Venous Thromboembolism In Multiple Myeloma Patients Research Articles

Risk Factors of Multiple Myeloma Complicated with Venous Thromboembolism

To analyze the clinical characteristics of venous thromboembolism (VTE) in patients with multiple myeloma (MM) and to identify the risk factors of VTE in MM patients. 179 newly diagnosed MM (NDMM) patients admitted to The Second Hospital of Shanxi Medical University from January 2014 to December 2020 who were followed up for more than 6 months were collected, and they were divided into VTE group and control group according to whether combined with VTE. The clinical and laboratory data were compared between the two groups. Mann-whitney U test was used for inter-group comparison of measurement data, Chi-square test or Fisher's exact test was used for inter-group comparison of count data, and multivariate logistic regression analysis was performed to explore the risk factors of VTE in MM patients. Compared with control group, the serum albumin (ALB) level in VTE group was significantly lower (P =0.033), the fibrinogen (FIB) level was significantly higher (P =0.016), and the proportion of patients with D-dimer≥2 000 ng/ml was significantly higher than that in the control group (26.3% vs 4.4%, P =0.002). There was a significant difference in M-component type between the two groups (P =0.028), and the proportion of IgG type in VTE group was higher. There were no statistically significant differences between two groups in age, sex, body mass index (BMI), the proportions of patients with hypertension, diabetes, coronary heart disease and cerebral infarction, white blood cell (WBC) count, platelet (PLT) count, liver and kidney function, plasma cells ratio in bone marrow, serum globulin (GLO), lactate dehydrogenase (LDH), β2-microglobulin (β2-MG) level, C-reactive protein (CRP) level, erythrocyte sedimentation rate (ESR), prothrombin time (PT), activated partial thromboplastin time (APTT), disease stage, thrombosis prevention and the use of immunomodulators (P >0.05). Multivariate logistic regression analysis showed that FIB level (OR=1.578, 95%CI:1.035-2.407, P =0.034), D-dimer≥2 000 ng/ml (OR=5.467, 95%CI:1.265-23.621, P =0.023) and IgG type (OR=4.780, 95%CI: 1.221-18.712, P =0.025) were independent risk factors for VTE in MM patients. MM patients are prone to VTE, and FIB level, D-dimer≥2 000 ng/ ml and IgG type are independent risk factors for VTE in MM patients.

Comparison of three risk assessment models for thromboembolism in multiple myeloma patients receiving immunomodulators: a Brazilian historical cohort.

Venous thromboembolism (VTE) is among the complications of Multiple Myeloma (MM) and may occur in up to 10% of this patient population. However, medications used in MM therapy such as immunomodulators (IMID) may raise these rates. Thus, risk prediction models have been developed to quantify the risk of VTE in MM patients. The aim of this study is to compare the performance of three risk assessment models for VTE in newly diagnosed MM (NDMM) patients using immunomodulatory agents. A historical cohort study during a 10-year period in a Brazilian metropolis with NDMM treated with IMID. Data were collected from patient's medical charts for the period of one year to calculate the scores using IMPEDE VTE, SAVED, and International Myeloma Working Group (IMWG) guidelines. The area under the curve (AUC) of the Receiver Operating Characteristic curve analysis was calculated to assess the discriminative power of three risk assessment models. We included 131 patients (9 in the VTE group versus 122 in the non VTE group). According to IMPEDE, 19.1, 62.6, and 18.3% of patients were considered low, intermediate, and high risk, respectively. SAVED classified 32.1% as high risk and 64.9% had ≥2 risk factors based on IMWG guidelines. The AUC of the IMPEDE VTE score was 0.80 (95% CI 0.66-0.95, p = 0.002), of the SAVED score was 0.69 (95% CI 0.49-0.89, p = 0.057), and of the IMWG risk score was 0.68 (95% CI 0.48-0.88, p = 0.075). IMPEDE VTE was the most accurate in predicting the development of VTE in Brazilian patients on IMID therapy. The SAVED score and the IMWG guidelines did not show discriminative ability in predicting VTE based on the population involved in this study.

Risk of Venous Thromboembolism in Multiple Myeloma Patients During the Immediate Peri-Autologous Hematopoietic Cell Transplantation Phase.

Venous thromboembolism (VTE) is a serious complication commonly experienced in cancer patients. Incidence of VTE typically brings poor prognosis as it represents the second most common cause of mortality in cancer patients just after the malignancy itself. Studies suggest that multiple myeloma (MM) is among the malignancies with further enhanced risk of VTE, especially in patients undergoing autologous hematopoietic cell transplantation (AHCT). However, risk factors and preventative approaches remain poorly explored. Here, we explore the incidence of VTE in MM patients undergoing AHCT, while also highlighting risk factors and preventions that may aid in preventing VTE in patients who are at higher risk.

Risk of Venous Thromboembolism in Multiple Myeloma Patients Undergoing Autologous Hematopoietic Cell Transplant

Introduction: Venous thromboembolism (VTE) is a common complication that could affect multiple myeloma (MM) patients. Previous studies suggested the incidence of VTE in MM patients not on VTE prophylaxis to be as high as 10.7% in the peri-transplant period. Usage of antiplatelet or anticoagulant VTE prophylaxis is often a challenging clinical decision especially in patients with profound thrombocytopenia. Here, we aimed to explore the incidence and risk factors for VTE in MM patients undergoing AHCT. Methods: The electronic medical records of all MM patients who underwent AHCT at Cleveland Clinic between January 1st, 2011 and January 15th, 2021 were reviewed. We evaluated the incidence and type of venous thrombosis occurring in the immediate peri-transplant period, defined as extending from the start of stem cell apheresis up to 30 days post-AHCT. Baseline patient, demographic, disease, and transplant factors were evaluated to analyze risk factors for VTE occurrence within the studied period. Statistical Package for Social Sciences (SPSS) was used for statistical analysis. Results: A total of 493 patients with available records were included in our study. The median age was 61.4 years (range 33.1-77.7 years) at the time of AHCT with a male preponderance of 59%. Symptomatic VTE was recorded in 23 events involving 17 patients (3.5%) within the defined peri-transplant period, of which 34.8% of the events occurred between the start of stem cell apheresis and the date of transplant (i.e. day 0). Around 34.8% of VTE events, involving 6 (35.3%), patients occurred during hospitalization for the transplant procedure. All VTEs were non-catheter related, and most were lower extremity deep venous thromboses (DVT) (52.2%), followed by pulmonary emboli (17.4%), DVT of upper extremities (13%), internal jugular thromboses (13%) and superficial vein thrombosis (4.4%). Of the 17 VTE patients, 41% had history of previous VTE prior to the defined peri-transplant period, 88.2% were recently on immunomodulatory drugs (IMiD), 76.5% were on either antiplatelet (41.2%) or anticoagulant (53%) therapy or both (17.7%), while 23.5% were on none. Most of the VTE patients were never smokers (70.6%), while the rest (29.4%) were ex-smokers. Of note, 35.3% of VTE patients had thrombocytopenia (Platelets <150 x109/L) but median platelet count of 184 x109/L. Patients who developed VTE were of similar age (median 62.1 vs 61.4 years, P=0.9) but had a higher female preponderance (64.7 vs 40.1%, P=0.04) compared to those who did not. In addition, they had similar albumin levels at diagnosis (75 vs 71.7% ≥ 3.5 g/dL, P=0.8), similar cytogenetic risk categorization (high risk in 35.3 vs 25.8%, P=0.4), ISS stages (P=0.5), disease remission status prior to AHCT (P=0.3), mobilization regimens (G-CSF + Plerixafor in 88.2 vs 88.2%, P=0.1), and recent IMiD use (88.2 vs76.7, P=0.26) (Table 1). However, VTE patients were more likely to have IgG MM (70.6 vs 62%, P=0.06), Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) ≥1 (100 vs 81.1%, P=0.05), infection at AHCT (12.5 vs 3.2%, P=0.05), longer length of AHCT hospital stay (median 17 vs 14.9 days, P<0.0001), and had higher prevalence of prior history of VTE (41.2 vs 11.6%, P<0.0001) (Table 1). With regards to prophylaxis therapy, VTE patients were less likely to be on antiplatelets (41.2 vs 65.6%, P=0.039), were on similar prophylactic anticoagulation (11.8 vs 19.5%, P=0.42), but were more likely to be on therapeutic anticoagulation (41 vs 14%, P=0.002) compared to non-VTE pts, suggesting a higher impact of a history of prior VTE than therapeutic anticoagulation on recurrence of VTE during the studied time period. Among patients with no history of previous VTE, non-VTE patients were more likely to be on either antiplatelet or prophylactic anticoagulation (82.6 vs 50%, P=0.02). Interestingly, no difference was seen in the incidence of VTE with antiplatelet vs prophylactic anticoagulation in patients without history of previous VTE (1.86 vs 0%, P=0.9). Moreover, among those with a history of previous VTE, the addition of antiplatelets to therapeutic anticoagulation did not significantly lower the risk of VTE recurrence in the studied time period (9 vs 16%, P=0.9). Conclusion: The use of VTE prophylaxis among MM patients undergoing AHCT may lower its incidence. The main risk factors for VTE are female sex, history of previous VTE, infections at AHCT, HCT-CI ≥1, and longer hospital stay. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Factors Associated to VTE in Multiple Myeloma Patients Treated with Daratumumab

Introduction: Hematologic malignancies, especially multiple myeloma (MM), are associated with a high risk for venous thromboembolism (VTE). In MM, multiple factors increase the risk of VTE including, but not limited to, different treatments. The most recognized therapies that increase VTE risk for MM are immunomodulator drugs (IMIDs), steroids, and carfilzomib. Monoclonal antibodies (mAbs), usually in combination with other treatments, have become the therapy of choice for transplant- and non-transplant candidates in newly diagnosed MM (NDMM) as well as those with relapsed and/or refractory disease (RRMM). Daratumumab is an anti-CD38 monoclonal antibody incorporated in several combination regimens, and its specific effect on VTE risk is not well known. Previous studies have tried to identify clinical and therapy-related factors associated with VTE risk, with limited data on VTE risk and monoclonal antibodies (Wang, J Leuk Lymphoma, 2021). This study aims to identify if an increased risk of VTE exists for patients undergoing treatment with daratumumab-based regimens in efforts to develop a future risk assessment model that incorporates mAbs. Methods: We retrospectively reviewed the medical records of consecutively identified patients who received daratumumab, registered in a data warehouse designed to study the interference of monoclonal antibodies and blood typing procedures, at MD Anderson Cancer Center (MDACC) for the treatment of MM between April 2014 and February 2021. The study was approved by the institutional review board at MDACC. Eligible patients were screened for upper and lower extremity deep venous thrombosis (DVT) and pulmonary embolism (PE) through doppler ultrasound and contrast enhanced radiology reports, respectively, within 365 days after the date of the first dose of daratumumab. A natural language processing algorithm was used to determine the likely VTE positive cases and then was confirmed with manual chart review. Patients were divided into two categories, based on the timing of VTE diagnosis relative to the first dose of daratumumab: VTE post-daratumumab versus non-VTE post-daratumumab. The co-variates of interest were derived from three previous VTE risk stratification systems (SAVED, IMPEDE-VTE, and IMWG) and the differences were compared within the two category-VTE groups. All variables of interest were analyzed using descriptive statistics. Chi-square test or Fisher exact test were used to assess the association between categorical variables, and non-parametric methods were used for continuous numeric variables. Variables with statistically significant differences between VTE-category groups (p≤ 0.05) were analyzed using a binary logistic regression to determine their effect on the VTE occurrence. Results: Out of 258 eligible patients, 32 had evidence of VTE post-daratumumab, for a VTE incidence of 12.4% at 12 months from the initiation of daratumumab. The median time to VTE from the first dose of daratumumab was 3.9 months (IQR 1.6 - 6.1 months). Of the variables tested, we identified that the presence of central venous access (PICC), surgery within the previous 90 days before the initiation of daratumumab, and the history of comorbidities (cardiac disease, CKD, acute infection, or immobilization) were more prevalent in patients with VTE (Table 1). In the logistic regression analysis, only the presence of comorbidities (p = 0.007) was significant to the risk of VTE, but PICC line insertion (p = 0.064) and surgery within the previous 90 days (p = 0.078) were not (Figure 1). The odds of having a new VTE was 3.3 (95% CI, 1.4-7.7). Conclusions: The incidence of VTE during daratumumab therapy appears to be high (>10% in 12 months). The use of concurrent chemotherapy and thalidomide-derivative agents did not appear to increase the risk of VTE in those patients. The presence of comorbidities was the only independent factor associated to the risk of VTE in that cohort. This study suggests that while the incidence of VTE in MM patients is high, the main contributing risk factors for VTE are dynamic and the interplay between those factors changes along the disease course. After validation, these findings could influence and improve current VTE risk assessment models and update primary thromboprophylaxis guidance for improved patient outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 738: Increasing uptake of direct oral anticoagulants for thromboprophylaxis among newly diagnosed multiple myeloma patients initiating immunomodulatory drug-based regimens, 2010 to 2017

Abstract Background: Multiple myeloma (MM) is associated with an increased incidence of venous thromboembolism (VTE) which results in greater morbidity and mortality in MM patients. Several MM treatments including receiving immunomodulatory drugs (IMiDs), cytotoxic chemotherapy, and high-dose dexamethasone also increase VTE risk. Clinical guidelines recommend thromboprophylactic regimens to mitigate the risk of VTE in MM patients. However, practices vary with respect to medications used for thromboprophylaxis, ranging from prescribing of aspirin to anticoagulant regimens with direct oral anticoagulants (DOAC) and warfarin. We aimed to describe patterns of warfarin- and DOAC-based thromboprophylaxis in newly diagnosed MM patients initiating IMiD-based treatment. Methods: We conducted a retrospective cohort study of MM patients using the IBM MarketScan Commercial Claims and Encounters and Medicare Supplemental databases. We included newly diagnosed MM patients initiating IMiD-based treatment between 2010 and 2017 with continuous health plan enrollment 12 months prior to and following diagnosis. We collected information on comorbidities, VTE risk factors and other MM therapies. The primary outcome of interest was initiating thromboprophylaxis with warfarin or DOAC within 90 days of treatment initiation. We evaluated prescribing trends over time and characteristics associated with DOAC- or warfarin-based thromboprophylaxis, we used univariate and multivariate multinomial logistic regression models comparing these two forms of thromboprophylaxis to those who did not receive thromboprophylaxis. Results: In a cohort of 6227 MM patients initiating IMiD-based regimens, the median age was 62 years and 43% were female. Over the entire study period, warfarin-based thromboprophylaxis was more prevalent relative to DOACs (10.5% vs. 6.9%). However, we observed a trend of increasing adoption of DOAC thromboprophylaxis from 2.4% of patients in 2010 to 12.7% in 2017; and the use of warfarin thromboprophylaxis consistently declined over time from 16.5% of patients in 2010 to 3.2% in 2017. In multivariable analyses, trends associated with increasing or decreasing odds of thromboprophylaxis with these agents were robust after adjustment for demographic and clinical characteristics including VTE risk factors and other MM treatment (DOAC: OR 1.35, 95% CI 1.28-1.44 and warfarin: OR 0.81, 95% CI 0.77-0.86). Conclusions: Over the study period, our findings indicate that DOAC-based thromobprophylaxis regimens were increasingly used over warfarin-based treatment in newly diagnosed commercially insured MM patients initiating IMiD therapy. Further research is needed to determine whether these patterns are associated with differences in clinical outcomes. Citation Format: Abdullah I. Abdelaziz, Karen Sweiss, Pritesh R. Patel, Brian C-H Chiu, Gregory S. Calip. Increasing uptake of direct oral anticoagulants for thromboprophylaxis among newly diagnosed multiple myeloma patients initiating immunomodulatory drug-based regimens, 2010 to 2017 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 738.

P-157: The safety and efficacy of Apixaban in patients with Multiple Myeloma on immunomodulatory therapy: real-world, single centre experience

<h3>Background</h3> Multiple myeloma (MM) is an incurable haematological malignancy associated with a high risk of venous thromboembolism (VTE). Studies have shown a significantly higher risk of VTE in MM patients compared to the general population. Moreover, it was shown that VTE in MM patients is an independent risk factor for increased mortality. Immunomodulatory agents (IMiDs) form an integral part in the treatment of MM but can be associated with a further increased risk of thrombosis especially with the addition of steroids. The incidence of VTE was quoted to be as high as 26% in one study with lenalidomide and dexamethasone combination. The IMWG recommends risk stratifying VTE thromboprophylaxis for patient treated with IMiDs to receive aspirin, low molecular weight heparin or warfarin. However, data from myeloma XI trial showed patients receiving VTE prophylaxis based on IMWG recommendations still experienced high rates of thrombosis. Since the publication of IMWG criteria, direct oral anticoagulants (DOACs) have been used as safe and effective alternatives to enoxaparin and warfarin for the treatment and prevention of VTE. Their use for VTE prophylaxis in myeloma lacks randomised comparisons with conventional approaches. <h3>Methods</h3> We present our experience on the use of apixaban for VTE prophylaxis in MM patients treated with IMiDs as an alternative to standard thromboprophylaxis. We conducted a retrospective observational analysis of VTE prophylaxis for all myeloma patients treated with IMiDs at the Royal Derby Hospital between October 2019-October 2020. Data were collected from electronic patient records. We analysed 115 episodes of IMiDs use in 109 patients (72 males and 44 females). The median age was 73 (range 42-89). Apixaban was used in 63 patients (54.8%). The remainder received enoxaparin (4,3.4%), antiplatelets (40, 34.8%), enoxaparin and antiplatelets (7, 6%) or warfarin (1, 0.8%). 44 (42%) patients were treated with IMiDs at 1st line whilst 72 (68%) were treated at relapse. The median number of lines of therapy was 2 (range 1-6). <h3>Results</h3> The number of thrombotic events on treatment was 6 (5.2%); 4 VTEs (2 PEs and 2 DVTs) and 2 arterial events (1 stroke and 1 NSTEMI) with one patient in each group on apixaban. The incidence of thrombotic events with apixaban was 1.7% vs. 3.4% with non-DOAC prophylaxis. Patients developed venous and arterial thrombotic events after a median of 2 (range 1-3) and 2.5 (range 1-4) lines of therapy respectively. VTE occurred on VTD and on lenaldiomide and dexamethasone chemotherapy in 1 and 3 patients respectively. Both arterial events occurred on lenalidomide and dexamethasone. There were no major haemorrhagic events. <h3>Conclusion</h3> Although this is a retrospective comparison of apixaban against a heterogenous non-DOAC prophylaxis arm, apixaban showed lower rates of thrombosis with no increased bleeding. Our analysis supports apixaban as a safe and effective alternative to conventional thromboprophylaxis.

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.

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

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.

Thrombotic Risk from Chemotherapy and Other Cancer Therapies.

Cancer patients have an increased risk of thrombosis. The development of cancer thrombosis is dependent on a number of factors including cancer type, stage, various biologic markers, and the use of central venous catheters. In addition, cancer treatment itself may increase thrombotic risk. Tamoxifen increases the risk of venous thromboembolism (VTE) by two- to sevenfold, while an impact on risk of arterial thrombosis is uncertain. Immunomodulatory imide drugs (IMiDs) such as thalidomide and lenalidomide increase the risk of VTE in patients with multiple myeloma (MM) by about 10-40% when given in combination with glucocorticoids or other chemotherapy agents; the risk of VTE in MM patients treated with IMiD-containing regimens necessitates that such patients receive thromboprophylaxis with aspirin, low-molecular-weight heparin, or warfarin. Among cytotoxic chemotherapy agents, cisplatin, and to a lesser extent fluorouracil, has been described in association with thrombosis. L-asparaginase in treatment of acute lymphoblastic leukemia is significantly associated with increased thrombosis particularly affecting the CNS, which may be due to acquired antithrombin deficiency; at some centers, plasma infusions or antithrombin replacement is used to mitigate this. Bevacizumab, an inhibitor of vascular endothelial growth factor, increases arterial and possibly venous thrombotic risk, although the literature is conflicting about the latter. Supportive care agents in cancer care, such as erythropoiesis-stimulating agents, granulocyte colony stimulating factor, and steroids, also have some impact on thrombosis. This review summarizes the mechanisms by which these and other therapies modulate thrombotic risks and how such risks may be managed.

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

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. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Elevated Levels of Circulating Nucleosomes Are Not Associated with Venous Thrombosis or Neutrophil Activation in Patients with Multiple Myeloma

Background: Patients with multiple myeloma (MM) are at a 9-fold increased risk of venous thromboembolism (VTE). Mechanisms underlying the increased VTE risk in MM have not yet been clarified. Recently, extracellular DNA, e.g. nucleosomes, has been shown to play a central role in coagulation activation and propagation in vivo and in animal models. Increased nucleosome levels were demonstrated in patients with VTE, supporting their role in VTE development. The prothrombotic activity of nucleosomes may be of importance in systemic inflammatory states, in which activated immune cells can release nucleosomes, such as neutrophils by forming neutrophil extracellular traps (NETs). However, during inflammation and upon chemotherapy, parenchymal cells and tumor cells, respectively, can also release extracellular DNA in the form of nucleosomes, which could promote coagulation. As MM is regarded as a systemic inflammatory disease, we hypothesized to find elevated levels of nucleosomes in MM patients, with an association between the highest levels of nucleosomes and development of VTE. Therefore, we assessed levels of nucleosomes and neutrophil activation, and their association with VTE, in a cohort of patients with newly diagnosed MM.Methods: We assessed levels of circulating nucleosomes and systemic neutrophil activation, by presence of elastase-α1-antitrypsin (EA) complexes, in 131 patients with newly diagnosed MM using plasma samples. Interleukin (IL)-6 and IL-8 levels were also assessed to estimate the inflammatory state. We used a case-cohort design to investigate the association between nucleosomes, neutrophil activation and VTE, by calculating odds ratios (ORs) with corresponding 95% confidence intervals (CIs) using nucleosomes and EA complexes as categorical variables, based on the 80th percentile for MM patients without VTE, with ≤80th percentile being the reference category. To compare levels of nucleosomes and neutrophil activation complexes in MM patients with patients with other malignancies, a comparison was made with a cohort of cases with objectified deep-vein thrombosis (DVT) of the leg and screened controls without DVT, stratified by malignancy status.Results: 19 of 131 MM patients (14.5%) developed VTE during MM treatment. Levels of nucleosomes (median 39.5 U/mL; interquartile range [IQR] 7.9-156.8, vs. median 25.6 U/mL; IQR 10.9-76.4; p=0.61) and neutrophil activation, as evidenced by presence of EA complexes (median 30.1 U/mL; IQR 22.6-39.3, vs. median 31.6 U/mL; IQR 24.3-46.0; p=0.45), did not differ between MM patients with and without VTE. No association was found between high levels (>80th percentile of non-VTE MM patients) of nucleosomes or neutrophil activation, and VTE (OR 0.5; 95% CI 0.2-1.6, and OR 2.1; 95% CI 0.5-9.7, respectively) in MM patients. IL-6 and IL-8 levels were low in all MM patients, irrespective of VTE. Nucleosome levels were similarly high in MM patients compared with DVT patients with other malignancies, and significantly higher compared with DVT patient without malignancies, and with DVT controls, irrespective of malignancy status (Fig. 1A). In contrast, levels of neutrophil activation were significantly lower in MM patients in all comparisons (Fig. 1B).Conclusions: Elevated levels of nucleosomes were found in MM patients, but without correlating high levels of neutrophil activation. Nucleosome levels in MM patients with and without VTE were similar, and there was no association between high levels of circulating nucleosomes or neutrophil activation, and VTE in MM patients. Our results suggest that elevated levels of nucleosomes in MM patients are independent of neutrophil activation or inflammatory status, but rather a marker of plasma cell injury or death. This could also explain absence of a clear association with VTE. Future studies are necessary to confirm the source and the clinical relevance of high levels of nucleosomes in MM patients. [Display omitted] DisclosuresLeebeek:Baxter: Research Funding; UniQure: Consultancy; Netherlands Hemophilia Foundation: Research Funding; CSL Behring: Research Funding.

Incidence and Risk Factors of Venous Thromboembolism in Patients with Multiple Myeloma Receiving Immunomodulatory Agents

Multiple myeloma (MM) is an incurable plasma cell disorder representing 10% of all hematologic malignancies. Cancer is a known risk factor for venous thromboembolism (VTE). Patients with MM are at a particularly high risk of developing VTE owing to patient characteristics (e.g. previous history of VTE), disease characteristics, and treatment characteristics including use of the immunomodulatory agents (IMIDs). Unfortunately, standard criteria to identify the patients most at risk for developing VTE in MM while receiving IMIDs are unknown. We sought to assess the incidence of VTE and its associated risk factors in MM patients receiving IMID therapy.A retrospective cohort study including 1680 consecutive patients with multiple myeloma treated at our centre between January 01, 1995 and January 26, 2016 was conducted. The annual incidence of VTE on immunomodulatory agents including thalidomide, lenalidomide, and pomalidomide was derived. Univariate incidence ratio analyses of VTE for different risk factors was performed including: previous history of VTE, concomitant use of dexamethasone, and ≥/< 6 months after IMID initiation.A total of 309 MM patients treated with an immunomodulatory agent were identified. Nineteen patients were excluded (incomplete data, lost to follow). Of the remaining 290 patients, the mean age was 67.9 and 42.4% were female. Twenty-seven VTE events were recorded. The overall risk ratio was 6.1 for the development of VTE. Patients with a personal history of VTE had an increased risk of suffering a VTE while on IMID therapy (IRR 5.4; CI, 1.9-13.6). The time from the initiation of the IMID therapy (less than 6 months) also increased the risk of developing a VTE (IRR 51.7; CI,19.4-160.1). The concomitant use of dexamethasone was not associated with a statistically significant increased risk (IRR 1.7; CI, 0.3-69.5). Incidence risk ratios for these risk factors are depicted in Table 1.Our results suggest that a personal history of VTE and the time from the initiation of the IMID (less than 6 months) are associated with an increased risk of VTE in MM patients receiving IMID therapy. This may be helpful in determining which multiple myeloma patients treated with an IMID agent warrant more aggressive thromboprophylaxis. Further prospective studies are needed to determine the optimal agent, intensity, and duration of thromboprophylaxis in patients with MM on IMID therapy. [Display omitted] DisclosuresMcCurdy:Celgene: Honoraria.

Ginkgo Biloba Extract Blunts the Prothrombotic Effect of Thalidomide on Human Umbilical Endothelial Cells

Patients with multiple myeloma (MM) are at increased risk of developing venous thromboembolism (VTE) compared to general individuals. With the introduction of immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide, substantially elevates the incidence of VTE. It was reported that patients with MM have significantly increased plasminogen activator inhibitor (PAI-1) level resulting in a decrease of fibrinolytic activity. To prevent VTE in MM patients receiving IMiDs, different prophylactic strategies such as low molecular weight heparin, aspirin and warfarin have been recommended. But most of those recommendations are based on limited evidence.Ginkgo biloba extract (GBE) is one of the most widely used herbal supplements, which has been used in thrombosis prevention. It prompts us to investigate the impact of thalidomide on fibrinolysis and whether GBE has affection on fibrinolysis. In this study, the human umbilical vein endothelial cells (HUVECs) were cultured alone or co-cultured with human multiple myeloma cell line (MMCs) in the medium with or without thalidomide and in the presence or absence of GBE. After 48 hours, culture supernatants were collected and protein concentration of t-PA and PAI-1 were analyzed by enzyme-linked immunosorbent assay.Results showed that MMCs and thalidomide can both altered the profibrinolytic potential of HUVECs by decreasing t-PA and increasing PAI-1 levels. When co-cultured with MMCs, thalidomide can further elevate PAI-1 levels but not further reduce t-PA. Whether HUVECs alone or co-cultured with MMCs, GBE was able to counteract these effects caused by thalidomide through increasing t-PA and decreasing PAI-1 levels.Results in this study indicate that GBE blunts the prothrombotic effect of thalidomide on HUVECs. It supports GBE clinic use for the prevention of VTE induced by IMiDs. DisclosuresNo relevant conflicts of interest to declare.

Efficacy and Safety of Danshen Compound Tablets in Preventing Thalidomide-Associated Thromboembolism in Patients with Multiple Myeloma: A Multicenter Retrospective Study.

BackgroundCurrently available antithrombotic prophylaxis is not perfectly reliable in elderly patients. The aim of this retrospective study was to evaluate the efficacy and safety of Compound Danshen Tablet (CDT) in preventing thromboembolism in multiple myeloma (MM) patients treated with thalidomide-based regimens.Material/MethodsMM patients treated with thalidomide-based regimens were retrospectively reviewed between January 2008 and March 2015. Patients were categorized into 3 cohorts based on thromboembolic prophylaxis used: CDT, Warfarin Tablet, and no prophylaxis. Venous thromboembolism (VTE), other adverse effects (AEs), and the changes of D-dimer and fibrinogen levels were monitored.ResultsSeven out of 313 MM patients (2.24%) developed venous thrombosis events (VTE) in this retrospective study, all clustering in the no prophylaxis cohort. Three patients of the Warfarin cohort (3.19%) experienced hemorrhage. Neither VTE events nor serious AEs were observed in the CDT cohort. Following Compound Danshen or Warfarin treatment for 3 months, the D-dimer and fibrinogen levels (in particular the D-dimer level) (all P<0.05), were obviously decreased relative to their respective baselines and the no prophylaxis cohort. In contrast, the 2 blotting parameters were significantly increased in the no prophylaxis cohort relative to the baseline level (All P<0.05), and were even higher in the patients experiencing VTE compared to the no VTE patients (P<0.0001 and P=0.016, respectively).ConclusionsOur findings indicate CDT is an effective therapy for preventing VTE in MM patients treated with thalidomide-based regimens, and is well tolerated in long-term use.

Clinical outcomes of venous thromboembolism with dalteparin therapy in multiple myeloma patients

This study focused on the clinical outcomes in multiple myeloma (MM) patients with venous thromboembolism (VTE) who received low-molecular-weight heparin (dalteparin) therapy. Changes in D-dimer levels before and after VTE were also evaluated. Among 549 patients treated with various chemotherapeutic agents, a total of 52 (9.47%) patients including 32 newly diagnosed with MM and 16 with relapsed/refractory MM developed VTE, 48 of whom received dalteparin. Among the 48 treated patients, 37 (77%) had proximal deep vein thrombosis (DVT), four had (8%) pulmonary embolism (PE), and seven (15%) had both DVT and PE. In 32 patients with available paired samples (at baseline and VTE occurrence), significant conversion of D-dimer levels from 2.2±0.4mg/L to 11.8±1.6mg/L (P<0.001) was observed, which decreased from 10.9±0.4mg/L to 1.9±0.6mg/L one month after initiating dalteparin therapy. A total of 44 patients received dalteparin with a median duration of 4.2months (range, 2.7–9.4), and four patients were discontinued early due to death (n=3) and major bleeding (n=1). After a median follow-up of 9.0months (range, 0.7–35.8) since the first VTE episode, five patients showed recurrence of VTE with a cumulative incidence of 17.5±7.9%. Major bleeding occurred in three patients. In summary, dalteparin seems to be a promising drug for the treatment of VTE in MM. In addition, the significant difference in D-dimer levels observed before occurrence of VTE and after dalteparin treatment may suggest the usefulness of D-dimer testing as a surrogate marker for VTE in MM patients.

The Challenge of Myeloma-Related Thromboembolic Disease: Can Thrombin Generation Assay May Detect Disease-Related Hypercoagulability?

RATIONAL/BACKGROUND: Venous thromboembolism (VTE) is a major complication of multiple myeloma (MM). Mortality and morbidity related to VTE in multiple myeloma patients remain a challenging health problem. The incidence of deep venous thrombosis with thalidomide plus dexamethasone therapy is 15-17%. The reported incidence of thrombosis with lenalidomid treatment in MM is 9 – 17.5%. The risk is higher when lenalidomid is used in combination with high dose of dexamethasone. The guidelines therefore recommend thromboprophylaxis but serious uncertainties remain concerning the optimal thromboprophylaxis. The optimal dose of LMWH for thromboprophylaxis, the potential interest of aspirin as an alternative strategy in these patients have not been clearly established. Thus, antithrombotic prophylaxis remains underused also due to the lack of a laboratory assay which can reliably detect hypercoagulability and predict the VTE risk in each patient with MM. Thrombin generation assay is a global haemostasis assay reflecting the overall function of the blood clotting system. Both platelet-poor and platelet-rich plasma samples can be tested. In platelet rich plasma, the test also reveals the role played by platelets in supporting haemostasis.With this pilot study, we aimed to evaluate thrombin generation assay (TGA) measuring the overall coagulation capacity of each patient, as a reliable, standardized over-all hemostasis assay for the detection of MM-related hypercoagulability.PATIENTS/MATERIALS & METHODS:Patients: Hundred and three adult patients, 62 males and 41 females, with MM followed in Lyon and Nantes University Hospitals were included in the study, after obtaining informed consent. The control group included 100 healthy adult volunteers with no personal history of bleeding or thrombosis and with no treatment which may interfere on hemostasis. Fifty three patients were included at the diagnosis before any treatment, 9 patients had a treatment with lenalidomid only, 41 patients were on lenalidomid and anti-thrombotic treatment e.g. 15 warfarin, 9 low molecular weight heparin (LMWH) and 20 aspirin.TGA: TG was measured using the calibrated automated TGA (CAT; Thrombinoscope bv) as previously described by Hemker et al, using TF1pM and phospholipids 4µM (final concentrations) in platelet poor plasma (PPP). Platelet Rich Plasma (PRP) samples were tested with TF1pM only.RESULTS & DISCUSSION:Our results showed that patients with MM had significantly higher thrombin generation capacity in PPP (p=0.01, Mann Whitney test) and in PRP (p<0.0001, Mann Whitney test). The in vitro addition of increasing concentrations of lenalidomid and dexamethasone had no significant effect on thrombin generation capacity of patients (p=0.99, Anova). In vivo thrombin generation results of patients treated with lenalidomid was significantly higher in PRP compared to untreated MM patients (p=0.04, Mann Whitney test). In the presence of platelets, prophylaxis with aspirin induced a significant reduction of thrombin generation (p=0.003) which was similar to that observed with LMWH, whilst patients on warfarin had very low thrombin generation results compared to prophylactic doses of LMWH (p<0.0001). These results are in line with clinical studies showing a similar prophylaxis efficacy of aspirin and LMWH in MM patients treated with lenalidomid. Our results emphasize a crucial role of platelets in the hypercoagulability induced by MM and immunomodulatory therapy. Platelet flow cytometry analysis showed that platelets were more activated in patients treated with lenalidomid and dexamethasone compared to untreated myeloma patients, with a statistically significant higher expression of platelet CD 62P (n=6; p=0.03 Mann Whitney test).CONCLUSIONS: TGA can be an interesting biomarker to detect hypercoagulability induced by MM. Our results suggest that platelets are involved in the pathophysiology of MM and lenalidomid-related hypercoagulability. In PRP of patients treated by lenalidomid, aspirin and LMWH have similar antithrombotic effect on thrombin generation. Warfarin induces the highest inhibition of thrombin generation in this population. The mechanisms involving platelets in the hypercoagulability of MM are currently further explored in our laboratory. The correlation between thrombin generation capacity and clinical VTE events needs to be investigated in further clinical studies. DisclosuresNo relevant conflicts of interest to declare.

Family History of Venous Thromboembolism As a Risk Factor for Thrombosis in Multiple Myeloma Patients: A Population-Based Study,

Abstract 3987 Background:Patients with multiple myeloma are at an increased risk of venous thromboembolism (VTE), especially when treated with thalidomide and lenalidomide. The etiology of this is largely unknown, but probably involves both genetic and environmental factors. Family history of VTE is a known risk factor for VTE in the general population, including known inherited thrombophilic abnormalities. The influence of a family history of VTE as a potential risk factor for VTE in multiple myeloma patients is unknown. To expand our knowledge on this topic, we conducted a large population-based study based on all multiple myeloma patients diagnosed in Sweden 1958–2004. Patients and Methods:We assessed the impact of family history of VTE as a risk factor for VTE among 21,067 multiple myeloma patients and 83,094 matched controls. Data on multiple myeloma patients was gathered from the Swedish Cancer Registry, information on first-degree relatives from the national Multigenerational Registry, and occurrence of VTE from the nationwide Patient Registry. We calculated odds ratios (OR) and 95% confidence intervals (CI) using chi-square. Results:Of the 21,067 multiple myeloma patients included in the study (54% males, median age at diagnosis 71 years), 66% had an identifiable first-degree relative. VTE was diagnosed in 1,429 multiple myeloma patients, and 921 had a family history of VTE. Compared to multiple myeloma patients without a family history of VTE, multiple myeloma patients with a family history of VTE had a 2.2-fold (95% CI 1.8–2.7; p<0.001) higher risk of VTE. Among 4,986 controls that were diagnosed with VTE, 316 had a family history of VTE. Controls with a family history of VTE had a 1.5-fold (95% CI 1.3–1.7; p<0.001) increased risk of VTE compared to controls without a family history of VTE. The difference of the impact of family history of VTE on the risk of VTE in multiple myeloma patients versus controls was significant. Summary and Conclusions:In this large population-based study including more than 20,000 multiple myeloma patients, we found family history of VTE to have a larger impact on VTE risk in multiple myeloma than in matched controls. Our findings confirm that genetic factors contribute to thrombophilia in multiple myeloma and may have therapeutic implications regarding thromboprophylaxis and treatment. Disclosures:No relevant conflicts of interest to declare.

Venous thromboembolism in multiple myeloma: Current perspectives in pathogenesis

Patients with multiple myeloma are at increased risk of venous thromboembolism (VTE) compared to the general population. The introduction of immunomodulatory agents, such as thalidomide and lenalidomide, substantially increases the incidence of VTE in multiple myeloma patients, especially when used in combination with high-dose dexamethasone and/or anthracycline-based chemotherapy. Thromboprophylaxis is recommended for reducing VTE in patients receiving immunomodulatory agent-based regimens. On the other hand, bortezomib, a proteasome inhibitor, is not associated with an increased risk of VTE, as observed by a very low incidence of thrombotic complications in the absence of thromboprophylaxis. Currently, the mechanisms underlying the impact of these agents on VTE are not well-understood. Further studies to investigate the pathogenesis of VTE in multiple myeloma are warranted. These studies may not only yield greater insight into the pathogenesis of disease but may also define novel targets for the prevention and treatment of thromboembolic events in patients with multiple myeloma.

Microparticle-Associated Tissue Factor Activity and Venous Thrombosis in Multiple Myeloma.

Background: Multiple myeloma (MM) is associated with an increased risk of venous thrombo-embolic complications. The pathogenesis of venous thromboembolism (VTE) in MM is not yet clarified. Recently an association between microparticle-associated tissue factor (MP-TF) activity in plasma and thrombosis in patients with adenocarcinoma has been reported. Aim of this study was to measure MP-TF activity in patients with MM before and after treatment with chemotherapy and to investigate whether MP-TF activity is associated with VTE in these patients.Patients and results: MP-TF activity was assessed in 123 patients with newly diagnosed multiple myeloma who were eligible for combination chemotherapy and in 20 healthy volunteers. MP-TF activity levels were higher in untreated MM patients compared to the healthy volunteers (17.8 fM Xa/min [8.8–32.8] (median [Inter Quartile Range] versus 4.7 fM Xa/min [2.3–6.6], p<0.001). After three courses of chemotherapy the level of MP-TF activity had decreased significantly to 11.8 fM Xa/min [7.0–18.3], but were still higher than in controls (P<0.001). VTE occurred in 12 patients (10%). In MM patients with VTE the level of MP-TF activity remained elevated after induction chemotherapy (17.9 [9.3– 36.3]), in contrast to MM patients not developing VTE (11.1 [6.9–16.6] ). MP-TF levels after chemotherapy were significantly associated with the risk of VTE, with a 4% increase of VTE risk for every fM Xa/ min MP-TF activity increase (95% CI: 1–8%, p=0.03)Conclusion: MP-TF activity levels in plasma are increased in patients with multiple myeloma and they decrease significantly after induction chemotherapy. Persistent high MP-TF activity is observed in patients who developed VTE during the induction phase chemotherapy, and is associated with VTE risk. Our findings suggest that MP-TF activity levels may have a pathogenetic role in VTE in multiple myeloma patients.