Clinical trial NCT03428373: Rivaroxaban or Aspirin As Thromboprophylaxis in Multiple Myeloma
Official title: Rivaroxaban for Improvement of Thromboembolism Outcomes in Patients With Multiple Myeloma on Lenalidomide-based Therapy: RithMM Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
PHASE3
Conditions: Multiple Myeloma in Relapse
Multiple Myeloma Progression
Multiple Myeloma Stage II
Multiple Myeloma Stage I
Multiple Myeloma With Failed Remission
Multiple Myeloma Stage III
Keywords: Multiple Myeloma
Lead sponsor: London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's
Sponsor class: OTHER
Collaborators: name: The Ottawa Hospital
name: Dalhousie University
name: Niagara Health System
name: Hamilton Health Sciences Corporation
First posted: 2018-02-09
Enrollment: 57
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Diagnosis of Multiple Myeloma
2. Scheduled to start on Len-Dex therapy
3. Be ≥ 18 years of age
4. Able to provide written informed consent
5. Pre-clinical laboratory must meet the following criteria at enrollment

   * Platelet count \>50 × 109/L
   * Creatinine clearance (CrCl) \>15mL/min using Cockcroft-Gault Equation

Exclusion Criteria:

1. Major bleeding event within the previous 3 months prior to commencement of Len Dex therapy
2. Documented severe liver disease in the past 6 months (eg. acute clinical hepatitis, chronic active hepatitis, or cirrhosis)
3. Patient with a history of antiphospholipid syndrome especially if he/she is triple positive for lupus anticoagulant, anticardiolipin antibodies, and/or anti-b2 glycoprotein I antibodies.
4. 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.
5. Patient with history of gastric or duodenal ulcer within 2 years
6. Plasma cell leukemia; systemic amyloidosis
7. 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.
8. Patient on antiplatelet agents due to an absolute indication (e.g.; coronary stent, carotid stent).
9. Patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp such as ketoconazole, itraconazole, posaconazole or ritonavir)
10. Patient on single agent lenalidomide
11. Life expectancy less than 3 months as determined by the investigator.
12. Unstable medical or psychological condition that would interfere with trial participation, as determined by the investigator
13. Patient not able or not willing to give consent to participate in the study
14. Uncontrolled cardiovascular disease within 6 months prior to enrollment
15. Uncontrolled or poorly controlled diabetes or renal disease
16. Major surgery within 2 weeks before randomization
17. Known allergies, hypersensitivity, or intolerance to any of the study drugs.
18. Patients not able or not willing to give consent to participate in the Study.

Primary outcomes:
measure: 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
timeFrame: 6 months
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v6.0
timeFrame: 6 months
Secondary outcomes:
measure: External validation of the IMWG criteria for risk assessment of thromboembolic events in multiple myeloma patients
timeFrame: 6 months
measure: Assessment of correlation of between levels of biomarkers of myeloma and thrombosis with the risk of ATE or VTE
timeFrame: 6 months
Other outcomes:
Locations:
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
Study officials:
affiliation: London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's
name: Martha Louzada, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kamat AV Rivaroxaban Is an Effective and Well Tolerated Anti Thrombotic Agent in Patients on Lenalidomide Therapy and in Multiple Myeloma Blood 2014 124:5095;
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