Monoclonal Plasma Cell Proliferative Disorder Research Articles

The Journey to Diagnosis of Light Chain Amyloidosis: A Real-World Experience from a Single Center in Latin America

Light chain (AL) amyloidosis is a form of systemic amyloidosis, causing organ dysfunction; mainly affecting heart and kidneys. Due to the non-specific clinical manifestations, diagnosis is challenging and patients experience a long journey and treatment delay. Consequently, AL amyloidosis patients have extensive organ involvement at the time of diagnosis which implies a poor prognosis. Early diagnosis of AL amyloidosis is of paramount importance. There is limited real-world data from Latin America regarding the time from initial patient reported symptom onset to diagnosis. This retrospective cohort study aimed to assess clinical and laboratory characteristics, diagnostic journey, and outcomes of patients with AL amyloidosis treated in a medical care program in Argentina. AL amyloidosis patients were identified using a 12-year follow-up data (January 1, 2010 to December 31, 2022) from the institutional registry of amyloidosis (IRA).The IRA is registered in ClinicalTrials.gov (NCT01347047) and is approved by the IRB (CEPI 1635). Diagnosis of AL amyloidosis was confirmed by tissue biopsy staining positive with Congo red in addition to the demonstration of a monoclonal plasma cell proliferative disorder and the presence of amyloid-related systemic syndrome.The symptoms and signs related to amyloidosis were selected based on previously reported data in the literature. The number of medical consultations and health care resource utilization was collected from electronic medical records of patients in the medical care program. fThe statistical analyses were performed with Stata version 13.0. The continuous variables were presented as mean and standard deviation (SD) or median and interquartile range (IQR), and the categorical variables were presented as absolute frequencies and percentages. The survival rate was estimated by Kaplan-Meier. From 181807 community patients included in the comprehensive health care program, 28 patients were diagnosed with AL amyloidosis and included in the study. The median age at diagnosis was 73 (IQR, 66.5-80.5) years old and 64% (n=18) were female (Table 1).Heart and kidney were the most frequently affected organs. The median time from the first sign and/or symptom related to AL amyloidosis to diagnosis was 15.9 months (IQR, 8.8-38.2). Only 4 patients (14%) were diagnosed within the first six months since the onset of symptoms. Prior to diagnosis, the median number of symptoms and/or signs presented by the patients was 4 (IQR, 3.5-7). The median number of medical consultations prior to diagnosis was 3 (IQR, 1-5). The most consulted medical specialties were internal medicine (n=24, 86%), cardiology (n=14, 50%) and nephrology (n=10, 36%). Twelve patients (43%) were hospitalized at least once before diagnosis and 4 (14%) were hospitalized at least 3 times. Ten (36%) patients were diagnosed during a hospitalization. Involvement of more than three organs was present in 25% (n=7) of the patients. Fifty-seven percent (n=16) had cardiac involvement, mostly in advanced stages. Out of 23 patients that underwent treatment, 22 patients were treated with bortezomib based regimens in first line; 3 in combination with anti CD38. The median overall survival was 21 months (IQR, 4.6-49.8). The one-year overall survival rate after diagnosis was 55% (95% CI 34-71). The one-year overall survival rate for patients diagnosed within the first 12 months from the onset of symptoms was 70% (95% CI 32-89), while for those diagnosed after 12 months from the onset of symptoms, it was 45% (95% CI 20-67). This study provides real-world evidence about the diagnostic journey of AL amyloidosis patients in Latin America. AL amyloidosis is a complex disease with diverse manifestations, leading to diagnostic challenges even with growing awareness among the medical community. Patients often underwent a diagnostic odyssey involving multiple specialists and hospitalizations before the definitive diagnosis is reached.

Socioeconomic factors associated with a late-stage multiple myeloma diagnosis: An analysis of the National Cancer Database.

e20036 Background: Multiple myeloma is an aggressive monoclonal plasma cell proliferative disorder that is the second most common hematologic malignancy. On a global scale, multiple myeloma led to an estimated 106,000 deaths in 2018 alone. The exact cause of multiple myeloma is not well understood. Later stage of diagnosis is correlated with worse outcomes; thus, it is critical to assess the socioeconomic factors associated with diagnosis at early versus late stages. Methods: Using the National Cancer Database, we aimed to identify associations between socioeconomic factors of patients that present with Revised International Staging System (R-ISS) stage I multiple myeloma in comparison to R-ISS stage III at diagnosis. In this study, 5,512 patients from the National Cancer Database who were diagnosed with R-ISS stage I and stage III multiple myeloma were analyzed based on age, ethnicity, race, education, insurance type, income, education, geographic location, facility type, sex, Charlson-Deyo score, and urban or rural setting. Demographic factors of patients that presented with stage I and stage III disease were analyzed using chi square, ANOVA, and multivariate analyses. All patients included in the study were diagnosed with multiple myeloma between 2004 and 2020. Results: We identified significant (P < 0.05) associations between insurance type, median income, education, rural setting, and Charlson-Deyo score with diagnosis of R-ISS stage III multiple myeloma. For insurance type, private insurance, other government insurance, and Medicaid had lower percentages of R-ISS stage III diagnosis than patients without insurance (P < 0.001). Medicaid and over government insurance were up to 70% less likely to present with stage III MM than patients without insurance (P < 0.001). Regarding income and education, patients from a zip-code associated with an income of < $38,000 and zip-codes with lower levels of high school diploma had higher rates of stage III multiple myeloma diagnosis (P < 0.001). Patients from completely rural or less than 2,500 urban population adjacent to a metro area (P < 0.005) and not adjacent to a metro area (P < 0.025) showed significant increase in later stage multiple myeloma diagnosis than those from a metro setting with population above one million. Patients with Stage III at presentation were older than patients with stage I on average (P < 0.001). There were no significant differences seen based on race, sex, ethnicity, or region in the United States. Conclusions: Factors associated with increased likelihood of later stages of diagnosis of multiple myeloma include insurance type, median income, education, and rural location. Future analysis should further investigate the specific barriers to early patient diagnosis and treatment due to insurance type, education level, and rural setting.

Systemic AL amyloidosis: current approach and future direction

Systemic Light chain (AL) amyloidosis is a monoclonal plasma cell proliferative disorder characterized by deposition of amyloidogenic monoclonal light chain fragments causing organ dysfunction. It is a fatal disease and if not diagnosed and treated early can lead to organ failure and potentially death. The renal system along with the cardiovascular system are the most common organs involved but other organs such as gut and liver can be involved as well. The initial evaluation of patients requires confirming the diagnosis with tissue biopsy and staining with Congo red followed by confirmatory typing with mass spectrometry of the Congo red positive tissue. Then establishing the extent of the organs involvement by various staging and biomarkers testing. The treatment options and the tolerability of therapy depend on the disease staging, frailty, and co-morbidities. The autologous hematopoietic cell transplantation (HCT) after high dose melphalan therapy is an effective strategy which is usually done after initial bortezomib induction therapy. Unfortunately, most systemic AL amyloidosis patients are not candidate for HCT due to frailty, old age, multi-organ involvement, renal and heart failure at the time of diagnosis. While it is widely accepted that the patients need to be treated until they achieve complete hematologic response, the maintenance therapy after HCT is not well established in AL amyloidosis. In this review, we report the literature on the latest treatment updates of AL amyloidosis and the ongoing clinical trials highlighting the future treatments.

POEMS syndrome associated with vitiligo (P13-8.007)

<h3>Objective:</h3> To report a case of POEMS syndrome with vitiligo. This is the second case to be reported and the first in an Afro-American patient. <h3>Background:</h3> POEMS syndrome is a rare plasma-cell disorder with multisystem involvement, characterized by the acronym composing its name: Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein (M-protein), and Skin changes. Major criteria include mandatory polyneuropathy and monoclonal plasma cell proliferative disorder in addition to Castleman’s disease, sclerotic bone lesions, or elevated vascular endothelial growth factor (VEGF). Minor criteria, still helpful for diagnosis, include organomegaly, endocrinopathy, papilledema, thrombosis, and skin changes, the most common being hyperpigmentation. <h3>Design/Methods:</h3> Case Presentation <h3>Results:</h3> A 50-year-old Afro-American male presented with 3 years of ascending stocking-glove pattern numbness and skin discoloration in his feet. Other positive history included anhidrosis, heat intolerance and erectile dysfunction suggestive of dysautonomia. Medical history included hypoparathyroidism and idiopathic cirrhosis. He did not have history of alcohol overuse, diabetes, or glucose intolerance. Examination revealed confluent hypopigmented macules in feet, vibratory sensation impairments up to knees, absent temperature sensation in feet, and abnormal Romberg test and tandem gait. Remainder of the neurological examination was normal. Laboratory tests were significant for elevated free kappa and lambda light chains, plasma VEGF levels twice over normal range, and an IgA monoclonal band on serum protein electrophoresis. Other relevant laboratory findings included PTH-independent hypercalcemia and alkaline phosphatase elevation. Radiographs of hands, elbows, shoulders, and knees disclosed non-sclerotic lytic lesions. Nerve conduction studies were consistent with a sensorimotor axonal polyneuropathy. The patient met diagnostic criteria for POEMS syndrome. Autologous stem cell transplantation was recommended but the patient declined. His vitiligo, neuropathy, and monoclonal gammopathy remain stable under surveillance at 4 years without pharmacotherapy. <h3>Conclusions:</h3> POEMS syndrome should be suspected in any patient with new onset of vitiligo in the presence of an underlying polyneuropathy and a monoclonal plasma cell proliferative disorder. <b>Disclosure:</b> Dr. Landman has nothing to disclose. Dr. Escobar-Montealegre has nothing to disclose. Dr. Singh has nothing to disclose. Dr. Morales has nothing to disclose. Dr. Rossi has nothing to disclose.

A Case of POEMS Syndrome Previously Diagnosed with Extramedullary Plasmacytoma

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) syndrome is a rare multisystem disorder associated with osteosclerotic myeloma. It is characterized by peripheral polyneuropathy, presence of monoclonal plasma cell proliferative disorder, and one or more of the following features – sclerotic bone lesions, Castleman disease, elevated levels of vascular endothelial growth factor, organomegaly, extravascular volume overload, endocrinopathy, skin changes, papilledema, and thrombocytosis. Extramedullary plasmacytoma (EMP) is a rare plasma cell neoplasm that arises in isolated tissues without bone marrow involvement or systemic characteristics of multiple myeloma. Herein, we report a male patient who was previously diagnosed with EMP and later developed POEMS.

POEMS SYNDROME WITH CASTLEMAN DISEASE - AN UNUSUAL PRESENTATION

Chronic Inflammatory Demyelinating Polyneuropathy(CIDP) is an acquired immune mediated disorder presenting as symmetric proximal and distal sensory motor polyneuropathy. It is treatable with immunosuppressant. CIDP may be associated with HIV-1 infection, SLE, para neoplastic disorders and Paraproteinemias. Paraproteinemias is abnormal monoclonal antibody or light chain in blood secondary to plasma cell disorder like multiple myeloma, Waldenstrom macroglobulinemia, monoclonal gammopathy of undetermined significance (MUGS), POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, monoclonal plasma cell proliferative disorder and Skin Changes) syndrome and Castleman disease with or without POEMS syndrome. These account for approximately 10% of CIDP. Diagnosing Paraproteinemic neuropathy is necessary to prevent delay in diagnosis, start appropriate treatment and estimate prognosis of the condition. POEMS syndrome is due to clonal proliferation of plasma cells. Castleman disease (CD), also known as angiofollicular or giant lymph node hyperplasia, is a rare non-neoplastic lymphoproliferative disorder . We present a Case report of relatively young male with right parotid swelling with chronic sensorimotor quadriparesis with wasting, with no predominant neuropathic pain and cranial nerve involvement. On Nerve Conduction Studies it was found to have severe sensori-motor neuropathy which was not associated with pain, an unlikely feature of either CIDP or Castleman disease; on further evaluation was found to have POEMS syndrome. Thus high index of suspicion is necessary to diagnose this condition. This case report emphasizes the fact that patients with Castleman disease-POEMS Syndrome may present at younger age than usual with short duration of illness, with severe sensorimotor neuropathy which may not be associated with pain. High index of suspicion and appropriate investigations may lead to early diagnosis and prompt treatment.

Extranodal diffuse gastrointestinal mucosal involvement in castleman variant of poems syndrome, presenting as chronic diarrhea

<br>POEMS syndrome is a rare paraneoplastic condition associated with polyneuropathy, organomegaly, monoclonal gammopathy, and endocrine and skin changes. It is a fatal disease and associated with compromised quality of life through volume overload, neuropathy, thromboembolic events, and weight loss. A diagnosis of POEMS syndrome is made with three of the major criteria, two of which must include polyneuropathy and monoclonal plasma cell proliferative disorder and at least one minor criterion Gastrointestinal (GI) involvement with initial predominant presentation as chronic diarrhea is extremely rare and rarely reported in the literature. Here, we highlight a case of Castleman disease variant of POEMS syndrome with predominant GI involvement and discuss plausible pathogenesis mechanism in relevance to the available literature.<br>

Clinical and Pathological Characteristics of Related-Renal Damage in Patients with POEMS Syndrome

To investigated the clinical and pathological characteristics of related-renal damage in patients with POEMS syndrome. Five patients diagnosed as POEMS syndrome in our hospital were selected. Their clinical manifestation, pathological characteristics of kidney and laboratory examination were analyzed retrospectively. Among the 5 patients, three males and two females with a median age of 50 years old. The mean interval before diagnosis was 13.0±7.2 months. All the patients showed neuropathy, endocrinopathy, monoclonal plasma cell-proliferative disorder, skin changes and extravascular volume overload, in which 4 patients showed organomegaly. Proteinuria was found in 5 patients, and microhematuria was found in 4 patients. Moreover, 4 patients showed an elevated blood urea, while 2 patients showed creatinine elevation. 1 patient at chronic kidney disease (CKD)-G1 stage, 2 patients at CKD-G2 stage, and 1 patient at CKD-G3b stage, moreover, 1 patient at CKD-G5 stage. Endothelial injury and mesangial lesion were the main characteristics of renal pathology. 3 patients were pathologically diagnosed as thrombotic microangiopathy kidney damage, while 2 patients as light chain amyloidosis. POEMS syndrome is a multi-systemic disease with complex clinical manifestations. 5 patients had different degrees of renal insufficiency. Endothelial injury and mesangial lesion are the main features of renal pathology.

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.

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.

Clinical heterogeneity and diagnostic challenges in poems syndrome and variant: A case series from Southeast Asia

POEMS syndrome is a rare paraneoplastic disorder associated with an underlying plasma cell dyscrasia presenting with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes. Diagnosis can be challenging especially among those with atypical presentation. The diagnosis of POEMS was based on published criteria. We reviewed the clinical, laboratory and imaging characteristics of 4 patients in Kuala Lumpur Hospital from year 2012-2018. Clinical spectrum and disease variant were determined. Three had POEMS syndrome and 1 had Castleman disease variant. Mean age of onset was 40 (SD 11.5), with male predominant (75%). All had refractory chronic demyelinating polyneuropathy to standard CIDP treatment as common presentation. Paraprotein IgA lambda from monoclonal plasma cell-proliferative disorder were found in 2 patients. Sclerotic bone lesion (100%) was the most common major criteria fulfilled. Organomegaly (75%) was the most common minor criteria fulfilled, followed by extravascular volume overload (oedema, 50%, pleural effusion 25%), papilledema (25%), thrombocytosis (25%) and acrocyanosis (25%). Finger clubbing was seen in 50% of the patients. The only surviving patient with Castleman variant had improvement of neuropathy following IV rituximab and was in remission following autologous bone marrow transplant. Rapidly progressive disease was observed in one patient, with clinical deterioration to completely bedbound within a year. In conclusion, POEMS syndrome is a rare disorder and should be suspected in atypical cases of CIDP particularly when there is treatment resistance. Extensive investigation is often needed to meet diagnostic criteria for POEMS and rapid referral to haematology team for definite treatment is warranted.

Proposal of new clinical diagnostic criteria for POEMS syndrome

ObjectiveTo propose the optimal diagnostic criteria for polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome using appropriate statistical methods and disease controls.MethodsThis retrospective cohort study included 104 consecutive patients...

TAFRO syndrome with refractory thrombocytopenia responding to tocilizumab and romiplostim: a case report.

Thrombocytopenia, anasarca, fever, reticulin fibrosis, organomegaly (TAFRO) syndrome is a unique clinicopathologic subtype of multicentric Castleman's disease that has recently been identified in Japan. However, little is known about its renal histological changes and the optimal treatment for TAFRO syndrome. An 80-year-old Japanese woman was admitted to our hospital for evaluation of severe anasarca and weight gain (10kg in a month). She had polyneuropathy, monoclonal plasma cell proliferative disorder with positive kappa M-protein, a sclerotic bone lesion, elevation of vascular endothelial growth factor (VEGF), skin changes, and extravascular volume overload, which fulfilled the diagnostic criteria for POEMS (polyneuropathy, organomegaly, endocrinopathy, and monoclonal protein, skin changes) syndrome. However, kappa-type M-protein and thrombocytopenia with positivity of platelet-associated immunoglobulin G antibody were unusual, and fitted the diagnostic criteria for TAFRO syndrome. Renal biopsy showed diffuse endocapillary proliferative glomerulonephritis with endothelial swelling and the infiltration of monocytes and neutrophils without specific immunoglobulin deposits. Her systemic symptoms were refractory to initial treatment with high-dose melphalan and glucocorticoids. Alternative therapy with an anti-interleukin-6 (IL-6) receptor antibody (tocilizumab) effectively controlled the symptoms, while a thrombopoietin receptor agonist (romiplostim) was effective for her thrombocytopenia. Results suggest that IL-6-VEGF axis and an autoimmune mechanism may be responsible for TAFRO syndrome with clinical features of POEMS and refractory thrombocytopenia, which can be successfully treated with combination of tocilizumab and romiplostim.

1025P - Independent predictors of one year mortality in patients with primary systemic immunoglobulin light chain cardiac amyloidosis

Background: Immunoglobulin light chain amyloidosis (AL amyloidosis) is a monoclonal plasma cell proliferative disorder that is characterized by tissue deposits of misfolded insoluble κ and λ light chain derived amyloid fibrils, leading to organ dysfunction. The prognosis of patients depends on the number and severity of organ involvement, especially cardiac involvement. Nearly half of the patients with amyloidosis die within a year of diagnosis. We analysed factors predicting early mortality (within one year) in patients with systemic immunoglobulin light chain cardiac amyloidosis. Methods: Retrospective analysis of patients between January 2007 and January 2016 from our hospital database. In patients with AL cardiac amyloidosis, cardiac involvement was defined as per American society of echocardiography (ASE) criteria. We evaluated the clinical, ECG and ECHO parameters of early relapse (ER) within one year in these cardiac AL amyloidosis patients. Log rank test was done to identify independent predictors of one year all cause mortality. Results: Among the 72 patients (mean age 58.2 + 8.2 years, 59.7% males) of AL amyloidosis with cardiac involvement, 32 (44.4%) died within one year. Sixty five patients (90%) received melphalan/thalidomide/bortezomib/cyclophosphamide/dexamethasone based chemotherapy as a monotherapy or in combinations. Logistic regression analysis revealed NYHA Class III/IV (p = 0.024), BNP (p = 0.031), Troponin I (p = 0.042), Free light chain difference (p = 0.011) and restrictive pattern of diastolic dysfunction (E/E1 > 20) to be independent predictors of all cause mortality (p = 0.021). Kaplan Meir survival analysis showed a worse prognosis in patients with E/E1 > 20 (Log rank, p < 0.001). In addition, in patients who completed atleast 6 months of chemotherapy, a decrease in E/E 1 (survivors delta E/E1 5.2+ 0.8, nonsurvivors 0.8+ 0.3, p = 0.001) is associated with better one year survival. Conclusions: AL Cardiac amyloidosis carries a poor outcome. Baseline Troponin I, NYHA class III/IV, difference in free light chain, restrictive pattern of diastolic dysfunction and BNP were the independent predictors of early mortality within 1 year in patients with AL cardiac amyloidosis. In patients who completed atleast 6 months of chemotherapy, a decrease in the ECHO parameter E/E1 is associated with better one year survival. This will help us in better prognostication of patients with AL cardiac amyloidosis. Legal entity responsible for the study: Amrita institute of medical sciences Funding: None Disclosure: All authors have declared no conflicts of interest.

Predictors of Early Relapse Following Initial Therapy for Systemic Immunoglobulin Light Chain Amyloidosis

IntroductionImmunoglobulin light chain amyloidosis (AL Amyloidosis) is a monoclonal plasma cell proliferative disorder that is characterized by tissue deposits of misfolded insoluble κ or λ light chain derived amyloid fibrils, leading to organ dysfunction. The prognosis of patients depends on the number and severity of organ involvement, especially cardiac involvement. Autologous stem cell transplant (ASCT), if eligible, alkylator (melphalan) and novel drugs like proteasome inhibitors (PI) and immunomodulators (IMiD) have improved the overall survival (OS) during the past decades. But still, nearly half of the patients die within a year of diagnosis. We analyzed the factors predicting early relapse / progression or death (within 12 months) after first line therapy for systemic AL amyloidosis.MethodsClinical and laboratory data of all consecutive patients with systemic AL amyloidosis seen at Mayo Clinic within 90 days of their diagnosis, between 2006 and 2015, was collected by chart review and analyzed retrospectively. Patients who died within 3 months of starting the first line treatment were excluded from analysis. Early relapse (ER) was defined as relapse / progression requiring treatment change / re-institution or death within 12 months of starting first line treatment. Patients in the cohort with ER were compared with patients with a follow up of more than 12 months who had a relapse / progression beyond 12 months or had continuing response at the time of analysis. Categorical variables were analyzed using chi - square and Fisher's exact test and continuous variables using Kruskal- Wallis test and Wilcoxon rank sum test. Multivariate analysis was done using logistic regression model.ResultsSeven hundred and eighty six patients with newly diagnosed systemic AL amyloidosis met the study criteria and were included in the analysis. Among these, 230 (29.3%) patients had ER within 12 months of starting initial therapy while 556 (70.7%) patients either relapsed after 1 year or had continuing response at the time of analysis. Baseline demographics, organ involvement and type of first line therapy are presented in Table1.The median estimated follow up for the entire cohort from start of initial therapy was 62.9 months (95% CI; 59.9, 67.3). The variables included in the univariate and multivariate analyses for factors predicting ER were age at diagnosis (≤ vs > 70 years ), revised mayo stage (I and II vs III and IV), bone marrow plasma cell percentage (BMPC; ≤ 10% vs > 10%), presence of any chromosomal abnormalities, trisomies or IgH translocations by fluorescence in situ hybridization (FISH), multiorgan involvement [(>1 vs 1) (heart, liver, kidney, gastrointestinal tract, autonomic neuropathy), incorporation of ASCT in initial therapy.In univariate analysis, mayo stage (p<0.0001), multiorgan involvement (p=0.0008) and inclusion of ASCT as part of initial therapy (p<0.0001) were significantly associated with ER, while age (p=0.06), BMPC(p=0.9), FISH abnormalities (p=0.2) were not. However, in multivariate analysis, only mayo stage (III + IV vs I + II; p=0.01) and non-inclusion of ASCT in first line treatment (p=0.0001) were significantly predictive of ER.ConclusionsDespite the introduction of ASCT and novel drugs, the early mortality in systemic AL amyloidosis remains high. This study demonstrates that patients with ER are older with higher prevalence of cardiac involvement and multiorgan involvement and higher Mayo stage (III and IV). Incorporation of ASCT as part of the initial therapy was associated with reduced early relapse, but it is difficult to separate the influence of the eligibility for ASCT from the effect of ASCT itself. This will help us in characterizing these patients to better understand their mechanisms of resistance to therapy and gives an insight to the type of initial therapy that benefits them. [Display omitted] DisclosuresDispenzieri:GSK: Membership on an entity's Board of Directors or advisory committees; Jannsen: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Research Funding; pfizer: Research Funding. Kapoor:Takeda: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Kesios: Consultancy; BMS: Consultancy; Sanofi: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Glycomimetics: Consultancy; Millennium: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; AbbVie: Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding.

Durable responses with autologous hematopoietic SCT in patients with POEMS syndrome

Durable responses with autologous hematopoietic SCT in patients with POEMS syndrome

Treatment for POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome.

POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome is a rare cause of demyelinating and axonal mixed neuropathy with monoclonal plasma cell proliferative disorder and multiorgan involvement. The pathogenesis of POEMS syndrome is not well understood, but overproduction of vascular endothelial growth factor (VEGF), probably secreted by plasmacytomas, is likely to be responsible for most of the characteristic symptoms. POEMS syndrome is a potentially fatal disease, and patients' quality of life deteriorates because of progressive neuropathy, massive pleural effusion or ascites, or thromboembolic events. There is a need for efficacious therapy to improve prognosis. This is the first update of a review first published in 2008. To assess the effects of treatment for POEMS syndrome. We searched the Cochrane Neuromuscular Disease Group Specialized Register (23 February 2012), CENTRAL (2012, Issue 2), MEDLINE (January 1966 to February 2012), EMBASE (January 1980 to February 2012) and CINAHL Plus (January 1937 to February 2012) for all papers on POEMS syndrome We sought all randomized and quasi-randomized controlled trials, and non-randomized controlled studies. Since we discovered no such clinical trials, we assessed and summarized all retrospective case series including five or more patients in the 'Discussion' section. Two review authors independently reviewed and extracted details of all potentially relevant trials with any treatment for POEMS syndrome. We then collated and summarized information on the outcome. We found no randomized or non-randomized prospective controlled trials of treatment for POEMS syndrome. We summarized the results of retrospective case series containing five or more patients in the 'Discussion' section. There are no randomized or quasi-randomized controlled clinical trials of treatment for POEMS syndrome on which to base practice.

Involvement of the central nervous system myelin in a POEMS patient

POEMS (polyneuropathy, organomegaly, endocrinopathy, Mrotein and skin changes) syndrome is a rare cause of mixed emyelinating and axonal neuropathy with multi-organ involveent and a monoclonal plasma cell proliferative disorder [1]. ther important traits of the syndrome are sclerotic bone lesions, astleman disease, papilledema, peripheral edema, ascites, effuions, thrombocytosis, polycythemia, clubbing and increased level f the plasmacytomas-secreted vascular endothelial growth factor VEGF) [1]. The pathogenesis is not well understood but a role for VEGF has een suggested [2]. POEMS syndrome is a potentially fatal disease and patients’ uality of life deteriorates because of progressive neuropathy,masive pleural effusion, ascites or thromboembolic events. Cerebral vasculitis, multiple vascular abnormalities, hyperrophic cranial pachymeningitis, bilateral internal carotid rtery occlusion, amyloidosis, diffuse white matter edema and apilledema have been associated with POEMS syndrome [3–8]. n one case, cranial magnetic resonance imaging disclosed diffuse

Changes in Serum Free Light Chain Rather Than Intact Monoclonal Immunoglobulin Levels Predict Outcome with Therapy in Patients with Light Chain Amyloidosis.

Abstract 747 Background:Light chain amyloidosis is a monoclonal plasma cell proliferative disorder characterized by multiorgan deposition of monoclonal light chain derived amyloid fibrils. The diffuse organ infiltration by the amyloid fibrils leads to various AL related clinical features. Therapy of AL has been primarily aimed at elimination or control of the monoclonal plasma cells, thus decreasing the light chain available for amyloid formation. Assessment of response to therapy has been grouped into hematological response demonstrating elimination or reduction of the monoclonal population and organ response demonstrating actual improvement in its structure or function. Given the potentially long delay in observing organ improvement, hematological response has been the surrogate short term marker for long term outcome given the relatively rapid decline seen in the monoclonal protein with effective therapy, as well as studies showing improved long term outcome with a hematological response, especially complete response. However, conventional hematological response criteria give priority to the intact monoclonal protein rather than the light chain, which is the amyloidogenic protein. We hypothesized that a light chain response will correlate better with outcome than changes in the intact monoclonal protein levels. Methods:We identified 348 patients who had undergone stem cell transplant (SCT) for AL from among a large group of patients undergoing different treatments for AL, and in whom serial tests results were available. We identified the lowest value attained following SCT for various hematological response parameters (intact serum M-protein [MP], the difference between involved and uninvolved serum free light chain [FLC-diff], and urine M-protein [UP]) before an alternate therapy was instituted. We first estimated the best cutoff for the degree of change in each parameter that predicted 5-year survival from SCT. Cox proportional hazards model was used for multivariable analysis of factors influencing overall survival (OS). Results:We first examined the relative contribution of the MP and the FLC-diff on the overall survival following transplant. The best cutoff for reduction in FLC-diff to predict OS at 5 years from SCT was 88% if all patients were considered and 90% if only those with a baseline FLC diff > 7.5 mg/dL were considered. The best cutoff for MP reduction was 40% for 5 year survival for all patients and 67% for those with a baseline MP > 1.0 gm/dL. We then looked at the impact of FLC reduction and MP reduction in a multivariable analysis using OS as endpoint. For all patients, FLC reduction, but not MP reduction significantly impacted outcome, and results were similar when considering patients with MP>1.0 gm/dl and FLC-diff > 7.5 mg/dl at baseline. Among those with a baseline FLC-diff >7.5 mg/dL (n=125), the overall survival was 35 mos from SCT for those with less than 90% decrease in FLC-diff (45 pts) compared to not reached for those with at least 90% decrease (80 pts); P < 0.001 (Figure). Conclusions:The current study supports the notion that reductions in the free light chain parameters represent a more useful measure of hematological response that translates into better overall survival and possible better chance at organ improvement. A reduction in the FLC difference of 90% appears to correlate best with prolonged survival. [Display omitted] Disclosures:Kumar:CELGENE: Research Funding; MILLENNIUM: Research Funding; BAYER: Research Funding; GENZYME: Research Funding; NOVARTIS: Research Funding. Gertz:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lacy:celgene: Research Funding.

Primary cutaneous diffuse large B-cell lymphoma, leg type, with features simulating POEMS syndrome

A 91-year-old woman presented with a rapidly proliferative cutaneous lesion on the left lower limb, which was identified as a primary cutaneous diffuse large B-cell lymphoma (PCLBCL), leg type, on biopsy. The patient also showed complications of hepatomegaly, endocrinopathy, edema, skin change, and polyneuropathy without monoclonal plasma cell proliferative disorder, and was therefore diagnosed with POEMS-like syndrome owing to the lack of monoclonal plasma cell proliferative disorder. Levels of serum vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) were high with the lymphoma cells immunostained positively for VEGF and IL-6. To the best of our knowledge, this is the first case report of PCLBCL, leg type, with POEMS-like syndrome. The findings in this case suggest that the symptoms of POEMS-like syndrome might be caused by the cytokines produced by the lymphoma cells. Furthermore, a wider range of diagnostic criteria associated with the result of abnormal secretion of cytokine may have to be considered for the diagnosis and evaluation of patients with possible POEMS syndrome, as against the present criteria specifying monoclonal plasma cell proliferative disorder as the essential criterion.