Final Analysis of MELISSE, a Large Multicentric Observational Study to Determine Risk Factors of Venous Thromboembolism in Patients with Multiple Myeloma Treated with Immunomodulator Drugs

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1235-1235 ◽  
Author(s):  
Xavier Leleu ◽  
Laurent Daley ◽  
Philippe Rodon ◽  
Cyrille Hulin ◽  
Charles Dauriac ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
High Risk ◽  
Incidence Rate ◽  
Research Funding ◽  
Final Analysis ◽  
Vte Prophylaxis ◽  
High Risk Patients ◽  
Increased Risk ◽  
Risk Patients

Abstract Abstract 1235 Background. Immunomodulator drugs (IMiDs) are associated with an increased risk of thromboembolic events (TE). Multiple Myeloma patients (MM) that can not benefit from novel agents, including IMiDs, only have 9 months survival. IMiDs must be stopped when TE occurs with the consequence of potential shortened life expectancy. MELISSE was designed to prospectively evaluate the incidence and risk factors of venous TE (VTE) associated with IMiDs in MM. We have presented the interim analysis of MELISSE at ASH 2010. A reduced incidence rate of early VTE was observed when a prophylaxis for VTE was started as compared to patients that had no prophylaxis. Interestingly, we also reported that most of the patients had received aspirin, while aspirin is not considered to exert any venous prophylactic effect. LMWH was primarily proposed to patients with high risk of TE according to physician's evaluation. We present the final analysis of MELISSE with updated results at 1 year. Method. A total of 524 MM treated with IMiDs-based therapy were included in 52 IFM centers. VTE prophylaxis was recommended prior to start IMiDs, the choice of which was left at the discretion of the investigator. Patients gave written informed consent according to the declaration of Helsinki. The physicians were to record the risk of VTE occurrence, categorized as low, moderate and high, based on guidelines and their own appreciation of the risk. Occurrence of any VTE was to be recorded along with the management of the event and the patient's outcome. The data were collected at entry in the study, and then after 4 and 12 months. Results. The median age was 70 years old, with 64.67% of patients >65 years old. Overall 36.0% had thalidomide-based and 64.0% had lenalidomide-based therapy, with 180 patients in first line and the remaining patients in 2nd and 3rd lines of therapy. The observed repartition of TE risk factors was as expected in a European population with myeloma. The risk of VTE was assessed as high in 14.2% patient and small or intermediate otherwise. Interestingly, approximately 70% of patients rated as low and intermediate risk received aspirin as a routine prophylaxis for VTE as compared to 20% in high risk patients. LMWH was primarily given to high risk patients, 45.8%. Surprisingly, 16.0% of patients had no VTE prophylaxis. Investigators recorded 29 (5.5% annual incidence rate) TE at 12 months, including 12 associated with PE. The incidence rate of TE was similar within the first 4 months (early occurrence, 3.5%) versus after 4 months (late, 2.5%). We have not identified any risk factor that would explain early versus late occurrence of VTE. Interestingly, the incidence of VTE was higher in patients that had no prophylaxis treatment, 8.5%, as compared to 4.4% and 5.9% in the LMWH and aspirin groups, respectively. There was no PE recorded in patients that were on LMWH prophylaxis. The VTE was equally breakdown across the 3 groups of risk factors. The bleeding adverse events were reported for 27 patients, mainly patients with aspirin. We isolated a model with 3 variables that independently predicted a higher risk to develop VTE in the multivariate model, and that comprised the male gender [OR 4.31 (95% CI 1.60 – 13.90)], the smoking habit [6.76 (1.73–22.42)] and the association to EPO [2.66 (1.04–6.58)]. Aspirin showed no significance, but with a p value at 0.55. The multivariate analysis is limited as certain subgroups with high risk factors might have received the optimal VTE prophylaxis, such as patients with bed rest and patients with prior history of VTE. These 2 groups rarely had aspirin. Survival data will be updated and presented at ASH 2011. Conclusion. This study further demonstrates that TE prophylaxis is required for MM treated with IMiDs-based therapy. There is a slight increase risk of VTE/PE with the use of aspirin as compared to LMWH, but a significant increase in bleeding events. Although we have identified risk factors of VTE in MM treated with IMiDs, for the first time, we could not identified VTE risk factors to guide investigators between LMWH and aspirin-based prophylaxis. The optimal dose and duration of LMWH remains to be determined. Disclosures: Leleu: LeoPharma: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; Roche: Research Funding; Amgen: Honoraria; Novartis: Research Funding. Daley:LeoPharma: Employment. Hulin:Janssen: Honoraria; Celgene: Honoraria. Lamblin:LeoPharma: Employment. Natta:LeoPharma: Employment.

scholarly journals VTE Incidence in RRMM Patients Treated with NOVEL Agents: A Monocentric Real Life Experience

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4972-4972
Author(s):  
Gaetano Giuffrida ◽  
Concetta Conticello ◽  
Valeria Calafiore ◽  
Enrica Antonia Martino ◽  
Silvia Giamporcaro ◽  
...  
Keyword(s):  
Risk Factors ◽  
High Risk ◽  
Research Funding ◽  
Real Life ◽  
Low Risk ◽  
Novel Agents ◽  
Vte Prophylaxis ◽  
High Risk Patients ◽  
Risk Patients ◽  
Low Incidence

INTRODUCTION: Venous thromboembolism (VTE) is very common in patients with malignancies. Compared to the general population, patients with multiple myeloma (MM) have a 9-fold increased risk of developing VTE. In patients treated with thalidomide or lenalidomide, current guidelines recommend systematic VTE prophylaxis with ASA in low risk patients while vitamin K antagonists (VKA) or low weight molecular heparin (LWMH) or unfractionated heparin (UFH) in high-risk patients, based on the type of anti-MM treatment that patients receive and patient-related individual risk factors (e. g. history of VTE). However, little is known on VTE prophylaxis in patients treated with next generation anti-myeloma drugs, such as pomalidomide, carfilzomib and monoclonal antibodies daratumumab and elotuzumab. Here, we describe the incidence of VTE in MM patients treated with third generation novel agents in real life. In addition, we stratify patients on drugs category-based regimens to evaluate strategy of VTE prophylaxis between different groups of patients. MATERIALS AND METHODS: A retrospective cohort of 137 patients affected by relapsed and/ or refractory multiple myeloma treated with novel agents was analyzed. Patients were followed at the Division of Hematology of Catania from April 2013 to June2019. Our series includes 75 patients exposed to Pomalidomide and Dexametasone (PomaD), 46 patients receiving Carfilzomib, Lenalidomide and desamethasone regimen (KRd), 14 patients exposed to Daratumumab(Dara), 27 patients to Daratumumab, Bortezomib and desamethasone (DaraVD), 4 patients to Daratumumab lenalidomide and desamethasone (DaraRd), and12 patients exposed to Elotuzumab and Lenalidomide (EloRd). Several patients were exposed to multiple lines of treatment with novel agents: the total number of analyzed treatments are 178. Patients were stratified to high or low risk for VTE: risk factors taken into account were obesity, history of VTE, central venous catheter, inhered thrombophilia, surgical procedures and comorbidities such as infections, immobilization, cardiac disease, chronic renal disease. Low risk patients had no or one risk factor; in case of two or more risk factors, the patients were classified as high risk. Low-dose aspirin (ASA 100 mg per os once daily) or equivalent was prescribed in low risk patients, low-molecular-weight heparin (LMWH) or equivalent was given to high risk patients. Only Dara treatment did not include standard prophylaxis in patients without risk factors. RESULTS: Real life observation revealed a low incidence of VTE (6 VTE-4,3%) in patients exposed to novel agents together with a standard prophylaxis in case of risk of thromboembolic complications. Forty patients were at high risk of VTE, while 97 patients were classified as low risk; VTE/PE occurred in 2 high risk patients who refused to make correct LMWH prophylaxis due to the discomfort of the subcutaneous administration, developing distal DVT respectively after cycle 1 and 2 of KRd. Two low risk patients treated with PomaD developed DVT of lower extremities during cycle 2 and 4; 2 low risk patients had pulmonary embolism during PomaD cycle 8. CONCLUSIONS: Low incidence of VTE in patients with RRMM receiving PomaD, KRd, EloRd, DaraVD, DaraRd, Dara or EloRd treatment is probably due to a correct risk assessment and subsequent prophylaxis in case of therapies including immunomodulators or in case of patients with high risk for thromboembolic complications. These data support the use of VTE risk stratification-based prophylactic strategies in myeloma patients treated with new drugs. Disclosures Conticello: Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Di Raimondo:Takeda: Consultancy; Amgen: Consultancy, Honoraria, Research Funding.

Abstract 78: Risk Factors Associated with Failure of Aggressive Medical Therapy in the SAMMPRIS Trial

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Michael F Waters ◽  
Brian L Hoh ◽  
Michael J Lynn ◽  
Tanya N Turan ◽  
Colin P Derdeyn ◽  
...  
Keyword(s):  
Risk Factors ◽  
High Risk ◽  
Medical Therapy ◽  
Primary Endpoint ◽  
Univariate Analysis ◽  
Baseline Risk ◽  
Medical Group ◽  
High Risk Patients ◽  
Increased Risk ◽  
Risk Patients

Background: The SAMMPRIS trial showed that aggressive medical therapy was more effective than stenting for preventing stroke in high-risk patients with symptomatic intracranial stenosis. However, 15% of patients in the medical group still had a primary endpoint (any stroke or death within 30 days of enrollment or stroke in the territory beyond 30 days) during a median follow-up of 32.7 months. We sought to determine baseline risk factors that were associated with a primary endpoint in the medical arm of SAMMPRIS. Methods: Data on 227 patients randomized to the medical group in SAMMPRIS were analyzed. Baseline demographic features, vascular risk factors, qualifying event, brain imaging and angiographic features were analyzed. The hazard ratio and p-value from a Cox proportional hazard regression model relating time until a primary endpoint to each factor were calculated. Results: Female gender, diabetes, stroke as the qualifying event (especially non-penetrator stroke), old infarct in the territory of the stenotic artery, and > 80% stenosis were associated (p < 0.10) with a higher risk of the primary endpoint on univariate analysis (see accompanying table) (multivariate analysis will be available by the time of ISC). Variables not associated with a higher risk of a primary endpoint in the medical arm included: age, race, antithrombotic therapy at the time of a qualifying event, time from qualifying event to enrollment (< 7 days vs. > 7 days), and location of stenosis. Conclusions: Several features were associated with an increased risk of the primary endpoint in the medical group in SAMMPRIS. On univariate analysis, the most important risk factors were an old infarct in the territory of the stenotic artery and stroke (especially non-penetrator stroke) as the qualifying event. These features will be useful for identifying particularly high-risk patients who should be targeted for future clinical trials testing alternative therapies to aggressive medical management.

Real-World Clinical Outcomes By Cytogenetic Risk Category in Relapsed or Refractory Multiple Myeloma: Evidence from a Cohort Review in France

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4784-4784
Author(s):  
Huamao Mark Lin ◽  
Keith L Davis ◽  
James A. Kaye ◽  
Katarina Luptakova ◽  
Lu Gao ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Partial Response ◽  
Research Funding ◽  
Complete Response ◽  
Line Treatment ◽  
Second Line ◽  
High Risk Patients ◽  
Risk Patients ◽  
Standard Risk

Abstract INTRODUCTION: Multiple Myeloma (MM) is an incurable hematologic cancer characterized by multiple recurrences. With each recurrence, patients have a lower probability of response and duration of response is shorter. Therefore, there is an unmet need to improve outcomes in relapsed/refractory multiple myeloma (RRMM). There is a shortage of data describing clinical features and outcomes in these patients in real-world practice, particularly with regard to differences in outcomes by baseline cytogenetic risk. To help address this information gap, this study analyzed data from a cohort of RRMM patients in France. METHODS: A retrospective observational review of medical records was conducted in a cohort of 200 patients with RRMM in France. Patients were selected (based on randomly generated first letter of last name) from the caseloads of 40 hematology/oncology providers across France practicing mainly in academic hospitals. Inclusion criteria were: ≥18 years of age at initial MM diagnosis; first determined to have RRMM between January 1, 2009 and December 31, 2011, where RRMM was defined by (1) first-line (induction) regimen of chemotherapy with or without stem cell transplant (SCT) and with or without other post-induction/SCT therapy and (2) disease progression while on or at any time after completion of first-line therapy. Patients could be alive or deceased at the time of record abstraction. Baseline cytogenetic risk was defined as follows: high-risk: cytogenetic abnormalities del(17p), t(4:14), or t(14;16); unknown/unassessed risk: patients for whom cytogenetics were unavailable; or standard-risk: all patients with known cytogenetics not classified as high-risk. Patients were assessed for treatment response, overall survival (OS) and progression-free survival (PFS) from date of first relapse (study index date). All analyses were descriptive. Survival was assessed using the Kaplan-Meier (K-M) method. RESULTS: Demographic and clinical characteristics of the study sample are presented in Table 1. A total of 55 high-risk and 113 standard-risk patients were identified; risk category was unknown or unassessed for 32 patients. Among all patients, mean (SD) age at RRMM diagnosis was 66.3 (8.9) years and 62% of the sample was male. Lenalidomide + dexamethasone was the most common second-line systemic regimen initiated (50% of high-risk patients, 59.5% of standard-risk patients receiving second-line treatment). A total of 114 patients (57%) initiated a third-line treatment. Despite clinical response in second-line treatment occurring sooner in high-risk patients (median: 106 days) than in standard-risk patients (median: 237 days), physician-assessed overall response rate (ORR) was lower in high-risk patients (63%: 17% complete response, 46% partial response) than standard-risk patients (91%: 26% complete response, 65% partial response) across all second-line treatments combined (Table 2).. For third-line treatment, ORR was lower in high-risk patients (54%: 12% complete response, 42% partial response) than standard-risk patients (74%: 9% complete response, 65% partial response). Among patients who initiated a second-line treatment (n = 192), 47.4% were deceased at the time of data collection. From second-line initiation, K-M estimates of 1- to 5-year OS and PFS were substantially lower for high-risk patients versus standard-risk. Specifically, the proportions of patients still alive 1, 3, and 5 years after second-line treatment initiation were 73%, 51%, and 36%, respectively, for high-risk patients and 94%, 73%, and 61% for standard-risk patients. The proportions of patients without disease progression at 1, 3, and 5 years after second-line initiation were 48%, 13.5%, and 5% for high-risk patients and 82%, 42%, and 14% for standard-risk patients. CONCLUSIONS: The importance of cytogenetic risk classification as a prognostic factor in RRMM was apparent in this retrospective review, in which patients with high-risk cytogenetics had less favorable outcomes in terms of ORR, OS, and PFS than standard-risk patients. Decreased response rate and lower PFS and OS was documented among patients with high-risk cytogenetics, which is in contrast to shorter time needed to achieve best clinical response in this subgroup. Results from this real-world study provide further confirmation of the unmet medical need presented by RRMM, especially for patients with high-risk cytogenetics. Disclosures Lin: Takeda: Employment. Davis:Takeda: Research Funding. Kaye:Takeda: Research Funding. Luptakova:Takeda Oncology: Employment. Gao:Takeda: Employment. Nagar:Takeda: Research Funding. Seal:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership.

scholarly journals The Risk of Stroke Using CHA2 DS2 -VASc Score in Hemodialysis Patients at a Tertiary Hospital in Riyadh, Saudi Arabia

2019 ◽  
Vol 4 (7) ◽  
Keyword(s):  
Risk Factors ◽  
High Risk ◽  
Stroke Risk ◽  
Hemodialysis Patients ◽  
Low Risk ◽  
High Risk Patients ◽  
Stroke Risk Factors ◽  
Increased Risk ◽  
Risk Patients ◽  
History Of

Introduction: Patients undergoing hemodialysis are at increased risk of stroke. However, less known about the impact of some of the stroke risk factors, and the value of stroke risk scores in determining the risk in those patients. Our main goal. To assess the risk factors for stroke in hemodialysis patients and the use of the new CHA2DS2-VASc score for stroke assessment. Methods: Single center, retrospective cohort study of 336 patients undergoing hemodialysis from June 24, 2018, to September 6, 2018, was recruited. Baseline demographics, clinical, and laboratory data were collected. We calculated the CHA2 DS2 -VASc score for stroke assessment in all patients and categorized them into high, moderate and low risk patients according to CHA2 DS2 - VASc score and subcategorized them to two groups atrial fibrillation (AFib) and Non- Atrial fibrillation (Non AFib) patients. Results: 336 patients were included in our study; the majority of patients were at high risk with a CHA2 DS2 -VASc Score mean of 2.9± 1.5, although history of stroke was observed only in 15 patients (4.46%). According to CHA2 DS2 - VASc score, 280 patients were at high risk, 172 (51.19%) were high-risk patients on treatment (anticoagulant or antiplatelet) and 108(32.14%) patients were high risk patients not on treatment 48 were at moderate risk (14.28%) and 8 were at low risk (2.38 %). Patients were divided into subgroups as non-AFib and AFib. In non-AFib patients 320 (95.23%), high-risk patients 103 (32.18%) were not treated; high-risk patients with treatment are 162 (50.62%), moderate patients were 47 (14.68%), 8(2.5%) was in low risk. AFib patients were 16 with a mean CHA2 DS2 -VASc score of 4.4±1.1. Patients with AFib were all at high risk except 1 was at moderate risk (6.25%). There were 11 (68.75%) patients on treatment and 5 (31.25%) patients not on treatment. The risk factors for stroke that were statistically significant in increasing score risk for all patients were: age > 65 (95% CI, -2.04– -1.29; p = 0.000), being female (95% CI, -1.36– -0.68; p = 0.000) hypertension (95% CI, -2.59– -1.37; p = 0.000), diabetes (95% CI, -2.10– -1.50; p = 0.000), CVD (95% CI, -2.07– -1.24; p=0.000), history of stroke or TIA (95% CI, -3.70– -2.03; p = 0.000), CHF or LVEF (95% CI, -2.28– - 0.91; p = 0.000). Conclusions: The risk of stroke in hemodialysis patients is significant according to the use of CHA2 DS2 -VASc score in Non-AFib hemodialysis patients shows supportive evidence of increased risk of stroke in those patients, which suggest the importance of close monitoring of patients with stroke risk factors by the nephrologist and the stroke team which will lead to the initiation of early prophylaxis in those patients.

Improving rates of venous thromboembolism prophylaxis in multiple myeloma patients on immunomodulatory drugs through a pharmacy-based system

2021 ◽  
pp. 107815522199588
Author(s):  
Aric Parnes ◽  
Houry Leblebjian ◽  
Joanna Hamilton ◽  
Sydney Smith ◽  
Jacob Laubach ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Oral Anticoagulants ◽  
Bleeding Complications ◽  
Minor Bleeding ◽  
Immunomodulatory Drugs ◽  
Improvement Project ◽  
High Risk Patients ◽  
Increased Risk ◽  
Risk Patients

Introduction Immunomodulatory drugs used to treat multiple myeloma carry an increased risk of venous thromboembolic (VTE) disease. Previously published guidelines outline consensus opinion on how to mitigate this risk. Methods We collected baseline data to analyze how these strategies are utilized at our single institution and sought to improve the rates of anticoagulation for high-risk patients. This was done through a quality improvement project that added pharmacy/haematology oversight to the VTE risk assessment. Results Thirty-nine patients newly started on IMiDs were assessed for VTE risk. This information was passed on to the myeloma provider for consideration. Twenty-two patients were classified as high risk for VTE. Of the high-risk patients, 14 (64%) were placed on an anticoagulant for thromboprophylaxis. Eleven (79%) of the 14 used direct oral anticoagulants (DOACs). Eight high-risk patients did not receive an anticoagulant for thromboprophylaxis; 4 of these developed VTE. No patients on anticoagulation developed a VTE. This strategy had rare minor bleeding complications. Conclusion This quality action verifies guideline-based thromboprophylaxis in multiple myeloma and supports the benefit of pharmacy oversight in improving VTE rates. The use of DOACs in myeloma should be further explored.

scholarly journals SARS, MERS, COVID-19: Identification of Patients at a Higher Risk: A Narrative Review

2021 ◽  
Vol 2 (1) ◽  
pp. 57-70
Author(s):  
Hussein Noureldine ◽  
Georges Chedid ◽  
Jad Gerges Harb ◽  
Wared Nour-Eldine ◽  
Mariam Nour Eldine ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Risk Factors ◽  
Cardiovascular Disease ◽  
High Risk ◽  
Pregnant Women ◽  
Early Identification ◽  
Factors Associated ◽  
High Risk Patients ◽  
Increased Risk ◽  
Risk Patients

The different presentations, comorbidities, and outcomes of COVID-19 highlight the importance of early identification and proper triage of patients. High-risk patients can be divided into patients with common comorbidities and patients with special categories. Common comorbidities include, but are not limited to, Cardiovascular Disease (CVD), Diabetes Mellitus (DM), immunosuppression, underlying respiratory disease, and obesity. Certain categories of COVID-19 patients are also at increased risk, including neonates and pregnant women.  In the present article, we delineate the reported risk factors for acquisition of infection, and for increased severity of the clinical disease. We also comparatively analyze those risk factors associated with COVID-19 and with the antecedent human acute respiratory syndrome-causing viruses, SARS-CoV-1 and MERS-CoV. We hypothesize that the structural similarities of the three viruses predict a similarity in the profile of high-risk patients. Several pathophysiological patterns have been detected to support this theory.

scholarly journals Practice-Relevant Revision of Ipset-Thrombosis Based on 1019 Patients with WHO-Defined Essential Thrombocythemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4055-4055
Author(s):  
Tiziano Barbui ◽  
Alessandro M. Vannucchi ◽  
Veronika Buxhofer-Ausch ◽  
Valerio De Stefano ◽  
Silvia Betti ◽  
...  
Keyword(s):  
Risk Factors ◽  
High Risk ◽  
Research Funding ◽  
Risk Group ◽  
Low Risk ◽  
P Value ◽  
Jak2 Mutation ◽  
Risk Status ◽  
High Risk Patients ◽  
Risk Patients

Abstract Background In the recent International Prognostic Score for Thrombosis in essential thrombocythemia (IPSET-thrombosis), age and history of thrombosis were confirmed as independent risk factors for future thrombosis and the study also identified independent prothrombotic role for cardiovascular (CV) risk factors and JAK2 V617F mutation (Barbui et al. Blood 2012). Methods In the current study, we re-analyzed the original IPSET-thrombosis data in 1019 patients with WHO-defined ET in whom JAK2 mutational status was available, in order to quantify the individual contributions of JAK2 mutations and CV risk factors in conventionally-assigned low and high risk ET, as well as in age- versus thrombosis-defined high risk status. Results After a median follow-up of 6.8 and 5.0 years in conventionally-assigned low- and high-risk patients, respectively, the overall annual rate of total thrombosis (108 events) in conventionally-assigned low- and high-risk patients was 1.11%-pt/y (CI 0.81-1.52) and 2.46%-pt/y (CI 1.94-3.11) respectively (p=0.001), and the difference was mainly due to a higher frequency of arterial thrombosis in high-risk patients (p<0.001).The influence of JAK2 mutational status and CV-risk factors on the rate of thrombosis in conventionally assigned low- and high-risk groups is presented in the table. Table 1. Additional risk factors N (%) Event Rate % pts/yr (95% CI) P-value P-value P-value trend Low risk 506 (50) 39 1.11 (0.81-1.52) None 200 (40) 7 0.44 (0.21-0.92) ref Cardiovascular risk factor 36 (7) 3 1.05 (0.34-3.25) 0.220 0.227 JAK2V617F 213 (43) 21 1.59 (1.04-2.44) 0.001 0.217 Both 52 (10) 8 2.57 (1.29-5.15) <0.001 ref <0.001 High risk 513 (50) 69 2.46 (1.94-3.11) None 111 (22) 10 1.44 (0.78-2.68) ref Cardiovascular risk factor 44 (9) 4 1.64 (0.62-4.37) 0.909 0.067 JAK2V617F 222 (43) 30 2.36 (1.65-3.38) 0.168 0.082 Both 136 (27) 25 4.17 (2.82-6.17) 0.011 ref 0.005 The number of major arterial and venous thrombosis was reported as rates per 100 patient-years and the difference among groups was assessed by Mantel Cox log-rank test i) Conventionally-assigned low-risk group. Amongst 506 patients, 200 (40%) displayed neither JAK2 mutation nor CV risk factors and their annual rate of thrombosis was 0.44%, as opposed to 1.05% in the presence of CV risk factors (P=NS), 1.59% in the presence of JAK2 mutation (p=0.001) and 2.57% in the presence of both CV risk factors and JAK2 mutation (P<0.001). There was no significant difference when low-risk patients with both JAK2 mutation and CV risk factors were compared with either those with CV risk factors only (p=0.227) or those with JAK2 mutation only (p=0.217). ii) Conventionally assigned high-risk group: The absence or presence of one or both of the aforementioned additional risk factors for thrombosis were documented in 111 (22%), 44 (9%), 222 (43%) and 136 (27%) patients, respectively, with corresponding annual rates of thrombosis at 1.44%, 1.64%, 2.36% and 4.17% (Table). High-risk patients with both risk factors had a significantly higher risk of thrombosis compared to their counterparts with the absence of JAK2 mutations and CV risk factors (p=0.011). Additional analysis revealed limited enhancement of thrombosis risk by either JAK2 mutations or CV risk factors or both in patients whose high-risk status was defined by the presence of thrombosis history, regardless of age (P=NS). In contrast, the presence of JAK2 mutations, with or without CV risk factors, might have affected thrombosis risk in patients where high-risk status was defined by age alone (p=0.05). Conclusions The current study suggests the possibility of considering four risk categories in ET: "very low risk" group (age ≤60 years and without thrombosis history, JAK2 mutations or CV risk factors); "low risk" (age ≤60 years and without thrombosis history but with JAK2 mutations or CV risk factors); "intermediate risk" (age>60 years but without thrombosis history or JAK2 mutations); and "high risk" (thrombosis history at any age or JAK2 -mutated patients who are older than 60 years of age). Treatment recommendations for each one of the above-mentioned new risk categories should be examined in the context of prospective controlled studies. Disclosures Barbui: Novartis: Speakers Bureau. Vannucchi:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees. Buxhofer-Ausch:AOP Orphan: Research Funding. De Stefano:Novartis: Research Funding, Speakers Bureau; Janssen Cilag: Research Funding; Shire: Speakers Bureau; GlaxoSmithKline: Speakers Bureau; Bruno Farmaceutici: Research Funding; Roche: Research Funding; Amgen: Speakers Bureau; Celgene: Speakers Bureau. Gisslinger:Janssen Cilag: Honoraria, Speakers Bureau; AOP ORPHAN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Geron: Consultancy; Sanofi Aventis: Consultancy; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau.

MELISSE, a Large Multicentric Observational Study to Determine Criteria and Risk Factors of Thromboembolism for Patients with Multiple Myeloma Treated with Immunomodulator Drugs

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 809-809
Author(s):  
Xavier Leleu ◽  
Laurent Daley ◽  
Philippe Rodon ◽  
Cyrille Hulin ◽  
Ahmad AL Jijakli ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Research Funding ◽  
Vascular Complications ◽  
Vte Prophylaxis ◽  
Line Therapy ◽  
Risk Patients ◽  
Data Missing ◽  
Third Line ◽  
Line Of Therapy

Abstract Abstract 809 Background. Immunomodulator drugs (IMiDs) are new and very promising oral agents for initial treatment and for treatment of relapse in Multiple Myeloma (MM); however, IMiDs are also associated with an increased risk of venous thromboembolism (VTE) which necessitates routine prophylaxis. Guidelines (Palumbo et al, Leukemia 2008) have proposed either aspirin or low weight molecular heparin (LWMH) for VTE prophylaxis based on a VTE risk stratification. Controversies remain regarding the best choice of VTE prophylaxis regimen in MM patients treated with IMiDs-based therapy and the criteria for the VTE risk definition. More studies are needed to better determine the criteria required for patients to receive either aspirin or LWMH as VTE prophylaxis. We designed a large multicentre observational study aimed at prospectively evaluating the incidence and risk factors of thromboembolism associated with IMiDs [either lenalidomide (Len) or thalidomide (Thal)] therapy in MM. Method. A total of 519 patients with MM treated with first to third line of therapy were included in this study. Patients were treated with IMiDs-based therapy at entry in the study, and those receiving VTE prophylaxis had to start this prior to start IMiDs (the choice was solely that of the clinician). Patients gave written informed consent according to the declaration of Helsinki. Various patient characteristics were recorded, such as age, sex, criteria of vascular complications, including adjuvant treatment such as EPO, bisphosphonates, radiotherapy, and previous history of either deep venous thrombosis (DVT) or pulmonary embolism (PE), or arterial vascular complications. The physicians were to record the risk of VTE occurrence, breakdown as low, mild and high, based on guidelines and their own appreciation of the risk. Occurrence of any thrombosis event (either venous or arterial) was to be recorded along with the descriptive characteristics of the event, how the event was managed and the outcome of the patient. The data were collected at entry in the study, and then at 4 and 12 months. Results. Out of the 519 patients, 35.66% had Thal-based and 64.34% had Len-based therapy. Overall, median age was 71, with 64.67% >65 years old and sex ratio was 249 male/268 female, similar in the 2 groups (data missing for n=2). One hundred and eighty patients were in first line therapy, 169 in second line therapy and 153 in third line therapy (data missing for n=17). Patients were treated with VTE prophylaxis as follow (data missing for n=8); 293 (57.34%) aspirin, 91 (17.81%) LWMH and 46 (9.00%) vitamin K antagonists. Surprisingly, 81 (15.85%) patients had no VTE prophylaxis. Aspirin was administered in 164 (69.79%) of low risk patients and LWMH in 33 (45.83%) of high risk patients. Investigators recorded 13 (3.65%) VTE at the 3564-months visits currently completed, with 7 DVT, 2 PE and 4 DVT+PE. Of these 13 VTE, 8 patients had aspirin, 1 had LWMH and 4 had no prophylaxis treatment. Of the 13 VTE, 1 patient was considered to have high risk of vascular complication and 12 patients either low or moderate risk, according to guidelines. The occurrence of VTE was unrelated to the regimen-based IMiD therapy and the line of therapy. Conclusion. This study further demonstrates that occurrence of VTE is low in IMiDs-based treated MM patients upon VTE prophylaxis, and that VTE prophylaxis is needed for patients treated with IMiDs-based therapy. However, despite VTE prophylaxis, we observed occurrence of VTE. These results question whether the current guidelines on VTE prophylaxis in MM patients treated with IMiDs-based therapy are accurate. Final results will be proposed with updated results at ASH 2010. Disclosures: 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. Daley:LEO Pharma: Employment. Lamblin:LEO Pharma: Employment. Natta:LEO Pharma: Employment.

scholarly journals Multiple Myeloma Epigenetic Programming Prognostic of Outcome Converges with Loci Reprogrammed in Relapsed/Refractory Disease

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 858-858
Author(s):  
Benjamin G Barwick ◽  
Sheri Skerget ◽  
Jonathan J Keats ◽  
Daniel Auclair ◽  
Sagar Lonial ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Multiple Myeloma ◽  
High Risk ◽  
Research Funding ◽  
Outcome Analysis ◽  
Pwwp Domain ◽  
High Risk Patients ◽  
Poor Outcome ◽  
Epigenetic Programming ◽  
Risk Patients

The genetic and transcriptional program of multiple myeloma has identified novel markers of high-risk disease and mechanisms of pathogenesis. However, there remains a significant gap between prospective identification of high-risk patients and our ability to determine all patients that experience poor outcomes. Epigenetic alterations in myeloma have been less studied, but have significant potential as a translatable biomarker. To better understand how epigenetic programming may contribute to myeloma pathogenesis, we characterized the myeloma DNA methylome. DNA from CD138+ enriched myeloma specimens from the Multiple Myeloma Research Foundation (MMRF) CoMMpass study (NCT01454297) were obtained after receiving permission from the CoMMpass Tissue Use Committee and Emory IRB. Whole genome bisulfite sequencing (WGBS) was performed by adapter ligation (Kapa HyperPrep) using fully methylated sequencing adapters followed by bisulfite conversion (Qiagen Epitect), library amplification (Kapa Uracil+ HiFi polymerase), and sequencing (NovaSeq 6000 S4 150bp paired-end reads). Sequencing data were mapped with Bismark and CpG methylation calls were extracted using R. WGBS DNA methylation data was generated for 120 specimens, including 87 baseline, 24 paired relapse, and 9 paired peripheral blood specimens. This yielded ≥5x coverage at 21,393,650 CpGs in 90% of samples with an average coverage of 20x. Myeloma exhibited extensive genomic hypomethylation such that the median level was 42% (range 21-67%) as compared to 64% in plasma cells from healthy individuals. Principle component analysis indicated most variation corresponded with hypomethylation, which occurred in megabase domains devoid of gene expression. In contrast, DNA methylation was retained in the bodies of expressed genes. Principle components 2 and 3 separated samples with t(4;14) translocations from others. This may be due to overexpression of WHSC1 driving excessive histone 3 lysine 36 di-methylation (H3K36me2), which in turn impacts the function of PWWP-domain containing DNA methyltransferases (DNMT3A, DNMT3B). Given the 3-fold variability observed in average methylation, we sought to understand if this was indicative of outcome. Analysis of 87 baseline specimens identified 23,386 loci where DNA methylation (or lack thereof) was prognostic of outcome (FDR ≤0.01) (Figure 1a). These prognostic loci were clustered into contiguous regions often found in gene bodies and could be used to stratify patients by progression-free and overall survival (P-value &lt;1e-7; Hazard ratio &gt;8) (Figure 1b). Importantly, the prognostic value of these CpG were independent of t(4;14) status and ISS stage, indicating these high-risk patients would not have otherwise been identified. Furthermore, analysis of 24 relapse specimens from 22 patients indicated epigenetic remodeling occurred at these prognostic loci. Specifically, loci where the presence of DNA methylation was indicative of poor outcome gained DNA methylation in relapsed samples, and loci where lack of DNA methylation was indicative of poor outcome lost DNA methylation in relapse samples (Figure 1c). These relapse/refractory DNA methylation changes occurred in contiguous regions proximal to genes including PRKCE, MGMT, FHIT, WWOX, and HDAC9 (Figure 1d and data not shown). Cumulatively, these data identify myeloma epigenetic markers of outcome that undergo reprogramming in relapsed samples suggesting they may be indicative of therapeutic resistance. Disclosures Lonial: Genentech: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy; BMS: Consultancy; Janssen: Consultancy, Research Funding; GSK: Consultancy; Karyopharm: Consultancy; Celgene Corporation: Consultancy, Research Funding. Boise:AstraZeneca: Honoraria, Research Funding; Genentech Inc.: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Improving Rates of Venous Thromboembolism Prophylaxis in Multiple Myeloma Patients on Immunomodulatory Drugs

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2235-2235
Author(s):  
Houry Leblebjian ◽  
Joanna Hamilton ◽  
Sydney Smith ◽  
Jacob Laubach ◽  
Nancy Berliner ◽  
...  
Keyword(s):  
Risk Factors ◽  
Risk Assessment ◽  
Multiple Myeloma ◽  
Venous Thromboembolism ◽  
High Risk ◽  
Low Risk ◽  
Immunomodulatory Drugs ◽  
Vte Prophylaxis ◽  
Nccn Guidelines ◽  
Risk Patients

Abstract BACKGROUND: Multiple myeloma patients who receive immunomodulatory drugs (IMiDs: lenalidomide, thalidomide, and pomalidomide) have an increased risk of developing venous thromboembolism (VTE). Guidelines for thromboprophylaxis are based on additional patient and disease characteristics. We describe our single-institution experience with VTE prophylaxis and an intervention to improve VTE risk assessment and prophylaxis. METHODS: A retrospective review using an internal patient database assessed VTE in multiple myeloma patients being treated with IMiDs from 2000-2016. VTE risk factors for each patient were assessed to determine alignment with thromboprophylaxis guidelines. A Quality Improvement (QI) phase from April 1, 2017 to December 31, 2017 added pharmacy oversight to perform an independent VTE risk assessment. Every patient started on an IMiD during this period underwent a separate VTE risk assessment by a pharmacist or hematologist. Each patient was categorized as high or low VTE risk based on NCCN guidelines. The results and recommendations for VTE prophylaxis were given to the myeloma provider. Results: In the initial retrospective review, 107 patients were identified who developed VTE during treatment of multiple myeloma with an IMiD despite thromboprophylaxis in 91 patients (85% of total; 78% on aspirin). The most common VTE risk factors per NCCN guidelines included cardiac disease (n=70), obesity (n=32), chronic kidney disease (n=27), and prior history of VTE (n=18). Eight patients received anticoagulant-based thromboprophylaxis. In the QI phase, 39 multiple myeloma patients were started on IMiDs. The risk assessment classified 17 as low-risk and 22 as high-risk. Of the high-risk patients, 14 (64%) were placed on an anticoagulant for thromboprophylaxis. Eleven (79%) of the anticoagulants used were direct oral anticoagulants (DOACs), 2 (14%) were a low-molecular weight heparin, one (7%) warfarin. The number of thromboembolic events that occurred were 6 (15%): 4 were high-risk on aspirin and 2 were low-risk on aspirin. The 2 low-risk patients who developed VTE had additional provoking factors (active infection, central line placement, smoking, a long driving trip). Eight high-risk patients were given aspirin. Out of the 8, 3 patients developed VTE and were then switched to anticoagulation. One high-risk patient received aspirin because of moderate thrombocytopenia and subsequently developed a VTE. No patients on anticoagulation developed a VTE. The number of complications attributed to thromboprophylaxis were 2 (5%). Two minor bleeding events occurred in patients who were on DOACs (1 epistaxis and 1 grade 1 GI bleed). Both patients continued DOAC anticoagulation after the event resolved. Conclusions: This two-phase QI study showed that multiple myeloma patients at high risk for VTE benefit from guideline-based thromboprophylaxis facilitated through a pharmacy-based system. DOAC's ease of use offer patients and providers an agreeable option that may improve compliance of VTE guidelines. However, prospective studies with DOACs in multiple myeloma are urgently needed to support this. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

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