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

NCT03792763 | Completed Phase 2 DMC

• 1 other identifier: AGMT_MM-3
• Study Type: interventional
• Target: 8
• Locations: 3 countries
• Sites: 10

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.

Conditions

Multiple Myeloma

Keywords

early multiple myeloma; smoldering multiple myeloma; SLiM CRAB; denosumab; Austrian Study Group of Medical Tumour Therapy (AGMT); high risk smoldering myeloma

Outcome Measures

Primary Outcomes (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

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

Secondary Outcomes (5)

• Percentage of patients transforming in 3 years

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

• Overall survival

  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

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

• Incidence of bone lesions as MM defining events

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

• Time to first anti-myeloma treatment

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

Study Arms (2)

Arm A, denosumab

EXPERIMENTAL

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]

Arm B, placebo

PLACEBO COMPARATOR

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

Interventions

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

Arm A, denosumab

Placebo 1.7 ml Subcutaneous Solution 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

Arm B, placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.)

Sponsors & Collaborators

• Arbeitsgemeinschaft medikamentoese Tumortherapie: lead
• Amgen: collaborator
• Assign Data Management and Biostatistics GmbH: collaborator

Study Sites (10)

IIIrd Medical Department, Private Medical University Hospital Salzburg

Salzburg, Salzburg, 5020, Austria

Location

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

Graz, A-8036, Austria

Location

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

Innsbruck, 6020, Austria

Location

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

Leoben, A-8700, Austria

Location

Kepler Universitaetsklinikum Klinik f. Interne 3, Med Campus III

Linz, 4021, Austria

Location

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

Linz, A-4020, Austria

Location

Hanusch Krankenhaus der Österreichischen Gesundheitskasse, 3. Med. Abteilung

Vienna, 1140, Austria

Location

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

Zams, 6511, Austria

Location

University Hospital Würzburg, Department of Internal Medicine 2

Würzburg, 97080, Germany

Location

Tel Aviv Sourasky Medical Center, Department of Hematology,

Tel Aviv, 6423906, Israel

Location

Related Publications (2)

• 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.

  PMID: 29895887 BACKGROUND

• 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.

  PMID: 27696254 BACKGROUND

Related Links

• Description sponsor

MeSH Terms

Conditions

Multiple Myeloma; Smoldering Multiple Myeloma

Interventions

Denosumab

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Precancerous Conditions; Hypergammaglobulinemia

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Heinz Ludwig, MD

  Wilheminenspital

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Placebo controlled, randomized

Study Record Dates

• First Submitted: December 21, 2018
• First Posted: January 3, 2019
• Study Start: September 30, 2019
• Primary Completion: September 14, 2023
• Study Completion: September 14, 2023
• Last Updated: February 11, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1); AU (8); IL (1)