Serum Monoclonal Protein Level Research Articles

Focal Plasmacytoid and Fibrotic Hepatic Lesion In An Autopsy Examination Of A Patient With Multiple Myeloma

Abstract Introduction/Objective Multiple Myeloma (MM) is a plasma cell neoplasm mainly affecting the bone marrow. Common sites of extramedullary dissemination are skin, liver, kidneys, and the central nervous system. Though diffuse plasma cell infiltration of the liver has been described in autopsy literature in about 50% of patients with multiple myeloma, it is usually not associated with focal infiltration. Rare cases of plasma cell infiltration leading to non-obstructive cholestasis and acute hepatic failure have been described. Methods/Case Report We hereby present a case of 54-year-old decedent male with past medical history of obesity, hypertension, and diabetes mellitus who presented to the emergency department with complains of productive cough, dyspnea, vomiting and back discomfort. Labs showed leukocytosis, thrombocytopenia and hypercalcemia. Additionally, there was an increase in lactate and serum monoclonal protein levels and derangements in renal and liver function tests. Skeletal bone survey showed a 1.4 cm well-circumscribed lucent lesion within the distal third of the left clavicle and in the calvarium which raised concern for multiple myeloma and tumor lysis syndrome. During the hospital course, the patient’s overall clinical condition declined rapidly, and he passed away on the third day of admission. During the autopsy examination, the patient’s bone marrow revealed diffuse infiltration of plasma cells confirming multiple myeloma. In addition, the histopathological examination of the liver revealed focal plasmacytoid fibrosis, moderate periportal inflammation with plasma cell infiltration and microsteatosis. Immunohistochemical stains with CD138, MUM-1, ISH kappa and lambda and trichrome highlighted the focal plasma cell infiltration and fibrosis in the liver, respectively. Results (if a Case Study enter NA) NA Conclusion Our case shows the importance of utilizing histopathological and immunohistochemical examination in confirming the diagnosis of multiple myeloma, specifically in the autopsy cases where there is no previous diagnosis of multiple myeloma. In addition, it highlights the awareness of rare focal plasmacytoid fibrosis and infiltration as an extramedullary presentation of multiple myeloma.

Utilizing a Machine Learning Approach to Define Racial Difference in Multi-Systemic Impact of Monoclonal Protein in Patient with Multiple Myeloma

Multiple myeloma (MM) is the second common hematologic malignancy characterized by the clonal proliferation of plasma cells. While the clinical outcomes of MM have been improved significantly, there remains an intriguing observation regarding the potential influence of race on disease biology and treatment response. In MM, the malignant plasma cell clone not only disrupts the local bone marrow microenvironment but also exerts a systemic impact on various physiological processes result in significant derangements in immune function, hematopoiesis, renal function, bone metabolism, and electrolyte homeostasis. Understanding the extent of this systemic impact and its potential variation between racial groups is crucial for optimizing patient care and treatment strategies. Here, we hypothesized that the systemic impact of the plasma cell clone does not differ significantly between African American and Caucasian patients. We employed a machine learning approach to capture the full spectrum of systemic effects comprehensively. Our novel model was trained to predict the magnitude of the plasma cell clone, as represented by serum monoclonal protein levels. By systematically comparing model performance with and without the inclusion of race as a variable, we sought to evaluate the potential influence of race on the systemic impact of the plasma cell clone. Method: A total of 171 patients with plasma cell dyscrasias including 1,472 observations were analyzed. where the upper limit of the observed M-spike was 3.5 gr/dL. Forty three clinical and lab variables as predictors of M-spike were fed into the machine learning model. Two lagged variables as the last two preceding M-spike values by the same subject were included. The random forest model was used, where regression forests are an ensemble of different regression trees and are used for nonlinear multiple regression. The goal of using a large number of trees was to train enough that each feature had a chance to appear in several models. The data was randomly split into a training set (80%) and a test set (20%), and a regression tree was built with the training set and then validated using the test set. Bootstrapping was used to generate a collection of data sets (n=500). Importance was measured by leaving a covariate out of models and comparing performance with its inclusion. Result: The training set used to develop the ML algorithm comprised 749 patient-based observations, which represented ~50% of the patient-based observations. The number of observations at each M-Spike value and the distribution of M-Spike values measured by SPEP are shown (Fig. 1). The residual distribution of the RF model indicated that nearly all M-spike values determined using the 43 variables distributed equally on either side of zero. The addition of race as variables did not significantly change the residual plots. The weighted value of each of the 43 independent variables was determined by individually removing a variable from the ML algorithm and measuring its effect on the mean squared error (MSE). As shown, removal of the first lagged M-spike, serum total protein, second-lagged M-spike, serum IgG, serum IgM, and serum IgA, had the greatest effects on the ML algorithm. The effect of race was then added to the ML algorithm. However, patient race had a low weighted value compared to the other variables included in the ML algorithm (Fig-2). M-spike values determined using the ML algorithm correlated highly with M-spike values determined using the laboratory measured SPEP values as indicated by the proximity of the Pearson and Spearman correlation coefficients to +1 . Using the 43 independent variables, the Pearson coefficient was 0.96 and the Spearman coefficient was 0.91, when M-spike values determined using the ML algorithm were compared to laboratory determined M-spike values. When race was added as a variable in the ML algorithm, the Pearson coefficient was 0.95 and the Spearman coefficient was 0.94 which is not significantly different. Conclusion: Here, we present the results of our machine learning analysis, which further supports our hypothesis and sheds light on the potential racial difference in the overall systemic impact of MM. Understanding the factors underlying racial disparities in MM will pave the way for more personalized and equitable treatment strategies, ultimately improving patient outcomes and overall disease management.

Evolution of monoclonal gammopathy of undetermined significance in patients treated with JAK inhibitors for rheumatic diseases: data from the MAJIK-SFR registry.

Monoclonal gammopathy of undetermined significance (MGUS) is common, but there are scarce data regarding the effect of DMARDs on this premalignant condition. We aimed to evaluate the impact of JAK inhibitors (JAKis) on MGUS when initiated for an active rheumatic disease. Patients with monoclonal abnormality prior to JAKi initiation for an active rheumatic disease were identified through the MAJIK-SFR Registry, a French multicentre prospective study. Clinical and biological data were collected using a standardized case report form. Twenty patients were identified with a mean age of 65 years and a diagnosis of RA (n = 15), PsA (n = 3), and axial SpA (n = 2). The JAKi prescribed was baricitinib (n = 9), tofacitinib (n = 6) or upadacitinib (n = 5), with a mean duration of 15.5 months. Seventeen patients had individualized serum monoclonal protein (IgG kappa n = 9; IgG lambda n = 4; IgM kappa n = 3; IgA lambda n = 1) ranging from 0.16 to 2.3 g/dl, and three patients did not have an initial measurable spike but they had a positive serum immunofixation. With a follow-up of 4-28 months, the serum monoclonal protein level decreased in 8 of 17 patients (47%), remained stable in 8 patients (47%) and increased in 1 patient (6%). The maximal decrease observed was an initial IgG kappa of 2.3 g/dl, decreasing to 0.2 g/dl at month 14. This study provides reassuring and promising data on MGUS evolution in patients treated with JAKis for rheumatic diseases, which may guide the choice of treatment in patients with both conditions.

P970: SAFETY AND EFFICACY OF BCMA-CAR-T IMMUNE CELLS DERIVED FROM CORD BLOOD IN THE TREATMENT OF RELAPSED AND REFRACTORY MULTIPLE MYELOMA

Background: Multiple myeloma (MM) is the second most prevalent hematologic malignancy. The prognosis of MM patients varies, with low-risk patients surviving more than 10 years with standard care and high-risk patients surviving less than 1 year. CAR-T therapy shows promising clinical results on relapsed or refractory MM (R/RMM) patients. However, generating clinically significant doses of CAR-T cells from heavily pre-treated patients for autologous CAR-T therapy is not always possible. Although allogeneic CAR-T cells therapy could potentially overcome such limitations, it poses a considerable risk of graft-versus-host disease (GVHD). Cord blood (CB) is a convenient source of T cells with clear advantages. T cells in CB have low immunogenicity and a relatively low risk of GVHD. Here we present a novel approach to CAR-T cells production from CB, which we hope could overcome the constraints mentioned above. Aims: The study aims to evaluate the safety and efficacy of the CB-generated BCMA-CAR-T infusion in R/RMM patients. Methods: This study is based on a clinical investigation during Jan 2021 and Dec 2021 in Shaanxi Provincial People’s Hospital. In this study, CD3+ T cells from the CB samples were selected, activated, and modified by lentivirus to produce anti-BCMA CAR-T cells. The cells were administrated intravenously to patients with R/RMM after expanding for 5-10 days in vitro. 2-3 days after being administered the lymphodepleting chemotherapy regimen of cyclophosphamide and fludarabine, patients received CAR-T cells infusion. We followed the occurrence of adverse events, the level of inflammatory cytokine concentration, CAR-T cells expansion in the peripheral blood, serum monoclonal protein levels, and the proportion of plasma cells in bone marrow smears after CAR-T cells infusion. Results: This study included 11 patients with R/RMM (7 males and 4 females). The median age was 58 years (ranging from 44 to 65). 18.2% (2/11) of the patients had received other CAR-T therapies and relapsed before the enrolment. 72.73% (8/11) of the patients had the extramedullary disease (EMD). 63.64% (7/11) of the patients had received autologous hematopoietic stem cell transplantation (Auto-HSCT). All patients received CAR-T infusion at the average dose of 7.11 (4.4-15) ×106/kg. After infusion, 18.2% (2/11) of the patients had a fever lasting for 48 hours, and 18.2% (2/11) of them had an increase in heart rate. Nausea and diarrhea occurred in 18.2% (2/11) of the patients. No patients had transient consciousness disorder. No patients received dexamethasone to relieve symptoms. CAR-T cells had expanded in all patients, with no increase in the levels of IL-6, IL-8 and IFN-r in peripheral blood in 2 weeks after infusion. Grade 1 cytokine release syndrome (CRS) was found in 2 patients. No patients had GVHD after infusion. The ORR was 54.5% (6/11), with 18.2% (2/11) of the patients achieving CR, and 36.4% (4/11) achieving PR. Except 1 female died from severe pulmonary infection, other 10 patients were followed up for more than 1 month. Unfortunately, 1 patient who reached CR relapsed during 3 months of follow-up. Those 4 patients who didn’t achieve PR received autologous CAR-T therapy afterwards and had responses better than PR (1 CR, 1 VGPR, 2 PR). Summary/Conclusion: BCMA-CAR-T cells manufactured from CB show a promising safety profile and certain clinical efficacy for R/RMM patients who are not eligible for autologous CAR-T cells therapy. We also found allogeneic CAR-T cells manufactured from CB could prepare patients for later subsequent autologous CAR-T therapy.

Validation of Dynamic Biomarker-Based Risk Progression Model for Smoldering Multiple Myeloma

Validation of Dynamic Biomarker-Based Risk Progression Model for Smoldering Multiple Myeloma

Clinical Features and Outcomes of Light-Chain Dominant Multiple Myeloma: A Population-Based Study

Background: There is a certain subgroup of multiple myeloma(MM) patients shows serum and urine monoclonal protein level that is negative or below thresholds considered to be measurable (Oligosecretory and non-secretory MM). In this subgroup the serum free-light-chain (FLC) assay can be used to monitor treatment response if the patient shows abnormal FLC ratio and more than 100 mg/L of involved FLC level. Yet studies about treatment outcome and clinical features in this particular patient group are still lacking. We aimed to conduct a population based study about light-chain dominant MM (LcDMM) in Korea.Methods: We performed a single-center retrospective study based on the MM patients referred to the Hematology Unit of Seoul National University Hospital from 2005 to 2015. LcDMM was defined as oligosecretory or non-secretory MM with more than 1,000 mg/dL of involved light chain. We analyzed for demographic and clinical characteristics as well as overall survival (OS) and progression free survival(PFS). Also we wanted to see whether there was a difference between characteristics of kappa and lambda LcDMM.Results: A total of 157 LcDMM cases were identified including 37 (23.5%) patients with non-secretory MM. Comparing with previously published general MM population data. LcDMM patients were younger (Median age at diagnosis = 60 years, with 66.2% of diagnosed patients being <60 years) and showed higher proportion of female (Male 51.6%). The International Staging System (ISS) distribution in stage I, II, and III was 40.4%, 19.9% and 39.7%. Among patients with available cytogenetic data, half of the patients had normal karyotype (49.0%) and the prevalence of several cytogenetic abnormalities with poor prognosis including t(4;14), del(17/17p) and t(14;16) was 1.9%, 7.0%, and 1.3% respectively.More than half of the patients were lambda-FLC involved MM (54.8%). Half of the lambda. LcDMM was ISS stage II at diagnosis (46.2%), and in contrast, half of the kappa LcDMM was Stage I (48.5%). The incidence of extramedullary organ involvement was not significantly different between kappa and lambda LcDMM. The median overall survival (OS) from diagnosis of whole LcDMM patients was 59.4 months and of each (ISS) stage was 62 months, 57 months, and 44 months in Stage I, II and III. The median OS of kappa and lambda LcDMM was 69.2 months (95% confidence interval (CI) = 38.6 to 99.7) and 40.3 months (95% CI = 16.4 to 64.1), but there was no statistically significant difference (Plogrank = 0.317)Previous exposure to thalidomide, lenalidomide, and bortezomib was 56.7% (n=89), 21.7% (n=34), and 72.3% (n=112), respectively, and 43.9% (n=69) of patients underwent hematopoietic stem cell transplantation (HSCT). Median PFS of kappa and lambda LcDMM after thalidomide treatment was 11.8 months vs 5.5 months. After lenalidomide treatment, median PFS was not reached yet. In bortezomib, lambda LcDMM showed higher median PFS than kappa LcDMM (9.0 vs 30.0). But, again, there was no statistically significant difference (Plogrank =0.214, 0.506, 0.786)Conclusion : Patients with LcDMM shows several clinical characteristics that clearly is distinguished from secretory MM. In general, the type of light chain is known to have no effect on the prognosis of MM. Yet there was a certain tendency of worse prognosis to lambda FLC involved patients in this study, and bortezomib might be considered for better response in this population. There is a limitation in statistical power of this study due to small population. But this is the largest population based study of all previously published single-center oligosecretory or non-secretory MM study and is also the first study on Asian population. DisclosuresNo relevant conflicts of interest to declare.

Body Mass Index and Clinical Factors Associated with Monoclonal Gammopathy of Undetermined Significance (MGUS) Progression in Olmsted County, Minnesota

Introduction Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal disorder, which progresses at a rate of 1% per year to multiple myeloma (MM), or other plasma-cell or lymphoid disorders. MGUS is common and occurs in approximately 3% and 5% of persons 50 and 70 years of age or older, respectively. Clinical factors reported to be associated with MGUS progression include MGUS isotype, abnormal serum free light-chain ratio (FLCr), and high serum monoclonal protein (M protein) level (&amp;gt;=1.5 g per deciliter). Body mass index (BMI) has also been seen associated with MGUS progression, but has not been evaluated in context of established clinical prognostic factors. Here, we evaluate the contribution of BMI to MGUS progression beyond clinical prognostic factors in a population-based study and examine differential associations by sex. Methods We studied 594 patients residing in Olmsted County Minnesota, who were identified with MGUS in a screening study conducted between1995 through 2003. Patients with light-chain MGUS were not included. Patients were screened for M-protein [normal (&amp;lt;1.5 g/dl) or high (≥1.5 g/dl)], FLCr [normal (0.26-1.65) or abnormal (&amp;lt;0.26 and/or &amp;gt;1.65)], and isotype (IgG, IgM, IgA, bi-clonal). Follow-up time was calculated from date of MGUS screening to date of last follow-up, death, or progression to MM or another plasma-cell or lymphoid disorder. BMI (kg/m2) was calculated using height and weight values reported close to sample date (80% of patients within 2 years), and then categorized into BMI&amp;lt;25 and BMI≥25. We used Cox regression to estimate the association of BMI with risk of MGUS progression to MM or another plasma-cell or lymphoid disorder, univariately, and accounting for clinical factors. Analyses were also stratified by sex. We report hazard ratios (HR) and 95% confidence intervals (CI). Results Of the 594 patients, 51% were male, and the median age at screening date was 73 (range:50-98 years). The immunoglobulin type was IgG in 71% of patients, IgM in 17%, IgA in 10%, and bi-clonal in 2%. High M protein level was observed in 22% and abnormal FLCr in 28%. BMI≥25 was observed in 67% of patients. The median follow-up time was 10.5 years (range:0-25). Over a median of 6,846 person-years, 465 patients (78%) died and 57 patients progressed and developed MM (N=39), amyloidosis (N=8), lymphoma (N=5), or Waldenstrom macroglobulinemia (N=5). The overall rate of progression was 0.87 events (CI:0.67-1.12) per 100 person-years, and higher among males (1.01, CI:0.73-1.42) than in females (0.72, CI:0.48-1.08), however, the difference was not statistically significant (P=0.24). In univariate analyses, BMI≥25 (HR=2.14, CI:1.05-4.36, P=0.04), non-IgG isotype (HR=2.84, CI:1.68-4.80, P=0.0001), high M protein (HR=2.57, CI: 1.50-4.42, P=0.001), and abnormal FLCr (HR=3.39, CI:1.98-5.82, P&amp;lt;0.0001) were associated with increased risk of progression (Table 1.A). These four factors were independently associated with MGUS progression in a multivariable model, with a c-statistic=0.75 (CI:0.68-0.82). When stratifying by sex, associations of BMI with progression were stronger among females than males (Table 1.B) [c-statistic=0.81 (CI:0.72-0.90) vs 0.71 (CI:0.60-0.82) for females vs. males respectively], however, a test for interaction between BMI and sex was not statistically significant (P=0.15). Conclusions In this study we found evidence that high BMI is a prognostic factor independent of isotype, M protein, and FLC ratio in the full cohort, however, this was mainly driven by the effect in females rather than males. Future studies should further investigate sex differences in evaluating prognostic factors among MGUS patients. Disclosures Dispenzieri: Intellia: Research Funding; Pfizer: Research Funding; Alnylam: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Janssen: Research Funding. Kumar:Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Cellectar: Other; Kite Pharma: Consultancy, Research Funding; Tenebio: Other, Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Sanofi: Research Funding; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Merck: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Genecentrix: Consultancy; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Carsgen: Other, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member.

Markers of Initial and Long-Term Responses to Idecabtagene Vicleucel (Ide-Cel; bb2121) in the CRB-401 Study in Relapsed/Refractory Multiple Myeloma

†These authors contributed equally. Introduction Ide-cel, an anti-BCMA CAR T cell therapy, has demonstrated promising efficacy in the phase I CRB-401 trial in relapsed/refractory multiple myeloma (MM) (objective response rate, 85%; median progression-free survival [PFS], 11.8 months [95% CI: 6.2, 17.8]), but a subset of patients failed to respond and the duration of response varied across patients (Raje et al, N Engl J Med. 2019). A systematic examination of patient, product, and post-infusion correlates of overall and long-term response could offer biological insight into heterogeneous efficacy as well as provide biomarkers to guide post-CAR T disease management and future CAR T manufacturing and patient enrollment efforts. Soluble BCMA was of particular interest due to its expression on malignant and healthy plasma cells and its role as a composite measure of disease burden in MM. Methods We performed a retrospective analysis of 33 patients from the phase I CRB-401 study of ide-cel. The concentrations of ten immune-related factors in the blood (GMCSF, IFN-γ, IL-10, IL-1b, IL-2, IL-6, IL-8, MCP-1, TNF-α) and soluble BCMA were measured by ELISA before and after infusion with ide-cel along with 290 ide-cel CAR T-cell drug product attributes measured by flow cytometry and immunoassays. The absolute concentrations and fold-changes from baseline were assessed for correlation with overall and long-term response using univariate and multivariate (random forests) approaches. Results Several CAR T-cell drug product covariates nominally associated with longer PFS included reduced senescence phenotype in CD4 CAR T-cells and increased IL-2 and TNF-α production (P &lt; 0.05). Pre-infusion levels of soluble BCMA correlated with serum monoclonal protein (M-protein) levels in 20 of 33 patients for whom M-protein levels were measurable (ρ = .49; P = 0.03) and with concentrations of the involved free light chain (ρ = .59; P = 0.005) in 23 of 33 patients with measurable levels. Our investigation of soluble BCMA levels in patients achieving a partial response (PR) or better confirmed significant decreases in soluble BCMA levels relative to nonresponders (NR) as early as seven days post-infusion (median reduction of 50% for ≥ PR vs. median increase of 27% for NR, P = 0.02). The fold-change in soluble BCMA 1 month after infusion stratified patients who achieved a PR or better from those who did not (P = 0.0001). Notably, patients who maintained a response to ide-cel for ≥ 18 months (M18 R) experienced a greater depth of clearance of soluble BCMA at month 2 (median concentration of 1835 ng/L for M18 R vs. 6299 ng/L for M18 NR, P = 0.002). The induction of IL-6 and TNF-α in blood on days 1-9 post-infusion was also higher in patients with a PR or better in response to ide-cel (e.g. IL-6 median fold change increase at day 2 of 2.9 for ≥ PR vs. 0.7 for NR, P = 0.001), consistent with an active inflammatory response and higher levels of CAR T expansion. Conclusions These data from CRB-401 identify candidate drug product attributes and soluble factors that correlate with response to ide-cel and potentially MM-directed cellular therapies in general. These data suggest that changes in soluble BCMA may be a robust biomarker of both early and durable responses to ide-cel and the depth of clearance of soluble BCMA at 2 months post-infusion may identify patients at risk of progression before standard markers of myeloma progression have emerged. Further molecular characterization of drug product attributes, including CyTOF and RNA sequencing, is ongoing to identify additional biomarkers associated with clinical outcomes following ide-cel treatment. These data will help inform future strategies to improve the efficacy of ide-cel and validation in a larger cohort is ongoing. Disclosures Thompson: Celgene Corporation: Employment, Equity Ownership. Jiang:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Campbell:Celgene Corporation: Employment, Equity Ownership. Fuller:Celgene Corporation: Employment, Equity Ownership. Kaiser:Celgene Corporation: Employment. Mashadi-Hossein:Celgene Corporation: Employment, Equity Ownership. Rytlewski:Adaptive Biotechnologies: Equity Ownership; Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Martin:Celgene Corporation: Employment, Equity Ownership. Finney:bluebird bio Inc.: Employment. Kleinsteuber:bluebird bio Inc.: Employment, Equity Ownership. Alonzo:bluebird bio Inc.: Employment, Equity Ownership. Pandya:bluebird bio Inc.: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership, Patents &amp; Royalties; Arcus Biosciences: Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Membership on an entity's Board of Directors or advisory committees; Mersana Therapuetics: Membership on an entity's Board of Directors or advisory committees. Raje:Merck: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Celgene Corporation: Consultancy; Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy. Munshi:Celgene: Consultancy; Oncopep: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Abbvie: Consultancy; Adaptive: Consultancy. Hause:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. OffLabel Disclosure: ide-cel /bb2121 is an investigational agent and not yet approved in the US

TIGIT immune checkpoint blockade restores CD8+ T-cell immunity against multiple myeloma

AbstractImmune-based therapies hold promise for the treatment of multiple myeloma (MM), but so far, immune checkpoint blockade targeting programmed cell death protein 1 has not proven effective as single agent in this disease. T-cell immunoglobulin and ITIM domains (TIGIT) is another immune checkpoint receptor known to negatively regulate T-cell functions. In this study, we investigated the therapeutic potential of TIGIT blockade to unleash immune responses against MM. We observed that, in both mice and humans, MM progression was associated with high levels of TIGIT expression on CD8+ T cells. TIGIT+ CD8+ T cells from MM patients exhibited a dysfunctional phenotype characterized by decreased proliferation and inability to produce cytokines in response to anti-CD3/CD28/CD2 or myeloma antigen stimulation. Moreover, when challenged with Vk*MYC mouse MM cells, TIGIT-deficient mice showed decreased serum monoclonal immunoglobulin protein levels associated with reduced tumor burden and prolonged survival, indicating that TIGIT limits antimyeloma immune responses. Importantly, blocking TIGIT using monoclonal antibodies increased the effector function of MM patient CD8+ T cells and suppressed MM development. Altogether our data provide evidence for an immune-inhibitory role of TIGIT in MM and support the development of TIGIT-blocking strategies for the treatment of MM patients.

Long-Term Follow-up of Monoclonal Gammopathy of Undetermined Significance

BackgroundMonoclonal gammopathy of undetermined significance (MGUS) occurs in approximately 3% of persons 50 years of age or older.MethodsWe studied 1384 patients who were residing in southeastern Minnesota and in whom MGUS was diagnosed at the Mayo Clinic in the period from 1960 through 1994; the median follow-up was 34.1 years (range, 0.0 to 43.6). The primary end point was progression to multiple myeloma or another plasma-cell or lymphoid disorder.ResultsDuring 14,130 person-years of follow-up, MGUS progressed in 147 patients (11%), a rate that was 6.5 times (95% confidence interval [CI], 5.5 to 7.7) as high as the rate in the control population. The risk of progression without accounting for death due to competing causes was 10% at 10 years, 18% at 20 years, 28% at 30 years, 36% at 35 years, and 36% at 40 years. Among patients with IgM MGUS, the presence of two adverse risk factors — namely, an abnormal serum free light-chain ratio (ratio of kappa to lambda free light chains) and a high serum monoclonal protein (M protein) level (≥1.5 g per deciliter) — was associated with a risk of progression at 20 years of 55%, as compared with 41% among patients who had one adverse risk factor and 19% among patients who had neither risk factor. Among patients with non-IgM MGUS, the risk of progression at 20 years was 30% among those who had the two risk factors, 20% among those who had one risk factor, and 7% among those who had neither risk factor. Patients with MGUS had shorter survival than was expected in the control population of Minnesota residents of matched age and sex (median, 8.1 vs. 12.4 years; P<0.001).ConclusionsSignificant differences were noted in the risk of progression between patients with IgM MGUS and those with non-IgM MGUS. Overall survival was shorter among patients with MGUS than was expected in a matched control population. (Funded by the National Cancer Institute.)

Retrospective Analysis of Prognostic Factors for Waldenström Macroglobulinemia: A Multicenter Cooperative Study in Japan

Background: Analysis of prognostic factors and clinical trials of novel agents for Waldenstrӧm macroglobulinemia (WM) are ongoing in Western countries, but few studies of WM have been performed in Japan. As a step toward future investigations, we retrospectively analyzed clinical features and prognostic factors in Japanese patients with WM.Methods: We retrospectively analyzed clinical and laboratory characteristics, treatment and outcomes of 110 patients with WM, IgM-MGUS or lymphoplasmacytic lymphoma (LPL) diagnosed from January 2001 to March 2013 at 12 institutes. Overall survival (OS) was analyzed using Kaplan-Meier methods and survival was compared using log-rank testing. Several clinical characteristics at diagnosis were assessed by Cox regression for uni- and multivariate analysis for OS.Results: Median age at diagnosis was 69 (range, 41-96) years, 73.6% were male, 12.0% had an ECOG performance status 2-4 and 6.4% presented with B-symptoms. Hyperviscosity, peripheral neuropathy, amyloidosis, cryoglobulinemia and cold agglutinin disease were shown in 9.1%, 4.5%, 1.8%, 4.5% and 2.7%, respectively. In 94 patients with available CT findings at diagnosis, lymphadenopathy, hepatosplenomegaly, pleural effusion, lung involvement, bone involvement and skin involvement were shown in 41.5%, 14.9%, 8.5%, 4.3%, 4.3% and 6.4%, respectively. Median serum monoclonal protein level was 2.62 g/dl (range, 0.70-9.35 g/dl). Symptomatic WM was present in 76 patients, asymptomatic WM in 23 and IgM-MGUS in 2 according to criteria of the Second International Workshop on WM. Seven patients showed IgG- or IgA-secreting LPL and 2 showed LPL without bone marrow infiltration. In patients with symptomatic WM, international prognostic scoring system for WM (ISSWM) was low in 9.2%, intermediate in 34.2%, high in 39.5% and unknown in 17.1%. Among patients with asymptomatic and symptomatic WM, watchful waiting was performed in 91.3% and 40.0%, respectively, with 61.9% and 36.7% remaining untreated, respectively. Median time to treatment from diagnosis of asymptomatic or symptomatic WM was 240 days (range, 3-1238 days) and 31 days (range, 0-2011 days), respectively. Oral alkylating agents were administered to 34.7% of patients with WM, 19.4% were treated with CHOP or CHOP-like regimen with or without rituximab, 8.2% received fludarabine mono- or combination therapy and 6.1% received rituximab monotherapy. Rituximab-containing therapy was administered as the initial treatment in 33.8% of patients who received treatment. Overall response rate (ORR) (complete + partial response rate) was 48.6%, and patients treated with rituximab-containing therapy displayed higher ORR (64.0%) compared to those with non-rituximab therapy (40.8%). Plasmapheresis was performed in 3.7% of patients. Three patients (2.7%) showed transformation to diffuse large B-cell lymphoma, and 7 (6.4%) developed second primary malignancies. Median follow-up was 38 months, 5-year OS rate for all patients was 74.9% (95% confidence interval (CI) 62.5-83.7) and rates for those with symptomatic WM, asymptomatic WM and other LPL were 66.0% (95%CI 50.6-77.6), 100% and 88.9% (95%CI 43.3-98.4), respectively. Significant differences in survival between risk groups of ISSWM in patients with symptomatic WM were not seen (5-year OS: high, 62.4%; intermediate, 64.3%; low, 75.0%; p=0.86). Although no significant difference in OS was observed compared to initial treatment (p=0.265), patients treated with rituximab during the observation period showed significantly prolonged OS compared to those treated without rituximab (5-year OS rates: 78.9% vs. 45.6%, p=0.036). In univariate analysis, age, pleural effusion, serum albumin, C-reactive protein and serum IgM levels were poor prognostic factors for OS. In multivariate analysis, age >65 years (hazard ratio (HR)=3.294; 95%CI 1.097-9.888, p=0.0336) and pleural effusion (HR=4.55; 95%CI 1.602-12.930, p=0.0045) were identified as significant prognostic factors for OS.Conclusion: Prognostic factors for WM in Western countries may not be applicable to Japanese patients. This study suggested presence of pleural effusion at diagnosis is associated with poor clinical outcomes. Further investigations including histopathological examinations and molecular analyses are required to elucidate prognostic factors in Japan. DisclosuresNo relevant conflicts of interest to declare.

Real-World Data on Multiple Myeloma: A Prospective National Registry in Uruguay

IntroductionUruguayan population is 3,4 million, mostly caucasian (88%). Life expectancy is 77 years. Cancer is the second cause of death and the estimated incidence of Multiple Myeloma (MM) is 120 cases/year. Its diagnosis and monitoring are standardized and feasible, available nationwide. Treatment with Bortezomib, Thalidomide and stem cell transplant are available for all patients, regardless of their health care provider. However, there is no accurate data on MM incidence, care, treatment-results or mortality. The Uruguayan National Myeloma Registry is designed to document current clinical characteristics of newly diagnosed MM, management and outcome in a real-world setting. This information will be useful to plan strategies to improve our local approach and follow-up of this disease, reducing problems derived from extrapolating data from other realities.MethodsThis prospective national registry will include all MM diagnosed between January 2012 and January 2015 in all institutions, public and private, nationwide. Smoldering MM are not included. Data collection started in October 2014 and is being obtained from medical and day hospital reports at each institution. Our database includes detailed data of clinical characteristics, laboratory, citogenetics and FISH, treatment indicated, disease-related and treatment-related adverse events, response to treatment at onset and relapses, and cause of death.ResultsUp to now, 163 patients have been included in the registry (45% coverage). Median age at diagnosis was 67 years (range 33-94 years), 43% younger than 66 years. Distribution according Ig subtype was: IgG 52%, IgA 27,5%, Light chains 17%, non-secretor 2,6% and IgM <1%. At diagnosis, most patients had advanced disease: 82% Durie-Salmon III, 49% ISS 3. Median bone marrow plasmacytosis was 33% and median serum monoclonal protein level was 2,14 g/dl (range 0 - 10,7 g/dl).Anemia (hemoglobin <10 g/dl) was detected in 67% of the patients; 70% had osteolytic lesions whereas impaired kidney function (serum creatinine > 2 mg/dl) was observed in 38% and hypercalcemia in 19,7% at the time of diagnosis.Conventional cytogenetic was performed in 66% (n=108) being normal in 78% and high-risk in 5,5%. Fluorescence in situ hybridization (FISH) for del17p, t(4;14) and t(14,16) was evaluated in 66%, being negative in 76% and positive in 24%.The characteristics of the patients are described in Table 1.First-line treatment included at least one of the new drugs in 94% of patients younger than 65 years and in 62% of those older than 65 years. Treatment regimens are shown in Figure 1.First-line response was available in 54% (n=88). Response rate (≥ PR) was 78%, VGPR+CR=51% and CR=19 %. Ten patients had stable disease at the end of treatment and 5 (5,7%) were relapsed-refractory MM. In ≤ 65 years, VGPR + CR was higher than in > 65 years (56% vs 33%).Suspension or dose reductions due to treatment-related toxicity were required more frequently in patients > 65 years (50% vs 20%). Neuropathy was the most common adverse effect reported (14%).Overall, 26% of patients received autologous stem cell transplantation (ASCT) after first line therapy; 46% in ≤ 65 years and 9% in > 65 years.After a median follow-up of 19 months, progression free survival (PFS) was 88,6% and overall survival (OS) 78,8% (82,9% in ≤ 65 years and 78,8% > 65 years).DiscussionThis first MM National Registry provides a thorough insight into the characteristics of MM patients in our country, which may become a useful instrument to improve MM care. With a 45% coverage, we show that MM is detected in advanced stage, with a high percentage of patients with impaired renal funcion. ASCT is indicated in a low percentage, particularly in those younger than 65 years; reasons for this should be addressed in future research. Longer follow-up is needed to address the impact of new drugs in survival. To the best of our knowledge there is no other MM registry of this kind ongoing in our region. This could become a suitable platform to share with other countries in order to perform high-quality population-based research on the field.Table 1MM clinical characteristics at diagnosis≤ 65 years (N=70)>65 years (N=93)Sex: F/M (%)44/5645/55Age (median)5673Creatinin >2 mg/dl (%)44,933Hemoglobin<10g/dl (%)59,466,7Calcium ≥11,5mg/dl (%)139,7Osteolytic lesions (%)7858 [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Multiple myeloma as a major cause of false-positive galactomannan tests in adult patients with cancer

The galactomannan (GM) test is a useful method for early diagnosis of invasive aspergillosis. Recently, multiple myeloma has newly been suggested to be related to false-positive results of GM. We performed a case-control study to validate this finding. Electronic medical records were reviewed for patients admitted March through June 2014. Patients with false-positive GM results were selected as cases and those with negatives as controls. To verify the results of the four-month analysis, additional analysis was performed in multiple myeloma patients over a three-year period. There were 30 false-positive and 316 negative cases during the four-month period. Among the factors evaluated, multiple myeloma was the only significant factor in the adjusted analysis (OR=3.59, CI 1.28-10.04). In the three-year analysis of 145 multiple myeloma patients, 25.5% showed false-positive results, which was 3 times higher than overall. GM false-positivity was not related to serum monoclonal protein level or type of immunoglobulin. GM optical density indexes (ODIs) in all false positives were lower than 3.0. Multiple myeloma was a major cause of GM false-positivity in adult cancer patients. GM was false-positive in 25.5% of multiple myeloma patients with GM ODIs lower than 3.0.

Bence Jones Proteinuria in Smoldering Multiple Myeloma As Predictor Marker of Progression to Symptomatic Multiple Myeloma

BACKGROUNDSmoldering multiple myeloma (SMM) is a plasma cell proliferative disorder with no related organ or tissue impairment. It is associated with a risk of progression to symptomatic multiple myeloma (MM) of approximately 10% per year. Several prognostic factors for the progression to active disease have been identified, such as those defined by the Mayo Clinic including the proportion of bone marrow plasma cells, the serum monoclonal protein level at diagnosis and the serum immunoglobulin free light chain ratio (FLC); or those defined by the Spanish Group including the proportion of bone marrow aberrant plasma cells assessed by flow cytometry plus immunoparesis.The presence of Bence Jones (BJ) proteinuria is a myeloma feature associated with renal function and tumor burden as well. There is lack of evidence about the role of BJ proteinuria in SMM as predictor marker of progression to symptomatic disease.AIMSThe goal of the present study was to investigate the role of the presence of Bence Jones proteinuria at diagnosis in SMM as predictor of progression to symptomatic disease.METHODSWe reviewed 147 medical records of SMM patients from area of Castilla y León (Spain), diagnosed between 1983 and 2013, according to the criteria of the International Myeloma Working Group. The primary endpoint was time to progression to active multiple myeloma (hypercalcemia, renal insufficiency, anemia or bone lesions).RESULTS147 patients with SMM were included in the analysis. The median age at diagnosis was 69 years-old (range: 34-90).The serum M-protein at diagnosis ranged from 1 to 26 g/l (median,25). 70% of SMM were Ig G subtype. The proportion of bone marrow plasma cells ranged from 1% to 55% (median, 14). In 64 % of SMM, the percentage of aberrant plasma cells assessed by flow cytometry was superior to 95% and 51% had immunoparesis. Bence Jones proteinuria was detected at diagnosis in 40 patients (27%) and the average amount of urinary monoclonal light chain was 236 mg per 24h. Of those patients, 58% had a monoclonal kappa light chain. The FLC ratio was assessed in 18 patients and it was abnormal (<0.26 or >1.65) in 83% of them. The median level of involved Immunoglobulin was 88.5 mg/l (range, 13-1200) and the median ratio of involved to uninvolved was 10.8 (range, 2.2-3360). In 4 patients, FLC ratio was greater than 100.At a median follow-up of 54 months, progression to active disease occurred in 49%. Anemia was the most common CRAB feature at the time of progression. Median time to progression (TTP) to symptomatic disease in the whole series was 63 months. SMM with BJ proteinuria had a significantly shorter median TTP to active disease as compared with patients without BJ proteinuria (21.7 months vs 82.9 months ;HR: 2.44, IC 95%: 1.48-4.02; p<0.001). The progression risk at 2 years in the BJ group of SMM was 53%.Multivariate analysis selected BJ proteinuria at diagnosis as an independent variable for progression to symptomatic MM (HR: 2.47, IC 95%: 1.32-4.63; P=0.005). Using this independent variable, we identified 4 risk categories according to amount of urinary monoclonal light chain: 0 mg per 24h; 1-250 mg/24h; 251-500 mg/24h ; or more than 500 mg/24h, with a median TTP of 83, 37, 16 and 7 months, respectively; p <0.001.CONCLUSIONSThe presence of Bence Jones proteinuria at diagnosis in SMM patients is associated with significantly higher risk of progression to active MM (53% risk of progression at 2 years). Moreover, the presence of more than 500 mg of BJ proteinuria can be considered as a marker for the identification of ultra high risk SMM. DisclosuresNo relevant conflicts of interest to declare.

Phase 1b/2a Open-Label, Multiple-Dose, Dose-Escalation Study To Evaluate The Safety and Tolerability Of Intravenous Infusion Of SNS01-T In Patients With Relapsed Or Refractory Multiple Myeloma, Mantle Cell Lymphoma, Or Diffuse Large B Cell Lymphoma

Eukaryotic translation initiation factor 5A (eIF5A) has been implicated in the regulation of cell proliferation, apoptosis, and inflammation, and is the only known protein to be modified by hypusination. Hypusinated eIF5A, the predominant form of eIF5A in cancer cells, is involved in cell survival and activation of inflammatory pathways. In contrast, accumulation of the unhypusinated form of eIF5A is associated with apoptosis and mutants of eIF5A that cannot be hypusinated (e.g. eIF5AK50R) are pro-apoptotic. SNS01-T was designed to treat B-cell cancers and consists of two active components: a plasmid DNA expressing the pro-apoptotic eIF5AK50R under the control of a B cell-specific promoter, and an siRNA against an untranslated region of native eIF5A mRNA. When these two components are combined with linear polyethyleneimine (PEI), the nucleic acids are condensed into nanoparticles for protection from degradation in the blood and enhanced cellular delivery. The mode of action of SNS01-T is siRNA-mediated inhibition of hypusinated eIF5A and simultaneous over-expression of pro-apoptotic eIF5AK50R to induce cell death. In vitro cell studies and in vivo xenograft studies have demonstrated the efficacy of this approach.The safety and tolerability of intravenous administration of SNS01-T is being investigated in a first-in-human Phase1b/2a study in patients with relapsed or refractory multiple myeloma (MM), mantle cell lymphoma (MCL) or diffuse large B cell lymphoma (DLBCL). Eligible patients are being enrolled sequentially into four cohorts at increasing doses. Each patient receives an intravenous infusion of SNS01-T twice weekly for 6 consecutive weeks. Eligible patients must have been diagnosed with MM according to IMWG criteria, or with MCL or DLBCL with histologic confirmation. Patients also must have measurable disease, have relapsed or refractory disease after two or more prior treatment regimens, have a life expectancy of at least 3 months, and not be eligible to receive any other standard therapy known to extend life expectancy. The primary objective is to evaluate the safety and tolerability of multiple escalating doses of SNS01-T. Secondary objectives include analysis of pharmacokinetics, immunogenicity, pro-inflammatory cytokines, and therapeutic efficacy.The required 3 patients per cohort have completed the dosing schedule in cohorts 1 and 2 from a total of 10 patients enrolled (9 patients with MM and 1 with DLBCL). Of the ten patients enrolled, four completed the full treatment period, two did not complete dosing but were evaluable for safety, and four (three in cohort 1 and one in cohort 2) discontinued treatment after fewer than 8 doses and were not evaluable. There were no drug-related serious adverse events or dose limiting toxicities in either cohort 1 or 2.In cohort 1 (0.0125 mg/kg SNS01-T), two of three evaluable patients did not progress on treatment and were considered stable at week 3 and week 6, the end of the dosing regimen. The third patient progressed after receiving 10 of the 12 doses and was evaluable for safety.In cohort 2 (0.05 mg/kg), 3 patients (2 with MM and 1 with DLBCL) were evaluable for safety. Stabilization of serum monoclonal protein levels was observed in one MM patient of cohort 2. Two patients (1 with MM and 1 with DLBCL) progressed after receiving 8 of the 12 doses and were evaluable for safety.Results from ongoing pharmacokinetic studies, immunogenicity studies, and quantification of pro-inflammatory cytokines will be discussed. The planned dose levels for the third and fourth groups are 0.2 and 0.375 mg/kg, respectively. The results to date of this first-in-human clinical trial indicate that SNS01-T can be administered safely and the MTD has not yet been reached (Clinical Trials.gov Identifier: NCT01435720). Disclosures:Barranco:Senesco Technologies: Consultancy. Usmani:Celgene, Onyx, Millenium: Consultancy, Research Funding, Speakers Bureau. van Rhee:Jansen&Jansen: Research Funding. Thompson:Senesco Technologies: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Taylor:Senesco Technologies: stock options Other. Dondero:Senesco Technologies: Employment. Browne:Senesco Technologies Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Siegel:Celgene, Millenium, Onyx (same for all): Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Exercise Is Medicine

This study aimed to evaluate the influence of a supervised training program on the changes in serum monoclonal protein level (i.e., IgG), percentage of bone marrow plasma cells (BMPCs), fitness performance, and cardiac autonomic control (i.e., HR variability [HRV] and HR complexity [HRC]) in a female diagnosed with smoldering multiple myeloma (SMM). A middle-age female patient with smoldering multiple myeloma and former elite athlete was monitored for 4 yr while participating in a supervised multimodal training regimen designed for the development of various physical capacities. The patient had the possibility of self-selection of daily training volume. Changes in fitness components, IgG levels, and BMPCs were evaluated throughout a 4-yr monitoring period (i.e., follow-up). HRV was examined via 24-h HR recordings during a 6-wk period at the second and the third year of the follow-up. Exercise performance in all fitness components was improved while IgG levels and BMPCs decreased (from 2.53 to 1.84 g · dL(-1) and from 20% to 10%, respectively). Time and frequency domain HRV parameters exhibited significant increases (18%-29%) with HRC remaining unchanged. The current case report results indicated that a multimodal training program designed for the development of various physical capacities improved exercise performance, hematological function, and cardiac autonomic control that may improve long-term prognosis for SMM. Examination of similar exercise training regimens for hematological and other cancer populations may assist in the development of simple nonpharmacological treatments for improved prognosis.

Extensive Bone Marrow Infiltration and Abnormal Free Light Chain Ratio Identifies Patients with Smoldering Myeloma At High Risk for Progression to Symptomatic Disease,

Abstract 3926Asymptomatic/smoldering multiple myeloma (SMM) is a proliferative plasma cell disorder characterized by a substantial risk of progression to symptomatic myeloma. According to current recommendations, patients with SMM should be followed without treatment until they develop symptomatic disease. However, the risk of progression to symptomatic myeloma varies between different series and for individual patients; thus, significant effort is needed in order to identify factors that could discriminate those who are at high risk for progression. Such patients should be followed closer and should be considered candidates for clinical trials. In order to evaluate previously recognized risk factors and study patterns of progression we analyzed our series of patients with SMM, who have been diagnosed and followed in the Department of Clinical Therapeutics in Athens, Greece.SMM was defined as serum monoclonal (M) protein (IgG or IgA) level of ≥3 g/dL and/or bone marrow plasma cells ≥10%, absence of end-organ damage, such as lytic bone lesions, anemia, hypercalcemia, or renal failure, that can attributed to a plasma cell proliferative disorder (IMWG criteria, Br J Haematol 2003;121:749–57). Progression to symptomatic myeloma was defined as per the IMWG proposed criteria.We analyzed 95 patients with SMM, 53% of whom were females, 70% had IgG heavy chain, 22% had IgA, 5% had a biclonal SMM and 3% had light chain only SMM, while 65% had a kappa light chain and 35% a lambda light chain. Median infiltration by clonal plasma cells in BM trephine biopsy was 20% (range 10–90%), 10% of patients had ≥60% clonal plasma cells in BM biopsy. Fifty patients had MRI of the spine at the time of diagnosis of SMM and 19.5% had an abnormal pattern of BM infiltration (diffuse, focal or variegated pattern). In patients with available bone marrow immunohistochemistry data, 61% had clonal plasma positive for CD56, 17% for CD20 and 19% for cyclin D1.The median follow up of the cohort was 27 months (range 1–253 months) and 23 (24%) patients have progressed to symptomatic myeloma. The one-year, 2-year and 3-year cumulative probability of progression was 7%, 12% and 20% respectively. Nine patients (9.5%) progressed within the first two years from the diagnosis of SMM. All these patients had an M-protein of ≥1 g/dl (10 g/L), 67% had bone marrow plasma cells >60% and 80% had an abnormal MRI pattern of BM infiltration. The 3-year probability of progression to symptomatic myeloma was 4%, 18% and 87% for patients with <20%, 20–59% and ≥60% clonal plasma cells in bone marrow biopsy (P<0.001). The 2-year probability of progression to symptomatic myeloma was 0%, 13% and 60% for patients with <20%, 20–59% and ≥60% clonal plasma cells in BM biopsy (P<0.001). Patients with significantly abnormal free light chain ratio (either kappa/lambda ≥8 or kappa/lambda ≤0.125, according to Dispenzieri et al, Blood 2008;111:785–9) had a 3-year probability of progression to symptomatic MM of 41% vs. 15% (p=0.07). There was no significant difference in the risk of progression to symptomatic MM for patients with IgA vs. IgG myeloma. In multivariate analysis, abnormal FLC ratio less than 0.125 or more than 8 (HR: 6.4, 95% CI 1.3–34.5 p=0.032) and BM clonal plasma cells infiltration ≥60% (HR: 23, 95% CI 5–125, p<0.001) were independent risk factors for progression to symptomatic myeloma.Progression to symptomatic MM was manifested by the development of anemia in 52% of patients who progressed to symptomatic MM, development of lytic bone lesions or pathologic fracture in 48%, an increase of serum creatinine to ≥2 mg/dl in 13%, development of a soft tissue plasmacytoma in 4% and development of hypercalcemia in 4%.In conclusion, in our series of patients the 3-year probability of progression to symptomatic myeloma is about 20%, but there is a subgroup of patients with extensive bone marrow infiltration (≥60%) and highly abnormal FLC ratio, who have a substantial risk of progression to symptomatic disease within the first two years from the diagnosis of SMM. These high risk patients may also have other features such as abnormal MRI of the spine. Patients at high risk for progression should be considered for clinical trials evaluating the role of treatment before the development of symptomatic disease, which in most cases is manifested with anemia and/or lytic bone disease or pathologic fractures. Disclosures:No relevant conflicts of interest to declare.

Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma

Monoclonal gammopathy of undetermined significance (MGUS) is characterized by the presence of a serum monoclonal (M) protein level less than 3 g/dL, less than 10% clonal plasma cells in the bone marrow, and the absence of hypercalcemia, renal insufficiency, anemia, or bone lesions attributable to a clonal plasma cell disorder. Patients may be tested for a monoclonal gammopathy by serum protein electrophoresis, immunofixation, and the free light chain (FLC) assay. The prevalence of MGUS is 3% for persons more than 50 years of age and 5% in those more than 70 years of age. The risk of progression to multiple myeloma or a related disorder is 1% per year. The size and type of M protein, the number of bone marrow plasma cells, and the results of the FLC ratio are independent risk factors for progression. Smoldering multiple myeloma (SMM) is a more advanced premalignant phase than MGUS and is characterized by more than 3 g/dL of serum M protein, more than 10% clonal plasma cells in the bone marrow, or both, with no evidence of end-organ damage.

Toxic epidermal necrolysis following thalidomide and dexamethasone treatment for multiple myeloma: a case report

Dear Editor, Toxic epidermal necrolysis (TEN) is a life-threatening idiosyncratic adverse drug reaction characterized by fullthickness epidermal necrosis and eventual development of subepidermal bullae [1, 2]. Carbamazapine, phenytoin, and allopurinol are frequent causes of TEN in Asia [1]. Although thalidomide has been suggested as a cause of TEN, to the best of our knowledge, only two cases had been reported worldwide [3, 4]. We present the case of a 65-year-old male patient who was initially diagnosed with Immunoglobulin G-κ (IgG-κ) multiple myeloma stage IIIA, and had been treated with combination chemotherapies including a VAD (vincristine, doxorubicin, and dexamethasone) regimen as well as an MP (melphalan and prednisone) regimen. About 3 years after finishing MP treatment, the patient presented with bone pain and a serum monoclonal protein level of 4,170 mg/dl. We initiated treatment with 200 mg thalidomide per day for 12 days and 40 mg dexamethasone per day for 4 days, and the dose of thalidomide was then increased to 400 mg per day. Eleven days after the boost, the patient’s course was complicated by the development of sloughing from the periorbital and perioral regions. Three days after the onset of the initial event, the patient was admitted to the emergency department with fever, dysphagia, and itching. The same day, oral mucositis, angioedema of lips and eyebrow, and diffuse erythematous to purpuric patches and plaques appeared on the face, neck, trunk, and extremities. On the third day of hospitalization, a skin biopsy showed subepidermal bullous change with an infiltration of lymphocytes and polymorphonuclear cells in the epidermis which suggested TEN (Fig. 1). On the fifth day, the clinical course was complicated by the worsening rash over the entire trunk, and the patient was started on 400 mg/kg intravenous immunoglobulin (IV-Globulin S®, Green Cross Inc., Korea) per day for five consecutive days. In addition, the patient was intensively treated as a burn patient. On the sixth day, focal skin detachment was noticed and, after 2 days, was followed by generalized detachment from the face to the lower extremities. The patient’s severity-ofillness score for TEN (SCORTEN) was 4 with an expected W. K. Eo : S. H. Cheon : S. H. Lee : J. S. Jeong Integrative Cancer Center, Kyung Hee University, East-West Neo Medical Center, Seoul, South Korea

Clinical Course and Prognosis of Smoldering (Asymptomatic) Waldenstrom's Macroglobulinemia

Smoldering Waldenström's Macroglobulinemia (SWM) is defined as a serum IgM monoclonal protein ≥3 g/dL and/or ≥10% bone marrow lymphoplasmacytic infiltration but no evidence of constitutional symptoms, symptomatic anemia, or hyperviscosity. Forty-eight patients with SWM were identified at Mayo Clinic from 1974 to 1995. Patients with a diagnosis of chronic lymphocytic leukemia or lymphoma or history of any antineoplastic therapy before diagnosis of SWM were excluded. The median age at diagnosis was 63 years (range 39–87 years). Only one patient (2%) was < 40 years of age, but 14 percent were < 50 years old. Thirty-two (67%) were men, and 16 (33%) were women. At diagnosis, hepatomegaly was noted in 10%, splenomegaly in 4%, and lymphadenopathy in 8%. The initial hemoglobin level ranged from 8.7 to 15.3 g/dL (median 11.8). The anemia in all 4 patients with an initial hemoglobin < 10 g/dL was due to other causes such as myelodysplastic syndrome, bronchopleural fistula, Barrett's esophagus, and Coumadin administration. The initial leukocyte level ranged from 3.2 to 13.2 × 109/L (median 5.7), and platelets ranged from 101 to 578 × 109/L (median 285.5). Only one patient had a serum creatinine > 2.0 mg/dL and it was unrelated to SWM. The serum monoclonal protein level at the time of diagnosis ranged from 1.5 to 5.2 g/dL (median 3.3); 12 (25%) were < 3 g/dL, while 10 (21%) were ≥4 g/dL. IgM kappa accounted for 75%, IgM lambda 21%, and 2 (4%) were biclonal. Immunofixation of the urine was positive in 97% (kappa 80%, lambda 17%, indeterminate 3%) of those tested. The size of the urine M protein ranged from unmeasurable to 1.4 g/24h (median 0.04 g/24h). Serum albumin ranged from 2.5 to 4.3 g/dL (median 3.6). Five patients (10%) had an albumin value < 3 g/dL. Ten (26%) had a reduction of 1 uninvolved immunoglobulin, while 8 (21%) had a reduction of both IgG and IgA immunoglobulins. Lymphoplasmacytic infiltration of the bone marrow ranged from 3% to 80%, (median 30%). Three (6%) had less than 10% infiltration, while 13 (27%) had 50% or greater infiltration. The 48 patients were followed for a total of 292 (range 0.5 to 22.6 years; median 3.7) person-years, during which time 33 progressed to symptomatic WM and one to AL amyloidosis. The expected number of WM based on the SEER data was 0.004 cases. Thus, relative risk of progression to WM was increased 7,586-fold (95% CI, 5,083 to 10,373). The median time to progression was 4.6 years. The absolute risk of progression to WM was 6% at 1 year, 39% at 3 years, and 55% at 5 years. The median survival after progression to symptomatic WM was 5.1 years. Seventy-three percent of patients died, indicating a robust follow-up. We evaluated sex, hemoglobin level, size of serum M protein, reduction of uninvolved immunoglobulins, presence of urinary monoclonal light chains, serum albumin level, and the proportion of lymphoplasmacytic infiltration of the bone marrow as risk factors for progression. Significant risk factors for progression with univariate analysis included size of the serum M protein, hemoglobin level, reduction in uninvolved immunoglobulins, and degree of bone marrow lymphoplasmacytic cell infiltration. Multivariate modeling revealed that the size of the M protein and the degree of bone marrow infiltration were the most important risk factors. We conclude that smoldering WM is a distinct clinical entity that needs to be differentiated from IgM MGUS and symptomatic Waldenstrom's Macroglobulinemia.