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

Primary Purpose

Multiple Myeloma

Status
Active
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Denosumab 120 MG/1.7 ML Subcutaneous Solution [XGEVA]
Placebo 1.7 ml Subcutaneous Solution
Sponsored by
Arbeitsgemeinschaft medikamentoese Tumortherapie
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Multiple Myeloma focused on measuring early multiple myeloma, smoldering multiple myeloma, SLiM CRAB, denosumab, Austrian Study Group of Medical Tumour Therapy (AGMT), high risk smoldering myeloma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Medizinische Universitaet Graz, Univ.-Klinik f. Innere Medizin, Onkologie
  • Medizinische Universität Innsbruck Univ.-Klinik für Innere Medizin V Hämatologie und Onkologie
  • LKH Hochsteiermark, Standort Leoben, Abteilung für Innere Medizin und Hämatologie und internistische Onkologie
  • Kepler Universitaetsklinikum Klinik f. Interne 3, Med Campus III
  • BHS Linz: Interne I: Internistische Onkologie, Hämatologie und Gastroenterologie
  • IIIrd Medical Department, Private Medical University Hospital Salzburg
  • Hanusch Krankenhaus der Österreichischen Gesundheitskasse, 3. Med. Abteilung
  • Krankenhaus St. Vinzenz Zams, Innere Medizin, Internistische Onkologie und Hämatologie
  • University Hospital Würzburg, Department of Internal Medicine 2
  • Tel Aviv Sourasky Medical Center, Department of Hematology,

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Arm A, denosumab

Arm B, placebo

Arm Description

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

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

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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
Overall survival
To determine the overall survival of patients receiving either denosumab or placebo
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
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.
Time to first anti-myeloma treatment
To determine the time to first anti-myeloma treatment for patients receiving either denosumab or placebo

Full Information

First Posted
December 21, 2018
Last Updated
September 4, 2023
Sponsor
Arbeitsgemeinschaft medikamentoese Tumortherapie
Collaborators
Amgen, Assign Data Management and Biostatistics GmbH
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1. Study Identification

Unique Protocol Identification Number
NCT03792763
Brief Title
Denosumab for High Risk SMM and SLiM CRAB Positive, Early Myeloma Patients
Acronym
DEFENCE
Official Title
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)
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
September 30, 2019 (Actual)
Primary Completion Date
July 2024 (Anticipated)
Study Completion Date
July 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Arbeitsgemeinschaft medikamentoese Tumortherapie
Collaborators
Amgen, Assign Data Management and Biostatistics GmbH

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Myeloma
Keywords
early multiple myeloma, smoldering multiple myeloma, SLiM CRAB, denosumab, Austrian Study Group of Medical Tumour Therapy (AGMT), high risk smoldering myeloma

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Placebo controlled, randomized
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
8 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm A, denosumab
Arm Type
Experimental
Arm Description
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
Arm Title
Arm B, placebo
Arm Type
Placebo Comparator
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Denosumab 120 MG/1.7 ML Subcutaneous Solution [XGEVA]
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Placebo 1.7 ml Subcutaneous Solution
Intervention Description
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
Primary Outcome Measure Information:
Title
Time to progression
Description
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
Time Frame
78 months (the first 6 cycles are 28 days, thereafter each cycle is 3 months for a maximum of 36 months)
Secondary Outcome Measure Information:
Title
Percentage of patients transforming in 3 years
Description
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
Time Frame
36 months (the first 6 cycles are 28 days, thereafter each cycle is 3 months)
Title
Overall survival
Description
To determine the overall survival of patients receiving either denosumab or placebo
Time Frame
78 months (the first 6 cycles are 28 days, thereafter each cycle is 3 months for a maximum of 36 months)
Title
Time to first skeletal-related event
Description
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
Time Frame
78 months (baseline and every 6 months thereafter until progression or maximum of 3 years).
Title
Incidence of bone lesions as MM defining events
Description
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.
Time Frame
78 months (baseline and every 6 months thereafter until progression or maximum of 3 years).
Title
Time to first anti-myeloma treatment
Description
To determine the time to first anti-myeloma treatment for patients receiving either denosumab or placebo
Time Frame
78 months (the first 6 cycles are 28 days, thereafter each cycle is 3 months for a maximum of 36 months)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Heinz Ludwig, MD
Organizational Affiliation
Wilheminenspital
Official's Role
Study Director
Facility Information:
Facility Name
Medizinische Universitaet Graz, Univ.-Klinik f. Innere Medizin, Onkologie
City
Graz
ZIP/Postal Code
A-8036
Country
Austria
Facility Name
Medizinische Universität Innsbruck Univ.-Klinik für Innere Medizin V Hämatologie und Onkologie
City
Innsbruck
ZIP/Postal Code
6020
Country
Austria
Facility Name
LKH Hochsteiermark, Standort Leoben, Abteilung für Innere Medizin und Hämatologie und internistische Onkologie
City
Leoben
ZIP/Postal Code
A-8700
Country
Austria
Facility Name
Kepler Universitaetsklinikum Klinik f. Interne 3, Med Campus III
City
Linz
ZIP/Postal Code
4021
Country
Austria
Facility Name
BHS Linz: Interne I: Internistische Onkologie, Hämatologie und Gastroenterologie
City
Linz
ZIP/Postal Code
A-4020
Country
Austria
Facility Name
IIIrd Medical Department, Private Medical University Hospital Salzburg
City
Salzburg
ZIP/Postal Code
5020
Country
Austria
Facility Name
Hanusch Krankenhaus der Österreichischen Gesundheitskasse, 3. Med. Abteilung
City
Wien
ZIP/Postal Code
1140
Country
Austria
Facility Name
Krankenhaus St. Vinzenz Zams, Innere Medizin, Internistische Onkologie und Hämatologie
City
Zams
ZIP/Postal Code
6511
Country
Austria
Facility Name
University Hospital Würzburg, Department of Internal Medicine 2
City
Würzburg
ZIP/Postal Code
97080
Country
Germany
Facility Name
Tel Aviv Sourasky Medical Center, Department of Hematology,
City
Tel Aviv
ZIP/Postal Code
6423906
Country
Israel

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
29895887
Citation
Lakshman A, Rajkumar SV, Buadi FK, Binder M, Gertz MA, Lacy MQ, Dispenzieri A, Dingli D, Fonder AL, Hayman SR, Hobbs MA, Gonsalves WI, Hwa YL, Kapoor P, Leung N, Go RS, Lin Y, Kourelis TV, Warsame R, Lust JA, Russell SJ, Zeldenrust SR, Kyle RA, Kumar SK. Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer J. 2018 Jun 12;8(6):59. doi: 10.1038/s41408-018-0077-4.
Results Reference
background
PubMed Identifier
27696254
Citation
Mateos MV, Landgren O. MGUS and Smoldering Multiple Myeloma: Diagnosis and Epidemiology. Cancer Treat Res. 2016;169:3-12. doi: 10.1007/978-3-319-40320-5_1.
Results Reference
background
Links:
URL
http://www.agmt.at
Description
Description sponsor

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

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