of these novel antigens in relapsed refractory myeloma. No off-target binding was observed in normal human tissues and binding was limited to occasional leukocytes in secondary lymphoid tissue. Figure 1 Figure 1. Disclosures Hu: HaemaLogiX Pty Ltd: Current Employment. Dunn: HaemaLogiX Pty Ltd: Current Employment.

COVID-19 Vaccine Response in Patients with Hematologic Malignancy: A Systematic Review and Meta-Analysis

Introduction: Emerging data suggests that seroresponse (SR) in patients with hematologic malignancy following COVID-19 vaccination is likely lower than in patients without blood cancer. The objective of this study was to perform a systematic review and meta-analysis on SR in patients with hematologic malignancy who received COVID-19 vaccination (submitted to PROSPERO for registration). Methods: We searched PubMed and EMBASE from December 1, 2020, to July 22, 2021, to identify studies of SR following COVID-19 vaccine in adult patients with hematologic malignancy (including studies in which patients with hematologic malignancy represented a subset of a broader population). Patients with positive serologic response at baseline (prior to vaccination) or known COVID-19 infection were excluded. The primary outcomes were pooled SR estimates following COVID-19 vaccination in patients with hematologic malignancy, and pooled SR estimates of subgroups based on hematologic malignancy type. Secondary outcomes were pooled relative risk ratio (RR; compared to non-cancer controls) based on dichotomous-effect SR in all patients, and subgroups based on hematologic malignancy type, treatment status, and use of anti-CD20 therapy. Pooled estimates and RR with its associated 95% confidence intervals (CIs) were calculated using MetaXL (EpiGear), and Reference Manager (Cochrane) using random effects model. Results A total of 17 studies comprising 2834 patients with hematologic malignancy from Europe, United Kingdom and North America were included (Figure 1). The pooled estimate for SR was 58% (95% CI 48-67%, I 2 95%), with a RR of 0.53 (95% 0.42-0.66, I 2 94%) when compared to controls (10 studies with comparison group, 1092 hematologic malignancy patients, 830 controls; Figure 2). The pooled estimate for SR varied by type of hematologic malignancy: lymphomas SR 52% (95% CI 36-68%, 7 studies, 832 patients, I 2 94%); chronic lymphocytic leukemia (CLL) SR 42% (95% CI 25-60%, 6 studies, 921 patients, I 2 93%); plasma cell dyscrasias SR 66% (95% CI 47-83%, 8 studies, 611 patients, I 2 95%); myeloproliferative neoplasms (MPNs, including chronic myelogenous leukemia) SR 83% (95% CI 68-95%, 6 studies, 227 patients, I 2 58%); acute leukemia SR 86% (95% CI 77-94%, 2 studies, 67 patients, 46 acute myelogenous leukemia [AML] and 15 acute lymphocytic leukemia], I 2 0%). The RR for SR also varied by type of hematologic malignancy: lymphomas (excluding CLL) RR 0.48 (95% CI 0.34-0.68, 4 studies, 337 patients, I 2 89%); CLL RR 0.37 (95% CI 0.25-0.53, 3 studies, 194 patients, I 2 54%); plasma cell dyscrasias RR 0.73 (95% CI 0.62-0.86, 5 studies, 323 patients, I 2 70%); RR MPN 0.78 (95% CI 0.62-0.99, 3 studies, 199 patients, I 2 90%). The pooled estimate for SR in those receiving treatment was 42% (95% CI 26-58%, 9 studies, 683 patients, I 2 94%). The pooled estimates for SR for those receiving anti-CD20, bruton tyrosine kinase inhibitor (BTKi), or venetoclax were 13% (95% CI 1-32%, 6 studies, 367 patients, I 2 88%), 42% (95% CI 17-71%, 3 studies, 319 patients, I 2 75%), and 20% (95% CI 0-54%, 3 studies, 39 patients, I 2 66%), respectively. The RR for those receiving treatment for their hematologic malignancy compared to those who were not receiving treatment was 0.51 (95% CI 0.37-0.71, 8 studies, 579 patients, I 2 89%; Figure 3). . The RR of patients receiving anti-CD20 therapy compared to non-cancer controls was 0.13 (95% CI 0.02-0.93, 102 patients, I 2 73%). For patients treated with anti-CD20 therapy, the RR of those receiving vaccination within 9-12 months compared to beyond 9-12 months was 0.12 (95% CI 0.06-0.25, 2 studies, 74 patients, I 2 0%; Figure 4). Conclusion: Our systematic review and meta-analysis suggests that patients with hematologic malignancy have a lower SR rate following vaccination compared to controls. Furthermore, SR is variable across different types of hematologic malignancy, with very good response rates seen in patients with myeloid diseases (MPN and AML) and poor response rates seen in lymphoma and CLL. Active treatment, particularly anti-CD20 therapy within 12 months of vaccination, is associated with a particularly low SR following vaccination. Additional studies are needed to understand non-humoral responses to vaccination, and to guide decisions regarding how to optimize vaccine response in patients with blood cancer. We plan to update the systematic review and meta-analysis as more data become available. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Solitary Ovarian Plasmocytoma: A Rare localization of Extramedullary Plasmocytoma. A Case Report

Background: Solitary plasmacytoma is a rare malignant neoplasm of plasma cells accounting 5-10% of all plasma cell dyscrasias with extramedullary plasmocytoma in 3- 5%. Their localization in the female genital tract is quite rare, either as solitary plasmacytomas or as part of a disseminated MM. Solitary ovarian plasmocytoma is extremely rare. Case: A 52-year-old woman, presented presented postmenopausal recurring episodes of metrorrhagia with left ovarian mass. She was diagnosed with solitary ovarianplasmocytoma without systemicdisease. The patient underwent complete surgery resection and a full work up to rule out multiple myeloma that objectived a small serum monoclonal protein that had resolved postoperatively. At 17 months of follow-up, the patient is still alive and doing well with no signs of recurrence or progression to mutliple myeloma. Although rare, solitary plasmacytoma of the ovary can occur without any overt symptoms or laboratory abnormalities tests and require prompt and adequate treatment and rigorous monitoring due to their ability to relapse or progress to MM. Complete surgical resection followed by activesurveillance is appropriate.

The Role of the Gut Microbiome in Pathogenesis, Biology, and Treatment of Plasma Cell Dyscrasias

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.

Biclonal Multiple Myeloma- A Case Series

Multiple myeloma is a prototype of plasma cell dyscrasias characterized by monoclonal abnormal proliferation of immunoglobulin secreting plasma cell in the bone marrow ; resulting in production of monoclonal (M) protein (IgG,IgA,IgM,IgD) and or light chain concentrations (kappa or lamda) identified by protein electrophoresis and or immunofixation of serum or urine. The term biclonal multiple myeloma are defined by coexistence of two different M components, which could be either from a single clone or two separate clones producing two distinct bands in electrophoresis and or immunofixation of serum or urine. Biclonal gammopathy is a rare entity with upto 1% of newly diagnosed case of multiple myeloma have two M component in serum immunofixation electrophoresis. Here we share our experience of four cases of biclonal myeloma successfully diagnosed and treated with standard chemotherapy with satisfactory clinical outcome from a single tertiary care centre.

Clinical and Biological Characteristics of Medullary and Extramedullary Plasma Cell Dyscrasias

Background: Extramedullary plasma cell (PC) disorders may occur as extramedullary disease in multiple myeloma (MM-EMD) or as primary extramedullary plasmocytoma (pEMP)/solitary osseous plasmocytoma (SOP). In this study, we aimed to obtain insights into the molecular mechanisms of extramedullary spread of clonal PC. Methods: Clinical and biological characteristics of 87 patients with MM-EMD (n = 49), pEMP/SOP (n = 20) and classical MM (n = 18) were analyzed by using immunohistochemistry (CXCR4, CD31, CD44 and CD81 staining) and cytoplasmic immunoglobulin staining combined with fluorescence in situ hybridization (cIg-FISH). Results: High expression of CD44, a cell-surface glycoprotein involved in cell-cell interactions, was significantly enriched in MM-EMD (90%) vs. pEMP/SOP (27%) or classical MM (33%) (p < 0.001). In addition, 1q21 amplification by clonal PC occurred at a similar frequency of MM-EMD (33%), pEMP/SOP (57%) and classical MM (44%). Conversely, del(17p13), t(4;14) and t(14;16) were completely absent in pEMP/SOP. Besides this, 1q21 amplification was identified in 64% of not paraskeletal samples from MM-EMD or pEMP compared to 9% of SOP or paraskeletal MM-EMD/pEMP and 44% of classical MM samples, respectively (p = 0.02). Conclusion: Expression of molecules involved in homing and cytogenetic aberrations differ between MM with or without EMD and pEMP/SOP.

Treatment Induced Cytotoxic T-Cell Modulation in Multiple Myeloma Patients

The biology of plasma cell dyscrasias (PCD) involves both genetic and immune-related factors. Since genetic lesions are necessary but not sufficient for Multiple Myeloma (MM) evolution, several authors hypothesized that immune dysfunction involving both B and T cell counterparts plays a key role in the pathogenesis of the disease. The aim of this study is to evaluate the impact of cornerstone treatments for Multiple Myeloma into immune system shaping. A large series of 976 bone marrow samples from 735 patients affected by PCD was studied by flow analysis to identify discrete immune subsets. Treated MM samples displayed a reduction of CD4+ cells (p&lt;0.0001) and an increase of CD8+ (p&lt;0.0001), CD8+/DR+ (p&lt;0.0001) and CD3+/CD57+ (p&lt;0.0001) cells. Although these findings were to some extent demonstrated also following bortezomib treatment, a more pronounced cytotoxic polarization was shown after exposure to autologous stem cell transplantation (ASCT) and Lenalidomide (Len) treatment. As a matter of fact, samples of patients who received ASCT (n=110) and Len (n=118) were characterized, towards untreated patients (n=138 and n=130, respectively), by higher levels of CD8+ (p&lt;0.0001 and p&lt;0.0001, respectively), CD8+/DR+ (p=0.0252 and p=0.0001, respectively) and CD3+/CD57+ cells (p&lt;0.0001 and p=0.0006, respectively) and lower levels of CD4+ lymphocytes (p&lt;0.0001 and p=0.0005, respectively). We demonstrated that active MM patients are characterized by a relevant T cell modulation and that most of these changes are therapy-related. Current Myeloma treatments, notably ASCT and Len treatments, polarize immune system towards a dominant cytotoxic response, likely contributing to the anti-Myeloma effect of these regimens.