Denosumab for High Risk SMM and SLiM CRAB Positive, Early Myeloma Patients

Study Overview
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Brief Summary
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This is a randomized, 2-arm phase II, placebo-controlled, multi-center study, where the investigators aim to evaluate whether the reported benefits of denosumab, delay of SRE and decrease in myeloma growth promotion, reduce the risk of progression of high-risk SMM and of early 'SLiM CRAB' myeloma into active, symptomatic CRAB positive myeloma or serological progression. In addition, tolerability of long-term treatment will be assessed.

Detailed Description
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The aim of this study is to evaluate whether the transition of early Multiple Myeloma (High Risk Smouldering Multiple Myeloma SMM or Ultra High Risk SMM) or SLiM CRAB positive multiple myeloma to a symptomatic multiple myeloma (MM) can be reduced or delayed by the administration of denosumab. With the exception of clinical studies, there are currently no standardized treatment options for SMM. Ultra-high risk SMM is already part of early active myeloma and is therefore in some cases treated according to a standard myeloma protocol (Revlimid-Dexamethasone, Velcade melphalan prednisone, melphalan prednisone thalidomide, or others). However, most practitioners recommend a wait-and-see strategy, since depending on the initial situation within two years only 58-95% of patients develop an 'active' MM and 5-42% of the patients had a stable disease and therefore do not necessarily have to be treated immediately. Denosumab is a human monoclonal antibody (IgG2) which binds to RANKL with high affinity and specificity. RANKL (receptor activator of NF-κB Ligand) is a protein that is responsible for the formation, function and survival of osteoclasts (cell type responsible for bone resorption) Increased osteoclast activity, stimulated by RANKL, is a key mediator of the bone resorption in bone metastases and MM. Thus the activity of denosumab is resulting in a reduced number and function of osteoclasts and thus decreases the bone resorption and tumor-induced bone destruction. After an initial phase of about 14 days (screening), the patients will be randomized 1:1 in one of the two study groups (arm A: denosumab or arm B: placebo). The study is double-blinded. The planned duration of therapy is 3 years. Patients receive denosumab or placebo every 4 weeks for 6 months, then every 3 months until a total of 3 years or progression. After completion of the therapy, an observation and follow-up phase is carried out with patient visits every 3 months until the end of the treatment.

Official Title
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Denosumab for High Risk SMM and SLiM CRAB Positive, Early Myeloma Patients- a Randomized, Placebo Controlled Phase II Trial DEFENCE (DEnosumab For the rEductioN of the Smoldering Myeloma transformatioN inCidence ratE)

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Denosumab 120 MG/1.7 ML Subcutaneous Solution [XGEVA]
* Drug: Placebo 1.7 ml Subcutaneous Solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Able to provide written informed consent in accordance with federal, local, and institutional guidelines Must meet criteria of high-risk smoldering MM or early SLiM CRAB MM based on the criteria described below: High-risk SMM is defined here according to the revised Mayo Clinical criteria (2 out of 3 criteria must be fulfilled): Bone marrow clonal plasma cells > 20% Serum M protein > 2.0g/dL Serum-free light chain ratio > 20, measured with Binding site Kit Early 'SLiM CRAB' multiple myeloma Patients must present with only one of the following features Bone marrow clonal plasma cells ≥ 60%, or Serum FLC ratio ≥ 100 (kappa-LC leading) or ≤ 0.01 (lambda-LC leading), measured with Binding site Kit, or >1 Focal bone lesion of ≥5mm (not associated with osteolysis, detected by PET-CT or whole-body low-dose CT (WBLDCT)) Time from diagnosis of high-risk SMM or SLIM CRAB positive, early MM to study enrollment: <5 years Exclusion Criteria: ECOG >3 Active, symptomatic MM (fulfilling CRAB-criteria) Non-secretory MM, extramedullary plasmacytoma, plasma cell leukemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) MGUS Hypocalcemia (can be corrected by drug intervention before start of treatment) Second malignancy within the past 5 years except: Adequately treated basal cell or squamous cell skin cancer Carcinoma in situ of the cervix Prostate cancer Gleason score ≤ 6 with stable prostate-specific antigen (PSA over 12 months) Ductal breast carcinoma in situ with full surgical resection (i.e., negative margins) Treated medullary or papillary thyroid cancer Similar condition with an expectation of > 95% five-year disease-free survival Active infection within the 14 days prior to randomization requiring systemic antibiotics and/or antiviral therapy Patients with known active or latent tuberculosis Known human immunodeficiency virus (HIV) seropositivity or active hepatitis C or hepatitis B infection (subjects with past hepatitis B virus [HBV] infection or resolved HBV infection defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test are eligible; subjects positive for hepatitis C virus [HCV] antibody are eligible only if polymerase chain reaction [PCR] is negative for HCV RNA.) Participation in another interventional study within the 28 days prior to randomization Any other clinically significant medical disease or social condition that, in the investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent, be compliant with study procedures, or provide accurate information. Prior administration of denosumab Prior exposure to any experimental or approved anti-myeloma agent Use of oral bisphosphonates with a cumulative exposure of more than 1 year (washout period for allowed bisphosphonate exposure 1 month) More than 1 previous dose of IV bisphosphonate or teriparatide administration (washout period for allowed bisphosphonate exposure 1 month) Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw Active dental or jaw condition which requires oral surgery, including tooth extraction Subject is pregnant or breastfeeding, or planning to become pregnant within 7 months after the end of treatment Female subject of childbearing potential is not willing to use, in combination with her partner, a highly effective and in addition an effective method of contraception during treatment and for 5 months after the end of treatment Known sensitivity to denosumab (including all components of the formulation) or any of the products to be administered during the study (eg, mammalian derived products, calcium, or vitamin D) Subject is receiving or is less than 30 days since ending other experimental devices or drugs (no marketing authorization for any indication). Subject will not be available for follow-up assessment

Ages Eligible for Study
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Minimum Age: 18 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Placebo controlled, randomized
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A, denosumab<br>Denosumab 120 MG/1.7 ML Subcutaneous Solution [XGEVA] Every 4 weeks (Q4W) for 6 months then every 3 months (Q3M) for a total of 3 years or until progression to active, symptomatic MM Calcilac 500 mg/400 I.E. (Calcium/Vitamin D3) Concomitant medication, oral, 1 chewable tablet / day | Drug: Denosumab 120 MG/1.7 ML Subcutaneous Solution [XGEVA]<br>* Administration every 4 weeks (Q4W) for 6 months then every 3 months (Q3M) for a total of 3 years or until progression to active, symptomatic MM<br>|
| Placebo Comparator: Arm B, placebo<br>Placebo 1.7 ml Subcutaneous Solution SC every 4 weeks (Q4W) for 6 months then every 3 months (Q3M) for a total of 3 years or until progression to active, symptomatic MM Calcilac 500 mg/400 I.E. (Calcium/Vitamin D3) Concomitant medication, oral, 1 chewable tablet / day | Drug: Placebo 1.7 ml Subcutaneous Solution<br>* Administration every 4 weeks (Q4W) for 6 months then every 3 months (Q3M) for a total of 3 years or until progression to active, symptomatic MM<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to progression | Time from randomization to transformation to symptomatic, active MM (defined as progression to active multiple myeloma according to IMWG diagnosis criteria 2014) or progression of disease according to IMWG response criteria 2016 | 78 months (the first 6 cycles are 28 days, thereafter each cycle is 3 months for a maximum of 36 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients transforming in 3 years | Percentage of patients with high-risk SMM and early 'slim CRAB' positive MM transforming to CRAB positive multiple myeloma and/or developing serological progression (as defined by IMWG criteria 2016 for MM) within 3 years | 36 months (the first 6 cycles are 28 days, thereafter each cycle is 3 months) | 
| Overall survival | To determine the overall survival of patients receiving either denosumab or placebo | 78 months (the first 6 cycles are 28 days, thereafter each cycle is 3 months for a maximum of 36 months) | 
| Time to first skeletal-related event | To determine the time to first skeletal-related event for patients receiving either denosumab or placebo. • Imaging: low dose wbCT (details will be described in a separate guidance document) or PET-CT mandatory | 78 months (baseline and every 6 months thereafter until progression or maximum of 3 years). | 
| Incidence of bone lesions as MM defining events | To determine the incidence of bone lesions as MM defining events. • Imaging: low dose wbCT (details will be described in a separate guidance document) or PET-CT mandatory. | 78 months (baseline and every 6 months thereafter until progression or maximum of 3 years). | 
| Time to first anti-myeloma treatment | To determine the time to first anti-myeloma treatment for patients receiving either denosumab or placebo | 78 months (the first 6 cycles are 28 days, thereafter each cycle is 3 months for a maximum of 36 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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early multiple myeloma, smoldering multiple myeloma, SLiM CRAB, denosumab, Austrian Study Group of Medical Tumour Therapy (AGMT), high risk smoldering myeloma