Plasma Cell Proliferative Disorder Research Articles

Relapse of primary hyperparathyroidism concurrent with a plasma cell proliferative disorder: report of a case

Relapse of primary hyperparathyroidism concurrent with a plasma cell proliferative disorder: report of a case

A novel biomarker score for the screening and management of patients with plasma cell proliferative disorders.

Monoclonal plasma cell proliferative disorders comprise a wide spectrum of diseases associated to clonal B-cell expansion. Serum protein electrophoretic profile (SPEP) and circulating free light chains (FLCs) levels are the mainstay of diseases management. Recently, soluble (s) Syndecan-1 (SDC1, CD138) produced by myeloma plasma cells has been suggested in the monitoring and follow-up of patients with myeloma. The aim of our study is to evaluate sCD138 in addition with FLCs and SPEP for the screening of patients with different evolutive disease pathways. Sera from 73 patients with monoclonal gammopathy of undetermined significance (MGUS), 120 smoldering and 42 multiple myeloma (SMM and MM, respectively), 70 HCV-related mixed cryoglobulinemia (MC), 35 B-cell non-Hodgkin's lymphoma (B-NHL) and sera from 50 healthy donors (HD), were tested for sCD138, FLCs (assessed by means of ELISA and turbidimetric assay, respectively) and electrophoresis pattern (performed on Capillarys system) for the generation of a novel biomarker score (BS). Our results were grouped according to the two main lines of disease progression (vs. MM or B-NHL): in one group we found BS mean values of 0.2, 3.4, 5.3, 7.1 for HD, MGUS, SMM and MM, respectively; in the other group of 0.2, 4.4, 6.7 for HD, MC and B-NHL. We showed that BS mean values follow the ingravescence disease status towards the two main lines of progression to cancerous conditions; it could represent an additional useful tool in the management of screening and/or follow-up.

Comparison of two serum free light chain assays for the diagnosis of primary plasma cell malignant proliferative disease.

Background and aimsThe serum free light chain assay (sFLC) is well established for aiding in the diagnosis, prognosis, and monitoring of plasma cell proliferative disorders. There are currently two commercially available sFLC immunoassays, Freelite, based on polyclonal antibody technology, and N Latex FLC, based on monoclonal antibodies. This study aimed to compare the analytical and clinical performance of these two assays in a Chinese population.MethodsThis study included 74 consecutive patients who were newly diagnosed with monoclonal gammopathies (MGs) including multiple myeloma (MM), AL amyloidosis, and light chain deposition disease (LCDD) between January 2014 and May 2015 at the First Affiliated Hospital of Zhejiang University. Alongside serum and urine electrophoresis analysis, the serum samples were retrospectively tested with both sFLC assays according to the manufacturers' instructions.ResultsThe two sFLC assays showed a moderate correlation for κFLC (Passing‐Bablok slope = 0.645, coefficient of determination (R 2) = 0.83, and Spearman coefficient = 0.904). However, for λFLC, a poor correlation was found (Passing‐Bablok slope = 0.690, R 2 = 0.39, and Spearman coefficient = 0.852). The concordance rate of κFLC, λFLC, and κ/λ FLC ratio were 83.78%, 75.68%, and 86.49%, respectively. The clinical sensitivity of the κ/λ ratios were 83.8% for the Freelite assay and 75.7% for the N Latex FLC assay.ConclusionAlthough the concordance and the clinical sensitivity of the two assays appeared comparable, a number of discrepancies were observed. There is a low correlation between the two assays in clinical practice, suggesting that the assays are not equivalent and, thus, current IMWG guidelines, based on Freelite, cannot be cross‐applied to N Latex FLC.

POEMS syndrome: clinical update

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) is a rare paraneoplastic syndrome, caused by a plasma cell proliferative disorder, which is most commonly lambda restricted. The neurological hallmark, which forms one of the mandatory criteria for diagnosis, is a subacute onset demyelinating neuropathy, which can be rapidly disabling and painful. A number of multi-system features are also characteristic of this disorder, and certainly not restricted to those included in its acronym, which though limited, remains a useful and memorable name, helping distinguish POEMS syndrome from other paraproteinaemic neuropathies. The discovery of vascular endothelial growth factor (VEGF) in association with POEMS syndrome has been extremely useful in aiding clinical diagnosis, and monitoring response to treatment, as well as helping understand the underlying mechanism of disease. Interestingly, however, treatment targeting VEGF has been disappointing, suggesting other disease mechanisms or inflammatory processes are also important. Current understanding of the pathogenesis of POEMS syndrome is outlined in detail in the accompanying article by Cerri et al. Here, we review the clinical features of POEMS syndrome, differential diagnosis and available treatment options, based on current literature.

The Critical Role of HDAC1-IRF4-Pim-2 Axis in Myeloma Cell Growth and Survival: Therapeutic Impacts of Targeting the HDAC1-IRF4-Pim-2 Axis

Multiple myeloma (MM) is a heterogeneous clonal plasma cell proliferative disorder with CRAB features. Although survival of MM patients has been greatly prolonged by recent implementation of various combinatory treatments with novel anti-MM agents, MM still remains incurable. MM cells preferentially grow and expand in the bone marrow to elicit the alteration of gene expression and thereby drug resistance. To improve the therapeutic efficacy, we urgently need to develop novel treatment strategies targeting the BM microenvironment-mediated drug resistance. The serine/threonine kinase Pim-2 is constitutively over-expressed and acts as a pro-survival mediator in MM cells. We have reported that cocultures with bone marrow stromal cells (BMSCs) or osteoclasts (OCs) further up-regulate Pim-2 expression in MM cells to confer drug resistance (Leukemia 2011, 2015). Therefore, Pim-2 appears to be an important therapeutic target to impair the BM microenvironment-mediated drug resistance in MM.Histone deacetylases (HDACs) are generally accepted to be therapeutic targets for MM treatment. However, clinical application of currently available pan-HDAC inhibitors is limited with their adverse effects induced by a non-selective HDAC inhibition. To develop safe and effective HDAC inhibitor-based treatment, the therapeutic roles of HDAC isoform-specific inhibition should be elucidated. In this regard, we have recently reported therapeutic impacts on MM cells of inhibition of class-I HDACs, especially HDAC1 and HDAC3. HDAC3-selective inhibitor BG45 induces anti-MM activity in combination with DNA methyltransferase (DNMT) inhibitor azacytidine (Leukemia 2017). In the present study, we aimed to clarify the underlying mechanisms for impairment of MM cell growth and survival by HDAC1 inhibition.We first referenced the expression of class-I HDACs using a publicly available GSE6691 data set. Among class-I HDACs, HDAC1 and HDAC3 were highly expressed in MM cells. We then knockdowned HDAC1 gene using lentiviral shRNA system in MM cell lines. The HDAC1 gene silencing induced MM cell death with caspase-3 activation, indicating the critical role of HDAC1 in MM cell growth and survival. To determine target molecules of HDAC1, we carried out RNA-sequencing with and without the HDAC1 gene silencing in RPMI 8226 cells. Among genes whose expression significantly changed by the HDAC1 knockdown (adjusted P values < 0.05, log fold change > 0.5), we focused on IRF4 together with PIM2, because MM cell has been demonstrated to addict to aberrant IRF4-c-Myc regulatory network (Nature 2008). Downregulation of IRF4 and Pim-2 by the HDAC1 knockdown was further confirmed by quantitative PCR (Q-PCR) and immunoblotting in RPMI 8226 and MM.1S cells. Treatment with the class I HDAC-selective inhibitor MS-275 (entinostat) also induced MM cell death along with reduction of IRF4 and Pim-2 expression.Since previous study has shown that IRF4 binds to PIM2 promoter in MM cells (Nature 2008), we examined whether IRF4 regulates PIM2 expression. We found that IRF4 binds to the PIM2 promoter region by analyzing ChIP-Seq data in KMS-12 cells (GSE22901). We further confirmed the binding of IRF4 on PIM2 promoter by ChIP-Q-PCR. Indeed, the IRF4 knockdown downregulated Pim-2 expression in RPMI 8226 cells. These results suggest that HDAC1 inhibition downregulates IRF4 expression, thereby transcriptionally reducing PIM2 expression in MM cells.Pim-2 expression can also be augmented by multiple signaling pathways, including HIF-1a, JAK-STAT and NF-kB-mediated ones in MM cells through the interaction with BM microenvironment. Interestingly, the Pim inhibitor SMI-16a and MS-275 cooperatively induced apoptotic cell death in MM cell lines and CD138-positive primary MM cells even in the presence of BMSCs.Taken together, our results demonstrate the critical role of the HDAC1-IRF4-Pim-2 axis in MM cell growth and survival, and provoke the novel treatment strategy targeting the HDAC1-IRF4-Pim-2 axis in MM cells. DisclosuresAnderson:Takeda Millennium: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Oncopep: Equity Ownership; C4 Therapeutics: Equity Ownership; Celgene: Consultancy; Bristol Myers Squibb: Consultancy.

Exosomes Play a Key Role in Multiple Myeloma Bone Disease and Tumor Development

Multiple Myeloma (MM) is an often incurable plasma cell proliferative disorder, representing about 10% of all hematologic malignancies. Osteolysis is one of the hallmarks of this malignancy, meaning that almost every patient will manifest with an osteolytic lesion during their disease course, resulting in increased morbidity and pain with ultimately a severe impact on the quality of life.The development and progression of MM is largely dependent on the bone marrow (BM) microenvironment wherein communication through different factors including extracellular vesicles (EVs) takes place. This crosstalk not only leads to drug resistance but also to the development of osteolysis. Targeting vesicle secretion could therefore simultaneously ameliorate drug response and bone disease.Here we examined the effects of MM exosomes on different aspects of osteolysis using the 5TGM1 murine model. This syngeneic murine model highly mimics human MM disease and presents with typical MM characteristics such as osteolysis, angiogenesis and a serum M-spike.We first investigated the effects of 5TGM1 small EVs or exosomes, sized 50-120nm in diameter, on osteoclasts and osteoblasts in vitro. 5TGM1 exosomes were able to enhance the resorptive active of osteoclasts. In contrast, these exosomes induced apoptosis in pre-osteoblasts while also blocking their differentiation to mature osteoblasts. RT-PCR showed a downregulation of Runx2, Osterix and Collagen 1A1 expression, while DKK-1 expression was upregulated. Mechanistically, we confirmed the presence of DKK-1 on the 5TGM1 exosomes, which led to a downregulation of the Wnt pathway in osteoblasts.In vivo, we uncovered that 5TGM1 exosomes could induce osteolysis in a similar pattern as the MM cells themselves. We injected C57BL/KalwRij intravenously during three weeks with 5TGM1 exosomes, and analyzed the femurs by micro-computed tomography. These mice had a significantly lower trabecular bone volume, as the result of a lower trabecular number combined with a higher trabecular separation.Next, we inhibited exosome secretion in 5TGM1-inoculated mice to prevent bone loss and increase sensitivity to bortezomib. For blocking exosome secretion we used the neutral sphingomyelinase inhibitor GW4869. This increased cortical bone volume and decreased bone resorption markers (C-terminal telopeptide of collagen type I) without significantly affecting tumor load. This indicates that inhibiting exosome secretion in the MM microenvironment has a protective effect on myeloma bone disease, not associated with effects on tumor load. Furthermore, blocking exosome secretion by GW4869 also sensitized the myeloma cells to bortezomib, leading to a strong anti-tumor response in vivo when GW4869 and bortezomib were combined.Altogether, our results indicate a key role for exosomes in the myeloma BM microenvironment and suggest a novel therapeutic target for anti-myeloma therapy. DisclosuresNo relevant conflicts of interest to declare.

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...

Myeloma light chain cast nephropathy, a review.

Multiple Myeloma is a plasma cell proliferative disorder that commonly involves the kidney. Renal impairment is a serious complication during the course of the disease that is associated with increased morbidity and mortality. Light chain cast nephropathy is the predominant pattern of renal injury in Multiple Myeloma. This review article focuses on the pathophysiology and diagnostic approach of myeloma cast nephropathy. The management of precipitating factors as well as anti-plasma cell treatment modalities in the context of renal impairment are also discussed.

Smoldering multiple myeloma: prevalence and current evidence guiding treatment decisions.

Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell proliferative disorder associated with risk of progression to symptomatic multiple myeloma (MM) or amyloidosis. In comparison to monoclonal gammopathy of undetermined significance (MGUS), SMM has a much higher risk of progression to MM. Thanks to advances in our understanding of the risk factors, the subset of patients with ultra-high risk of progression to MM (80%–90% at 2 years) has been identified. The revision of the diagnostic criteria resulted in changes in the management of this cohort of patients. In contrast to the management guidelines for MGUS patients, SMM patients need to be studied more intensively in order to identify biomarkers necessary for accurate risk stratification. In this review, we focus on the risk of progression from SMM to MM, as well as the influence of early treatment on overall survival, time to progression and quality of life.

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.

Multiple myeloma

Multiple myeloma is a malignancy of terminally differentiated plasma cells, and patients typically present with bone marrow infiltration of clonal plasma cells and monoclonal protein in the serum and/or urine. The diagnosis of multiple myeloma is made when clear end-organ damage attributable to the plasma cell proliferative disorder or when findings that suggest a high likelihood of their development are present. Distinguishing symptomatic multiple myeloma that requires treatment from the precursor stages of monoclonal gammopathy of undetermined significance and smouldering multiple myeloma is important, as observation is the standard for those conditions. Much progress has been made over the past decade in the understanding of disease biology and individualized treatment approaches. Several new classes of drugs, such as proteasome inhibitors and immunomodulatory drugs, have joined the traditional armamentarium (corticosteroids, alkylating agents and anthracyclines) and, along with high-dose therapy and autologous haemopoietic stem cell transplantation, have led to deeper and durable clinical responses. Indeed, an increasing proportion of patients are achieving lasting remissions, raising the possibility of cure for this disease. Success will probably depend on using combinations of effective agents and treating patients in the early stages of disease, such as patients with smouldering multiple myeloma.

IgMk paraprotein from gammopathy patient can bind to cardiolipin and interfere with coagulation assay: a case report

BackgroundThe monoclonal gammopathies are a group of plasma-cell proliferative disorders characterized by the secretion of monoclonal immunoglobulin (M protein or paraprotein). Some rare cases have revealed the specific affinity of paraprotein as autoantibody. Here we report a patient with monoclonal gammopathy of undetermined significance (MGUS) accompanied by a remarkable increase of anticardiolipin antibody (aCL) and an extensively decreased coagulation factor activity, however, without any clinical signs of antiphospholipid syndrome (APS) and bleeding.ResultsOur further investigation indicated that IgMκ paraprotein of this patient possessed an antibody activity against phospholipids so as to bind to cardiolipin and interfere with coagulation assay in vitro.ConclusionsThis case might be indicative that an abnormality of coagulation tests, disturbed by IgMκ paraprotein, does not predict a risk of bleeding in this patient.

Role of Flow Cytometry in Plasma Cell Proliferative Disorders

Role of Flow Cytometry in Plasma Cell Proliferative Disorders

Immunophenotyping Patterns of Plasma cells in Plasma Cell Proliferative Disorders

Immunophenotyping Patterns of Plasma cells in Plasma Cell Proliferative Disorders

Association between abnormal serum free light chains ratio and known prognostic factors in lymphoma; a nephrology viewpoint.

Introduction: The serum immunoglobulin free light chain (FLC) assay quantities of free kappa (κ) and lambda (λ) light chains. This assay has prognostic value in plasma cell proliferative disorders. There are limited data on serum FLC in B-cell malignancies. Objectives: The aim of this study was to compare the known prognostic factors in non-Hodgkin’s lymphoma of the type B-cell and Hodgkin disease with an abnormal secretion amount of light chains in these lymphomas. Patients and Methods: The association of pretreatment FLC and FLC ratio (κ:λ) with previously known prognostic factors for lymphoma such as the international prognostic index (IPI) and B symptoms were evaluated in 50 patients with Hodgkin’s and non-Hodgkin’s lymphoma. IPI is a prognostic score given based on the clinical variables including age, disease stage, serum LDH and extra-nodal involvement. Elevated FLC and an abnormal κ:λ ratio was defined based on the previous publications. Results: The prevalence of abnormal FLC ratio was 38% in all patients and 40.9% in patients with diffuse large B-cell lymphoma. Abnormal FLC ratio was significantly associated with IPI (P=0.04) and B symptoms (P=0.02) in both groups of the patients with Hodgkin’s and non-Hodgkin’s lymphoma. The stage of the disease in Hodgkin’s lymphoma patients showed a significant relationship with the abnormal FLC ratio (P=0.04). Presence of the B symptoms in patients with Hodgkin’s lymphoma had a modest but not statistically significant association with the abnormal FLC ratio (P=0.07). Conclusion: Abnormal FLC ratio as a new potent prognostic biomarker has a significant association with IPI which is the most common clinical tool used to predict outcome in lymphoma patients. Since there is a need for developing a reliable and quantitative prognostic biomarker for lymphoma, evaluation of the independent effect of the abnormal serum FLC ratio is suggested to be considered in future prospective studies. The result of these studies will also be useful for nephrologists, while serum immunoglobulin FLC is capable to damage kidney.

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.

Immunoparesis in newly diagnosed AL amyloidosis is a marker for response and survival.

Immunoparesis is an adverse prognostic marker in plasma cell proliferative disorders. Its impact in AL amyloidosis has not been explored in depth. Newly diagnosed AL amyloidosis patients (n=998) were evaluated for immunoparesis by two methods. The first method was qualitative, considering the number of suppressed uninvolved immunoglobulins below the lower limit of normal (LLN) (none, partial, all). The second method was quantitative, assessing the average relative difference (ARD) of the uninvolved immunoglobulins from the LLN. Patients with suppression of all the uninvolved immunoglobulins were less likely to achieve very good partial response (VGPR) or better to first-line treatment (44%) compared with patients with partial suppression (68%) or preserved uninvolved immunoglobulins (64%; P<0.0001). In addition, patients with suppression of all the uninvolved immunoglobulins had a shorter survival compared with the respective comparators (median 18 vs 54 vs 52 months; P<0.0001). In the quantitative method, patients with a negative ARD were less likely to achieve VGPR or better (48%) and had a shorter survival (median 24 months) compared with patients with a positive ARD (69%, 57 months, respectively; P<0.0001). In a multivariate analysis for survival, both assessment methods retained an independent impact. Significant immunoparesis has a negative impact on response and survival in newly diagnosed AL amyloidosis.

Quantification of β region IgA paraproteins - should we include immunochemical "heavy/light chain" measurements? Counterpoint.

Serum protein electrophoresis (SPE), serum immunofixation (s-IFE), free light chain measurement (FLC) and nephelometric measurements of total immunoglobulin in serum (IgTot) are some of the laboratory tests required for the management of plasma cell proliferative disorders. The monoclonal protein is usually visible on SPE as a spike (M-spike) in the γ region and the derived densitogram is used to quantify it relative to serum total protein concentration. IgA M-protein, however, often migrates in the β region on SPE and its quantification can be masked by other serum proteins that migrate in this region. The immunoassay Hevylite™ (heavy/light chain, HLC) seems to solve this problem: it quantifies the involved/uninvolved isotype, calculating the ratio IgAκ/IgAλ, considered indicative of clonal proliferation. However, this test seems redundant in the case of artifacts on SPE such as obvious hemolysis or lipemia, or if the IgA M-spike is clearly visible in the β region. In conclusion whereas the IgA HLC assay does not represent an alternative to SPE and s-IFE in the diagnostic patient workup, it may prove to be an alternative to SPE, s-IFE and total IgA quantification in risk stratification and evaluation of response to therapy in patients affected by MM and other monoclonal plasma proliferative disorders.

Uninvolved Immunoglobulins Predicting Hematological Response in Newly Diagnosed AL Amyloidosis

Introduction: Immunoparesis serves as a marker for progression in plasma cell proliferative disorders. However, the impact of immunoparesis in AL amyloidosis has not been addressed yet. Additionally, immunoparesis can vary from mild suppression to a major decrease in the uninvolved Immunoglobulins, but this has not been carefully studied.Methods: Immunoparesis was defined qualitatively as any decrease below the low reference levels of the uninvolved immunoglobulins and quantitatively, as the relative difference between the uninvolved immunoglobulins and the lower reference levels' values.Results: Forty-one newly diagnosed AL amyloidosis patients were included. The median age was 67.2 years (range, 46-87). At the time of treatment initiation, 14 patients (34%) had preservation of the uninvolved Ig's while 27 patients (66%) had suppression of the uninvolved Ig's. Patients with any degree of immunoparesis had higher percentage of marrow plasma cells compared to patients with preserved levels of the uninvolved Ig's (median 25% vs. 15%, P=0.02). Regarding quantitative assessment of immunoparesis, the median relative difference of the uninvolved immunoglobulins was 18% above the lower reference levels [range (-71%)-210%]. Ninety percent of patients were treated with novel agents-based regimens, mostly bortezomib-containing regimens. Nineteen percent of patients did not attain response to first line treatment. There was no difference in the overall response rate between patients with preserved levels of the uninvolved Ig's compared to patients with immunoparesis [odds ratio (OR) for partial response and better vs. no response - 4.55 (95% CI 0.5-41.4), P=0.22]. However, patients with a relative difference of the uninvolved Ig's below -25% from the lower reference levels were less likely to respond to first line treatment compared to patients with a relative difference of -25% and above [OR for no response vs. PR and better 30 (95% CI 4.1-222.2), P=0.0004]. Patients who failed first line treatment were successfully salvaged with lenalidomide-based treatment. Median follow-up was 13 months (range, 1-86). Median Progression-free survival (PFS) and overall survival were 14 and 42.5 months, respectively. PFS differed between those with a relative difference of the uninvolved Ig's below -25% compared to those with a relative difference of -25% and above (6.7 vs. 26.8 months), without statistical significance (P=0.17). There was no significant difference in overall survival between the sub-groups.Conclusions: This study suggests a correlation between the depth of immunoparesis and hematological response to bortezomib-containing regimens in newly diagnosed AL amyloidosis patients. Furthermore, its results imply a favorable response to lenalidomide in AL amyloidosis patients with significant immunoparesis. DisclosuresRaanani:Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Ariad: Consultancy, Research Funding; BMS: Consultancy.