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Patients with MM will receive Len-Dex combination and Rivaroxaban (10 mg) daily

Patients MM will receive Len-Dex combination and ASA 81 mg daily

Martha Louzada, MD

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.

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.

Rivaroxaban or Aspirin As Thromboprophylaxis in Multiple Myeloma

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

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).

Frequency and severity of adverse events and serious AEs based on hospital admission and patient-self reporting events

Subgroup analysis stratifying patients into low and high risk of thromboembolic events to assess any potential difference in the efficacy and safety outcomes.

The bio-markers are: D-dimer, LDH, B2 microglobulin and C-reactive protein (CRP) will be collected

The Ottawa Hospital

Dalhousie University

Niagara Health System

Hamilton Health Sciences Corporation

Lawson Health Research Institute

Antiemetics

Gastrointestinal Agents

Cyclophosphamide

Dexamethasone

Daratumumab

Dexamethasone acetate

Thalidomide

Eligible patients will be enrolled and treated according to the following elicited schema: Cyclo Thal Dex- Daratumumab (cyclophosphamide 500mg D1-8-15 + thalidomide 100-200mg D1-28 + dexamethasone 40mg/week (28 days cycle)- 4 cycles. ) + Daratumumab 16mg/Kg every week on cycles 1 and 2 and every other week at cycles 3 and 4- (total of 12 doses). Then Daratumumab 16mg/Kg after D+30, every other week as pre consolidation until starts full consolidation D+90-120 every other week (total of 4 doses) + thal100mg D1-28 during sixteen weeks as full consolidation. Follow by Daratumumab 16mg/Kg once a month as maintenance until progression or limiting adverse event (total of 28 planning doses).

Total scheme Daratumumab doses= 50 doses = PROTOCOL MAXDARA.

Cyclo Thal Dex Daratumumab

Edvan Q Crusoé

Débora Sacramento

Edvan Q Crusoe

Juliana Santos

The best induction protocol to eligible multiple myeloma patients was not established. Combination of three drugs demonstrated better outcomes than two drugs combo. Nevertheless, until now four drugs combo did not prove gain against three drugs One of the three drugs protocol studied as induction was CTD scheme (cyclophosphamide+ thalidomide+dexamethasone). Daratumumab has a novel mechanism of action that results in enhanced activity in combination with existing standards of care, including first-generation novel agents, such as thalidomide, as well as other therapeutics. Considerable responses have been observed in a cohort of heavily pretreated patients with relapsed/refractory MM. The use of a treatment combination with monoclonal antibody associated with immunomodulator (in a four drug combo) can lead to a improvement in response rates and in survival, reflects on a better free time interval. This trial will represent a new option of treatment with a combination of anti CD38 monoclonal antibody (DARATUMUMAB) as induction regimen with CTD protocol (four drug combination). And It use as consolidation and maintenance to give better immunomodulatory response and extended survival and disease control.

Multiple Myeloma (MM) is a molecularly heterogeneous disease with a high degree of genomic instability. Despite improvements in event-free survival and overall survival with the use of autologous stem cell transplantation and novel agents, MM remains an incurable disease (1,2). The best induction protocol to eligible patients was not established. Combination of three drugs demonstrated better outcomes than two drugs combo. Nevertheless, until now four drugs combo did not prove gain against three drugs One of the three drugs protocol studied as induction was CTD scheme (cyclophosphamide+ thalidomide+dexamethasone) (3). This is an induction protocol commonly used in Brazil , with largely access in the brazilian public health system. Several new molecules have been developed in an attempt to improve treatment. One of these new treatment is an anti CD38 (Daratumumab). This potential target is present on plasma cells. The CD38 is a transmembrane glycoprotein recognized by combining several functions including adhesion, receptor and enzymatic function. (4-6) The expression of CD38 is finely regulated during ontogenesis of B cells and is expressed by progenitors and early stages hematopoietic cells with loss during maturation and only re- expressed during cellular activation .(4) With the information derived from tissue distribution and from pioneer experience in vitro indicates that very early precursors of the hematopoietic stem cells do not express CD38.(7) Despite the description of CD38 on progenitor cells, there was no myelosuppressive effect observed in studies to date. Apart from immune cells, the molecule CD38 has also been found in the brain, pancreatic acinar cells, smooth muscle and osteoclasts although expression in these tissues is in the cytosol or nucleus rather than the cell membrane. (8). Daratumumab has shown a strong signal in preclinical modeling with broad-spectrum killing activity through complement-mediated cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and ADC phagocytosis . (9) Daratumumab was first evaluated clinically in a phase I trial involving patients with relapsed/refractory multiple myeloma (10). In combination with others agents (lenalidomide + dexamethasone) preliminary analysis involving 20 patients, the rate of partial response or better was 75% with 3 patients achieving complete response and 6 patients a very good partial response (VGPR). The most common adverse reactions were infusion- related events (IREs) such as fever, cough, nausea, dizziness, and bronchospasm. A total of 9% occurred during predosing and 26% during the first full infusion with a gradual decrease with subsequent infusions. The onset of IREs was within 3-4 hours of infusion. Prophylactic steroids were administered to reduce the incidence of IREs (up to a maximum dose equivalent of 27 mg of dexamethasone per week). There were six serious adverse events (SAEs) related to daratumumab. Treatment-related adverse events included anemia, thrombocytopenia, and infusion reactions. All patients recovered from their SAEs with treatment and the maximum tolerated dose has not yet been reached. There was a dose-dependent decrease in peripheral-blood NK cells that was noted, with full recovery after treatment (11). Daratumumab has a novel mechanism of action that results in enhanced activity in combination with existing standards of care, including first-generation novel agents, such as thalidomide, as well as other therapeutics. Considerable responses have been observed in a cohort of heavily pretreated patients with relapsed/refractory MM. (12) However, in order to harness the full potential of the antimyeloma effect of daratumumab, the identification of synergistic drug combinations that target various mechanisms to overcome drug resistance will be vital. The potential role of cytotoxicity induced by the anti-CD38 antibody and the activation of effector cells with the immunomodulatory drugs could make this a very attractive antimyeloma combination therapy. Thalidomide, an oral immunomodulatory drug (IMID), has revolutionized clinical management of patients with MM with responses rates of 30% at relapse (alone) and higher rates at first line and at relapse when in combinations (50-65%) . The mechanism of action of thalidomide in myeloma cells remains under investigation. Thalidomide was found to potently inhibit the proliferation of endothelial cells and angiogenesis.

Thalidomide has direct cytotoxic effects on myeloma cells lines. In addition to its direct effect, IMIDs appear to modulate the bone marrow microenvironment. They can inhibit the up regulation of IL-6, necrose factor-α production and Vascular Endothelial Growth Factor (VEGF). It has a direct effect on the T-lymphocytes stimulating cytotoxic T cell proliferation, and induction of secretion of interferon γ and IL-2. The authors mentioned that as thalidomide does not show haematological toxicity, it may be used in advance disease when the platelet count is low . Thalidomide and the iMIDs have been used in combination with other chemotherapeutic agents with known and investigational activity in myeloma in several clinical trials. In vitro studies have suggested synergy between these agents and dexamethasone. The use of a treatment combination with monoclonal antibody associated with immunomodulator (in a four drug combo) can lead to a improvement in response rates and in survival, reflects on a better free time interval. Another interesting point is the use of Daratumumab intensified during consolidation and maintenance.

This trial will represent a new option of treatment with a combination of anti CD38 monoclonal antibody (Daratumumab) as induction regimen with CTD protocol (four drug combination). And It use as consolidation and maintenance to give better immunomodulatory response and extended survival and disease control.

Daratumumab Intensified Treatment to Eligible MM New Patients CTD-Dara Induction, Follow by Dara Consolidation

A Conceptual Study of Daratumumab Intensified Treatment to Eligible Multiple Myeloma New Patients- Cyclophosphamide, Thalidomide, Dexamethasone and Daratumumab Induction, Follow by Daratumumab Consolidation and Maintenance

Number of patients that obtained better than VGPR after ASCT based on the IMWG description

Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0

Evaluate response rate as defined by the International Myeloma Working Group) IMWG- Minimal residual Disease (MRD), stringent complete Response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), and minimal response (MR) in patients treated with this protocol.

Evaluate duration of response in patients treated with Daratumumab Cyclophosphamide thalidomide and dexamethasone treatment

Evaluate the specific moment of time of partial response observed after Daratumumab Cyclophosphamide thalidomide and dexamethasone treatment

Number of bone and extra bone marrow disease observed by PET CT image at diagnosis and after consolidation therapy by International Myeloma Working Group recommendations

Measurement of neutrophil number in peripheral blood sample to evaluate the time of bone marrow engraftment

Flow cytometry of progenitor cell number collected

Time to Disease Progression (TTP). The TTP is defined as time from date of randomization to date of first documented evidence of PD, as defined by IMWG criteria

Progression-Free Survival (PFS) and PFS on Next Line of Therapy (PFS2).The PFS2 is defined as time from randomization to progression on next line of treatment or death, whichever occur first. Disease progression will be based on IMWG guide

The MRD assessment will be done by flow cytometry in bone marrow aspirate and in stem cell collected pack of participants four pre specified times- after induction, after ASCT, after consolidation and 1 year of maintenance

Peripheral blood lymphocytes analysis will be done by Flow cytometry in spite of look at T and B population. The analysis will be performing at the same time as MRD

Time To Next treatment. Time to next treatment is defined as the time from randomization to the start of next-line treatment.

Duration of Response (DR). The DR is time from date of initial documentation of response (PR or better) to date of first documented PD, as defined by IMWG criteria

Overall Survival (OS). The OS is the time from date of randomization to date of participant's death or follow- up lost

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Rivaroxaban or Aspirin As Thromboprophylaxis in Multiple Myeloma	NCT03428373	Multiple Myelom... Multiple Myelom... Multiple Myelom... Multiple Myelom... Multiple Myelom... Multiple Myelom...	Rivaroxaban ASA	18 Years - 90 Years	Lawson Health Research Institute
Daratumumab Intensified Treatment to Eligible MM New Patients CTD-Dara Induction, Follow by Dara Consolidation	NCT03792620	Multiple Myelom...	Cyclo Thal Dex ...	18 Years - 120 Years	Grupo de Estudos Multicentricos em Onco-Hematologia
Rivaroxaban or Aspirin As Thromboprophylaxis in Multiple Myeloma	NCT03428373	Multiple Myelom... Multiple Myelom... Multiple Myelom... Multiple Myelom... Multiple Myelom... Multiple Myelom...	Rivaroxaban ASA	18 Years - 90 Years	Lawson Health Research Institute

Spots Global Cancer Trial Database for multiple myeloma stage i