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Multiple MyelomaPhase 2DEFENCENCT03792763

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

A Phase 2 study testing Denosumab 120 MG/1.7 ML Subcutaneous Solution [XGEVA] in people with Multiple Myeloma, run by Arbeitsgemeinschaft medikamentoese Tumortherapie at 10 sites in 3 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Multiple Myeloma
What is being tested?
Denosumab 120 MG/1.7 ML Subcutaneous Solution [XGEVA]
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
8 participants
Where
10 sitesin 3 countries
Study dates
30 Sep 2019to 14 Sep 2023
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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

Who cannot join

  • 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:
Show all 28Show fewer
  • 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

Trial locations and contacts

10 sites in 3 countries.

10 sites in 3 countries

Austria8 sites
  • Medizinische Universitaet Graz, Univ.-Klinik f. Innere Medizin, Onkologie

    Graz, A-8036

  • Medizinische Universität Innsbruck Univ.-Klinik für Innere Medizin V Hämatologie und Onkologie

    Innsbruck, 6020

  • LKH Hochsteiermark, Standort Leoben, Abteilung für Innere Medizin und Hämatologie und internistische Onkologie

    Leoben, A-8700

  • Kepler Universitaetsklinikum Klinik f. Interne 3, Med Campus III

    Linz, 4021

  • BHS Linz: Interne I: Internistische Onkologie, Hämatologie und Gastroenterologie

    Linz, A-4020

  • IIIrd Medical Department, Private Medical University Hospital Salzburg

    Salzburg, State of Salzburg, 5020

  • Hanusch Krankenhaus der Österreichischen Gesundheitskasse, 3. Med. Abteilung

    Vienna, 1140

  • Krankenhaus St. Vinzenz Zams, Innere Medizin, Internistische Onkologie und Hämatologie

    Zams, 6511

Other trials in Austria

Germany1 site
  • University Hospital Würzburg, Department of Internal Medicine 2

    Würzburg, 97080

Other trials in Germany

Israel1 site
  • Tel Aviv Sourasky Medical Center, Department of Hematology,

    Tel Aviv, 6423906

Other trials in Israel

About this study

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)

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.

Read the 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.

Being tested
Denosumab 120 MG/1.7 ML Subcutaneous Solution [XGEVA], Placebo 1.7 ml Subcutaneous Solution
Keywords
early multiple myeloma, smoldering multiple myeloma, SLiM CRAB, denosumab, Austrian Study Group of Medical Tumour Therapy (AGMT), high risk smoldering myeloma
Medical subject headings
Multiple Myeloma, Smoldering Multiple Myeloma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Denosumab 120 MG/1.7 ML Subcutaneous Solution [XGEVA]Drug

    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

  • Placebo 1.7 ml Subcutaneous SolutionDrug

    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

Study groups in NCT03792763
Study groupRoleWhat they receive
Arm A, denosumabExperimentalDenosumab 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
Receives: Drug: Denosumab 120 MG/1.7 ML Subcutaneous Solution [XGEVA]
Arm B, placeboPlacebo comparatorPlacebo 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
Receives: Drug: Placebo 1.7 ml Subcutaneous Solution

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: 78 months (the first 6 cycles are 28 days, thereafter each cycle is 3 months for a maximum of 36 months)

Secondary outcomes (5)
  1. 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

    Measured: 36 months (the first 6 cycles are 28 days, thereafter each cycle is 3 months)

  2. Overall survival

    To determine the overall survival of patients receiving either denosumab or placebo

    Measured: 78 months (the first 6 cycles are 28 days, thereafter each cycle is 3 months for a maximum of 36 months)

  3. 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

    Measured: 78 months (baseline and every 6 months thereafter until progression or maximum of 3 years).

  4. 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.

    Measured: 78 months (baseline and every 6 months thereafter until progression or maximum of 3 years).

  5. Time to first anti-myeloma treatment

    To determine the time to first anti-myeloma treatment for patients receiving either denosumab or placebo

    Measured: 78 months (the first 6 cycles are 28 days, thereafter each cycle is 3 months for a maximum of 36 months)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted3 Jan 2019
  2. Study start30 Sep 2019
  3. Primary completion14 Sep 2023
  4. Study completion14 Sep 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Model description
Placebo controlled, randomized
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
8 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03792763
Sponsor's protocol ID
AGMT_MM-3
Acronym
DEFENCE
Status last verified
Feb 2025
First submitted
21 Dec 2018
Last updated
11 Feb 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 29895887
  • 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.

    PubMed 27696254

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Denosumab 120 MG/1.7 ML Subcutaneous Solution [XGEVA] in people with Multiple Myeloma, run by Arbeitsgemeinschaft medikamentoese Tumortherapie at 10 sites in 3 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 28 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 11 Feb 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 10 sites in Austria, Germany, Israel. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Time to progression (time frame: 78 months (the first 6 cycles are 28 days, thereafter each cycle is 3 months for a maximum of 36 months)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03792763, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Feb 2025.

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