Rivaroxaban or Aspirin As Thromboprophylaxis in Multiple Myeloma

Study Overview
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Brief Summary
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The intended study is designed as a a phase IV pragmatic multicenter randomized controlled clinical trial, comparing the impact of two different therapies including ASA vs. Rivaroxaban in newly diagnosed or relapsed and refractory multiple myeloma patients treated with Lenalidomide Dexamethasone (Len-Dex) combination therapy. The pilot feasibility study was conducted in preparation for this randomized controlled trial designed to assess the effect of an intervention.

Detailed Description
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RithMM is a phase IV, pragmatic, multicenter, open label Canadian trial. The study started with a pilot feasibility phase where 3 centres (London, Ottawa and Halifax) enrolled 34 patients within 12 months. Utilizing a roll-over design, the full RithMM trial will require a total of 304 patients to demonstrate that rivaroxaban 10 mg daily for 6 months is superior to ASA 81 mg daily for 6 months in preventing any thromboembolic events in newly diagnosed myeloma (NDMM) and relapsed/refractory (RRMM) patients on Len-Dex -based therapy. The study will require 8 participating centres in order to be able to achieve our recruitment goal within 12 to 18 months. Patients with NDMM or RRMM receiving Len-Dex based combination therapy with or without combination with other anti-myeloma drugs will be assessed for eligibility to be enrolled in the study. The research team intends to rollover the participants of our feasibility study into this current full randomized control trial comparing the efficacy outcome for the RithMM trial is the overall incidence of cardiovascular events, which includes arterial or venous thromboembolic events. By conducting this trial, the investigators plan to externally validate the International Myeloma Working Group (IMWG) criteria model for thromboembolic risk by assessing the relevance of measuring pre-specified myeloma and thrombosis activity biomarkers (D-Dimer, beta-2 microglobulin, C-reactive protein (CRP), LDH) at every follow-up visit and their potential association with thromboembolism (TE) risk.

Official Title
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Rivaroxaban for Improvement of Thromboembolism Outcomes in Patients With Multiple Myeloma on Lenalidomide-based Therapy: RithMM Trial

Conditions
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Multiple Myeloma in Relapse, Multiple Myeloma Progression, Multiple Myeloma Stage II, Multiple Myeloma Stage I, Multiple Myeloma With Failed Remission, Multiple Myeloma Stage III

Intervention / Treatment
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* Drug: Rivaroxaban
* Drug: ASA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Multiple Myeloma Scheduled to start on Len-Dex therapy Be ≥ 18 years of age 4. Pre-clinical laboratory must meet the following criteria at enrollment Platelet count >50 × 109/L AST <2.5x ULN ALT <2.5x ULN Total Bilirubin <2.0 xULN Creatinine clearance (CrCl) >15mL/min using Cockcroft-Gault Equation Able to provide written informed consent Exclusion Criteria: Major bleeding event within the previous 3 months prior to commencement of Len Dex therapy A history of malignancy (with the exception of MM) within 2 years before randomization or any previously diagnosed malignancy with evidence of residual disease. Patients with a history of basal cell or squamous carcinoma are not excluded. Patient with history of gastric or duodenal ulcer within 2 years Patient on therapeutic anticoagulation for treatment of VTE or ATE, or stroke prevention in non-valvular atrial fibrillation. Patients with a previous history of VTE who are not on any active anticoagulant therapy will not be excluded. Patient on antiplatelet agents due to an absolute indication (e.g.; coronary stent, carotid stent). Patient on single agent lenalidomide Life expectancy less than 3 months as determined by the investigator Unstable medical or psychological condition that would interfere with trial participation, as determined by the investigator Patient not able or not willing to give consent to participate in the study Uncontrolled cardiovascular disease within 6 months prior to enrollment Uncontrolled or poorly controlled diabetes or renal disease Major surgery within 2 weeks before randomization Known allergies, hypersensitivity, or intolerance to any of the study drugs

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Len-Dex+Rivaroxaban<br>Patients with MM will receive Len-Dex combination and Rivaroxaban (10 mg) daily | Drug: Rivaroxaban<br>* Rivaroxaban 10mg daily<br>* Other names: Xarelto;|
| Active Comparator: Len-Dex+ASA<br>Patients MM will receive Len-Dex combination and ASA 81 mg daily | Drug: ASA<br>* ASA 81mg<br>* Other names: aspirin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of venous thromboembolic (VTE) and/or arterial thromboembolic (ATE) events in patients with Multiple Myeloma placed on the Rivaroxaban vs Aspirin after starting with Len-Dex therapy | At each visit, patients will be asked standardized questions to capture the presence of primary. During these interviews the study coordinator will collect data related to resource utilization (e.g. health care services use) and ask whether the patient had a diagnosis of VTE, ATE or a bleeding event during this period. Any hospital or medical office encounters associated to any of the above-mentioned complaints will be checked and any test or procedures done will be recorded (e.g; echocardiogram, ECG, CT scan, MRI, transfusion). | 6 months | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v6.0 | Frequency and severity of adverse events and serious AEs based on hospital admission and patient-self reporting events | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| External validation of the IMWG criteria for risk assessment of thromboembolic events in multiple myeloma patients | Subgroup analysis stratifying patients into low and high risk of thromboembolic events to assess any potential difference in the efficacy and safety outcomes. | 6 months | 
| Assessment of correlation of between levels of biomarkers of myeloma and thrombosis with the risk of ATE or VTE | The bio-markers are: D-dimer, LDH, B2 microglobulin and C-reactive protein (CRP) will be collected | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma