Rivaroxaban or Aspirin As Thromboprophylaxis in Multiple Myeloma (RithMM)

• ClinicalTrials.gov Identifier: NCT03428373
• Recruitment Status: Recruiting
• First Posted: February 9, 2018
• Last Update Posted: October 5, 2022
• Sponsor: Lawson Health Research Institute
• Collaborators: The Ottawa Hospital; Dalhousie University; Niagara Health System; Hamilton Health Sciences Corporation
• Information provided by (Responsible Party): Lawson Health Research Institute

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Multiple Myeloma in Relapse; Multiple Myeloma Progression; Multiple Myeloma Stage II; Multiple Myeloma Stage I; Multiple Myeloma With Failed Remission; Multiple Myeloma Stage III	Drug: Rivaroxaban; Drug: ASA	Phase 2; Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 86 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Rivaroxaban for Improvement of Thromboembolism Outcomes in Patients With Multiple Myeloma on Lenalidomide-based Therapy: RithMM Trial
• Estimated Study Start Date: July 30, 2023
• Estimated Primary Completion Date: December 1, 2024
• Estimated Study Completion Date: July 30, 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Len-Dex+Rivaroxaban; Patients with MM will receive Len-Dex combination and Rivaroxaban (10 mg) daily	Drug: Rivaroxaban; Rivaroxaban 10mg daily; Other Name: Xarelto
Active Comparator: Len-Dex+ASA; Patients MM will receive Len-Dex combination and ASA 81 mg daily	Drug: ASA; ASA 81mg; Other Name: aspirin

Outcome Measures

Primary Outcome Measures :

1. 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 [ Time Frame: 6 months ]
   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).
2. Number of participants with treatment-related adverse events as assessed by CTCAE v6.0 [ Time Frame: 6 months ]
   Frequency and severity of adverse events and serious AEs based on hospital admission and patient-self reporting events

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 90 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

  1. Platelet count >50 × 109/L
  2. AST <2.5x ULN
  3. ALT <2.5x ULN
  4. Total Bilirubin <2.0 xULN
  5. Creatinine clearance (CrCl) >15mL/min using Cockcroft-Gault Equation
• Able to provide written informed consent

Exclusion Criteria:

1. Major bleeding event within the previous 3 months prior to commencement of Len Dex therapy
2. 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.
3. Patient with history of gastric or duodenal ulcer within 2 years
4. 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.
5. Patient on antiplatelet agents due to an absolute indication (e.g.; coronary stent, carotid stent).
6. Patient on single agent lenalidomide
7. Life expectancy less than 3 months as determined by the investigator
8. Unstable medical or psychological condition that would interfere with trial participation, as determined by the investigator
9. Patient not able or not willing to give consent to participate in the study
10. Uncontrolled cardiovascular disease within 6 months prior to enrollment
11. Uncontrolled or poorly controlled diabetes or renal disease
12. Major surgery within 2 weeks before randomization
13. Known allergies, hypersensitivity, or intolerance to any of the study drugs

Contacts and Locations

Contacts

Contact: Martha Louzada, MD MSc (Epid); 519-685-8500 ext 52391; Martha.Louzada@lhsc.on.ca

Contact: Kate Kelly, MSc MPH/Gero; 519-685-8500 ext 53639; kate.kelly@lhsc.on.ca

Locations

Canada, Ontario

London Health Sciences Centre; Recruiting

London, Ontario, Canada, N6A 5W9

Contact: Maisam Abouzeenni 5196858500 ext 56840 maisam.abouzeenni@lhsc.on.ca

Contact: Terryl Angle 519-685-8500 ext 57135 terryl.angle@lhsc.on.ca

Sponsors and Collaborators

Lawson Health Research Institute

The Ottawa Hospital

Dalhousie University

Niagara Health System

Hamilton Health Sciences Corporation

Investigators

• Principal Investigator: Martha Louzada, MD; Lawson Health Research Institute

More Information

Publications of Results:

Arain M, Campbell MJ, Cooper CL, Lancaster GA. What is a pilot or feasibility study? A review of current practice and editorial policy. BMC Med Res Methodol. 2010 Jul 16;10:67. doi: 10.1186/1471-2288-10-67.

Lancaster GA, Dodd S, Williamson PR. Design and analysis of pilot studies: recommendations for good practice. J Eval Clin Pract. 2004 May;10(2):307-12. doi: 10.1111/j..2002.384.doc.x.

Palumbo A, Rajkumar SV, Dimopoulos MA, Richardson PG, San Miguel J, Barlogie B, Harousseau J, Zonder JA, Cavo M, Zangari M, Attal M, Belch A, Knop S, Joshua D, Sezer O, Ludwig H, Vesole D, Blade J, Kyle R, Westin J, Weber D, Bringhen S, Niesvizky R, Waage A, von Lilienfeld-Toal M, Lonial S, Morgan GJ, Orlowski RZ, Shimizu K, Anderson KC, Boccadoro M, Durie BG, Sonneveld P, Hussein MA; International Myeloma Working Group. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008 Feb;22(2):414-23. doi: 10.1038/sj.leu.2405062. Epub 2007 Dec 20.

Al-Ani F, Bermejo JM, Mateos MV, Louzada M. Thromboprophylaxis in multiple myeloma patients treated with lenalidomide - A systematic review. Thromb Res. 2016 May;141:84-90. doi: 10.1016/j.thromres.2016.03.006. Epub 2016 Mar 5.

Levine MN, Gu C, Liebman HA, Escalante CP, Solymoss S, Deitchman D, Ramirez L, Julian J. A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer. J Thromb Haemost. 2012 May;10(5):807-14. doi: 10.1111/j.1538-7836.2012.04693.x.

Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005 Apr;3(4):692-4. doi: 10.1111/j.1538-7836.2005.01204.x.

Leleu X, Rodon P, Hulin C, Daley L, Dauriac C, Hacini M, Decaux O, Eisemann JC, Fitoussi O, Lioure B, Voillat L, Slama B, Al Jijakli A, Benramdane R, Chaleteix C, Costello R, Thyss A, Mathiot C, Boyle E, Maloisel F, Stoppa AM, Kolb B, Michallet M, Lamblin A, Natta P, Facon T, Elalamy I, Fermand JP, Moreau P. MELISSE, a large multicentric observational study to determine risk factors of venous thromboembolism in patients with multiple myeloma treated with immunomodulatory drugs. Thromb Haemost. 2013 Oct;110(4):844-51. doi: 10.1160/TH13-02-0140. Epub 2013 Aug 1.

Other Publications:

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;

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kahale LA, Matar CF, Tsolakian I, Hakoum MB, Yosuico VE, Terrenato I, Sperati F, Barba M, Hicks LK, Schunemann H, Akl EA. Antithrombotic therapy for ambulatory patients with multiple myeloma receiving immunomodulatory agents. Cochrane Database Syst Rev. 2021 Sep 28;9(9):CD014739. doi: 10.1002/14651858.CD014739.

• Responsible Party: Lawson Health Research Institute
• ClinicalTrials.gov Identifier: NCT03428373
• Other Study ID Numbers: 110804
• First Posted: February 9, 2018
• Last Update Posted: October 5, 2022
• Last Verified: October 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Lawson Health Research Institute:

Multiple Myeloma

Additional relevant MeSH terms:

Multiple Myeloma; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Rivaroxaban; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Protease Inhibitors; Anticoagulants