Monoclonal Plasma Cells Research Articles

Immunoglobulin variable domain high-throughput sequencing reveals specific novel mutational patterns in POEMS syndrome

AbstractPolyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare multisystem disease resulting from an underlying plasma cell (PC) dyscrasia. The pathophysiology of the disease remains unclear, but the role of the monoclonal immunoglobulin (Ig) light chain (LC) is strongly suspected because of the highly restrictive usage of 2 λ variable (V) domains (IGLV1-40 and IGLV1-44) and the general improvement of clinical manifestations after PC clone-targeted treatment. However, the diagnostic value of Ig LC sequencing, especially in the case of incomplete forms of the disease, remains to be determined. Using a sensitive high-throughput Ig repertoire sequencing on RNA (rapid amplification of cDNA ends-based repertoire sequencing [RACE-RepSeq]), we detected a λ LC monoclonal expansion in the bone marrow (BM) of 83% of patients with POEMS syndrome, including some in whom BM tests routinely performed to diagnose plasma cell dyscrasia failed to detect λ+ monoclonal PCs. Twenty-four (83%) of the 29 LC clonal sequences found were derived from the IGLV1-40 and IGLV1-44 germline genes, as well as 2 from the closely related IGLV1-36 gene, and all were associated with an IGLJ3*02 junction (J) gene, confirming the high restriction of VJ region usage in POEMS syndrome. RACE-RepSeq VJ full-length sequencing additionally revealed original mutational patterns, the strong specificity of which might crucially help establish or eliminate the diagnosis of POEMS syndrome in uncertain cases. Thus, RACE-RepSeq appears as a sensitive, rapid, and specific tool to detect low-abundance PC clones in BM and assign them to POEMS syndrome, with all the consequences for therapeutic options.

SAT-LB117 POEMS Syndrome: Rare Presentation of New Onset Diabetes Mellitus

Background: POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes) is characterized by the presence of a monoclonal plasma cell disorder, peripheral neuropathy, and one or more of the following features: osteosclerotic myeloma, Castleman disease, increased levels of serum vascular endothelial growth factor (VEGF), organomegaly, endocrinopathy, edema, typical skin changes, and papilledema. Clinical Case: 45 year old male with no chronic medical issues presented initially to the orthopedic clinic with right hip pain, pelvic MRI showed a right iliac crest lesion. CT Guided biopsy was done and showed plasmacytoma. SPEP showed elevated IgG lambda level in the gamma zone. In the meantime he was complaining of ascending numbness and weakness in hands and feet and he progressively became wheelchair bound. During his treatment and follow ups with Hematology/Oncology he was noted to have elevated blood sugars in the 500s. Hemoglobin A1C was elevated at 9.5 which confirmed the diagnosis of new onset diabetes. He was also noted to have splenomegaly which confirmed the diagnosis of POEMS syndrome. He was started on insulin and he managed to achieve good diabetes control with insulin and dietary changes. He is currently status post stem cell transplantation with a good response and the weakness and polyneuropathy improved with PT and OT. POEMS syndrome has major and minor criteria for diagnosis, mandatory major criteria includes polyneuropathy, monoclonal plasma cell proliferative disorder (almost always lambda). Additional major criteria are sclerotic bone disease, castleman disease, elevated VEGF. Minor criteria are organomegaly, extravascular volume load, endocrinopathy, and skin changes. In order to diagnose the syndrome, mandatory major criteria, and one major and one minor criteria need to be clinically present. Endocrinopathy includes the adrenal, pituitary, thyroid, gonadal, parathyroid, and pancreatic glands. Two-thirds of patients had at least one endocrine abnormality at presentation. Endocrine abnormalities can also develop later, during the course of the disease. Hypogonadism is the most common endocrine abnormality. Elevated levels of follicle stimulating hormone in the absence of primary hypogonadism levels have been reported, hence history and physical examination is crucial to detect the development of endocrinopathies in POEMS syndrome. There are no current guidelines or recommendations about the frequency of screening for endocrinopathies but it is suggested to obtain a baseline of thyroid function test, pituitary, gonadal, and adrenal axis. In addition to baseline parathyroid hormone level, close monitoring of calcium and blood glucose levels once the diagnosis is confirmed in patients with suggestive symptoms. Conclusion: POEMS syndrome is a rare condition that involves multiple endocrine organs, currently there are no guidelines or recommendations to obtain baseline endocrine labs once the diagnosis is confirmed, but it might be appropriate if there is a high clinical suspicion.

SAT-205 POEMS: A Medical Odyssey

Introduction: POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes) syndrome is a rare disorder with poorly understood pathogenesis. The incidence of endocrinopathy associated with POEMS syndrome has been recognized more frequently in the last two decades, ranging between 67-84%. The cause of endocrine dysfunction associated with the syndrome is not known, but has been described to include hypogonadism, hypothyroidism, abnormalities of glucose metabolism, hyperprolactinemia, gynecomastia in men, hyperestrogenemia, calcium abnormalities and adrenal insufficiency (AI).Case: A 38 y/o Hispanic male was initially referred to nephrology with complaint of leg swelling. Subsequently, the patient was referred to endocrinology for abnormal thyroid function studies and ongoing fatigue. Patient had prior medical history of recently diagnosed hypothyroidism treated with levothyroxine 100 mcg daily. The most bothersome complaint was pitting edema in the lower extremities with associated pain. He also endorsed right shoulder pain exacerbated by use of the right arm. He reported unintentional weight loss of about 30 pounds in the past 2-3 years, denying night sweats. He did endorse feeling fatigued, skin darkening, and erectile dysfunction. On exam patient was afebrile, BP 120/71 mm/Hg, HR 87 bpm, no goiter, no gynecomastia, skin hyperpigmentation, darkening creases of the palms, pitting edema in lower extremities. Work up showed abnormal lambda monoclonal bands in plasma and monoclonal lambda free light chain in urine. Bone survey showed lytic lesion in right scapula. [prolactin 15.6 ng/ml (normal (NL)= 0-25), free testosterone 23.1 pg/ml (NL= 35.0-155.0), total testosterone 205 ng/dl (NL= 250-1100), LH 8.2 MIU/ml (NL= 1.2-8.6), FSH 4.3 MIU/ml (NL=1.3-19.3), TSH 17.8 uIU/ml (NL= 0.45-5.33), free T4 0.62 ng/dl (NL= 0.58-1.64), free T3 3.05 pg/ml (NL=2.5-3.9), TPO antibody (AB) negative, IGF-1 41 ng/ml (NL=53-331), AM cortisol 8.2 ug/dl (NL=6.7-22.6), ACTH 99 pg/ml (NL=6-50), aldosterone 3 ng/dl (NL ≤28), renin activity 2.78 ng/ml/h (NL=0.25-5.82), 21-hydroxylase AB negative, 17-hydroxyprogesterone 54 ng/dl (NL=42-196), DHEA-S 88 mcg/dl (NL=106-464)]. ACTH stimulation test (250 mcg) was performed with basal cortisol 8.0 ug/dl (NL= 5.0- 21.0), basal ACTH 93 pg/ml (NL=6-50), 30min cortisol 9.7 ug/dl (NL=13.0-30.0), 60min cortisol 10.2 ug/dl (NL=14.0-36.0). Pt was diagnosed with primary AI and started on hydrocortisone. CT abdomen and pelvis with contrast showed normal adrenal glands.Discussion: Physicians should be cognizant of a unifying diagnosis in a syndrome of such a broad presentation. Endocrinopathies vary in extent of dysfunction and may fluctuate during the course of POEMS syndrome. Multidisciplinary management as well as regular reassessment of endocrine function is integral in managing this complex disease.

Mass Spectrometry–Based Method Targeting Ig Variable Regions for Assessment of Minimal Residual Disease in Multiple Myeloma

Multiple myeloma is a systemic malignancy of monoclonal plasma cells that accounts for 10% of hematologic cancers. With development of highly effective therapies for multiple myeloma, minimal residual disease (MRD) assessment has emerged as an important end point for management decisions. Currently, serologic assays lack the sensitivity for MRD assessment, and invasive bone marrow sampling with flow cytometry or molecular methods has emerged as the gold standard. We report a sensitive and robust targeted mass spectrometry proteomics method to detect MRD in serum, without the need of invasive, sequential bone marrow aspirates. The method detects Ig-derived clonotypic tryptic peptides predicted by sequencing the clonal plasma cell Ig genes. A heavy isotope-labeled Ig internal standard is added to patient serum at a known concentration, the Ig is enriched in a light chain type specific manner, and proteins are digested and analyzed by targeted mass spectrometry. Peptides from the constant regions of the λ or κ light chains, Ig heavy chains, and clonotypic peptides unique to thepatient monoclonal Igs are targeted. This technique is highly sensitive and specific for the patient-specific monoclonal Igs, even in samples negative by multiparametric flow cytometry. Our method can accurately and precisely detect monoclonal protein in serum of patients treated for myeloma and has broad implications for management of hematologic patients.

SUN-442 A CLINICAL ANALYSIS OF LIGHT-CHAIN AMYLOIDOSIS WITH RENAL

AL amyloidosis is a monoclonal plasma cells disorderwhich has a variety of symptoms. The common sites of involvementinclude kidney, liver, cardiac, peripheral neuropathy, musculoskeletal and skin. The kidney is involved in two-thirds of patients with AL amyloidosis. The disease manifests with albuminuria, evolving in nephrotic syndrome and progressing to renal failure eventually leading to end-stage renal disease if unrecognized or ineffectively treated. This was a retrospective study of patients with biopsy-proven renal amyloidosis over a period of ten years (2007–2016) at our hospital. A total of 31 cases of renal amyloidosis were diagnosed in the study period. Theimmunohistochemistry staining and immunofluorescencemicroscopy using specific antisera for AAand AL amyloid deposits were used to identify AL or AA type. AL amyloidosis was found in 29 % (9 cases) of all patients who underwent renal biopsy in a 10-year period. Biopsyindications for the patients during the initial diagnosis were proteinuria or renal dysfunction. The median age of patients was 59.67±9.01 years and 55.5% of patients were male. One patient(11%) with AL was younger than 40 years. All patients had different degrees of proteinuria, with amean level of 4.4 ± 3.9 g/24 h.Nephroticsyndrome was presented in 55% (5/9) ofpatients. The median of serum creatinine was 327μmol/L(range: 78–751 μmol/L). Eight (8/9, 88.8%) patientspresented with renal insufficiency at diagnosis, and only 3(33%) patients presented with serum creatinine level lowerthan 150 μmol/L. Five ( 55.5%) patients were found with overt anemia (hemoglobin lower than 100g/L) at diagnosis. Eight (88.8%) of the patients with echocardiographicexamination results had cardiac involvement. Hepatomegaly was detected in two (22.2%) patients. The involved light chain was lambda in over 70% patients. In AL amyloidosis, theprimary type was the most frequent (45%), followed bythe myeloma-associated type (33 %) and monoclonal gammapathy (22 %). During the follow-up period, 2 patients died, and one patient developed ESRD requiring dialysis therapy. Prevalence of AL amyloidosisnoted in our study was higher than previous Tunisian studies.

The Implications of B-lineage Cells in Kidney Allografts.

The majority of cells comprising the inflammatory infiltrates in kidney allografts undergoing acute and/or chronic rejection are typically T cells and monocyte/macrophages with B cells, plasma cells, and eosinophils accounting for <5%. In a significant minority of biopsies, B lineage cells (B cells and/or plasma cells) may be found more abundantly. Although plasma cell infiltrates tend to be more diffuse, B cells tend to aggregate into nodules that may mature into tertiary lymphoid organs. Given the ability to target B cells with anti-CD20 monoclonal antibodies and plasma cells with proteasome inhibitors and anti-CD38 monoclonal antibodies, it is increasingly important to determine the significance of such infiltrates. Both cell types are potential effectors of rejection, but both also have a tolerizing potential. B cell infiltrates have been associated with steroid resistance and reduced graft survival in some studies but not in others, and their presence should not prompt automatic depletional therapy. Plasma cell-rich infiltrates tend to occur later, may be associated with cell-mediated and/or antibody-mediated rejection, and portend an adverse outcome. Viral infection and malignancy must be ruled out. Randomized controlled trials are needed to determine the appropriateness of specific therapy when B cells and/or plasma cells are found. No strong therapeutic recommendations can be made at this time.

GLIPR1 expression is reduced in multiple myeloma but is not a tumour suppressor in mice.

Multiple myeloma, a plasma cell malignancy, is a genetically heterogeneous disease and the genetic factors that contribute to its development and progression remain to be fully elucidated. The tumour suppressor gene GLIPR1 has previously been shown to be deleted in approximately 10% of myeloma patients, to inhibit the development of plasma cell tumours in ageing mice and to have reduced expression levels in the plasma cells of patients with light-chain amyloidosis, a myeloma-related malignancy. Therefore, we hypothesised that GLIPR1 may have tumour suppressor activity in multiple myeloma. In this study, we demonstrate that plasma cell expression of GLIPR1 is reduced in the majority of myeloma patients and Glipr1 expression is lost in the 5TGM1 murine myeloma cell line. However, overexpression of GLIPR1 in a human myeloma cell line did not affect cell proliferation in vitro. Similarly, re-expression of Glipr1 in 5TGM1 cells did not significantly reduce their in vitro proliferation or in vivo growth in C57BL/KaLwRij mice. In addition, using CRISPR-Cas9 genome editing, we generated C57BL/Glipr1-/- mice and showed that loss of Glipr1 in vivo did not affect normal haematopoiesis or the development of monoclonal plasma cell expansions in these mice up to one year of age. Taken together, our results suggest that GLIPR1 is unlikely to be a potent tumour suppressor in multiple myeloma. However, it remains possible that the down-regulation of GLIPR1 may cooperate with other genetic lesions to promote the development of myeloma.

Identification of glutathione S-transferase π 1 as a prognostic proteomic biomarker for multiple myeloma using proteomic profiling.

Multiple myeloma (MM) is a B-cell hematological malignancy with monoclonal plasma cell proliferation in the bone marrow. Early diagnosis of MM remains difficult due to the lack of specific symptoms and biomarkers. In the present study, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and the ClinProt system was used to detect potential biomarkers for MM from the bone marrow samples of 30 patients and 30 healthy controls. A total of 10 of the most significantly differentiated peaks between the patients and controls were identified. When patients with MM were compared with controls, 6 peaks with m/z values of 1,779.24, 1,866.32, 2,022.36, 2,878.9, 4,417.76 and 7,155.38 were upregulated, and 4 peaks with m/z values of 1,466.54, 1,520.02, 1,546.53 and 2,991.05 were downregulated. Of these 10 peaks, 4 peaks (pk 8, 1,866.32 Da; pk 15, 2,878.90 Da; pk 17, 2,991.05 Da; and pk 3, 1,520.02 Da) were further sequenced and identified using liquid chromatography/electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). Furthermore, the expression of fibronectin 1 and glutathione S-transferase π 1 (GSTP1) were validated in patients with MM via ELISAs. Clinical data and statistical analysis indicated that GSTP1 expression was closely associated with the clinical stage of patients with MM. High GSTP1 levels were an independent risk factor for worse prognosis in patients with MM. These results demonstrate that GSTP1 may be a novel biomarker for early diagnosis, prognosis and monitoring of minimal residual disease in MM.

Association of Multiple Myeloma and Giant Cell Arteritis - A Case Report.

Autoimmune diseases (AID) have been associated with a variety of lymphoproliferative disorders. Multiple myeloma (MM), one of the most common haematologic malignancies characterized by clonal proliferation of bone marrow plasma cells, has been associated with a range of autoimmune disorders. In this report, we described a case study of a patient admitted to our Internal Medicine Department for a bone marrow biopsy and myelogram due to a monoclonal peak observed by his general practitioner. However, at admission he presented typical giant cell arteritis (GCA) complaints, suggesting the coexistence of both diseases. The possible pathogenesis, as found in the literature, explaining the association will be discussed.LEARNING POINTSA relationship between AID and lymphoproliferative diseases, although rare, may occur and some studies suggest that the diagnosis of autoimmune disease has a negative impact on survival in MM patients.Bone marrow plasmacytosis can present a diagnostic dilemma, since it may be due to neoplastic or non-neoplastic conditions (that is, reactive plasmacytosis associated with AID, chronic infection, metastatic carcinoma, liver diseases and acquired immunodeficiency).Immunophenotyping in a myelogram or immunohistochemistry in bone marrow studies are useful in confirming a monoclonal plasma cell proliferation.

Dual Monoclonal Antibody Therapy in Patients With Systemic AL Amyloidosis and Cardiac Involvement

BackgroundSystemic AL amyloidosis (AL) is a rare disease in which clonal immunoglobulin light chains produced by monoclonal plasma cells circulate and misfold, resulting in direct toxicity and fibrillar deposition of amyloid in numerous tissues. Early mortality from cardiac damage remains high. As depth of organ response carries a prognostic significance, combining anti-plasma cell and anti-amyloid therapies might hold the key to achieving long lasting responses. We report a series of patients who received 2 monoclonal antibodies, anti-CD38 and anti-amyloid, simultaneously. Materials and MethodsWe describe the characteristics and outcomes of 19 patients who received daratumumab (anti-CD38) on progression with front-line therapy for AL, 9 of whom were on concurrent dual monoclonal antibody treatment with daratumumab and NEOD001 (anti-amyloid), and also provide data on the schedule, safety, and tolerability of intravenous infusions of these monoclonal antibodies. ResultsThe 9 patients who received treatment with dual monoclonal antibodies achieved a high rate (100%) of hematologic response in a median of 33 days. There was no significant toxicity to dual monoclonal antibody therapy. Seven of the 8 met criteria for cardiac response, achieved in less than 3 months of combined therapy. Ten patients who received daratumumab alone also had high rates of hematologic and organ responses. ConclusionsMonoclonal antibodies with distinctly different targets can be safely combined in patients with AL and cardiac involvement. Patients experienced high rates of hematologic and cardiac response with combined anti-CD38 and anti-amyloid monoclonal antibody therapies. Further study of this combined approach is warranted.

Update on the Treatment of Heavily Pretreated, Relapsed Refractory Multiple Myeloma.

Multiple myeloma is the second most common hematologic malignancy in the United States, accounting for approximately 17% of all blood cancers. It is characterized by unchecked production of monoclonal plasma cells in the bone marrow, leading to high levels of dysfunctional (monoclonal) immunoglobulins in the blood and urine. According to recent estimates, more than 32,000 individuals will be diagnosed with multiple myeloma in the United States in 2020. Therapeutic advances over the last decade have led to prolonged survival, but the prognosis remains poor and the disease is incurable.

Chemotherapy-Induced Fulminant, Severe Hyperactive Delirium in A Patient with A New Diagnosed Multiple Myeloma

Multiple myeloma is an incurable haematological malignancy with complex pathogenesis, affecting mostly the elderly and characterized by the presence of monoclonal plasma cells within the bone marrow secreting an abnormal immunoglobulin, which results in gammapathy with organ or tissue injury. The chemotherapy used for the treatment of multiple myeloma causes various adverse effects, including serious psychiatric and cognitive problems, which pose a significant challenge to the clinician, present an impact on the quality of patient’s life and augment hospital stays and health care costs. We reported a clinical case of 73-year-old women with new diagnosed multiple myeloma developing severe, rapidly progressing and persisting hyperactive delirium with psychotic symptoms and mania-episodes during Velcade-Revlimid-Dexamethasone-based treatment. We discuss possible causes, clinical presentation, treatment and deficits maintained after recovery. Our report demonstrates the rare possibility of an association between chemotherapy and the development of combined psychiatric disorders.

Prognostic model for multiple myeloma progression integrating gene expression and clinical features.

BackgroundMultiple myeloma (MM) is a hematological cancer caused by abnormal accumulation of monoclonal plasma cells in bone marrow. With the increase in treatment options, risk-adapted therapy is becoming more and more important. Survival analysis is commonly applied to study progression or other events of interest and stratify the risk of patients.ResultsIn this study, we present the current state-of-the-art model for MM prognosis and the molecular biomarker set for stratification: the winning algorithm in the 2017 Multiple Myeloma DREAM Challenge, Sub-Challenge 3. Specifically, we built a non-parametric complete hazard ranking model to map the right-censored data into a linear space, where commonplace machine learning techniques, such as Gaussian process regression and random forests, can play their roles. Our model integrated both the gene expression profile and clinical features to predict the progression of MM. Compared with conventional models, such as Cox model and random survival forests, our model achieved higher accuracy in 3 within-cohort predictions. In addition, it showed robust predictive power in cross-cohort validations. Key molecular signatures related to MM progression were identified from our model, which may function as the core determinants of MM progression and provide important guidance for future research and clinical practice. Functional enrichment analysis and mammalian gene-gene interaction network revealed crucial biological processes and pathways involved in MM progression. The model is dockerized and publicly available at https://www.synapse.org/#!Synapse:syn11459638. Both data and reproducible code are included in the docker.ConclusionsWe present the current state-of-the-art prognostic model for MM integrating gene expression and clinical features validated in an independent test set.

Epidemiological and immunochemical parameters of monoclonal plasma cell dyscrasias of 2121 cases in Algeria

BackgroundPlasma cell dyscrasias (PCD) are a heterogeneous group of diseases characterized by the expansion of monoclonal bone marrow plasma cells that produce a monoclonal immunoglobulin (M-component). PurposeThis is a retrospective study that describes the epidemiological, immunochemical features and etiology of monoclonal gammopathies diagnosed between 1998 and 2016 in the Teaching Hospital Beni-Messous of Algiers. Patients and methods2121 cases of monoclonal gammopathies (MG) were collected during this period. Serum/urine protein electrophoresis, serum/urine immunofixation and serum free light chain measurements were used to demonstrate M protein. ResultsThe middle age of the patients at the time of the diagnosis were 62.96 ± 13.19 years with extremes ranging from 07 to 99 years. The study included 1013 (47, 76 %) men and 1108 (52, 23 %) women with a sex ratio 0,91.Isotypes repartition was: IgG (60.91 %), IgA (17.91 %), light chain (10.46 %), IgM (6.6 %), IgD (1.03 %) and IgE (0.09 %) of cases.The most frequent diagnosis was: Multiple Myeloma (55.20 %), followed by monoclonal gammopathy of undetermined significance (34.13 %). ConclusionIn our study, two particularities were noted. There is no male predominance in Algerian PCD patients. Moreover, we observed a higher frequency of light chain multiple myeloma and lower frequency of IgM isotype compared to western studies.

POEMS Syndrome - Rare Paraneoplastic Syndrome in a Young Female

POEMS syndrome is defined by the presence of peripheral neuropathy (P), organomegaly (O), endocrinopathy (E), a monoclonal plasma cell disorder (M) and skin changes (S). We report a case of POEMS syndrome in a 34-year-old female who presented with three month history of back pain, pain in lower limbs, weakness, numbness and edema in both lower limbs. Patient was unable to walk and bed ridden with worsening general condition, shortness of breath and fever for three days. Further clinical examinations (hyperpigmentation), systemic examination (hepato-splenomegaly), laboratory investigation (hypothyroidism), CT showed sclerosis in sacral bone and left acetabular lytic lesion, which on biopsy and immunohistochemistry showed plasma cell dyscrasia and confirmed by increased plasma cells in bone marrow biopsy and presence of M band in immunofixation study. Here we describe, in detail, an unusual clinical presentation of this rare paraneoplastic syndrome with multisystemic involvement which needs multidisciplinary approach with strong clinico-pathological &amp; radiological correlation to diagnose this rare entity.&#x0D; J MEDICINE JAN 2020; 21 (1) : 55-58

A Deptor Inhibitor Induces Its Degradation with Resulting Anti-Myeloma Cytotoxicity in Vitro and In Vivo

Multiple myeloma (MM) is a hematological disorder characterized by a proliferation of malignant monoclonal plasma cells in the bone marrow (BM) and / or in extramedullary sites. Despite recent progress in OS rates, MM remains an incurable disease and most patients will relapse and require treatment. Deptor is a component of mTOR complexes and a constitutive inhibitor of their activities. It is known that the inhibition of Deptor results in the inhibition of the proliferation and induction of apoptosis in MM cells. In addition, high levels of Deptor are predictive of a poor response to conventional therapies, indicating that Deptor expression are important as a prognostic marker for patients with myeloma and is a possible therapeutic target. Our group previously identified a drug which prevents mTOR-Deptor binding (NSC126405) and induces cellular cytotoxicity in MM (Shi Y, et al 2016). In this study, we developed a new related chemical inhibitor (43 M) capable of inducing the inhibition of the mTOR / Deptor interaction and results in the negative regulation of Deptor that leads to the inhibition of proliferation and induces apoptosis in several MM cell lines. The cytotoxic effect of 43 M is not dependent of caspase activation and induces the activation of p70 and AKT (T308). This leads to the induction of apoptosis in MM cell lines and tumor cells derived from MM patients. The degradation of Deptor induced by 43 M is dependent on the proteasome complex since it was prevented in the presence of MG132. In vivo, 43 M prevents the expression of Deptor in a xenograft tumor, and delayed tumor growth and interestingly, induces the eradication of tumors in 40% of mice in a murine model of MM, without significant toxic implications. Recent studies show that Deptor expression protects MM cells against Bortezomib treatment, suggesting that anti-Deptor drugs can synergize with proteasome inhibitors (PIs). However, the combination of 43 M + Bortezomib was not synergistic, and was antagonistic in vitro. These results are probably due to the prevention of the proteasomal degradation of Deptor, suggesting a possible use of the 43 M inhibitor in MM in the absence of the current PIs. This study describes for the first time the possible role of Deptor as a therapeutic target using a chemical inhibitor capable of degrading and inducing a cytotoxic effect in MM cell lines. In addition, Deptor is reported as an important therapeutic target in an in vivo MM model. Shi Y, Daniels-Wells TR, Frost P, Lee J, Finn RS, Bardeleben C, Penichet ML, Jung ME, Gera J, Lichtenstein A. Cytotoxic Properties of a DEPTOR-mTOR Inhibitor in Multiple Myeloma Cells. Cancer Res. 2016 Oct 1;76(19):5822-5831 Disclosures No relevant conflicts of interest to declare.

Treatment of Primary Plasma Cell Leukemia with Carfilzomib and Lenalidomide-Based Therapy: Results of the First Interim Analysis of the Phase 2 EMN12/HOVON129 Study

Treatment of Primary Plasma Cell Leukemia with Carfilzomib and Lenalidomide-Based Therapy: Results of the First Interim Analysis of the Phase 2 EMN12/HOVON129 Study

POEMS Syndrome: A Review of Our Patient Population

Introduction The "POEMS" Syndrome, defined by its hallmark features of polyneuropathy, organomagaly, endocrinopathy, monoclonal plasma cell proliferative disorder, and skin changes has long been an enigma in terms of diagnosis and treatment. In recent years, clinicians and researchers have attempted to clarify diagnostic criteria. It is known that "VEGF," vascular endothelial growth factor, plays a large role in the pathophysiology of this disease.1Most recently, Angela Dispenzieri proposed a set of diagnostic criteria, which were published in the American Journal of Hematology.2We applied this suggested diagnostic criteria retrospectively to patients in our institution who carried a diagnosis of POEMS Syndrome. Additionally, we recorded the VEGF of these patients and their outcomes. Methods The.medical record was queried for patients with POEMS diagnosed in the last 5 years. A total of 16 patients met criteria. The primary outcome was to determine the percentage of patients who met the criteria proposed by Dispenzieri. A secondary outcome was to determine, in those patients who did not meet the criteria, the reason that they were not met. Another secondary outcome was to determine the percentage of patients who were alive or deceased. The criteria proposed by Dispenzieri (Table 1) were applied to each patient to assess whether they were met. If the diagnostic criteria were not met, the reason as to why they were not was recorded. Each patient outcome of "alive," "deceased," or "unknown" was recorded. Results Of the 16 patients analyzed, 14 (88%) had enough information to be included. Of these 14 patients, nine (64%) met the criteria proposed by Dispenzieri. Of the five patients that did not meet the criteria, four (80%) did not meet them due to the lack of a presence of a major criteria. One patient of the five (20%) that did not meet the criteria did not have the mandatory finding of polyneuropathy. VEGF levels ranged from 26-9504pg/mL, with an average of 1190pg/mL. The range for the patients who met the diagnostic criteria proposed by Dispenzieri was 1755pg/mL. Of our total patient population analyzed, 10 out of 14 patients (72%) were alive at time of retrospective review, including six out of nine (66%) that met the diagnostic criteria. Two out of 14 patients (14%) were found on review to be deceased, including one out of the nine (11%) that met the diagnostic criteria. Two out of 14 patients (14%) were determined to be "unknown" if alive or deceased, both of whom met the diagnostic criteria. Discussion Patients with POEMS syndrome often experience a delay in diagnosis due to the rarity of the disease as well as a lack of high index of suspicion for the condition in many cases. Additionally, POEMS syndrome is often mislabeled as another neuropathic condition. Efforts have been made to establish a standard criteria for diagnosis. We applied the criteria proposed by Dispenzieri this year in the American Journal of Hematology. In our retrospective study, we found that that 64% of our patients who carried a diagnosis of POEMS syndrome met the criteria for POEMS diagnosis using these proposed criteria. We found that the most common reason for not meeting the criteria in our patient population was the lack of a major criterion. Major criteria (Table 1) include Castleman Disease, sclerotic bone lesions and VEGF elevation, one of which must be met to receive a diagnosis of POEMS syndrome. Additionally, one of our patients did not meet the criteria due to the lack of the mandatory finding of polyneuropathy. The average VEGF levels in our patients were 1190pg/mL, but were higher at 1755pg/mL in the cohort who met the diagnostic criteria. 72% of our total patients were alive at time of review, including 66% of the patients who met the diagnostic criteria. We conclude that the criteria proposed by Dispenzieri provide a concise guideline to identify patients with POEMS syndrome. These criteria are simple to apply, and would potentially help to increase the index of suspicion and earlier diagnosis of patients with POEMS syndrome. This would be expected to lead to earlier initiation of therapy. Additionally, this analysis supports previous studies that show that VEGF levels are correlated with disease activity and that overall prognosis for patients with POEMS syndrome is favorable. Disclosures No relevant conflicts of interest to declare.

High Level of CCL3 in the Bone Marrow Microenvironment Promotes Anemia By Suppressing the Erythropoiesis Differentiation of Hematopoietic Stem Cells in Myeloma

Background and aims: Multiple myeloma (MM) is a hematologic malignancy characterized by monoclonal plasma cells infiltrating the bone marrow. Anemia is the most common symptom and notably characteristic of myeloma patient. The mechanism of anemia of chronic disease (ACD) is impaired underlies that of MM-related anemia. However, the mechanisms underlying myeloma related anemia have not been fully elucidated. Clarify the pathogenesis of myeloma related anemia and identify the key molecular foundation will be helpful to develop the target treatment and reverse the inferior outcome of those patients. Methods: The correlation of tumor burden and the level of HGB was analyzed in the cohort of 776 newly diagnosed myeloma patients. The number and the differentiation activity of HSPCs under the MM microenvironment were analyzed using both primary myeloma patient samples and NSG myeloma mouse model. The HSPC of bone marrow was isolated by the sorting of CD34 positive cells. Colony- Forming Cell (CFC) assay was performed to identify the differentiation activity of HSPC derived from myeloma patient and healthy donor. Furthermore, 5TGM1 myeloma mouse model was utilized to verify the effects of myeloma cells on the differentiation activity of HSPCs during MM progression in vivo. Results: Our clinical analysis showed that more than 80% (620/776) myeloma patients had anemia (HGB&lt; 120g/L) and more than 60% patients had moderate or severe anemia (HGB&lt; 90g/L) at newly diagnosis . The degree of anemia was positively correlated with the tumor burden of CD138+ cells and also highly positive correlated with bone lesions in myeloma patients (p&lt;0.001). Moreover, the higher level of CD138+ cells was significantly negative correlated with the number of CD34+ HSPCs in the bone marrow (r=-0.526, p=0.0082). The flow cytometry data indicated that the percentage of HSPCs population in NDMM patients was significantly lower than that of normal controls (P&lt;0.001). We did not find the decrease of HSC (Lin-CD34+CD38-) in MM bone marrow compared with healthy control. However, the population of HPC (Lin-CD34+CD38+) significantly decreased (P&lt;0.001). The proportion of megakaryocyte-erythrocyte progenitors (MEP) was notably decreased (p&lt;0.0001) in MM patient samples. On the contrary, the proportion of granulocyte-macrophage progenitors (GMP) was increased in MM patients compared to healthy donors (p&lt;0.01). These data suggested that the myeloma bone marrow microenvironment suppressed the CD34+ HPSC proliferation and differentiation to MEP which may contribute the myeloma related anemia. 5TGM1 mouse model of myeloma was used to verify these clinic findings. The number of HSCs (LKS+) and HPCs (LKS-) during MM cell progression was monitored at different time point by flow cytometry after 5TGM1 MM cells injection. The results indicated clearly that the HSCs (LKS+) and HPCs (LKS-) were suppressed in the myeloma bone marrow microenvironment. Similar to MM patient, the proportion of MEP was the most significantly suppressed population among all of the hematopoietic subsets in this MM mouse model. CFC assays indicated that the BFU-E colony formation of CD34+ cells from MM patients was significantly suppressed (p&lt;0.01). RNA sequencing analysis indicated that the transcription factor in erythropoiesis differentiation, GATA1 and KLF1, was obviously decreased in myeloma CD34+ cells compared with that in healthy donor. Further investigated showed that high level of CCL3 in the bone marrow microenvironment suppressed the differentiation of erythropoiesis which played a pivotal role in myeloma related anemia. Administration of the CCL3 receptor (CCR1) antagonist partially recovered the yield of erythroid colonies in the presence of myeloma plasma. Conclusion: Bone marrow microenvironment of multiple myeloma suppresses the erythropoiesis differentiation of hematopoietic stem cells and promotes the myeloma associated anemia. High level of CCL3 may down regulate GATA1 and KLF1 and be one of the important reasons for myeloma-related anemia. Disclosures No relevant conflicts of interest to declare.

Diagnosis and Treatment of Cardiac Amyloidosis Related to Plasma Cell Dyscrasias.

Light chain amyloidosis is a deadly disease in which a monoclonal plasma cell dyscrasia produces misfolded immunoglobulin light chains (AL) that aggregate and form rigid amyloid fibrils. The amyloid deposits infiltrate one or more organs, leading to injury and severe dysfunction. The degree of cardiac involvement is a major driver of morbidity and mortality. Early diagnosis and treatment are crucial to prevent irreversible end-organ damage and improve overall survival. Treatment of AL cardiac amyloidosis involves eliminating the underlying plasma cell dyscrasia with chemotherapy and pursuing supportive heart failure management.