Hevylite®, a New Marker of Tumor Measurement In Waldenstrom Macroglobulinemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5076-5076 ◽  
Author(s):  
Salomon Manier ◽  
Remy Dulery ◽  
Alain Duhamel ◽  
Eileen Boyle ◽  
Julien Rossignol ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Progressive Disease ◽  
Tumor Burden ◽  
M Protein ◽  
Advisory Committees ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
M Spike

Abstract Abstract 5076 Background. Waldenstrom macroglobulinemia (WM) is a low grade B cell lymphoma characterized by bone marrow infiltration of lymphoplasmacytic tumor cells that secrete monoclonal IgM (M-protein) into the serum. Measurement of the serum M-protein [using serum protein electrophoresis (SPEP)] and measurement of total IgM (using nephelometry) are used to diagnose and monitor WM. There are, however, many limitations with these techniques and new markers are needed. IgG and IgA Hevylite® immunoassays have been reported to be more sensitive than SPEP and nephelometry for identifying monoclonal immunoglobulins in multiple myeloma and unlike immunofixation, provide quantitative information. We hypothesized that serum IgM Hevylite assays (specifically measuring IgMkappa and IgMlambda, separately) would accurately identify serum IgM M-proteins. We also evaluated the association between known tumor burden markers and prognostic factors with IgM Hevylite results in patients with WM. Method. We retrospectively measured IgMkappa and IgMlambda in sera from 59 WM patients: 44 patients were at diagnosis and 15 had relapsed disease. The diagnosis of WM was made according to the current guidelines. All serum samples were kept frozen in the Lille serum bank since collection. All patients gave informed consent prior to the collection and none were treated at time of collection of the serum. Approval of this protocol was obtained from the CHRU Lille and was in accordance with the Declaration of Helsinki. Hevylite measurements were made at The Binding Site Ltd, Birmingham, UK. A normal range was produced from normal (blood donor) sera (n=120), median (and 95%ile ranges) were; IgMkappa 0.634g/L (0.29-1.82), IgMlambda 0.42g/L (0.17-0.94), IgMkappa/IgMlambda ratio 1.6 (0.95-2.3). For ease of comparison IgM hevylite ratios were expressed as the involved monoclonal immunoglobulin/uninvolved polyclonal immunoglobulin (IgMi). To describe the distribution of IgMi Hevylite levels in patients with WM, the median and range (min-max) were reported. Median values were compared using the Wilcoxon rank-sum test and ANOVA. Fisher's exact test was used to compare proportions. All statistical tests were two-sided. All analyses were conducted using SPSSv12 software. Results. The baseline characteristics of the patients were as follows: the median (range) age was 68 years (41-86), male/female 38/21, serum b2M 3.0mg/L (1.2-9.0), hemoglobin 11.8g/dL (7.6-15.4), platelet count 267 ×109/mm3 (55-741), serum M-spike 19g/L (3.0-52.7). In our series, 18 (31%), 22 (37%) and 19 (32%) patients had low, intermediate and high risk disease respectively, in the WM-IPSS scoring system. The median (min-max) IgMkappa ratio was 134 (8.7-2850) and IgMlambda ratio was 0.03 (0.0007-0.39). IgMi Hevylite ratio was 98.07 (2.59-2850). The IgMi Hevylite correlated well with the M-spike measured using SPEP (r=0.601, p<0.0001). In our study, high IgMi Hevylite levels correlated well with markers of high tumor burden and of poor prognosis. The median (range) IgMi Hevylite level was higher in patients with hemoglobin <10g/dL versus ≥10 g/dL, 267 (8.1-1722) and 76 (2.6-2850) respectively (p=0.013). The median (range) IgMi Hevylite ratio level was significantly (p=0.033) higher in the high risk IPSS group 208 (2.6-2850) than in the intermediate 75 (15-1033) and low risk groups, 98 (8-571). The IgMi Hevylite levels also separated WM patients with progressive disease who required therapy. Twenty seven pts were symptomatic and required specific treatment for WM, and 32 pts were left untreated. The median IgMi Hevylite ratio was significantly higher in progressing patients, 210 (8.1-2850) and 60 (2.6-571) in the 2 groups, respectively (p=0.014). Conclusion. In this study we demonstrated that IgM Hevylite measurement is a new and reliable marker for monitoring WM disease. It is related to poor prognostic markers that separate WM patients with progressive disease who require therapy. We are currently expanding the cohort to confirm these observations. These findings have implications in the management of patients with WM. Disclosures: Leblond: Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Mundipharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Leleu:Celgene: Consultancy, Research Funding; Janssen Cilag: Consultancy, Research Funding; Leo Pharma: Consultancy; Amgen: Consultancy; Chugai: Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

scholarly journals Progression Risk-Based Classification of Asymptomatic Waldenström Macroglobulinemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 150-150
Author(s):  
Mark Bustoros ◽  
Romanos Sklavenitis-Pistofidis ◽  
Chia-jen Liu ◽  
Efstathios Kastritis ◽  
Geoffrey Fell ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Proportional Hazards ◽  
Risk Group ◽  
Advisory Committees ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Risk Of Progression

Abstract Background. Waldenström macroglobulinemia (WM) is a low-grade non-Hodgkin's lymphoplasmacytic lymphoma associated with overproduction of monoclonal IgM protein. It is preceded by an asymptomatic stage, called Smoldering Waldenström Macroglobulinemia (SWM), associated with a high risk of progression to overt disease. Current understanding of progression risk in SWM is based on a few small studies, and it is still unclear how to distinguish the asymptomatic patients who will progress from those who will not. Patients and Methods. We obtained clinical data of all WM patients who had been diagnosed and followed up at Dana-Farber Cancer Institute from 1982 to the end of 2014. Only patients with asymptomatic disease at the time of diagnosis were included in this study to identify risk factors for disease progression. Patients who received chemotherapy for a second cancer, before or after asymptomatic WM diagnosis (n =24), were excluded as chemotherapy might have affected the natural course of disease. Patients who progressed to or were diagnosed later with other types of B-cell lymphoproliferative disorders or Amyloidosis (n =71) and patients with myeloproliferative disorders or thalassemia (n = 4) were all excluded from our cohort. Furthermore, we excluded patients with no morphologic evidence of lymphoplasmacytic infiltration in the bone marrow biopsy (n =37), those without a bone marrow biopsy done at time of diagnosis (n =21), and those who were treated for peripheral neuropathy alone (n =13). Progression was defined based on the Consensus Panel recommendations of the Second International Workshop on WM. Survival analysis was performed using the Kaplan-Meier method and differences between the curves were tested by log-rank test. Effects of potential risk factors on progression rates was examined using Cox proportional-hazards models, with hazard ratios (HRs) and associated 95% confidence intervals (CIs). Results. A total of 439 patients were included in the study. During the 35-year study period and a median follow up of 7.8 years, 317 patients (72.2%) progressed to symptomatic WM. The median time to progression was 3.9 (95% CI 3.2-4.6) years. In the multivariate analysis, IgM ≥ 4,500 mg/dL (adjusted HR 4.65; 95% CI 2.52-8.58; p < 0.001), BM lymphoplasmacytic infiltration ≥ 70% (adjusted HR 2.56; 95% CI 1.69-3.87; p < 0.001), β2-microglobulin ≥ 4.0 mg/dL (adjusted HR 2.31; 95% CI 1.19-4.49; p = 0.014), and albumin < 3.5 g/dL (adjusted HR 2.78; 95% CI 1.52-5.09; p = 0.001) were all identified as independent predictors of disease progression, suggesting those thresholds could be clinically useful for determining high-risk patients. On the other hand, given the continuous nature of these variables, we built a proportional hazards model based on four variables (Bone marrow infiltration percentage, serum IgM, albumin, β2-microglobulin). The model divided the cohort into 3 distinct risk groups: a high-risk group with a median time to progression (TTP) of 1.9 years (95% CI 1.64-2.13), an intermediate-risk group with median TTP of 4.6 years (95% CI 4.31-5.15), and a low-risk group with a median TTP of 8.1 years (95% CI 7.33-8.13)(See Figure). To enhance its clinical applicability, we made the model available as user interface through a webpage and mobile application, where clinicians can enter an individual SWM patient's lab values and get information regarding their risk group and estimated individual risk of progression to symptomatic WM. Conclusion. We have assembled the largest cohort of SWM patients to date, which allowed us to identify four independent predictors of progression to overt disease: BM infiltration ≥ 70%, IgM ≥ 4,500 mg/dL, b2m ≥ 4.0 mg/dL and albumin < 3.5 g/dL. Using those variables in a proportional hazards model, we developed a robust, flexible classification system based on risk of progression to symptomatic WM. This system stratifies SWM patients into low-, intermediate- and high-risk groups and thus has the potential to inform patient monitoring and care. Most importantly, it can help identify high-risk patients who might benefit from early intervention in this rare malignancy. Figure 1. Figure 1. Disclosures Bustoros: Dava Oncology: Honoraria. Kastritis:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Soiffer:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Treon:Johnson & Johnson: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; BMS: Research Funding; Pharmacyclics: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding. Castillo:Genentech: Consultancy; Millennium: Research Funding; Abbvie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Dimopoulos:Amgen: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Ghobrial:BMS: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Celgene: Consultancy.

scholarly journals Identifying Ultra-High Risk Smoldering Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3192-3192 ◽  
Author(s):  
Theresia Akhlaghi ◽  
Even H Rustad ◽  
Venkata D Yellapantula ◽  
Neha Korde ◽  
Sham Mailankody ◽  
...  
Keyword(s):  
Risk Factors ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
Ultra High Risk ◽  
Risk Of Progression ◽  
Equity Ownership ◽  
M Spike ◽  
Risk Biomarkers

Abstract Introduction Smoldering multiple myeloma (SMM) is an asymptomatic precursor stage to active multiple myeloma (MM), comprised by a heterogenous group of patients with varying rates of progression. While the overall yearly progression rate is 10% the first 5 years, some patients progress at a considerably higher rate. A study from the Mayo Clinic showed that in a subset of 21 patients defined by ≥60% monoclonal bone marrow plasma cells (BMPC), 95% progressed within 2 years. It was subsequently concluded by the International Myeloma Working Group (IMWG) that patients with biomarkers predictive of a 2-year progression rate at 80%, and a median time to progression at 12 months were at ultra-high risk of progression and should be considered to have MM requiring treatment despite being asymptomatic. In 2014, ultra-high risk biomarkers were incorporated in the definition of MM, including BMPC ≥60%, free light chain (FLC) ratio ≥100 and ≥2 focal lesions on magnetic resonance imaging (MRI). While the updated myeloma definition changed the diagnosis of some patients with ultra-high risk SMM to MM, there remain patients classified as SMM progressing at a very high rate. In the present study, we aimed at further identifying ultra-high risk biomarkers predictive of a high rate of progression to active MM. Methods Patients with SMM presenting to Memorial Sloan Kettering Cancer Center between the years 2000 and 2017 were identified and included in the study. Diagnosis of SMM and progression to MM requiring therapy was defined according to the IMWG criteria at the time of diagnosis. Baseline patient and disease characteristics were collected at date of diagnosis with SMM, including pathology reports, laboratory results and imaging data. Time to progression (TTP) was assessed using the Kaplan-Meier method with log-rank test for comparisons. Optimal cut-off values for continuous variables were assessed with receiver operating characteristics (ROC) curve. Patients who had not progressed by the end of study or were lost to follow up were censored at the date of last visit. Univariate Cox regression was used to estimate risk factors for TTP with hazard ratios (HR) and 95% confidence intervals (CI). Significant univariate risk factors were selected for multivariate Cox regression. Results A total of 444 patients were included in the study. Median follow-up time was 78 months. During the study period, 215 (48%) patients progressed to active MM, with a median TTP of 72 months. Cut-off points for BMPC, M-spike, and FLC ratio were determined with ROC curves to be 20%, 2 g/dL, and 18, respectively, for predicting high risk of progression. The following factors were associated with significantly increased risk of progression to active MM: BMPC >20%, M-spike >2g/dL, FLC ratio >18, immunoparesis with depression of 1 and 2 uninvolved immunoglobulins respectively, elevated lactate dehydrogenase, elevated beta-2-microglobulin, and low albumin (Table 1). In the multivariate model, BMPC >20% (HR 2.5, 95% CI 1.6-3.9), M-spike >2g/dL (HR 3.2, CI 1.9-5.5), FLC ratio >18 (HR 1.8, CI 1.1-3.0), albumin <3.5 g/dL (HR 3.9, CI 1.5-10.0), and immunoparesis with 2 uninvolved immunoglobulins (HR 2.3, CI 1.2-4.3), predicted a decreased TTP (Table 1). A total of 12 patients had 4 or 5 of the risk factors from the multivariate model, 8 of these did not meet the 2014 IMWG criteria for MM. These patients had a significantly shorter TTP than patients with less than 4 risk factors (median TTP 11 vs 74 months, p<0.0001, Figure 1). At 16 months, 82% of these patients had progressed, and within 2 years, 91% of the patients progressed. Only one patient remained progression free after 2 years, progressing at 31 months. Of patients with less than 4 risk factors, 19% progressed within the first 2 years. Conclusion In addition to baseline BMPC >20%, M-spike >2g/dL, FLC-ratio >18, we found that albumin <3.5g/dL and immunoparesis of both uninvolved immunoglobulins at the time of diagnosis with SMM were highly predictive of a decreased TTP to MM requiring therapy. These biomarkers are readily available and routinely assessed in clinic. Patients with 4 or 5 of these risk factors represent a new ultra-high risk group that progress to active disease within 2 years, further expanding on the definition of ultra-high risk SMM. In accordance with the rationale on ultra-high risk biomarkers as criteria established by the IMWG in 2014, such patients should be considered to have MM requiring therapy. Disclosures Korde: Amgen: Research Funding. Mailankody:Janssen: Research Funding; Takeda: Research Funding; Juno: Research Funding; Physician Education Resource: Honoraria. Lesokhin:Squibb: Consultancy, Honoraria; Serametrix, inc.: Patents & Royalties: Royalties; Takeda: Consultancy, Honoraria; Genentech: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Research Funding. Hassoun:Oncopeptides AB: Research Funding. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Shah:Amgen: Research Funding; Janssen: Research Funding. Mezzi:Amgen: Employment, Equity Ownership. Khurana:Amgen: Employment, Equity Ownership. Braunlin:Amgen: Employment. Werther:Amgen: Employment, Equity Ownership. Landgren:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding; Pfizer: Consultancy; Celgene: Consultancy, Research Funding.

scholarly journals A Randomized Placebo-Controlled Phase 2 Study of Metformin for the Prevention of Progression of Monoclonal Gammopathy of Undetermined Significance and Low Risk Smoldering Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1659-1659
Author(s):  
Catherine R. Marinac ◽  
Robert A. Redd ◽  
Julia Prescott ◽  
Alexandra Savell ◽  
Courtney Igne ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Monoclonal Gammopathy ◽  
Research Funding ◽  
Controlled Trial ◽  
Low Risk ◽  
M Protein ◽  
Advisory Committees ◽  
Randomized Controlled ◽  
Bone Marrow Plasma

Abstract Background: Multiple Myeloma (MM) is thought to evolve from the precursor conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), which are common premalignant disorders that progress to overt MM in a subset of individuals for reasons that are poorly understood. Despite increasing interest in preventing disease progression in this patient population, the standard of care still consists of close surveillance until progression to MM; however, once MM develops it cannot be cured. Therefore, the identification of prevention and interception strategies for patients with MGUS and SMM is of considerable importance. A promising pharmacologic intervention to reduce the risk of progression of MGUS/SMM to MM is metformin, a drug commonly used to treat type 2 diabetes but that is also considered safe for use in non-diabetic populations. In vivo and in vitro studies have revealed that metformin has direct antitumor effects across a variety of cancers including MM, and recent epidemiological data suggests it may reduce the risk of MM in diabetic patients with MGUS. Here, we describe the first randomized controlled trial testing the efficacy of metformin in reducing clinical signs of disease progression in patients with MGUS and SMM (NCT04850846). Study Design and Methods: This is a phase II single center, randomized controlled trial of metformin vs. placebo in patients with high-risk MGUS and low-risk SMM. The primary objective of the study is to determine whether metformin can reduce or stabilize serum monoclonal (M-)protein concentrations from baseline to 6-months. Exploratory objectives include mass spectrometry quantification of M-protein, examination of molecular evolution of tumor cells in response to metformin, as well as changes in other clinical laboratory parameters in response to metformin. To be eligible, patients must have high-risk MGUS or low-risk SMM. High-risk MGUS is defined as bone marrow plasma cell concentration &lt;10% with one or more of the following higher-risk features: serum M-protein level ≥1.5 g/dL to &lt;3 g/dL or abnormal free light-chain (FLC) ratio (&lt;0.26 or&gt;1.65); a forthcoming amendment will include non-IgG subtype as an additional high-risk feature. Low-risk SMM is defined as bone marrow plasma cells ≥10%with the absence of any features of high-risk SMM. Metformin and its corresponding placebo are the pharmacological treatments. The metformin dose is 1500 milligrams/day, provided in 500 milligram pills. To minimize gastrointestinal symptoms, metformin is started at a low dose of 500 milligram (1 pill) per day and participants gradually increase the dosage over the course of the first month of treatment until the full 1500 milligram (3 pill) per day regimen is achieved. The study treatment period is 6 months, with primary outcomes assessed at the end of the 6-month treatment period. Conclusions and Future Directions: While the cornerstone of clinical management in MGUS and SMM is to delay therapy until progression to symptomatic MM, patients and oncologists continually seek new ways to prevent end organ damage and incurable malignancy. This trial is positioned to provide preliminary but robust mechanistic data to support the development of novel prevention strategies for MGUS and SMM patients. Disclosures Marinac: GRAIL Inc: Research Funding; JBF Legal: Consultancy. Sperling: Adaptive: Consultancy. Parnes: Sigilon: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; UniQure: Membership on an entity's Board of Directors or advisory committees; Sunovion: Consultancy; I-mAb: Consultancy; Aspa: Consultancy; Genentech/Hoffman LaRoche: Research Funding; Shire/Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Richardson: Protocol Intelligence: Consultancy; Regeneron: Consultancy; Sanofi: Consultancy; Secura Bio: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy; AstraZeneca: Consultancy; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy. Nadeem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: metformin, which is an anti-diabetic medication

IgA Hevylite® Test As a Surrogate to Serum Protein Electrophoresis (SPEP) or Nephelometry in the Management of IgA Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3970-3970
Author(s):  
Eileen Mary Boyle ◽  
Philip Young ◽  
Helene Demarquette ◽  
Julie Gay ◽  
Houria Debarri ◽  
...  
Keyword(s):  
Binding Site ◽  
Board Of Directors ◽  
Research Funding ◽  
Response To Therapy ◽  
M Protein ◽  
Response To Treatment ◽  
Advisory Committees ◽  
Reliable Marker ◽  
M Spike ◽  
The Impact

Abstract Abstract 3970 Background: Measurement of serum M-spike is used to assess response to therapy and treatment-free survival in IgA myeloma. However, its resolution on SPEP and the presence of IgA-dymers can make accurate measurement difficult. The more the M-spike decreases on SPEP, the more imprecise the M-spike measurement is using SPEP. IgA M-spike often migrates in the betaglobines that renders the M-spike measurement often complicated to analyze. Furthermore, quantification of the clonal IgA chain by nephelometry (IgAneph), which inherently includes monoclonal and polyclonal immunoglobulins, does not accurately reflect the tumour burden. Currently, there is a need in myeloma with IgA isotype (approximately 30–40% of patients) to identify new markers that better reflect the disease burden and the response to treatment, and correlate to patients' outcome. Hevylite® measures IgAkappa and IgAlambda and might provide precise quantitative measurement of the IgA M-spike. We sought to determine whether Hevylite® can be used as a reliable marker for diagnosis and response to therapy in IgA myeloma as compared to the M-spike measurement on SPEP and nephelometry. Methods: We conducted a retrospective analysis on 113, smoldering or symptomatic, IgA myeloma patients at diagnosis referred to our department from 1997 to 2011. All serum samples were collected prior to treatment or at relapse (for sequential data) and were kept frozen since collection. Hevylite® measurements were made at The Binding Site Ltd, Birmingham, UK. A normal range was produced from normal (blood donor) sera (n=138), and were for IgA kappa 0.48–2.82g/L, IgA lambda 0.36–1.98g/L and IgA K/L ratio 0.80–2.04. For ease of comparison we have studied the IgA hevylite ratios expressed as IgA K/L ratio. Results: The median age at diagnosis was 65 years (range: 33–93) and the M/F sex ratio was 0,91. Forty-eight percent of patients had an ISS greater than 2 (n=86). On nephelometry the median IgA level was 22g/L (range min-max, 0–100). Fifty patients had M-spikes migrating among the betablobulines, 27 among the gammaglobulines, 10 migrated in both and 23 unspecified. Fourteen patients had oligosecretory disease (M-component < 10g/L). Forty-two patients had an IgA kappa clonal chain, 70 others an IgA lambda and for one patient the data was not available. Among IgA kappa patients the mean HCLratio was 616.6 (median 117.7 [0.021–4323.7]) whereas it was 0.61 (0.21 [0.004–0.455]) among the IgA lambda patients. Across the entire population, 58 patients were identified by SPEP and HCL ratios. Among the 55 patients whose M-component was not quantified on SPEP, HCL ratios were abnormal in 53/55 (96%) cases. In the subgroup of patients whose M-protein migrates in the beta-region 29 out of 50 are identified by HCL ratios and SPEP. Another 19 patients (38%) had abnormal HCL ratios while unquantified on SPEP. The same was seen in patients whose M-protein migrates among the gammaglobulins with 16/27 and 11/27 (40%), respectively. In the last subgroup of patients with beta and gamma migrating M-proteins, all (10/10) were identified by HLC and SPEP. More interestingly, among the oligosecretory MM patients identified by an M-component < 10g/L, all (14 patients) had an abnormal HCL ratio. In our series of IgA myeloma, 51% of patients were accurately quantified on SPEP. When using HCLratios, an extra 47% of patients became measurable, with an abnormal HLC ratios allowing IgA myeloma in up to 98% of cases. When considering IgA measurement using nephelometry, 102 patients had both high IgA levels (90%) and abnormal HCL ratios. Interestingly, 7 patients had normal IgA levels with IgAneph and abnormal HCL ratio offering a useful diagnostic tool for 96% of patients as compared to IgAneph. In our series, IgA myeloma was neither associated with a poor outcome (median [range] OS: 119 months [0,5–604]) nor a poor response to therapy (median [range] TTP: 16 months (1–92). HCL involved chain ROC analysis identified a 37g/L cut-off as prognostic in IgA myeloma(p=0.039). Conclusion: Hevylite® is a new and reliable marker for diagnostic and monitoring of IgA myeloma. It enables to quantify accurately up to 98% of IgA-MM patients. These preliminary data need confirmation in further prospective trials in order to monitor further the impact of this marker in IgA myeloma patients before it becomes the gold standard to monitor the IgA M-protein in years to come. Disclosures: Boyle: Chugai: Consultancy, Honoraria. Combat:The Binding Site: Employment. Pietrantuono:The Binding Site: Employment. Facon:onyx: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees. Harding:The Binging Site: Employment. Leleu:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria; Onyx: Honoraria, Speakers Bureau; LeoPharma: Honoraria, Speakers Bureau.

scholarly journals Treatment Facility Volume and Outcomes in Waldenstrom Macroglobulinemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 622-622
Author(s):  
Jonas Paludo ◽  
Jithma Prasad Abeykoon ◽  
Stephen M. Ansell ◽  
Morie A. Gertz ◽  
Prashant Kapoor ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Treatment Facility ◽  
Advisory Committees ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Outcome Relationship ◽  
The Us ◽  
Volume Outcome

Abstract Introduction Waldenstrom macroglobulinemia (WM) is a rare disease accounting for only 1-2% of all hematologic malignancies and with an overall annual, age-adjusted incidence of approximately 3.5 to 5.5 cases per million-person years. With approximately 13,000 active hematologist/oncologists in the US, most of who are in the community oncology setting, it's estimated that a hematologist/oncologist will only diagnose a WM case approximately every 8 years. Therefore, the clinical experience of a general hematologist/oncologist in the management of WM is likely very limited compared to more prevalent malignances. Previous studies in the setting of rare cancers suggest a correlation between higher volume of care and improved outcomes. Therefore, we explored the volume-outcome relationship in WM using the National Cancer Data Base (NCDB). Methods Patient-level data from the NCDB, a nationwide, facility-based, database covering approximately 70% of all newly diagnosed cancer cases in the US, was queried for all new WM cases diagnosed between 2004 and 2014. Only patients requiring treatment were included. Treatment facilities were divided into quartiles based on the average annual volume of newly diagnosed cases of WM seen. Cox regression was used to analyze the association between facility WM volume and survival, adjusted by demographics (sex, age, race), socioeconomic status (income, education, insurance type), geography (area of residence, treatment facility type, travel distance), comorbidity factors (Charlson-Deyo score), and year of diagnosis. Time-to-event analysis was calculated from frontline therapy initiation date using the Kaplan-Meier method and the log-rank test. Results A total of 3,732 patients with WM treated in 831 facilities were included. The median age at diagnosis was 70 years and 75% of the patients were treated within 20 miles from their residency zip code. Patient characteristics per treatment facility volume quartile are shown in table 1. The median annual facility volume was 1 new WM patient/year (range 0.1 to 21). The median follow-up from frontline treatment was 5 years. The unadjusted median OS by facility volume was: Q1: 6.5 years (95% CI: 5.7-7.4), Q2: 7 years (95% CI: 6.3-8.2), Q3: 8.2 years (95% CI: 7.1-8.9), and Q4: NR (95% CI: 8.5-NR), p<0.0001 (figure 1). The estimated 5-year OS by facility volume was: Q1: 56%, Q2: 61%, Q3: 64%, Q4: 71%, p<0.0001. Multivariate analysis including all variables showed in Table 1 demonstrated that facility volume was independently associated with all-cause mortality. Compared to patients treated at Q4 facilities, patients treated at lower-quartiles facilities had a higher incremental risk of death (Q3 hazard ratio [HR], 1.07 [95% CI: 0.88 to 1.29] p=0.46; Q2 HR, 1.34 [95% CI: 1.11 to 1.63] p=0.002; Q1 HR, 1.52 [95% CI: 1.23 to 1.88] p=<0.0001). Conclusion Our results suggest that a volume-outcome relationship exits in WM as patients treated initially at higher-volume facilities had a lower risk of mortality. Although differences in the underlying disease biology, referral patterns after initial therapy, or cumulative treating-physician experience could not be assessed, these potential biases would only underestimate the magnitude of the volume-outcome relationship reported. Disclosures Ansell: Celldex: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Regeneron: Research Funding; Pfizer: Research Funding; Affimed: Research Funding; Merck & Co: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding. Gertz:Medscape: Consultancy; janssen: Consultancy; Alnylam: Honoraria; Ionis: Honoraria; Physicians Education Resource: Consultancy; Prothena: Honoraria; Teva: Consultancy; Research to Practice: Consultancy; spectrum: Consultancy, Honoraria; celgene: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; annexon: Consultancy; Apellis: Consultancy. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Ailawadhi:Amgen: Consultancy; Janssen: Consultancy; Pharmacyclics: Research Funding; Celgene: Consultancy; Takeda: Consultancy. Reeder:Affimed: Research Funding. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Lacy:Celgene: Research Funding. Kumar:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Identifying a Gene Expression (GEP)-Based Model Predicting for Progression from AMM to Cmm Requiring Therapy in S0120 Patients Treated at Mirt

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2078-2078
Author(s):  
Rashid Z Khan ◽  
Christoph Heuck ◽  
Adam Rosenthal ◽  
Caleb K Stein ◽  
Joshua Epstein ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Dose Effect ◽  
M Protein ◽  
Proliferation Index ◽  
Q Value ◽  
Advisory Committees ◽  
Cut Point ◽  
Risk Of Progression

Abstract Background: The definition of high risk smoldering multiple myeloma (HR-SMM) is in flux. There are several models using serologic, bone marrow and radiologic data that predict for time to progression (TTP) to clinical myeloma (CMM). Lenalidomide and Dexamethasone in HR-SMM is reported to delay onset of end organ damage and improve overall survival, stressing the clinical utility of early intervention. We previously reported a GEP70 based score cutoff (<-0.26), when applied to the S0120 population, that improved the predictive power (R2) of standard clinical variables by 11%. The combination of GEP70 score >-0.26, serum M spike ≥3g/dL, and involved SFLC >25 mg/dL identified a subset of patients with 67% risk of progression at 2 years. With longer follow up, we now examine whether unique gene probe sets can be identified at the AMM stage that portend an earlier time to therapy (TTT). Patients and Methods: We identified 105 patients with AMM who had baseline GEP data on our S0120 protocol, after IRB approval for retrospective data review, and evaluated each of 54,675 Affymetrix gene probes for their potential to predict TTT. Probes were ranked by their q-values; we found 40 probes with q-value < 0.05 and 7 probes with q-value < 0.01; the top probe had a q-value of 0.00066. Scores based on the number of significant probes at these cut-points were computed by subtracting the sum of the expressions of the up-regulated probes from the sum of the expressions of the down-regulated probes, then dividing by the total number of probes. Results: In the GEP40 model, an optimal cut-point for risk of progression was identified at 7.05. The 3-year TTT probability was 83% with scores >=7.05 and only 11% for patients with values under this threshold (Figure 1A; p<0.0001). TTT probabilities also differed markedly when examined by score quartiles, attesting to a gene dose effect (Figure 1B). For the Q1 subset of 26 patients, only 4% required therapy in 3 years. Univariate Cox analysis for TTT yielded age>65 (HR: 2.3), Albumin<3.5g/dl (HR: 3.7), M-protein>3g/dl (HR: 4.99), BM plasmacytosis>=10% (HR: 12.2), GEP70>-0.26 (HR: 3.4), GEP40>=7.05 (HR: 16.41), GEP proliferation index > -0.26 (HR: 2.8), GEP PR subgroup (HR: 9.4) and GEP PolyPC >11.6 (HR: 0.22) to be significant. In the multivariate model, GEP40>=7.05 was the most significant (HR: 13.7), followed by SFLC>10mg/dl and M-protein>3g/dl. GEP40 score positively correlated with proliferation index (R: 0.804), and showed no correlation with GEP polyPC score (R: -0.156). Next, we used recursive partitioning on data from 72 patients and identified 23 patients with GEP40 score >=7.05 of whom 22 suffered TTT by 3 years (87%). Among the remaining 49 patients with GEP40 <7.0325, a further cut-point of age >59 years identified 24 patients, of whom 11 suffered progression with a 3 year TTT estimate of 25%. In the 25 patients with GEP40 <7.0325 and age <59 years, no patient progressed to CMM, with a 3 year TTT estimate of 0%. The GEP7 and GEP1 models, at optimal cut-offs, yielded equivalent positive and negative predictive values compared to the GEP40 model, albeit with less power. Conclusion:Gene expression profiling can readily identify a subset of AMM patients who are high risk for progression to CMM. Further refinement of GEP based risk scoring can be achieved by combining clinical and correlative variables to select the super HR-SMM for intervention trials. Figure 1a Figure 1a. Figure 1b Figure 1b. Disclosures Zangari: Norvartis: Membership on an entity's Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding. Van Rhee:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Dhodapkar:Celgene: Research Funding. Morgan:Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Myeloma UK: Membership on an entity's Board of Directors or advisory committees; International Myeloma Foundation: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Membership on an entity's Board of Directors or advisory committees; MMRF: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Survival Outcomes in Patients with Waldenström Macroglobulinemia/ Lymphoplasmacytic Lymphoma According to MYD88 Mutation Status

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5248-5248
Author(s):  
Agrima Mian ◽  
Albert Aboseif ◽  
Wei Wei ◽  
Rajshekhar Chakraborty ◽  
Jack Khouri ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Initial Therapy ◽  
Wild Type ◽  
Advisory Committees ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Median Serum ◽  
Ecog Ps

Background: Waldenström Macroglobulinemia (WM) or Lymphoplasmacytic Lymphoma (LPL) is an indolent B-cell neoplasm accounting for only 1-2% of all hematological malignancies. More than 90% of patients with WM carry a point mutation L265P in the MYD88 gene which promotes tumor survival and is shown to be significant for diagnostic and risk stratification. Criteria for diagnosis requires presence of serum monoclonal IgM protein and > 10% bone marrow lymphocytes with plasmacytoid differentiation. We aimed to present the patients characteristics and survival outcomes of WM/LPL patients treated at our center, according to their MYD88 gene status. Methods: We reviewed medical records of all patients diagnosed with WM/LPL between May 2002 and May 2018 for whom MYD88 status was known. Baseline demographic characteristics, ECOG PS, pertinent laboratory values including IgM level at diagnosis, initial therapy, mutation status and cytogenetics was obtained. Kaplan-Meier survival estimation curves were used to illustrate the probability of survival over time stratified by MYD88 status and compared by the log rank test. Results: A total of 99 patients diagnosed with WM/LPL were included, 91 Caucasians (92%), 54 (55%) male, median age 67 years (range, 43-89) and with 63 (64%) patients having ECOG PS 0 or 1. IgM level at diagnosis was available for 88 patients, with a median of 2055 mg/dL (range, 10-11,700) and serum free light chain ratio was estimated at a median of 2.13 (range, 0.01- 37331). Other pertinent laboratory data were: median hemoglobin 11.4 g/dL (range, 6.2- 16.4), median serum viscosity 2.4 CP (range, 1.5- 6.7), median serum M protein 1.4 g/L (range, 0- 5.84), median 24 hour urine protein 11mg (range, 4- 1344) and median serum LDH 173 U/L (range, 71-476). The median international prognostic score (ISSWM) for our cohort was 3. A mutant MYD88 was positive in 85 (86%) patients, while 14 (14%) patients had wild- type MYD88. Complex karyotype was present in 24 (25%) patients. Rituximab monotherapy was the initial treatment in 48 (49%) patients. Twenty-two [22%] patients each received bortezomib-based and bendamustine-rituximab regimen as initial therapy and 7 (7%) patients received frontline rituximab- chemotherapy. Median follow-up of the cohort was 2.8 years (0.08-15.5). At last follow-up, 25 (25%) patients had died. Median OS from diagnosis for the entire cohort was 7.9 years (95% CI, 6.6 to N.R.). OS rate at 5 years was 0.73 (95% CI, 0.61 to 0.87). Patients with mutant MYD88 had significantly longer median OS as compared to those with wild-type MYD88 - 16.3 years (95% CI, 6.7 to N.R.) vs 6.6 years (95% CI, 1.9 to N.R.) [P=0.01] (Figure 1). Conclusion: Within the limitations of a retrospective study with a heterogeneously treated cohort, these data add to the body of literature supporting that outcomes of patients wild-type for MYD88 are worse than those with the L265P mutation when treated with rituximab alone, a proteasome inhibitor or conventional rituximab- chemotherapy. Also, despite an expansion on the therapeutic landscape, the treatment of choice in Waldenström Macroglobulinemia is still lead by rituximab monotherapy in newly diagnosed patients. Further studies should investigate the prognostic impact of MYD88 mutation in the context of BTK inhibitors. Disclosures Hill: Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding; TG therapeutics: Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria.

scholarly journals A Phase II Study of Daratumumab in Patients with High-Risk MGUS and Low-Risk Smoldering Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1649-1649
Author(s):  
Omar Nadeem ◽  
Robert A. Redd ◽  
Michael Z. Koontz ◽  
Jeffrey V. Matous ◽  
Andrew J. Yee ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Plasma Cells ◽  
Low Risk ◽  
M Protein ◽  
Advisory Committees ◽  
Bone Marrow Plasma

Abstract Introduction : Daratumumab (Dara) is an anti-CD38 monoclonal antibody that is approved for use in patients with newly diagnosed and relapsed multiple myeloma (MM). We hypothesized that early therapeutic intervention with Dara in patients with high-risk MGUS (HR-MGUS) or low-risk SMM (LR-SMM) would lead to eradication of the tumor clone by achieving deep responses, resulting in prevention of progression to MM. We present results of our phase II, single arm study of Dara in HR-MGUS and LR-SMM. Methods : Patients enrolled on this study met eligibility for either HR-MGUS or LR-SMM. HR-MGUS is defined as &lt;10% bone marrow plasma cells and &lt;3g/dL M protein and at least 2 of the following 3 high-risk criteria: Abnormal serum free light chain ratio (SFLC) of &lt;0.26 or &gt;1.65, M protein ≥ 1.5g/dL or non-IgG M protein. LR-SMM is defined by one of the following 3 criteria: M protein ≥3g/dL, ≥10% bone marrow plasma cells, SFLC ratio &lt;0.125 or &gt;8. Dara (16mg/kg) was administered intravenously on a weekly schedule for cycles 1-2, every other week cycles 3-6, and monthly during cycles 7-20. The primary objective of this study was to determine the proportion of patients who achieve very good partial response (VGPR) or greater after 20 cycles of Dara. Secondary objectives included duration of response, safety, and rates of minimal residual disease (MRD)-negativity in VGPR or greater patients. Correlative studies included assessing changes in immune microenvironment, evaluating clonal heterogeneity using deep sequencing, and determining association of genomic aberrations correlating with either response to therapy or progression of disease. Results : At the time of data cutoff, a total of 42 patients were enrolled on this study from 2018 to 2020 with participation of 5 sites. The median age for all patients at enrolment was 60 years (range 38 to 76), with 22 males (52.4%) and 20 females (47.6%). Majority of patients enrolled were classified as LR-SMM (n = 37, 88.1%) and the remaining 5 patients had HR-MGUS (11.9%). 41 patients have started treatment and are included in toxicity assessment, and 40 patients have at least completed 16 cycles (range 6-20). Grade 3 toxicities were rare and only experienced in 5/41 patients including diarrhea (n =1/41; 2%), flu like symptoms (n = 1/41; 2%), headache (n=1/41; 2%), and hypertension (n=2/41; 5%). Most common toxicities of any grade included fatigue (n = 24/41, 51%), cough (n = 19/41, 46%), nasal congestion (n = 18/41, 44%), headache (n = 14/41, 34%), hypertension (n = 11/41, 27%), nausea (n = 13/41, 32%), and leukopenia (n = 13/41, 32%). No patients have discontinued therapy due to toxicity. Minimal response or better was observed in 82.9% of patients (34/41) and PR or better was observed in 51.2% of patients (21/41). This included overall CR (n = 4, 9.8%), VGPR (n = 1, 2.4%), PR (n = 16, 39.0%), MR (n = 13, 31.7%), and SD (n = 7, 17.1%). In the 40 patients who completed at least 16 cycles, response rates were as follows: MR or better 85% (34/40), PR or better 52.5% (21/40) and VGPR or better 12.5% (5/40). Median time to VGPR was 7 months. Median overall survival and progression-free survival have not been reached and no patients have progressed to overt multiple myeloma while on study. Conclusion : Dara is very well tolerated among patients with HR-MGUS and LR-SMM with minimal toxicities. Responses are seen in majority of patients. Early therapeutic intervention in this precursor patient population appears promising but longer follow up is required to define the role of single agent Dara in preventing progression to MM, therefore avoiding more toxic interventions in this low-risk patient population. Disclosures Nadeem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Yee: GSK: Consultancy; Oncopeptides: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Sanofi: Consultancy; Bristol Myers Squibb: Consultancy; Adaptive: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy. Zonder: Caelum Biosciences: Consultancy; Amgen: Consultancy; BMS: Consultancy, Research Funding; Intellia: Consultancy; Alnylam: Consultancy; Janssen: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy. Rosenblatt: Attivare Therapeutics: Consultancy; Imaging Endpoints: Consultancy; Parexel: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Wolters Kluwer Health: Consultancy, Patents & Royalties. Mo: AbbVIE: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Consultancy; Epizyme: Consultancy; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sperling: Adaptive: Consultancy. Richardson: Karyopharm: Consultancy, Research Funding; AstraZeneca: Consultancy; AbbVie: Consultancy; Takeda: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Janssen: Consultancy; GlaxoSmithKline: Consultancy; Protocol Intelligence: Consultancy; Secura Bio: Consultancy; Regeneron: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

scholarly journals Pracinostat in Combination with Azacitidine Produces a High Rate and Rapid Onset of Disease Remission in Patients with Previously Untreated Acute Myeloid Leukemia (AML)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 947-947 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Ehab Atallah ◽  
Olatoyosi Odenike ◽  
Bruno C Medeiros ◽  
Jorge E. Cortes ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Adverse Events ◽  
Board Of Directors ◽  
Null Hypothesis ◽  
Research Funding ◽  
Progressive Disease ◽  
De Novo ◽  
Phase Ii Study ◽  
Advisory Committees

Abstract Background: Pracinostat is a potent oral inhibitor of histone deacetylases (HDAC’s), selective for class I, II and IV isoforms. In-vitro cytotoxicity assays in AML cell lines revealed an IC50 of <0.1µM, and the combination with azacitidine was synergistic (CI=0.44). A Phase I study of single agent pracinostat showed activity in AML and a pilot Phase II study of pracinostat in combination with azacitidine in higher risk MDS demonstrated a complete response (CR)/CR with incomplete blood count recovery (CRi) rate of 89% (Proc ASH:3821, 2012). We report initial results from a Phase II study of pracinostat with azacitidine in previously untreated, elderly AML. Methods: Eligibility includes previously untreated AML (≥ 20% bone marrow blasts), age ≥65 years, deemed inappropriate for intensive induction therapy, with intermediate or high risk cytogenetics based on SWOG criteria. De-novo, treatment-related, or AML evolved from an antecedent hematologic disorder (AHD) are allowed. Pracinostat is administered orally (60 mg) 3 days a week (e.g., Monday, Wednesday, Friday) for 3 weeks followed by a 1 week break. Azacitidine is administered subcutaneously or intravenously (75 mg/m2) day 1-7 or day 1-5 and 8-9 of each 28-day cycle. The primary endpoint is CR+CRi+ morphologic leukemia free state (MLFS) according to IWG criteria. Response assessments occur at the end of cycle 1 or 2 followed by every other cycle or when clinically indicated. A Simon 2-stage statistical design is utilized with the following assumptions: null=0.10, alternate=0.25, α=0.10, power=0.90. Transition from stage 1 to 2 requires ≥ 3/27 response events; the null hypothesis will be rejected if ≥ 7 response events are observed in the total planned sample of 40 patients. Results: As of August 01, 2014, 21 patients have been enrolled from 12 study sites and are evaluable for safety; 14 are evaluable for efficacy (Table 1), and 7 are ‘too early’ for response assessment. Baseline disease characteristics include: median age 77 (range 69-84); 16 de novo AML, 4 evolved from AHD, 1 treatment related; 11 intermediate-risk, 8 high-risk cytogenetics, and 2 are pending; baseline bone marrow blast counts ranged from 22% to 89%. The primary endpoint of CR +CRi+MLFS was observed in 8 of 14 evaluable patients (57%), the majority after 1 or 2 cycles. No responders have progressed. The most common treatment emergent adverse events (TEAE) were neutropenia/neutropenic fever (n=15), thrombocytopenia (n=12), nausea (n=10), fatigue (n=8), and anemia (n=7). Serious adverse events include febrile neutropenia (n=6) and pulmonary infiltrate/pneumonia (n=2). Three patients discontinued study therapy due to a TEAE, including one each with cellulitis, bacteremia, and subdural hematoma after a fall. There have been 3 deaths on study: 1 bacteremia, 1 subdural hematoma, and 1 progressive disease. Abstract 947. Table 1 Patient Number Days on Study Baseline BM Blast % 1st On-Study BM Blast % Subsequent On-Study BM Blast % Best Response on Study 2 172+ 22 1 (C2) --- CR 3 165+ 24 4 (C1) 0 (C4) CRi 5 162+ 27 9 (C1) 1 (C4) CRi 6 156+ 81 9 (C1) 0 (C4) CRi 7 148+ 78 44 (C1) 17 (C3), 0 (C5) CR 8 114+ 89 4 (C1) --- CR 10 86+ 45 3 (C1) --- CRi 12 81+ 41 2 (C2) --- CRi 4 90 22 43 (C2) Off due to SAE SD 11 56 37 60 (C2) --- PD 15 28 70 --- Patient Withdrew 17 28 60 --- PD 1 26 70 --- Off due to AE 9 26 38 --- Off due to AE +=Patients continue on study; C=cycle; SD=Stable Disease; PD=Progressive Disease Conclusions: The study has achieved the primary goal of rejecting the null hypothesis. The CR+CRi +MLFS response rate estimate of 57% is high compared to historical results with hypomethylating agents alone in this population, and the responses occur rapidly, most within the first 2 cycles. The combination appears tolerable with no unexpected toxicities. Recruitment continues to the final planned sample size of 40 to further define the tolerability and efficacy of the regimen, including remission duration. Updated data will be presented at the meeting. Disclosures Garcia-Manero: MEI Pharma, Inc.: Consultancy. Off Label Use: Azacitidine is not approved for use in acute myelogenous leukemia.. Odenike:Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Algeta Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Suneisis Pharmaceuticals : Honoraria, Membership on an entity's Board of Directors or advisory committees. Medeiros:MEI Pharma, Inc: Research Funding. Cortes:Celgene: Research Funding. Esquibel:MEI Pharma, Inc.: Employment. Cha:MEI Pharma, Inc.: Employment. Khaled:Sequenom: Research Funding.

scholarly journals High Prevalence of Monoclonal Gammopathy in a Population at Risk: The First Results of the Promise Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 152-152
Author(s):  
Habib El-Khoury ◽  
Jean-Baptiste Alberge ◽  
Hadley Barr ◽  
Ciara Murphy ◽  
D.J. Sakrikar ◽  
...  
Keyword(s):  
High Risk ◽  
Binding Site ◽  
Board Of Directors ◽  
Monoclonal Gammopathy ◽  
Research Funding ◽  
Cancer Worry ◽  
Degree Relative ◽  
Advisory Committees ◽  
High Prevalence ◽  
M Spike

Abstract Background Multiple myeloma (MM) evolves from monoclonal gammopathy of undetermined significance (MGUS), a clinically detectable but asymptomatic premalignant phase seen in ~3% of the general population 50 years of age or older. The prevalence of MGUS has not been described in a population at high risk of developing MM, specifically Black/African American (AA) individuals or first-degree relatives of patients with hematologic malignancies (HM). In 2019, we launched the first nationwide US screening study for individuals at high risk of MM to help better identify what population would benefit most from screening and early intervention for precursor MM stages. We aim to assess the prevalence of MGUS in a population at high risk of MM and characterize clinical variables of individuals who screen positive. Here, we report interim screening data on the first 2,960 participants. Methods Individuals aged 40 or older with an additional MM risk factor are eligible to be screened in the PROMISE Study. High-risk individuals include Black/AAs and those with a first-degree relative diagnosed with a hematologic malignancy or a precursor condition to MM. Blood from all participants was analyzed via serum protein electrophoresis, immunofixation, and Optilite® to measure the serum free light chains (sFLC), IgG, IgA and IgM. Results were returned to all participants, and those who tested positive for a monoclonal gammopathy (MGUS/SMM) were referred to a hematologist for clinical follow-up and invited to periodically complete epidemiologic exposure and psychosocial questionaries, including a 4-item cancer worry questionnaire and the RAND 36-item Short Form Survey (SF-36). To investigate the use of the higher-sensitivity matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) with the Optilite® IgG, IgA, IgM and sFLC results as a screening test for all participants, we rescreened 1,092 samples from PROMISE. The Binding Site Group proprietary software was used for the analysis of the combined MS/Optilite® results, allowing for the detection and quantification of M-protein. Heavy-Chain MGUS (HC-MGUS) was defined by the presence of one or more paired heavy and light chain monoclonal peaks detected by MS. Pairing was based on mass to charge ratio of identified peaks. To enrich the PROMISE cohort with Black/AA individuals, we identified and screened 1,868 Black/AA additional individuals from the Mass General Brigham (MGB) Biobank who met the PROMISE enrollment criteria. Screening was performed by MS/Optilite®, and results have not been returned to participants. Results We screened 2,960 participants with the combined MS/Optilite® approach. We report here the prevalence of HC-MGUS and plan on presenting the estimated rate of light chain MGUS in our cohort, at the meeting. We detected HC-MGUS in 9.6% (95% CI: 8.6-11%) of our cohort, with a prevalence of 10% (95% CI: 8.3-12%) in the PROMISE cohort and 9.4% (95% CI: 8.1-11%) in the MGB cohort (Table 1 and Figure 1). HC-MGUS prevalence increased with age in high-risk individuals from 4.9% (CI: 3.3-6.9%) for participants aged 40-49 to 13% (CI: 10-17%) in the 70-79 range (P &lt; 1.2E-5). Among monoclonal HC-MGUS, we found 65% IgG, 18% IgM, and 18% IgA. M-spike was quantified in 97% of samples. Median M-spike concentration was, 0.058g/dL (max. 2.6g/dL) for IgG, 0.0043g/dL (max. 0.6g/dL) for IgM, and 0.067g/dL (max. 0.8g/dL) for IgA. In the Promise cohort, no significant change in cancer worry was observed across the pre- and post-screening interval among participants who screened positive (P = 0.52). Health-related quality of life, as measured by the SF-36, was not significantly different in screen-positive vs. screen-negative individuals for any of the eight subscales (all P &gt; 0.20). Conclusions We present the largest dataset on monoclonal gammopathy prevalence and screening in individuals at high risk for MM, and more specifically the largest cohort of Black/AA, using a novel high-sensitivity testing approach. Our results confirm that older adults who are Black/AA or have a first-degree relative with an HM have a high prevalence MGUS and may benefit from precision screening approaches to allow for early detection and clinical intervention. Preliminary data on cancer worry and quality of life indicates that the psychosocial burden of screening in this population is likely minimal. Figure 1 Figure 1. Disclosures Sakrikar: The Binding Site: Current Employment. Krause: The Binding Site: Current Employment. Barnidge: The Binding Site: Current Employment. Bustoros: Takeda: Consultancy, Honoraria; Janssen, Bristol Myers Squibb: Honoraria, Speakers Bureau. Perkins: The Binding Site: Current Employment. Harding: The Binding Site: Current Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kapoor: Ichnos Sciences: Research Funding; Amgen: Research Funding; Pharmacyclics: Consultancy; Takeda: Research Funding; Sanofi: Consultancy; Regeneron Pharmaceuticals: Research Funding; AbbVie: Research Funding; BeiGene: Consultancy; Sanofi: Research Funding; Karyopharm: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Consultancy; Cellectar: Consultancy. Mo: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Eli Lilly: Consultancy; Janssen: Honoraria; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees. Murray: The Binding Site: Patents & Royalties: Potential Royalties for use of mass spectrometry in M-protein detection. Getz: Scorpion Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; IBM, Pharmacyclics: Research Funding. Marinac: JBF Legal: Consultancy; GRAIL Inc: Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

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