Venous Thromboembolism In Multiple Myeloma Research Articles

Thrombotic Risk and Calculated Whole Blood Viscosity in a Cohort of Patients With New Diagnosis of Multiple Myeloma.

The pathogenesis of venous thromboembolism in multiple myeloma is still poorly understood because multiple factors are involved. In particular, the increase in whole blood viscosity has a key role and, therefore, we performed an evaluation of some hemorheological determinants in multiple myeloma patients, putting them in relation to the thrombotic risk, with the aim to evaluate if an alteration of the hemorheological pattern was associated with a higher thrombotic risk. We performed an observational retrospective cohort study with data collected from January 2017 to September 2022. In a group of 190 patients with newly diagnosed multiple myeloma, we have examined the trend of calculated blood viscosity according to the Merrill formula, and we stratified the patients for the thrombotic risk in accordance with the IMWG/NCCN guidelines and with IMPEDE VTE score. Using the thrombotic risk stratification proposed by IMWG/NCCN any variation in calculated blood viscosity is evident, while, with the IMPEDE VTE score, we observed an increase in calculated blood viscosity in patients with "intermediate + high" risk. The calculated blood viscosity is higher in subjects presenting an "intermediate + high" thrombotic risk according to the IMPEDE VTE score. This association could therefore lay the groundwork for further research with the aim to confirm the role of hemorheological pattern in MM-related thrombotic risk.

Hematologists’ awareness of venous thromboembolism in multiple myeloma: a national survey in China

Background Venous thromboembolism (VTE) is one of the most common and severe complications of multiple myeloma (MM). The aim of this study was to learn about the current awareness regarding MM-associated VTE among Chinese hematologists. Methods A nationwide, online, questionnaire-based survey was sent to the specialized hematologists in mainland China. The questionnaire investigated respondents’ demographic and occupational characteristics, their ability to identify VTE risk factors, and their thromboprophylaxis decisions for different anti-MM regimens. Six clinical vignettes were used to evaluate hematologists’ awareness of stratified thromboprophylaxis. The data were analyzed using SPSS software. Results A total of 518 valid questionnaires were received. Of the 518 hematologists investigated, only 23.7% of them could identify VTE-related risk factors correctly. Most hematologists could select appropriate thromboprophylaxis for common anti-MM regimens such as VCd (bortezomib, cyclophosphamide, and dexamethasone) and VRd (bortezomib, lenalidomide, and dexamethasone), but not for uncommon ones such as VTD-PACE (bortezomib, thalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide) and KRd (carfilzomib, lenalidomide, and dexamethasone). The results from the vignettes suggested that only 19.5% of the hematologists could be defined as the ‘stratified thromboprophylaxis’ group, and the awareness of stratified thromboprophylaxis depended significantly on physicians’ age and working seniority. Conclusion The results of our study showed that a large proportion of Chinese hematologists failed to recognize the VTE risk factors, most of them cannot select appropriate thromboprophylaxis for different MM therapeutic regimens and lack awareness of stratified thromboprophylaxis for MM-associated VTE. A standard VTE prevention guideline is urgently needed for the Chinese myeloma group. Continuous education for new professionals should be encouraged. A VTE collaborative group is supposed to be established in each hospital to enhance the overall medical care for VTE patients.

External Validation of PRISM Score in Multiple Myeloma Patients in a Community Setting: A Retrospective Cohort Study

Background: Newly diagnosed Multiple Myeloma (MM) patients have a 10 to 20 times higher risk of developing venous thromboembolism (VTE) than the general population. The pathogenesis may involve several factors such as activation of procoagulant factors, acquired activated protein C resistance, and inflammation. In addition to the general risk factors for venous thromboembolism such as older age, immobility, and surgery, some MM treatment-related factors such as the use of immunomodulatory drug therapy and abnormal cytogenetics contribute to the increased risk. The PRISM score (Prior VTE, Race, IMiD, Surgery, Metaphase Cytogenetics) is a risk prediction tool for VTE in MM and was published in 2022. The score ranges from 0 to 18 and patients were stratified into three groups: low (0), intermediate (1-6), and high risk (≥ 7). Our primary objective was to assess the external validity of the PRISM score in our community hospital setting. Methods: All consecutive newly diagnosed MM treated at Saint Vincent Hospital from 1/1/2008 to 12/22/2022 were included in our analysis. Patients receiving therapeutic anticoagulation for other indications or a diagnosis of VTE within 6 months preceding the MM diagnosis were excluded. Variables were collected through a retrospective chart review during MM treatment initiation. Model discrimination was assessed by calculating the area under the receiver operating characteristic curve (AUROC). Logistic regression was used to calculate the odds ratio (OR) of VTE occurrence in the risk prediction model. Results: A total of 214 patients with newly diagnosed MM and available data on VTE occurrence were included. The median age of our cohort at treatment initiation was 74 years (range 31- 96). The median BMI was 27.8. 56% were male, and 44% were female. The mean PRISM score was 2.9, and 73% of MM were IgG/IgA subtype. IMiD-based induction regimen was used in 63 % of patients. A total of 24 patients (11.2%) were diagnosed with VTE after treatment initiation, of which 8 (3.7%) patients had a previous history of VTE. Prophylactic aspirin was used in 53.8% and abnormal metaphase cytogenetics was identified in 13% of MM cases. The median time to VTE from induction therapy was 4.8 months. The PRISM score was low in 116 patients, intermediate in 89, and high in 9 patients. The AUROC of the model was 0.759 (95% CI, 0.644-0.874) (1). The cumulative incidence of VTE at 6 months, 12 months, and more than 1 year was 6%, 7%, and 11.2% of the patients respectively. Each 1-point increase in the score was associated with a significantly higher chance of VTE occurrence in the model [ HR= 1.53, 95% CI (1.27-1.85), P<0.001]. Among the parameters, patients with a history of VTE [ HR= 1.55, 95% CI (1.26-1.91), P<0.001] and with abnormal metaphase cytogenetics [HR= 2.35, 95% CI (1.37-4.05), P<0.001] had a higher strength of association with the development of VTE after induction (2). Furthermore, among 9 patients with a high-risk PRISM score (≥ 7), 7 (77%) developed VTE within the first 6 months after treatment initiation. Conclusions: Our findings suggest that PRISM [AUROC=0.75, 95% CI (0.644-0.874), P<0.001] score could statistically predict VTE outcomes in our patient population. Abnormal metaphase cytogenetics was a significant predictor of VTE in the validation cohort. Abnormal cytogenetics has been well established to be an indicator of aggressive tumor biology and proliferation in stroma-independent MM. It has been established to be a predictor of VTE in acute myeloid leukemia as well. Also, high-risk scores were predictive of earlier development of VTE after treatment induction. Our study strengthens the evidence of using PRISM as a predictive tool. Further studies are needed to enhance the sensitivity of our existing tool.

Evaluation of Clinical Risk Factors and Thrombosis-Related Biomarkers in Newly Diagnosed Patients with Multiple Myeloma at Risk for Cancer-Associated Thrombosis. the Observational Roadmat-CAT-MM Study

Background: Hypercoagulability is a common blood alteration in newly diagnosed chemotherapy naïve patients with multiple myeloma. Multiple myeloma (MM) figures among malignancies that significantly increase the risk of venous thromboembolism (VTE). The rate of VTE is higher at the time of diagnosis and during the first months following initiation of first line therapy; approximately 10% of newly diagnosed MM (NDMM) will develop a VTE. Despite adequate thromboprophylaxis as per guidelines, the risk of residual VTE is not eliminated and remains as high as 12%. The optimization of VTE prevention in patients with MM is an unmet need. The exact mechanism of the increased risk of VTE is not yet fully understood. The identification of the procoagulant potential of cancer cells, which is related principally to tissue factor (TF) expression, attracts particular interest. Aim: We conducted a longitudinal prospective observational study, to explore the relationship of MM with cellular and plasma hypercoagulability as well as tissue factor positive microparticles, aiming to identify the most relevant biomarkers, which could be used in a Risk Assessment Model (RAM) for VTE in combination with clinical risk factors. Methods: Newly diagnosed patients (182) with multiple myeloma (NDMM) were prospectively enrolled. Patients were followed up for 12 months and the primary end-point was symptomatic objectively confirmed VTE. Patients were risk stratified and received thromboprophylaxis (none, aspirin on low molecular weight heparin (LMWH) based on previously published recommendations by the IMWG and EMN. Prior to treatment initiation and thromboprophylaxis initiation baseline biomarkers were obtained: Thrombin generation (TGT) in citrated PPP was assessed with the Thrombogram-Thrombinoscope® assay using PPP-reagent® 5 pm TF by Diagnostica Stago. The levels of P-Selectin and heparanase in plasma were measured with ELISA Kit (Cusabio Biotech and R&D Systems respectively). The procoagulant phospholipids clotting time was measured with STA-Procoag-PPL®, Levels of Factor VIIa were measured by Staclot VIIa-rTF®, D-Dimers (DDi) by Liatest D-Di (Diagnostica Stago, France), and Tissue Factor activity (TFa) by specific clotting based home test. TF expression MPC-derived microparticles (MPC-dMPs) were detected using a Zymuphen MP-TF activity kit (Hyphen BioMed, Neuville sur Oise, France). These were compared against values in a population of healthy individuals (n=30). Results: The distribution of patients enrolled in the study is as follows: Median age was 67 years (36-86) and 52% of the population was male. Median time to follow up was 7 months (1-12 months). The control group (30 healthy individuals). The overall rate of symptomatic VTE during follow-up was 11.5% (n = 21 patients). Eleven out of 21 events (52%) occurred within 3 months from treatment initiation. Six of these patients did not receive any thromboprophylaxis; six patients were on aspirin at the time of the event and three were on LMWH.At inclusion, patients showed significantly increased levels of TFa, FVIIa, D-Dimers and FM, and significantly shorter Procoag-PPL® as compared to the group of healthy individuals. Levels of P-selectin and TM were significantly lower in patients as compared to healthy individuals. The levels of heparanase were not significantly different in the group of patients as compared to the healthy individuals. Overall thrombin generation was attenuated in patients compared to healthy individuals. Lag-time and ttPeak were significantly increased and Peak, MRI, and ETP were significantly lower as compared to the control group, MP-TF activity measured in NDMM significantly increased 1.46± 0.38 pg/mL compared to control subjects 0.19 ± 0.05 pg/mL (Table 1). Multivariate logistic regression analysis demonstrated that ETP, Procoag-PPL® and MP-TF were independently associated with VTE occurrence. (Table 2) Conclusion: The prospective ROADMAP-CAT-MM study demonstrates the presence of pronounced cellular hypercoagulability in newly diagnosed chemotherapy naïve patients with MM characterized by decreased Procoag-PPL® clotting time, enhanced endothelial cell activation, and exhausted thrombin generation. The Procoag-PPL clotting time and the ETP and MP-TF were found to be independently associated with the risk of VTE and can be prospectively incorporated into a RAM for VTE in MM.

D-dimer predicts venous thromboembolism in multiple myeloma: a nested case-control study

BackgroundClinical risk assessment scores, such as IMPEDE VTE, can identify patients with multiple myeloma (MM) at high-risk of venous thromboembolism (VTE). Refinement of these scores, by including 1 or more biomarkers, could improve risk assessment. ObjectivesWe sought to determine the association between soluble P-selectin (sP-selectin) and D-dimer with VTE in MM. MethodsWe identified 545 patients with newly diagnosed MM. Using a nested case-control design, we identified 38 cases of VTE within 6-months of MM treatment and 137 randomly selected controls. Using logistic regression, we examined the association between D-dimer and sP-selectin with VTE. We also analyzed the association after adjusting for IMPEDE VTE. ResultsEach 1-point increase in IMPEDE VTE score was associated with a 27% increase in odds of VTE (odds ratio 1.27; 95% CI 1.08-1.51; c-statistic 0.61; 95% CI 0.51-0.71). There was no association between sP-selectin and VTE. Each one increase in natural log of D-dimer was associated with a 44% increase in odds of VTE, so we assigned points (ranging from −2 to +2) to D-dimer values and incorporated them into IMPEDE VTE, forming IMPEDED VTE. There was a 30% increase in odds of VTE per each 1-point increase in IMPEDED VTE (OR 1.30; 95% CI 1.12-1.52; c-statistic 0.65; 95% CI 0.55-0.75). ConclusionAmong patients with newly diagnosed MM starting chemotherapy, D-dimer was associated with increased odds of developing VTE within the subsequent 6-months. The addition of D-dimer to IMPEDE VTE—IMPEDED VTE—could improve prediction of VTE among patients with MM.

Venous thromboembolism in multiple myeloma: Increasing evidence in support of direct oral anticoagulants.

Venous thromboembolism (VTE) continues to cause significant morbidity and excess mortality in patients with multiple myeloma. The report by Costa and colleagues demonstrates superiority of direct oral anticoagulants over aspirin in terms of VTE prevention, without increased bleeding complications seen. Commentary on: Costa et al. Direct oral anticoagulants versus aspirin for primary thromboprophylaxis in patients with multiple myeloma undergoing outpatient therapy: A systematic review and updated meta-analysis. Br J Haematol 2023;203:395-403.

Prognostic significance of thromboembolism in multiple myeloma: a systematic review and meta-analysis.

This study sought to investigate the clinical characteristics and prognosis of thromboembolism in multiple myeloma (MM). The PubMed, Embase, Web of Science, Wanfang, and China National Knowledge Infrastructure (CNKI) databases were systematically searched to retrieve relevant articles from the establishment of the databases to May 2022. This meta-analysis was performed to investigate the relationship between thromboembolism and overall survival (OS), progression-free survival (PFS), event-free survival (EFS), and mortality in MM patients. The meta-analysis of the included studies was performed using Revman5.3 software after quality evaluation. A total of 9 studies from 7 articles, which included 38,047 MM patients and 6,412 cases of thromboembolism in the analysis. The levels of β2 microglobulin affected the occurrence of thromboembolism in MM patients [standard mean difference (SMD) =-0.09, 95% confidence interval (CI): -0.18 to -0.01, P=0.02]. Venous thromboembolism (VTE) predicted poorer OS [hazard ratio (HR) = 0.79, 95% CI: 0.64-0.98, P=0.03] and higher early mortality (HR =2.27, 95% CI: 1.26-4.08, P=0.006) in MM. There was no significant difference in PFS/EFS (HR =0.81, 95% CI: 0.64-1.01, P=0.06) between thrombosis/embolism and non-thrombotic embolism. Arterial thrombosis was associated with significantly higher risk of death at 5 years (HR =1.89, 95% CI: 1.33-2.69, P<0.01). β2 microglobulin levels were associated with VTE in MM. MM patients with VTE were more likely to have poorer prognosis and higher mortality rate than those without VTE. MM patients with arterial thromboembolism had higher 5-year mortality rate than those without arterial thromboembolism.

Mitigating the risk of venous thromboembolism in patients with multiple myeloma receiving immunomodulatory-based therapy

Patients with multiple myeloma (MM) have up to a 20-fold increased risk of venous thromboembolism (VTE) compared with the general population, with most events occurring within the first 6 months of diagnosis. Treatment with immunomodulatory drugs (IMiDs) is a strong risk factor for VTE in MM. In a meta-analysis of 2 large, randomized trials comparing anticoagulant thromboprophylaxis vs placebo in ambulatory patients with cancer at high risk of VTE based on a validated risk score, the risk of VTE decreased without increasing the risk of major bleeding. However, few patients with MM participated in these trials (1.1%). Initial guidance for risk-stratifying patients with MM resulted in persistent rates of VTE >10% and highlighted the need for improved VTE risk stratification in patients with MM. Three validated risk scores are now available to quantify risk of VTE in patients with MM: SAVED, IMPEDE VTE, and PRISM scores. Using best available data, thromboprophylaxis should be strongly considered in patients with MM assessed as high risk for VTE, especially newly diagnosed patients receiving IMiD-based combination therapies. However, prospective studies are needed to further validate available models and identify the optimal thromboprophylactic agent for each VTE risk category.

Mechanisms Contributing to Acquired Activated Protein C Resistance in Patients Treated with Thalidomide: A Molecular Dynamics Study.

There is a high incidence of venous thromboembolism (VTE) in patients with Multiple Myeloma (MM), however; until now, the exact mechanisms behind VTE in MM are unknown, and some of the elements that may play a significant role are the treatment with an immunomodulator (IMiD) and acquired resistance to activated protein C (APC). The study aims to reveal the possible mechanisms linked to the reduced antithrombotic activity of APC associated with thalidomide. The molecular docking approach was used to ascertain the in silico inhibitory potential of thalidomide on the APC protease domain in the architecture of the catalytic triad and its interaction with major substrate binding sites. The coupling showed that the inhibitory activity of thalidomide depends on the induction of structural changes in the protease domain of APC, at the level of the Ser/His/Asp catalytic triad, as a result of a significant increase between the distances of CαAsp102 and Cα Ser195 (11.175 angstroms, increase 14.83%) and between CαSer195 and CαHis57 (9.478 angstroms, increase 13.78 %). This can result in an inefficient transfer of the proton between these residues, the other possible mechanism of inhibition, is a potential reduced binding of the substrate as a result of a direct interaction through a carbon-hydrogen bond on His57, an H-bond on Arg306, and a carbon hydrogen bond on Arg506. We demonstrate the in silico inhibitory potential of thalidomide on APC, through two possible inhibition mechanisms, a pathophysiologically relevant finding to understand the factors that can affect the stability and functions of APC in vivo.

Validation of the Impede VTE Score for Prediction of Venous Thromboembolism in Chinese Patients with Multiple Myeloma: A Retrospective Cohort Study

Background: The risk of venous thromboembolism (VTE) was 9-fold increase in multiple myeloma (MM) compared to the general population. In addition, the mortality rate of MM patients with VTE is three times higher compared to patients without VTE, which makes it so important to identify those at high risk and commit to preventing VTE events. Recently, the IMPEDE VTE score has emerged as a novel risk prediction tool for VTE in MM and has been incorporated and adopted by the NCCN guidelines. The variation in IMPEDE VTE scores is greatly influenced by Asian ethnicity/race, however, it lacks validation, especially for the Chinese populations. Furthermore, the validation of the IMPEDE VTE score's predictive ability for VTE in Caucasian and Black MM is controversial (Blood (2021) 138 (Supplement 1): 2971; Br J Haematol. 2021 Jun;193(6):1213-1219). Therefore, our objective was to validate the predictive ability of the IMPEDE VTE score for VTE in Chinese patients with MM. Methods: We performed a retrospective chart review of all patients with newly diagnosed MM who started chemotherapy at Beijing Jishuitan Hospital between 2011 and 2021 with a minimum of 6 months follow-up. Patients with coexisting tumors, missing data used to calculate VTE scores were excluded. In addition, The SAVED score, simultaneously adopted by the current NCCN Guidelines in risk-stratification of patients with MM receiving IMiD therapy, were analyzed and compared. The scores for IMPEDE VTE and SAVED were calculated from the date of chemotherapy initiation. Statistical analysis included Chi-square, Fisher's test, Wilcoxon rank sum tests, COX hazard, log-rank and K-M survival analysis. A p-value ≤ 0.05 was considered significant and all analysis was completed in SPSS 23.0 and Graphpad Prism version 8.0. Results: Our cohort included 423 newly diagnosed MM patients, 100% Chinese, 221 of whom were male (52.2%) and 141 (33.3%) patients were older than 65 years. Median age and BMI at diagnosis were 60.8 (IQR: 54.0-68.0) years and 24.5 (IQR: 22.2-26.6) kg/m2, respectively. Kaplan Meier survival analysis showed a 5-year survival rate of 53.72%. In the entire cohort, 62 (17.17%) patients developed VTE and 361 patients did not experience VTE within 6 months of treatment onset. The IMPEDE VTE scores at the start of treatment were ≤3 (low risk), 4-7 (moderate risk) and ≥8 (high risk) in 171 (40.43%), 209 (49.41%) and 43 (10.17%) patients, respectively. The median IMPEDE VTE score was 4 (IQR: 2-5) in all patients and 6 (IQR: 4-9) vs. 4 (IQR: 2-5) in the VTE vs. no VTE cohort, respectively (P < 0.001). Patients with MM in the VTE cohort were more likely to have a history of previous VTE (32.3% vs. 3.9％, P < 0.001), paraplegia (9.7% vs. 2.8%, P = 0.011), and extramedullary plasmacytoma (14.5% vs. 4.7%, P = 0.001) compared with no VTE cohort. Within 6 months of treatment initiation, central venous catheter was more frequently used in the VTE cohort as compared to the no VTE cohort (53.2% vs. 20.8%, P < 0.001). The 6-month cumulative incidence of VTE among all patients was 14.7% (95% CI: 11.3%-18%). In univariate Cox hazard analysis, each 1-point increase in IMPEDE VTE score was associated with the occurrence of VTE within 6 months of treatment initiation (HR: 1.33, 95% CI: 1.23-1.44, P < 0.001). According to the IMPEDE VTE score, the 6-month cumulative incidence of VTE was 3.7% (95% CI: 0.1-7.3) , 14.9% (95% CI: 9.9%-20%) and 24.0% (95% CI: 16.3-31.7) in the low-, intermediate- and high-risk groups (P < 0.001, log-rank), respectively (Fig 1A). The c-statistic of the IMPEDE VTE and SAVED scores for predicting VTE within 6 months of treatment initiation was 0.722 (95% CI: 0.647-0.796) and 0.672(95% CI:0.593-0.752), respectively (Fig 1B). The median follow-up of patients was 27.8 months (IQR: 12.1-49.2). On multivariable Cox hazard analysis, VTE within 6 months of treatment initiation was not a predictor of PFS (HR: 0.854, 95% CI: 0.576-1.267, P = 0.434) and OS (HR: 0.853, 95% CI: 0.527-1.379, P = 0.516) after adjusted for age, prognostic stage, cytogenetics, and ASCT. Conclusions: Our findings suggest that the IMPEDE VTE score is a valid evidence-based risk stratification tool in Chinese patients with newly diagnosed MM. Both the IMPEDE VTE (P=0.722) and SAVED (P=0.672) scores could statistically predict VTE outcomes in our patient population, and the IMPEDE VTE score outperformed the SAVED score in risk-stratification of Chinese patients with MM treated with IMiD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Machine Learning Model Defines Higher Risk of Venous Thromboembolism in Young Adults with Multiple Myeloma

Introduction: Venous thromboembolism (VTE) is a common cause of morbidity and mortality in patients with multiple myeloma (MM). Up to 10% of them may develop a thrombotic complication, being the risk higher during the first year of diagnosis. Currently, the use of thromboprophylaxis is based on risk scales according to logistic regression that generally are not validated and present modest predictive values. Machine learning (ML) algorithms identifies patterns that help us predict risk factors in a given disease. Numerous studies have shown that ML improves outcome prediction over traditional multivariate analysis models. To optimize VTE management in MM patients, thrombotic risk assessment models (RAM) will be generated in order to predict VTE development in MM patients (VTE-MM). To test our objective, we retrospectively analyzed a total of 133 patients with MM from 5 Spanish hospitals between January 2014 and December 2018. MM cohort was enriched with a total of 45 VTE patients in order to help machine learning algorithms and solving the imbalance problem. To build our predictive models, 131 clinical and biological variables were included. Variables with more than 25% of missing data were removed. Feature pre-filtering was carried out using unsupervised Boruta algorithm. Subsequently, the supervised Artifitial Neural Network (ANN) algorithm (80% training and 20% test) was applied on an input layer of 10 dimensions. To evaluate our ML model, we performed 10-fold cross validation. A confusion matrix was also used in the testing sets to evaluate the accuracy of the model. Parallelly, a univariate logistic regression (ULR) analysis was performed to identify significant variables (P<0.05) to entering into a multiple logistic regression (MLR) model. To determine a score for each independent variable, we used beta coefficients. The model was validated and evaluated applying leave-one-out method and ROC curve respectively. All analyses were carried out in R 3.6.3 and SPSS 26.0. Among VTE-MM (median age 67y, RIQ=60-74), 53% were men, mostly with ECOG >1, BMI 28 kg/m2 (RIQ 24-32), 53% had IgG and 45% of VTE-MM had revised international staging system (R-ISS) high at diagnosis. PE was the most frequent event (55%), occurring after diagnosis or 1st line of treatment. (Table 1). Boruta significantly selected 10 features (Fig.1A) and ANN algorithm demonstrated an AUC of 0.82 (Fig.1B and 1C). ML model selected young patients with previous surgeries, CVC before VTE, acute infections and with a high R-ISS as risk predictor factors. Multivariate-derived model were constructed with 8 ULR-derived variables (Fig 1D) and showed an AUC of 0.82 (Fig 1E). MLR model highlighted age (> 65y) as a protective factor (score of -4, CI: 0.003-0.308) (Fig 1D). Deep analysis of this group showed women as the higher risk patients (p=0.02). Conclusion: Both RAM models are good predictors of VTE in MM. They share 4 variables. Among them, young adult MM women seem to have more risk to develop VTE. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Venous thromboembolism and risk stratification in hematological malignancies

Patients with hematologic malignancy have an increased risk of venous thromboembolism (VTE) compared to the general population. This risk is highest during the first months after diagnosis and subsequently decreases over time. The risk of VTE in leukemia ranges from less than 1% to almost 7% within the first 6-months of diagnosis, and is higher in patients with acute leukemia compared to chronic leukemia. The risk of VTE in lymphoma ranges from less than 1% to almost 20% in the first year of diagnosis, varying by lymphoma type. Risk is lowest in patients with indolent lymphoma and highest in those with aggressive lymphoma, including central nervous system (CNS) lymphoma. The risk of VTE in multiple myeloma is highest in the first 6-months of diagnosis and decreases over time. Despite incorporation of thromboprophylaxis strategies in many patients, 6-month incidence of VTE remains greater than 10%. Primary thromboprophylaxis has the potential to decrease risk of VTE in patients at high-risk. Clinical risk prediction models can quantify risk of VTE, thereby identifying those at high-risk. VTE risk prediction models are available for patients with leukemia, lymphoma and multiple myeloma. However, these models either require external validation or have room for improvement in VTE risk discrimination. Future efforts should focus in validation of available models, incorporation of biomarkers as predictors of VTE, and evaluation of the risk/benefit of thromboprophylaxis in high risk patients.

Evaluation of the Khorana score for prediction of venous thromboembolism in patients with multiple myeloma

BackgroundGuidelines recommend thromboprophylaxis for patients with multiple myeloma (MM) at high risk for venous thromboembolism (VTE). However, the optimal risk prediction model for VTE in MM remains unclear. Khorana et al developed a VTE risk score (Khorana score) in ambulatory cancer patients receiving chemotherapy. We aimed to evaluate the predictive ability of the Khorana score in patients with MM. MethodsWe identified patients with MM within the Veterans Affairs health care system between 2006 and 2013. The Khorana score was calculated before treatment initiation. Using logistic regression, the relationship between risk group and VTE was assessed at 3 and 6 months. We tested model discrimination using the concordance statistic. ResultsIn the cohort of 2870 patients with MM, there were 1328 at low risk (0 points), 1521 at intermediate risk (1‐2 points), and 21 at high risk (≥3 points) for VTE by the Khorana score. The 6‐month cumulative incidence of VTE was 5.1% (95% confidence interval [CI], 4.0%‐6.4%) in low risk, 3.9% (95% CI, 3.0%‐5.0%) in intermediate risk, 4.8% (95% CI, 0.3%‐20.2%) in high risk. The Khorana score did not strongly discriminate between patients who did and did not develop VTEs at 3 or 6 months (concordance statistic, 0.58; 95% CI, 0.54‐0.63; and 0.53, 95% CI, 0.50‐0.57, respectively. ConclusionsIn conclusion, in this cohort of 2870 patients with MM, the Khorana score did not predict VTE. Our study supports the need to use myeloma‐specific risk models to predict VTE risk in patients with MM.

Incidence of Venous Thromboembolism in Patients with Hematologic Malignancies Receiving Immunomodulators and Concurrent Anticoagulation Therapy: A Single-Center Retrospective Study

Introduction:The incidence of venous thromboembolism (VTE) has been shown to be 28-times higher in patients with hematologic malignancies when compared with the general population. Among all of the hematologic malignancies, multiple myeloma has been associated with the highest risk for VTE. The pathophysiology of VTE in multiple myeloma is complex and the exact mechanism has not been fully elucidated. Prior studies have found a higher risk of VTE in patients with newly diagnosed multiple myeloma receiving combination therapies when compared with patients with relapsed or refractory disease. In addition to the disease itself, myeloma treatment and individual patient factors may also contribute to the risk of VTE. Oral immunomodulators (IMiDs) such as thalidomide, lenalidomide, and pomalidomide are the mainstay of myeloma treatment. Immunomodulators have been shown to improve response rate in myeloma patients but further increase the risk of VTE, especially when given in combination with dexamethasone and other chemotherapy agents.The International Myeloma Working Group (IMWG) and the National Comprehensive Cancer Network (NCCN) recommend the use of thromboprophylaxis in myeloma patients receiving immunomodulator-based regimens. Enoxaparin or warfarin are recommended in patients with two or more risk factors or in patients receiving high-dose dexamethasone, doxorubicin or combination chemotherapy, while aspirin is recommended in patients with one or no known risk factors. However, the selection of the most appropriate thromboprophylaxis remains challenging due to the lack of an accurate risk prediction model. Several studies have demonstrated a reduced rate of VTE after implementation of thromboprophylaxis in myeloma patients receiving IMiDs. Another study found no statistical significant difference in the incidence of developing a first episode of thrombosis in previously untreated myeloma patients receiving thromboprophylaxis with warfarin, aspirin, or enoxaparin. This suggests that all three agents may have similar efficacy but the results may not be applicable to all myeloma patients. Conversely, a more recent observational study found an overall significantly higher rate of VTE in patients who received thromboprophylaxis with aspirin than with a vitamin K antagonist. Since the publication of these studies, there has also been a rise in the prescribing rates of new oral anticoagulants (NOACs) despite limited evidence for the use in patients with cancers. Given the mixed results that are demonstrated by prior research and the utilization of a new class of agents, further investigation is needed to establish the efficacy of different thromboprophylaxis strategies.Objectives: Our primary objective is to determine the incidence of VTE episodes in patients with hematologic malignancies receiving an immunomodulator-based regimen and any concurrent anticoagulation therapies. Our secondary objectives are to classify anticoagulation therapies being used in combination with IMIDs, to identify the relationship between occurrence of new acute thrombosis and various anticoagulation therapies and to determine the clinical efficacy of different aspirin doses that are used for thromboprophylaxis.Methods: This single center, retrospective study will include patient data from July 1, 2014 to December 31, 2016. Patients who are 18 years old and above are eligible for inclusion if they received at least 2 documented consecutive cycles of an oral IMID (thalidomide, lenalidomide, and pomalidomide) for a hematologic malignancy with or without concurrent anticoagulation therapy. Patients are only included if their IMiD prescriptions were written by one of the hematologists at our cancer center. Patients receiving IMiDs while enrolled in a clinical trial are also allowed for inclusion in our analysis. Basic demographic information, relevant past medical history, concurrent chemotherapy, anticoagulation agents, and rates of VTE will be collected through a review of the electronic medical record. Chi-square or Fischer's exact test will be used for group comparison of categorical variables and Mann-Whitney U test will be used for the comparison of continuous variables.Results: In process. DisclosuresNo relevant conflicts of interest to declare.

Thrombosis and myeloma: it is time to get the elephant out of the room.

Thrombosis and myeloma: it is time to get the elephant out of the room.

Heparin versus aspirin thromboprophylaxis adds independent value to IMPEDE-VTE score for venous thrombosis prediction in multiple myeloma.

Multiple myeloma (MM) is associated to an increased incidence of venous thromboembolism (VTE). IMPEDE-VTE score constitutes a valuable risk assessment tool for VTE prediction in first-line MM patients. Nevertheless, refinement of the primary thromboprophylaxis category of this score (which pools aspirin and heparin) seems desirable. To investigate the role of the type of thromboprophylaxis, within IMPEDE-VTE score, for VTE prediction in MM patients. Retrospective analysis of a single-center cohort of 438 MM patients receiving first-line antimyeloma treatment (1991-2020). IMPEDE-VTE score was calculated. Primary thromboprophylaxis was additionally stratified into aspirin- and heparin-based regimen subgroups. VTE risk was analyzed by Cox regression. Median follow-up during first-line antimyeloma treatment was 6.0months (IQR 4.1-9.0months). Twenty-three patients developed VTE (5.3%, 95%CI 3.4-7.8%). IMPEDE-VTE score showed a notable predictive value (area under the ROC curve: 0.70, 95%CI 0.60-0.80). Cox analysis confirmed that 1-point increase in the score resulted in a 1.3-fold increase in VTE risk (HR 1.30, 95%CI 1.13-1.53, p < 0.001). In the multivariable analysis, the type of primary thromboprophylaxis (heparin versus aspirin) was an independent predictive factor (HR 0.15, 95% CI 0.05-0.47, p = 0.001). The combined model showed a higher goodness-of-fit (Akaike Information Criterion [AIC]: 99) than IMPEDE-VTE separately (AIC:235). Our analysis contributes to the external validation of IMPEDE-VTE score for the prediction of VTE in MM. But more interestingly, our results demonstrate that among those patients receiving thromboprophylaxis, the type of regimen (heparin versus aspirin) adds independent predictive value and should be explored for a more accurate risk assessment.

Abnormal Metaphase Cytogenetics Adds to Currently Known Risk-Factors for Venous Thromboembolism in Multiple Myeloma: Derivation of the PRISM score

Background: Prevention and management of venous thromboembolic events [VTE] is an important component of supportive care in newly diagnosed multiple myeloma [MM], especially in the era of immunomodulatory drugs [IMiDs]. Recently, two validated risk assessment models [RAMs], SAVED and IMPEDE-VTE, were developed to identify patients at high risk of VTE. However, these models have following limitations: (1) Patients were not uniformly treated in the era of contemporary MM therapy (2) Disease-specific variables were not available in the databases from which these scores were derived. Our primary aim was to develop a simple predictive model for VTE in MM using patient-specific, disease-specific, and treatment-specific variables. Our secondary aim was to assess the impact of VTE on overall survival [OS]. Methods: All consecutive patients with newly diagnosed MM treated at Cleveland Clinic from 1/1/2008 to 12/31/2018 were included in our analysis. The primary objective was to identify baseline variables associated with VTE within 12 months of treatment initiation. Candidate variables included those in IMWG, SAVED, and IMPEDE-VTE models as well as additional risk-factors from literature review in MM and cancer-associated VTE. Stepwise selection with variable entry criterion of p&amp;lt;0.20 and a variable retention criterion of p&amp;lt;0.05 was used to identify significant factors on multivariable analysis [MVA]. RAM was developed by subtracting 1 from the hazard ratio of a potential variable, rounding to the nearest 0.5, and multiplying by 2 to obtain a whole number. The impact of VTE on OS was assessed with landmark analysis. Results: A total of 934 patients with newly diagnosed MM and available data on VTE occurrence were considered for inclusion. We excluded patients with VTE within 6 months before starting therapy [n=5] and patients on therapeutic anticoagulation or receiving &amp;gt;1 prophylactic regimen [n=146], resulting in a total of 783 patients for model development. The most common induction regimen was bortezomib [V]-lenalidomide [R]-dexamethasone [VRD; 41%], followed by VD [22%], RD [20%], V-cyclophosphamide-dexamethasone [VCD; 11%], and others [7%]. Median age at treatment initiation was 63 years [range, 22-91], 55% were males, and 20% were Blacks. ISS stage III disease was present in 32%, high-risk FISH in 23%, abnormal metaphase cytogenetics in 18%, and serum creatinine &amp;gt;2 mg/dl in 19% of patients. Notably, 76% had received a dexamethasone dose of 120-160 mg/cycle, with only 5.9% started on a higher dose [&amp;gt;160 mg/cycle]. The most common thromboprophylaxis agent was aspirin [60%], followed by low molecular weight heparin [LMWH; 3.8%]; 37% of patients received no thromboprophylaxis. Erythropoietin and intravenous immunoglobulin were used in 2.9% and 1.2% of patients respectively. Median time to VTE from treatment initiation was 3.2 months. Cumulative incidence of VTE at 6 and 12 months was 8.2% [95% CI, 6.6-10.1] and 11.5% [95% CI, 9.5-13.6] respectively. Factors significantly associated with development of VTE on MVA were combined to develop the PRISM score [Table 1]: Prior VTE history [HR 5.06; 8 points], Black Race [HR 1.71; 1 point], IMiD use [HR 2.17; 2 points], Surgery within 3 months [HR 3.44; 5 points], and abnormal Metaphase cytogenetics [HR 2.10; 2 points]. The theoretical score range is 0-18, with a HR of 1.28 per 1-point increase in score [c-statistic 0.62]. Internal bootstrap validation including 1,000 samples showed a c-statistic of 0.62 [IQR, 0.60-0.64]. Using three risk groups by recursive partitioning analysis, 17.8%, 74%, and 8.1% belonged to low [0], intermediate [1-6], and high-risk [&amp;gt;6] groups respectively. The 12-month cumulative incidence of VTE in the 3 respective groups were 2.7%, 10.8%, and 36.5% [Figure 1]. Occurrence of VTE in the first 12 months was not associated with worse OS on landmark analysis at 3, 6, 9, and 12 months. Conclusion: We have developed and internally validated a RAM for VTE in MM in the context of contemporary MM therapy including disease-specific variables. Studies of external validation and comparison with existing RAMs are warranted. The PRISM Score could be used to identify high-risk patients for thromboprophylaxis. Figure Disclosures Valent: Amgen Inc.: Other: Teaching, Speakers Bureau; Takeda Pharmaceuticals: Other: Teaching, Speakers Bureau; Celgene: Other: Teaching, Speakers Bureau. Khouri:Sanofi Genzyme: Other: Advisory Board. Anwer:Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau. Khorana:Pharmacyclics: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; Medscape: Honoraria; Leo Pharma: Honoraria; Seattle Genetics: Honoraria; Pharmacyte: Honoraria; Leap: Research Funding; Bayer: Honoraria; Janssen: Honoraria; Merck: Research Funding; Array: Other: Research funding (to institution); BMS: Honoraria, Research Funding.

Venous thromboembolism in multiple myeloma is associated with increased mortality

BackgroundIn multiple myeloma, venous thromboembolism (VTE) is common, and treatments for myeloma, such as lenalidomide, increase the risk of thrombosis while improving survival. The association between VTE and survival is not well known. ObjectivesTo determine the association between VTE and survival in multiple myeloma (MM) while adjusting for known confounders that affect risk of thrombosis and survival, including patient characteristics and treatment in a retrospective cohort of US veterans. Patients/MethodsA cohort of patients with newly diagnosed MM treated within Veterans Health Administration between September 1, 1999, and June 30, 2014, was created to assess the association between VTE and mortality using Cox proportional hazards regression modeling while accounting for known prognostic factors and treatments. ResultsThe cohort comprised 4446 patients with myeloma, including 2837 patients diagnosed after lenalidomide approval in July 2006. VTE occurred in 327 (7.4%) patients within 1 year and occurred at a median of 77 days (interquartile range, 37‐153) after starting therapy for MM. In all patients, VTE was associated with increased mortality at 6 months (adjusted hazard ratio [aHR], 1.67; 95% confidence interval [CI], 1.18‐2.37). Patients in the post‐lenalidomide cohort with VTE had an increased mortality at both 6 months (aHR, 2.31; 95% CI, 1.52‐3.51) and 12 months (aHR, 1.66; 95% CI, 1.19‐2.33) after treatment initiation. DiscussionThis study shows that VTE during the first 6‐12 months of therapy is associated with increased mortality in patients with MM. Studies evaluating thromboprophylaxis in patients at high risk of thrombosis are needed.

Assessing the risk of venous thromboembolism in multiple myeloma

Patients with multiple myeloma (MM) have an increased risk of venous thromboembolism (VTE) compared to the general population. This risk is highest during the first year of diagnosis and subsequently decreases over time. Development of VTE in patients with MM is associated with inferior outcomes, with patients with VTE and MM having an increased risk of death compared to those with MM without VTE. Primary thromboprophylaxis has the potential to decrease risk of VTEksanfilippo@wustl.edu (K.M. Sanfilippo) in MM and improve outcomes. Current studies assessing thromboprophylaxis in MM excluded patients at high risk of VTE. A meta-analysis of trials of primary thromboprophylaxis in ambulatory cancer patients at high risk of VTE identified by use of a risk-prediction score found a reduction in risk of VTE with prophylaxis with no significant increase in risk of major bleeding. However, these trials contained relatively few patients with MM. Three clinical risk prediction scores are available to assess risk of VTE in MM: 1) the International Myeloma Working Group (IMWG)/National Comprehensive Cancer Network (NCCN); 2) the SAVED score; and 3) the IMPEDE VTE score. The latter two have recently been shown to outperform the IMWG/ NCCN score for predicting VTE in MM. Biomarkers have the potential to improve prediction of VTE in patients with MM. Future research should focus on the addition of biomarkers to available risk scores in MM to improve discrimination in this high-risk patient population.

External Validation of the Impede VTE Risk Score in Newly Diagnosed Multiple Myeloma (MM) Patients

Background: Venous thromboembolism (VTE) is a prevalent cause of morbidity in MM patients. The IMPEDE VTE score was recently proposed by Sanfilippo KM et al. in 2018 ASH annual meeting to predict VTE in MM. Herein, we report on the external validation of this score. Methods: We reviewed consecutive newly diagnosed MM patients who were treated at the Cleveland Clinic between 2010 and 2012. All treatment variables were collected as time-varying variables. Poor cytogenetic features were defined as monosomy 13 or 17, t(4;14), or t(4;16). We calculated the total IMPEDE VTE score for each patient as previously defined; immunomodulatory drug (IMiD) use (+3), BMI &gt;25 kg/m2 (+1), pathologic pelvis/femur fracture (+2), erythropoiesis-stimulating agent use (+1), low/high dexamethasone use (+2/+4), doxorubicin use (+2), Asian race (-3), history of VTE (+3), central venous catheter use (+2), prophylactic aspirin or enoxaparin (-2), therapeutic anticoagulation (-5). Patients with IMPEDE VTE score of &lt;3, 3 to 6, and &gt;6 were defined as low-, intermediate-, and high-risk groups, respectively. Cumulative incidence of symptomatic VTE after initiation of systemic treatment was calculated with death as competing risk and compared with the Gray's test. Overall survival (OS) was estimated by the Kaplan-Meier method and compared with the log-rank test. Multivariable Cox analysis was used to identify independent predictors of OS. Results: We identified 210 MM patients, 102 (49%) were female, 31 (15%) were black, and median age at diagnosis was 63 years (range: 30 - 91). Fifteen (7%) patients had VTE prior to MM diagnosis and 30 (14%) patients had pathologic pelvic or femur fracture at or after MM diagnosis. Poor cytogenetic features were seen in 65 (31%) patients. ECOG performance status at diagnosis was ≥2 for 33 (16%) patients. Sixty-seven (32%), 65 (31%), and 57 (27%) patients had ISS stage I, II, and III disease, respectively. MM subtypes were IgG, IgA, and light-chain disease for 109 (52%), 46 (22%), and 52 (25%) patients, respectively. IMiDs and low-dose dexamethasone were given to 145 (69%) and 205 (98%) patients, respectively. Seventy-seven (37%) patients underwent autologous hematopoietic cell transplant. Patient and treatment characteristics were compared between patients with and without VTE after MM diagnosis in Table 1. Twenty-two (10%) patients had symptomatic VTE within 6 months after initiation of systemic treatment for MM. When IMPEDE VTE score was calculated based on the risk factors during this time period, 37 (18%), 157 (75%), and 16 (8%) patients were in low-, intermediate- and high-risk groups, respectively. Six-months cumulative incidence of VTE in low-, intermediate- and high-risk groups were 2.7% (95% CI: 0 - 7.9), 10.8% (95% CI: 6.0 - 15.7), and 25% (95% CI: 3.8 - 46.2), respectively (p=0.011) (Figure 1A). Whereas, 39 (19%) patients were diagnosed with symptomatic VTE during median follow-up of 86 months. When the highest IMPEDE VTE score for each patient was calculated based on the risk factors at any time after initiation of treatment, 16 (8%), 151 (72%), and 43 (20%) patients were in low-, intermediate-, and high-risk groups, respectively. Seven-year cumulative incidence of VTE in low-, intermediate- and high-risk groups were 9.0% (95% CI: 0 - 25.7), 16.3% (95% CI: 10.3 - 22.3), and 29.3 (95% CI: 15.2 - 43.3), respectively (p=0.014) (Figure 1B). Seven-year OS of patients with and without VTE within 6 months after initiation of treatment was 50% (95% CI: 32% - 79%) and 46% (95% CI: 39% - 55%), respectively (p=0.4). On multivariable analysis, VTE vs no VTE within 6 months after initiation of treatment did not predict OS (HR 1.10, 95% CI: 0.46 - 2.66, p=0.8), whereas each 1-year increase in age (HR 0.99, 95% CI: 0.96 - 1.02, p=0.61), each 1 increase in ECOG performance status (HR 1.77, 95% CI: 1.24 - 2.53, p=0.002) and ISS stage (HR 1.50, 95% CI: 1.06 - 1.14, p=0.024), poor vs non-poor cytogenetics features (HR 4.38, 95% CI: 2.25 - 8.57, p&lt;0.0001), high vs normal LDH (HR 1.94, 95% CI: 1.05 - 3.60, p=0.035), IMiD use vs non-use at first induction (HR 0.52, 95% CI: 0.29 - 0.43, p=0.026), and transplant vs no transplant (HR 0.40, 95% CI: 0.20 - 0.79, p=0.008) were statistically significant predictors of OS (Table 2). Conclusion: In this cohort of MM patients, we showed that IMPEDE VTE score was able to stratify patients into distinct risk groups and can be a helpful tool to provide personalized strategies for thromboprophylaxis. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Valent:Takeda pharmaceuticals: Speakers Bureau; Amgen corporation: Speakers Bureau; Celgene corporation: Speakers Bureau.