Rivaroxaban for Improvement in Thromboembolism Outcomes in Patients with Multiple Myeloma on Lenalidomide-Based Therapy: The Rithmm Feasibility Pilot Trial
Authors: Louzada Martha L , McCurdy Arleigh , Shivakumar Sudeep P , Quint Anthony , Salib Mary , Lazo-Langner Alejandro , Phua Chai Wye , Le Gal Gregoire , Lam Selay , Ho Jenny M. 
Published: November 2021

Abstract
Introduction:The association between thrombosis (TE) and cancer has been well established. The risk for thrombosis in Multiple Myeloma (MM) is further compounded by therapy-related factors, which increase the risk for both arterial and venous TE. Lenalidomide + dexamethasone (Ld) is the most widely used backbone therapy for MM and may increase the risk of TE. The current standard TE prophylaxis for patients on Ld is low dose aspirin (ASA) for low risk patients or low molecular weight heparin for high risk patients. Direct oral anticoagulants have been used empirically and have been evaluated in small prospective cohort studies with promising results.
Methods: RithMM is an ongoing open label Canadian multicenter pilot feasibility RCT to assess the efficacy and safety of daily oral rivaroxaban 10 mg (Riva) versus ASA 81 mg in patients with MM on Ld-based therapy. Our primary objective is to assess the feasibility of accrual of patients with MM starting on Ld-based therapy. Patients not on therapeutic anticoagulation or antiplatelet agents for another indication (e.g. atrial fibrillation) are eligible for RithMM. Primary clinical endpoints are major cardiovascular (CV) events or major bleeding as per the ISTH criteria. The study will be considered feasible if 86 patients in 4 Canadian sites (London, Ottawa, Halifax, Niagara) can be enrolled in 12 months after each site activation. Sites are expected to accrue an average of 1.8 patients per month. Patients are randomly assigned to receive ASA (control) or Riva (intervention) using a simple randomization sequence run by the Redcap system, utilizing an automated assignment procedure. Patients enter the study at the time of anticoagulant initiation and are followed for 6 months, or until they withdraw from the study; die or develop a primary clinical outcome; whichever comes first. Herein we present the interim analysis of RithMM after study completion in 2 of 4 sites.
Feasibility assessment: 17 patients were randomized to ASA and 17 to Riva (1 patient did not take the study drug). Feasibility assessment was severely impacted by the temporary but prolonged research activity closures secondary to the COVID-19 pandemic that limited direct patient accrual and led to significant delays in REB approval of the participating sites. The first patient was enrolled in January 2019 in London. Ottawa opened in October 2019, Halifax in December 2020 and Niagara in May 2021. A total of 34 patients have been enrolled: 22 London, 11 Ottawa and 2 Halifax. London was the only site actively accruing for 12 consecutive months. Ottawa opened for 3 months, held accrual for 9 months, then reopened for 7 months. Halifax was open for only 1 month. Niagara opened in May 2021, the time of study data lock for this abstract. In addition, 7 potentially eligible patients were not screened given that they were enrolled in a MM treatment trial that did not permit enrolment in another trial. The accrual rate was excellent for London (105%) and Ottawa (52% in 10 months). The drop-out rate was 6% (2 patients) and drug compliance 100%.
Clinical Outcomes: Baseline characteristics are depicted in the table. One patient in the ASA arm developed a proximal deep vein thrombosis 2 months after starting treatment, and another developed a clinically relevant nonmajor bleeding 6 weeks after starting ASA.
Discussion: This is the interim analysis of the RithMM pilot trial that aims to evaluate the feasibility of accrual of MM patients on Ld -base therapy to assess the efficacy and safety of Riva versus ASA in preventing TE complications. The study was initiated during the COVID-19 pandemic turmoil, which severely impacted in the proper activation of 3 of the 4 participating sites. Despite this significant limitation, 2 sites were able to maintain the accrual of patients. Only 1 site remained opened according to the pre-specified consecutive 12- month study period. Despite this barrier, we could still attain an excellent accrual rate of 39.5% in 2 sites (London and Ottawa). The incidence of TE or bleeding was low, with no difference between ASA and Riva. However, the study was not powered to assess these outcomes. Lastly, Ld is the most widely used backbone therapy in MM, both in upfront and relapsed settings. Our group does not anticipate any barriers to achieving successful completion of accrual provided the hospital's activities remain safe and research activities open.
Figure 1 Figure 1.

Disclosures
Louzada: Celgene: Honoraria; Janssen: Honoraria; Pfizer: Honoraria; Amgen: Honoraria. McCurdy: Sanofi: Honoraria; GSK: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Phua: Pfizer: Honoraria; Amgen: Honoraria; AstraZeneca: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Le Gal: Aspen: Honoraria; Bayer: Honoraria; Pfizer: Honoraria; LEO Pharma: Honoraria; BMS: Honoraria; Sanofi: Honoraria. Lam: Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; SeaGen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure:
Rivaroxaban 10 mg oral daily for thrombosis prophylaxis in myeloma patients on lenalidomide-based therapy. Health Canada approved the off label use for study purposes