ALBERT

Description: Abstract 4209 Background: The risk of recurrent venous thromboembolism (VTE) in patients with cancer-associated VTE, remains high even with the use of low molecular weight heparin (LMWH). However, due to the heterogeneity of the disease it is probable that recurrence risk varies widely. We have developed a prediction rule to classify risk of recurrence in the first 6 months of treatment: + 1 is scored for each of female gender, lung cancer and prior VTE and – 1 is scored for breast cancer and – 2 for TNM stage 1 disease. With a score of ≤ 0, 4.5% of patients recur (this represented 48% of the patient populations), and 〉 0, 19.7% recur. The rule was derived in a retrospective cohort study of patients followed at the Thrombosis unit of the Ottawa hospital and requires validation. Methods: We applied our rule in a new set of 819 consecutive patients with cancer-associated VTE from 2 multicentre randomized controlled trials comparing LMWH with vitamin K antagonists (VKA) (ClotCant group). In these studies the stage of disease was not separated by exact TNM classification, rather patients were classified as stage I, II (no metastasis) versus III, IV (metastasis). As such, we redid our derivation model with stage I and II grouped together, which gave this variable a score of – 1. This resulted in a prediction rule which gave a recurrence risk that no longer clearly dichotomized risk; rather gave a low, intermediate, and high risk groups. As in our derivation study, we evaluated patients' risk of recurrence regardless of type of anticoagulant use (VKA or LMWH). Results: Of 819 patients, 86 (10.5%) presented with a VTE recurrence during the anticoagulation period. When we applied our derivation rule in this population, we were able to demonstrate a significant difference in VTE recurrence risk dependent on gender, primary tumour site, stage and history of prior VTE. Patients with a score 〈 0 have low risk (5.1%) for VTE recurrence and this represented 19% of the patient population; patients with a score of 0 had a intermediate risk (9.8%) and this represented 42% of patients; a score ≥ 1 was high risk (13.9%), occurring in 38% of the population. Dichotomizing the results gave a recurrence risk of 8% in patients with a score ≤ 0 and a 15.2% recurrence risk with a score 〉 0. Conclusion: the validation dataset suggests reproducibility of our model. The dichotomized score is less discriminatory than our original model suggesting an advantage to classifying patients tumour stage as TNM stage I versus stage II, III and IV. Unfortunately, we could not test this hypothesis with the ClotCant dataset. Our model appears to differentiate risk for recurrence and should be utilized in treatment trials: attempting novel treatment strategies in high risk patients since LMWH alone does not seem to be enough; and using the less costly typical “LMWH followed by oral anticoagulants” in the low risk population to evaluate whether VKA can be as safe and effective as long term LMWH. Disclosures: Lee: Eisai: Research Funding; Sanofi Aventis: Consultancy, Honoraria; Leo Pharma: Consultancy; Pfizer: Consultancy, Honoraria; Bayer: Honoraria; Boehringer Ingelheim: Consultancy, Honoraria, Speakers Bureau.

Description: Abstract 4202 Background: It is unknown whether patients with cancer who develop VTE after a surgical procedure have the same risk of recurrent VTE as clinical patients cancer-associated thrombosis. VTE recurrence risk in non-cancer patients with VTE after surgery is approximately 1% in the 3 months following completion of anticoagulation. It is unknown whether surgical patients with cancer follow the low risk of recurrence as other provoked VTEs or whether they have the high recurrence risk typical of cancer patients. Methods: We performed a post-hoc analysis of a single centre retrospective cohort study conducted at the Thrombosis Unit of the Ottawa Hospital. The charts of patients with cancer and VTE followed from 2002 to 2004 and from 2007 to 2008 were reviewed. We sought to compare the risk of recurrent VTE between patients with cancer who developed a first VTE after major surgery with all other patients with cancer-associated thrombosis. We included patients 〉 or = 18 years of age with active malignancy and objectively diagnosed index VTE [pulmonary embolism (PE), proximal deep venous thrombosis (DVT) of the legs or arms, PE + DVT; unusual site thrombosis]. After the first VTE, all patients received a minimum of 6 months of anticoagulation. In the surgery group, index VTE was considered associated with the intervention if it occurred within the first 3 months after the procedure. Results: 543 patients were included. 121 patients had VTE after surgery and 17 (13.1%) developed a recurrence during therapeutic anticoagulation. Of 422 clinical patients, 61 (14.7%) had a recurrent VTE (Table). The relative risk of recurrent VTE comparing patients who had and who did not have surgery was non-significant (RR= 0.97 (95%CI: 0.587 – 1.574; p= 1.000) suggesting that patients with cancer who undergo surgery have similar risk of developing a recurrent VTE during anticoagulation as patients with cancer-associated VTE who do not undergo surgery. VTE recurrence occurred predominantly within the first 6 months of anticoagulation [Surgery: 9 of 17 patients (52.9 %); no surgery: 45 of 61 (73.7%) patients (p=0.1377)] (Figure). There was no significant difference in VTE recurrence risk according to anticoagulant strategy, tumor site, histology, TNM stage, age or gender between surgery and no surgery groups. Conclusion: Patients with cancer who develop VTE after surgery have similar risk of developing a recurrent VTE during the anticoagulation period as clinical patients with cancer-associated VTE. Disclosures: Rodger: Pfizer: Research Funding; Leo Pharma: Research Funding; Sanofi Aventis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Canadian Institutes of Health Research: Research Funding; Heart and Stroke Foundation: Research Funding.

Description: Background: Venous thromboembolism (VTE) remains the major cause of morbidity and mortality in hospitalized patients. Three randomized placebo controlled trials have demonstrated the superiority low molecular weight heparin (LMWH) and 1 heparinoid in the prevention of VTE in hospitalized medical patients with a 50% absolute risk reduction in VTE compared to placebo, but an overall failure rate of 5%. Current guidelines suggest that hospitalized cancer patients receive venous thromboprophylaxis with LMWH, if their hospital stay is longer than 3 days. In this study we sought to evaluate the incidence of VTE in hospitalized patients with cancer receiving VTE prophylaxis with subcutaneous 5000 units of dalteparin daily during the admission period. Methods: This is a single centre retrospective cohort study (London, Canada). We collected data from adult patients with active cancer admitted for acute medical reasons who received VTE prophylaxis with LMWH during their hospital stay. We considered failure of prophylaxis if objective diagnosis of pulmonary embolism or deep venous thrombosis occurred: a) during hospitalization; b) within 1 month or 3 months of most recent discharge from hospital. We included patients 18 years old or older; with any type of active cancer (except basal cell and squamous cell carcinoma of the skin) admitted for at least 3 days for treatment of an acute medical reason directly associated to their cancer or not. We did not include patients admitted at the intensive care unit. We need 713 patients to demonstrate a 5 to 7.5% failure rate in VTE prophylaxis (MCID 2.5%) in hospitalized patients with cancer with a 0.025 one-sided alpha and 80% power. Results: Between January 2011 and December 2013 our hospital registered 4262 admissions of patients with active malignancy for treatment of an acute medical illness. 875 patients (total 1132 admissions) fulfilled our eligibility criteria. 434 were males (49.5%), mean age 64.3 (SD= 13.5). There were 180 (20%) hematological and 695 (80%) solid malignancies. The most frequent tumor sites were genitourinary (n=170), lung (n=158), colorectal (n=128) and others (n= 239). 559 (70%) patients with solid tumors had stage III or IV. Reason for admission was failure to thrive (n=232); fever/ infection (n= 202); need for cancer treatment (n= 154); pain control (n=126); respiratory distress (n=108) or CNS symptoms (n=53). Mean hospitalization days were 14.7 (±12). 491 (56%) patients had a single admission. VTE occurred in 70 of 875 patients (8.0%). The incidence of VTE was most frequent during the hospitalization period [34 of 70 patients (48.0%)] compared to 1 month [14 (20.0%)] or 3 months [22 (31.5%)] following the most recent hospitalization. Univariate analysis suggested that being male (OR= 1.69; 95%CI: 1.03 – 2.78; p=0.039); age 65 or older (OR=1.39; 95%CI: 0.4 -1.8; p=0.052); admission due to respiratory distress (OR=2.61; 95%CI: 0.9 – 6.8; p=0.052) or failure to thrive (OR=2.52; 95%CI: 1.1 – 5.9; p=0.036) were significantly associated with VTE risk. Having pancreas or colorectal cancer approached significance (Table). Total bleeding rate was 18 of 875 (2%) with 5 major bleeding events. 175 (20%) patients died during the study period: 125 (75%) due to malignancy progression. Conclusion: Hospitalized patients with active cancer are at high risk for VTE prophylaxis failure (8%). It appears that reason of admission, age and male sex are significant risk factors of VTE prophylaxis failure. Having colorectal or pancreatic cancer may also pose a risk for VTE. New VTE prophylactic strategies for this population should be investigated in future prospective studies. Table. Univariate analysis to assess potential risk factors for LMWH prophylaxis failure in hospitalized patients with cancer Risk Factors Odds Ratio (95% CI) p-value Male 0.95 (0.6 -1.5) 0.808 Age ≥65 1.39 (0.4 -1.8) 0.052 Stage I - II Stage III - IV 1.03 (0.4 -2.5)1.27 (0.7 -2.4) 0.9090.478 Primary tumor site* Lung Colorectal Breast Pancreas Others 1.79 (0.8 - 7.4)2.67(0.9 - 4.7)1.63 (0.9 -10.7)3.11 (0.6 - 3.8)1.33 (0.9 - 5.6) 0.1690.0600.3630.0730.452 Reason for admission^ Fever CNS symptoms Respiratory distress Pain Failure to thrive 1.32 (0.5 - 3.4)1.703 (0.5 - 6.0)2.61 (0.9 - 6.8)1.79 (0.7 - 4.8)2.52 (1.1 - 5.9) 0.5720.4110.0520.2480.036 Number of admissions **

Description: Background Hospitalization is a significant risk factor for venous thromboembolism (VTE) with 25% of all VTE occurring in this setting. In patients with cancer this risk may be higher due to the inherent procoagulant state malignancy-induced, -cancer therapy and its complications. Current oncology guidelines suggest that hospitalized medical patients receive venous thromboprophylaxis with unfractionated heparin or low molecular weight heparin if their hospital stay is longer than 3 days. We sought to evaluate if patients with cancer hospitalized for management of an acute medical illness are at higher risk for failing standard anticoagulation prophylaxis with dalteparin compared to historical data. Methods This is a single-centre retrospective cohort study (London, Canada). We included adult patients; with any type of active cancer admitted for at least 3 days for treatment of an acute medical reason, who received prophylaxis with dalteparin during hospital stay. Acute medical illness was: failure to thrive; fever; need for cancer treatment as an inpatient; pain control; acute respiratory illness. The main study outcome was failure of VTE prophylaxis defined as symptomatic and objectively diagnosed pulmonary embolism (PE) or deep venous thrombosis (DVT) within 3 months of the most recent hospital discharge. Results Between January 2011 and December 2013 our hospital registered 4262 admissions of patients with cancer for treatment of an acute medical illness. 875 patients (1132 admissions) fulfilled our eligibility criteria. 681 (78%) patients were classified as having a single admission. Of those, 247 had previous but excluded admissions ("pseudo-single"), which leaves 434 patients with true single admissions. In total, there were 434 (49.5%) were males, mean age was 64.3 (SD= 13.5). Primary tumor sites were hematological (n=180); genitourinary (n= 170); lung (n=158); gastrointestinal (n=128) and others (n= 289).559 (70%) patients had stage III or IV. Reasons for admission were failure to thrive (n= 232; 26.6%); fever (n= 202; 23.3%); need for cancer treatment as inpatient (n= 154; 17.7%); pain (n=126; 14.5%); respiratory distress(n= 108; 11.6%) or pain (n= 53; 6.3%). Mean hospitalization days was 14.7 (±12). VTE occurred in 78 of 875 (8.9%) patients or 78 of 1132 admission (6.9%): 36(46%) DVT, 34 (43.5%) PE and 7 PE + DVT (8.9%). 34 of 78 (43.6%) VTE occurred within the first 14 days of admission. However, the overall risk for VTE appeared to be much more significant if the patient remained hospitalized for more than 14 days [RR=3.7 (95%CI= 1.99 - 4.71; p

Description: Background Malignancy is a well-recognized risk factor for venous thromboembolism (VTE). In multiple myeloma the incidence of VTE varies between 3% and 10%. Immunomodulatory drugs (IMiDs) play a crucial role in the treatment of myeloma and are known to be associated with an increased risk of arterial and venous thromboembolic events (TE). It appears that patients with newly diagnosed multiple myeloma (NDMM) are at higher risk for TE compared to patients with relapsed or refractory myeloma (RRMM) at the start of IMiD therapy. Lenalidomide is a second-generation IMiD which in combination to dexamethasone has shown to be an effective and well-tolerated therapy for patients with NDMM or RRMM. However, studies have consistently demonstrated the need for TE prophylaxis in patients receiving the combination lenalidomide-dexamethasone which leads to a 4.4-fold increased risk for VTE compared to dexamethasone alone in the absence of prophylactic anticoagulants. Panel consensus from the International Myeloma Work Group has agreed that the choice of thromboprophylaxis depends on the individual risk of TE, as determined by patient and treatment-related factors, such as obesity, prior VTE, central venous catheter, immobilization, recent surgery, comorbidities, use of erythropoietin stimulating agents and myeloma therapy. Aspirin (ASA) is recommended for patients with one or no risk factors, and LMWH for those with more than one risk factor. However, the optimal approach to thromboprophylaxis has not yet been established. In this study we sought to compare the efficacy of ASA or low molecular weight heparin (LMWH) or vitamin K Antagonists (VKA) in the prevention of VTE or arterial thromboembolism (ATE) in patients with myeloma using lenalidomide-based therapy. Methods We performed a retrospective chart review in 2 centres (London, Canada; and Salamanca, Spain) on patients with NDMM or RRMM multiple myeloma receiving lenalidomide-based therapy. We collected data from january 2010 to December2014. We included adult patients diagnosed with NDMM or RRMM receiving lenalidomide-based therapy. We did not include who received lenalidomide but refused or had contra-indication to thromboprophylaxis; or used single agent lenalidomide. Results We included 168 patients with multiple myeloma receiving lenalidomide-based therapy. 14 (8%) were NDMM and 154 (92%) had RRMM. Median age was 68 (31-89) and 106 (63%) were males. On average patients with RRMM had 1.6 previous treatments (range:1-11). 104 (62%) patients were low risk and 64 (38%) were high risk for TE. 140 (83%) patients received prophylaxis with ASA, 32 (19%) LMWH and 6 (4%) VKA. 10 patients started with prophylactic LMWH for an average of 2 months then were empirically switched over to ASA. In total, there were 18 (10.7%) TE of which, 16 (9.5%) were VTE: 3 PE, 12 DVT, 1 both. The relative risk for TE was the same regardless of risk stratification [RR=1.27 (95%CI 0.524 - 3.059; p=0.599)]. At TE diagnosis, 16 patients were on ASA, 1 on LMWH and 1 on VKA. The relative risk of TE was significantly higher for patients on ASA compared to LMWH or VKA [RR= 2.17 (0.522 - 9.03; p= 0.286). After the TE, all patients changed anticoagulation strategy: 15 of 16 (94%) patients with VTE switched to therapeutic LMWH and 1 who was on VKA had ASA added. In the 2 patients with ATE, 1 started on full dose LMWH and the other one continued on ASA. 16 of 18 patients with a TE continued on lenalidomide-based therapy. There was no recurrent arterial or venous TE within the first 6 months of anticoagulation after the TE. Univariate analysis suggested that BMI, use of ASA and sex could be potential predictors of TE; but the logistic regression was not statistically significant (Table). Conclusions In patients with multiple myeloma on lenalidomide-based therapy the preferred TE prophylactic approach is low dose ASA irrespective of patients' risk assessment for thromboembolism. However, VTE risk in these patients is not negligible (9.5%) and low dose ASA may not be the best prophylactic strategy for them. It appears that patients on ASA, obese and males are at higher risk for TE. Future studies are needed to confirm these assumpations. Table 1. Multivariate Analysis of the TE risk for patients with myeloma on lenalidomide-based therapy Odds Ratio Variable Point Estimate 95% CI p -value Sex 2.316 0.854 6.278 0.0989 BMI 1.705 0.501 5.804 0.3935 ASA 3.870 0.486 30.796 0.2010 Disclosures Louzada: Celegene: Consultancy, Other: advisory board and expert opinion; pfizer: Consultancy, Other: advisory board and expert opinion; janssen: Consultancy, Other: advisory board and expert opinion. Mateos:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ocio:Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy; Mundipharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; MSD: Research Funding; Pharmamar: Consultancy, Research Funding; Janssen: Honoraria. Porras:Celgene: Consultancy, Honoraria.

Description: MRD negativity has become an important goal of the initial treatment of MM pts. Our phase 2 multi-center clinical trial, conducted in 10 major Canadian transplant centers, was designed to increase the MRD negativity rate after ASCT by using conditioning with 2 high-dose alkylating agents followed by len maintenance. In addition to conventional response criteria, this trial evaluated serial bone marrow aspirate (BMA) samples for MRD analysis by 8-color multiparameter flow cytometry (MFC) along with serum Hevylite™ assays of the involved HLC that were obtained before and after ASCT and during maintenance therapy. After bortezomib (btz)-based induction therapy off study, pts without MM progression received BuMel (busulfan 3.2 mg/kg IV days -5 to -3 or days -6 to -4 + melphalan 140 mg/m2 day -2 or day -3) conditioning, followed by ASCT on day 0. On day 100 post-ASCT, len 10 mg/day was started, escalated after 3 cycles to 15 mg/day if appropriate, and continued until progression. BMA and serum samples were shipped centrally for MRD and Hevylite analysis before induction therapy, before ASCT, on day 100 post-ASCT, every 3 mos for the 1st year and every 6 mos until progression. Between 03/2013 - 05/2016, 125 newly diagnosed pts provided BMA samples for MRD analysis. To date, 76 pts (target 78), have completed induction therapy and undergone ASCT; 2 pts have provided initial samples and are expected to be enrolled. 46 of the 125 (36.8%) who provided BMA samples did not proceed to BuMel due to: poor samples - 4 (3.2%); MM not confirmed - 3 (2.4%); prior therapy - 1 (0.8%); death during induction - 1 (0.8%); consent withdrawal/opted for standard conditioning - 21 (16.8%); and no ASCT - 16 (12.8%) (8 were unfit, 4 had comorbidities, 2 progressed, 1 failed mobilization and 1 underwent preferential tandem ASCT). Median follow-up is 27.4 mos (range: 10.4-37.6). Median age is 57 (34-69); 65.8% are male. Median serum β2-microglobulin level is 3.07 mg/L (1.5-20) and albumin 37 g/L (2.8-48.1); 34 pts have ISS stage I; 21 stage II; 17 stage III MM and 5 have missing data. Ig isotype includes IgGκ in 34 (44.7%), IgGλ in 16 (21.1%), IgAλ in 10 (13.2%), IgAκ in 9 (11.8%) and κ in 7 (9.2%). Post-ASCT, 26 SAEs have occurred: Grade 2: atrial fibrillation (1) and URI (1); Grade 3: atrial fibrillation (1), acute kidney injury (4), infectious enterocolitis (2), gallbladder infection (1), URI (1), febrile neutropenia (3), bacteremia (1), pain in extremity (1), hypoxia (1), pleural effusion (1), and 3 lung infection (4); and Grade 4: sepsis (1), AML [with spontaneous regression] (1), respiratory distress (1) and acute kidney injury (1). There have been no ASCT-related deaths; 11(14.4%) pts have progressed. The best conventional Ig response post-induction in the 76 evaluable pts is CR in 6 (7.9%), VGPR in 29 (38.2%), PR in 35 (46.1%), MR in 5 (6.6%) and SD in 1 (1.3%). At day 100 after ASCT, the Ig response in the 73 evaluable pts is CR in 9 (12.3%), VGPR in 41 (56.2%), PR in 22 (30.1%) and MR in 1 (1.4%). The rates of MRD negativity also increased from 29% after btz-based induction to 41%, while the rates of achievement of a normal HLC ratio were 50% after induction and 48% at day 100 (Table 1). Among evaluable pts, 77.3% of those after induction and 53.3% of those at day 100 who were MRD-negative also had had normal involved HLC ratios, while 38.9% and 44.2% of those, who were MRD-positive, respectively, had had normal involved HLC ratios. At month 6 and 12 post-ASCT, 43% and 35% of evaluable pts, respectively, are MRD-negative. Individual patient patterns of len dose, MRD negativity and involved HLC ratios are under assessment and will be presented. Conclusions: 1) IV BuMel conditioning + ASCT is well-tolerated with few SAEs and no ASCT-related deaths; 2) at day 100 post-ASCT, 98.6% had achieved ≥ PR (≥ VGPR in 68.5% and CR in 12.3%); 3) MRD negativity rates improved from 29% to 41% after ASCT; 4) the rates of normalization of the involved HLC ratio remained stable (50% to 48%) pre- and post-ASCT; 4) conventional Ig and MRD responses were often discordant as only 41% of CR pts were MRD-negative at day 100; 5) the majority of MRD-negative patients (53.3%) also had normalization of their involved HLC ratios; 5) with a median follow-up of over 2 years, only 14% of pts have progressed; 6) the serial marrow samples mandated by this study will allow determination of relationships between len dose, conventional Ig response rates, MRD status and involved HLC ratios as these pts are followed for longer periods of time. Disclosures Reece: Takeda: Consultancy, Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Merck: Research Funding; BMS: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. White:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria. Venner:Takeda: Honoraria; Celgene: Honoraria, Research Funding; J+J: Research Funding; Janssen: Honoraria; Amgen: Honoraria. Stakiw:Roche: Research Funding; BMS: Honoraria; Novartis: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Jansen: Honoraria, Speakers Bureau. Sebag:Celgene: Honoraria; Novartis: Honoraria; Janssen: Honoraria. Comeau:Seattle Genetics: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy. Song:Otsuka: Honoraria; Janssen: Honoraria; Celgene: Honoraria, Research Funding. Louzada:Pfizer: Honoraria; Bayer: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. McCurdy:Celgene: Honoraria. Kukreti:Celgene: Honoraria. Trudel:Glaxo Smith Kline: Honoraria, Research Funding; Celgene: Honoraria; Novartis: Honoraria; Oncoethix: Research Funding. Prica:Janssen: Honoraria; Celgene: Honoraria. Tiedemann:Novartis: Honoraria; Takeda Oncology: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; BMS Canada: Honoraria. Chen:Takeda: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

Description: Introduction Upper extremity deep vein thrombosis (UEDVT) represents up to 10% of cases of venous thromboembolism (VTE) and is frequently associated with central venous catheter (CVC) placement in patients receiving chemotherapy for cancer. UEDVT may be treated with low molecular weight heparin (LMWH) either as monotherapy or subsequently transitioned to warfarin as we have previously shown (Kovacs 2007). Whereas for non-cancer VTE rivaroxaban is at least as efficacious and safe as warfarin, the latter is problematic in cancer patients and direct oral anticoagulants (DOACs) such as rivaroxaban have not been studied to date in this setting. In this study weevaluated thesafety and efficacy of rivaroxaban in the treatment of UEDVT secondary to CVC in patients with cancer. Methods We conducted a multicentre prospective cohort study at 3 centres in Canada between December 2012 and January 2016. We enrolled patients ≥18 years of age with active malignancy and symptomatic proximal UEDVT (axillary or more proximal) with or without pulmonary embolism (PE), associated with a CVC. Exclusion criteria included dialysis catheters, active bleeding, platelet count

Description: Abstract 475 Background: Current guidelines suggest that all cancer patients with venous thromboembolism be treated with long-term low molecular weight heparin (LMWH). However, whether treatment strategies should vary according to patient and malignancy characteristics, in particular whether patients with low risk of VTE recurrence can be identified, remains unknown. Methods: We performed a single centre retrospective cohort study conducted at the Thrombosis Unit of the Ottawa Hospital. The charts of patients with cancer and VTE followed from 2002 to 2004 and from 2007 to 2008 were reviewed to assess the feasibility of derivation of a clinical prediction rule that stratifies VTE recurrence risk in patients with cancer—associated venous thrombosis through identification and evaluation of characteristics of malignancy and other clinical characteristics. We analysed only the patients who had a recurrent VTE within the first 6 months of anticoagulation. A univariate analysis determined the strength of association between each potential predictor and VTE recurrence. All potential predictor variables (p 19%) for VTE recurrence (Tables 1 and 2). Conclusion: We were able to derive a simple and easy scoring system that stratifies patients with cancer-associated thrombosis into low or high risk of recurrent VTE. Future prospective validation of the model is warranted and may be very relevant to better tailor anticoagulation treatment in this heterogeneous population. Disclosure: No relevant conflicts of interest to declare.

Description: Background: Carfilzomib, a second generation proteosome inhibitor, is effective in the treatment of relapsed and refractory multiple myeloma (RRMM). Recent phase II and phase III trials have demonstrated the efficacy of weekly dosing strategies. The aim of this study was to examine high dose once weekly carfilzomib in combination with weekly dexamethasone and low dose weekly cyclophosphamide (wCCD) in RRMM. It was hypothesized that this may offer a potent yet convenient and more financially viable triplet-based treatment option than existing combinations. Methods: The MCRN-003/MYX.1 multi-centre single arm phase II clinical trial is run through the Myeloma Canada Research Network (MCRN) with support from the Canadian Cancer Trials Group (CCTG). Patients who had at least one but not more than three prior lines of therapy and who did not have proteosome inhibitor (PI) refractory disease were eligible. Treatment consists of carfilzomib (20 mg/m2 day 1 of first cycle then escalated to 70 mg/m2 for all subsequent doses) given on days 1, 8, and 15 of a 28-day cycle, plus weekly oral dexamethasone 40 mg and cyclophosphamide 300 mg/m2 capped at 500 mg on days 1, 8, 15 and 22. Treatment continues until progression or intolerance, except for cyclophosphamide which is discontinued after 12 cycles. The total sample size of 76 patients includes a 6 patient lead-in phase where safety at 70 mg/m2 was evaluated. The primary objective was to observe an overall response rate (ORR) ≥ 80% after 4 cycles of protocol therapy. Secondary endpoints include safety, toxicity, kinetics of and maximal response depth and overall survival. This analysis is based on the locked data base of 2018 July 13. Results: Of the 76 patients accrued 1 was subsequently determined to be ineligible on the basis of bortezomib refractory disease, and 1 did not receive any protocol therapy due to a cardiac event occurring post-study registration but prior to treatment commencement. All patients who received therapy were included in the analysis as per protocol inclusive of the bortezomib exposed patient. Among these 75 patients, median age was 66 years with 33% being 〉 70 years of age. Thirty-seven percent were female. Thirty-nine percent received 1 prior line, 44% received 2 prior lines and 17% received 3 prior lines of therapy. High risk cytogenetics [(t4;14), t(14;16) and del P53] were identified in 32%. Twenty percent had ISS stage III disease and 11% had R-ISS stage III disease. Prior PI and immunomodulatory drug exposure was noted in 87% and 81% respectively. Within the first 4 cycles of therapy 84% (95% CI, 76-92%) of patients achieved PR or better, with ≥ VGPR achieved in 52% and ≥ CR in 9% (table 1, p = 0.0006). There was a trend toward a better ORR after 4 cycles based on the presence or absence of high-risk cytogenetics (75% vs 94% respectively, p = 0.051) not meeting statistical significance. The median duration of follow-up at the time of data analysis was 13.9 months (range 0.2 to 22.8 months). 18 patients have died with an estimated 1-year OS of 80%. The cause of death as assessed by the investigator was myeloma in 13 patients with 3 dying from a cause possibly or probably related to the study intervention. During the first 4 cycles of treatment, non-hematologic toxicity ≥ grade 3 occurred in 33% of patients; most commonly infection (16%) and fatigue (7%). Grade 3/4 anemia was observed in 17%, thrombocytopenia in 33% and neutropenia in 20%. Grade 3 or greater hypertension was seen in 4%, dyspnea in 1%, pulmonary edema in 1% and thrombotic microangiopathy in 4%; all resolved with no long-term sequelae. To date 37 (49%) patients have discontinued carfilzomib, 11 due to toxicity and 16 due to disease progression. Conclusion: This prospective phase II study demonstrates that wCCD is a safe and effective regimen in the treatment of RRMM. The study met its primary endpoint demonstrating a ≥ 80% ORR after 4 cycles of therapy. These results compare favourably to published phase III data examining weekly carfilzomib and dexamethasone as well as the established twice-weekly dosing strategies. This regimen will be a useful triplet-based option for RRMM especially in patients refractory to immunomodulatory agents who would otherwise be ineligible for the carfilzomib-lenalidomide-dexamethasone combination. Disclosures Venner: Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria. Leblanc:Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Sandhu:Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Bioverativ: Honoraria. White:Amgen, Celgene, Janssen, Takeda: Honoraria. Chen:Amgen: Honoraria. Louzada:Celgene: Honoraria; Janssen: Honoraria; amgen: Honoraria; pfizer: Honoraria. Hay:Amgen: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Roche: Research Funding; Seattle Genetics: Research Funding; Kite: Research Funding.

Description: Although melphalan 200 mg/m2 (Mel 200) followed by ASCT has been a standard approach for eligible multiple myeloma (MM) patients (pts) for over 25 years, efforts to improve transplant results continue, particularly in high-risk (HR) pts. One approach has been to augment the high-dose (HD) regimen by adding agents to Mel or performing "tandem" ASCT using Mel each time. The first MCRN Canadian national trial (MCRN-001) was designed to optimize the results of ASCT by using bortezomib (BTZ)-based induction, augmented HD chemotherapy with busulfan + melphalan (BuMel) before ASCT, and lenalidomide (Len) maintenance post-ASCT. We now report longer-term outcomes from this study, including results in HR pts and the incidence of secondary primary malignancies (SPMs). METHODS: Following BTZ-based induction (typically weekly CyBorD), stem cells were harvested and pts received BuMel (busulfan 3.2 m/kg IV days -5 to -3 or days -6 to -4 and Mel 140 mg/m2 days -2 or -3), followed by ASCT on day 0. On day 100, Len maintenance was commenced at a dose of 10 mg/d, escalated if appropriate to 15 mg/d and continued until progression. IMWG criteria were used for clinical response and progression. Bone marrow 8-color multiparameter flow cytometry (10 -4 sensitivity) was measured at diagnosis, before ASCT, on day +100, every 3 months the first year and every 6 months until progression; serum heavy light chain (HLC) (Hevylite®) assay and serum M spike by mass spectrometry (spec) were also evaluated at the same time points. RESULTS: 78 newly diagnosed MM pts were entered between 03/2013-05/2016. Median age was 57 yrs (range 34-69); HR FISH cytogenetics were identified in 15 (19%) and included t(4;14) in 9 [3 also had t(14;16) and 1 also had del 17p]. Four others had t(14;16), including 1 with concomitant del 17p, while 2 additional pts had del 17p. Median follow-up (F/U) is 55.7 mos (range 6-68). There were no early ASCT deaths. Best response in all pts was CR in 44 (56%), VGPR in 31 (40%), for a ≥VGPR rate of 96%, and PR in 3 (4%). For HR pts, best response was ≥VGPR in 93% (CR in 47%). MRD negativity rates increased from 28% after induction to 39% at day +100; 6- and 12-mo MRD negativity rates were 44% and 41%, respectively. A normal HLC ratio was achieved in 58% after induction and 65% at day +100. Among evaluable pts who were MRD negative, 77% after induction and 83% at day +100 also had a normal HLC ratio, while 50 % and 55% who were MRD positive had a normal HLC ratio. Mass spec data will be presented separately. As of 05/31/2019, 24 pts have progressed and 12 have died, 8 from MM. Median PFS and OS for all pts have not yet been reached, but the estimated 5-year PFS is 60% (95% CI 47.5-70.8%) and OS 82% (95% CI 69.7-89.3%). For HR pts, the 5-year PFS is 28% (95% CI 7.2-54.3%) compared with 67% (95% CI 53.9-96.2%) for standard-risk (SR) pts (p=0.0169). 5-year OS was 61.3% (95% CI 30.2-81.9%) versus 86% (95% CI 72.2-93.2%) in HR and SR pts, respectively (p=0.0170). SPMs were diagnosed in a total of 16 (21%) individuals (5 HR), including 1 pt with 2 SPMs (colon and basal cell), at a median of 29 mos (7-55) post-ASCT; 3 were diagnosed after discontinuation of Len. There were 6 skin cancers (melanoma in 1; non-melanoma in 5) -all successfully treated; 4 heme malignancies (2 AML, 1 NHL and 1 Hodgkin's) with 1 death due to AML; and 7 adenocarcinomas (1 in situ endocervical and 6 invasive) with 3 causing death. Therefore, there were 4 deaths (5.1%) in total from SPM. SUMMARY AND CONCLUSIONS: 1) BTZ-based induction and BuMel + ASCT followed by Len maintenance produced an overall ≥VGPR rate of 96% and excellent 5-year PFS, particularly in SR pts; 2) despite a high initial VGPR rate of 93%, a shorter PFS and OS were noted in HR pts; 3) the PFS in HR pts in the current study appears somewhat shorter than that observed in the MD Anderson phase 3 study comparing BuMel versus Mel 200 (Qazilbash, ASH 2017); this observation might be due to the use of different criteria for HR FISH, variable induction and maintenance regimens and a different dose/schedule of Bu and Mel in addition to a shorter median F/U time in the phase 3 trial; 4) nevertheless, HR pts in the current trial still experienced a median PFS of 48.5 mos; 5) with a median F/U of almost 5 years, invasive SPMs were diagnosed in 10 pts; although most were successfully treated, the findings illustrate the need for long-term monitoring of MM pts, particularly in the setting of HD therapy with dual alkylating agents and the longer survival times now observed after ASCT. Figure Disclosures Reece: Otsuka: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. White:Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Venner:Janssen: Honoraria; Amgen: Honoraria, Research Funding; Takeda: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; J&J: Research Funding. Stakiw:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Sanofi: Honoraria; Amgen: Honoraria, Speakers Bureau; Roche: Research Funding; BMS: Honoraria; Janssen: Honoraria, Research Funding, Speakers Bureau; Lundbeck: Honoraria. Sebag:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Comeau:Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Seattle Genetics: Consultancy; Novartis: Consultancy. Song:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Roy:Celgene: Consultancy, Honoraria, Research Funding; Sanofi Canada: Research Funding; ExCellThera: Patents & Royalties: Royalties from sales of UM171, Research Funding; Amgen Canada: Honoraria; Janssen Canada: Honoraria. Louzada:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Bayer: Honoraria. McCurdy:Celgene: Honoraria; Janssen: Honoraria. Kukreti:Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Trudel:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria; Astellas: Research Funding; Genentech: Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria; Janssen: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria. Prica:Celgene: Honoraria; Janssen: Honoraria. Tiedemann:Celgene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Takeda: Honoraria. Chen:Amgen: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. OffLabel Disclosure: The combination of busulfan IV and melphalan conditioning for ASCT in myeloma is off-label.