Narlumosbart Compared With Denosumab in Patients With Multiple Myeloma Bone Disease

A Multicenter, Randomized, Controlled, Non-inferiority Study of Narlumosbart Compared With Denosumab in the Treatment of Bone Disease in Patients With Multiple Myeloma

The purpose of this study is to determine if narlumosbart is non-inferior to denosumab in the treatment of bone diseases from multiple myeloma (MM).

Study Overview

• Status: Not yet recruiting
• Conditions: Multiple Myeloma; Bone Diseases
• Intervention / Treatment: Drug: Denosumab; Drug: Narlumosbart

Detailed Description

Multiple myeloma is a plasma cell dyscrasia with a high likelihood of causing bone disease (ie, multiple myeloma-related bone disease); as a result, up to 80% of patients with newly diagnosed multiple myeloma present with osteolytic lesions.

Denosumab is recommended for the treatment of newly diagnosed multiple myeloma, and for patients with relapsed or refractory multiple myeloma with evidence of multiple myeloma-related bone disease.

Narlumosbart is a recombinant, fully human, anti-receptor activator of nuclear factor kappa-Β ligand (RANKL) IgG4 monoclonal antibody. Changing the IgG2 Fc portion of denosumab to IgG4, results in increased stability, higher specificity and affinity for RANKL than denosumab. The objective of this phase III trial is to compare the efficacy and safety between Narlumosbart and denosumab in patients with bone diseases from newly diagnosed multiple myeloma.

• Study Type: Interventional
• Enrollment (Estimated): 478
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Honghui Huang, M.D.; Phone Number: 00862168383141; Email: honghui_huang@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Subjects fully understand and voluntarily participate in this study and sign the informed consent;
2. Age≥18, no gender limitation;
3. Active multiple myeloma patients with newly diagnosed by International Myeloma Working Group (IMWG) 2014 criteria;
4. Measurable lesion per at least one of the following criteria : Serum monoclonal protein ≥10 g/L; Urinary monoclonal protein ≥200 mg/24h; Serum free Light Chain (FLC) assay showed an involved FLC level ≥100 mg/L with abnormal ratio for FLC (κ/λ);
5. Radiographic [X-ray, computer tomography (CT), magnetic resonance imaging (MRI), positons emission tomography coupled with a computer tomography (PET-CT)] evidence of at least one lytic bone lesion;
6. Plan to receive primary frontline anti-myeloma therapies, or receiving less than one cycle of frontline anti-myeloma therapy (less than 30 days, does not include radiotherapy or a single short course of steroid), the treatment regimens were limited to VRd, D-VRd, DRd, and VCd;
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

8. Adequate organ function, as defined by the following criteria (per laboratory values):

   1. Liver function: Serum total bilirubin ≤ 2.0 x upper limit of normal (ULN), Serum alanine aminotransferase ≤ (ALT) 2.0 x ULN, Serum aspartate aminotransferase (AST) ≤ 2.0 x ULN
   2. Renal function: Serum creatinine clearance (CrCL) ≥ 30 mL/min, calculated by the Cockcroft-Gault formula
   3. Serum calcium or albumin-adjusted serum calcium ≥2.0 mmol/L (8.0 mg/dL) and ≤ 2.9 mmol/L (11.5 mg/dL)
9. Reproductive potential subjects should be receiving effective contraception (Both male and female reproductive potential subjects, from the date of signing the informed consent to 6 months after the end of treatment);
10. Expected survival time ≥ 3 months;

Exclusion Criteria:

1. POEMS syndrome;
2. Plasma cell leukemia;
3. Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw; Non-healed dental/oral surgery, including tooth extraction; Active dental or jaw condition which requires oral surgery; Planned invasive dental procedures;
4. Planned radiation therapy or Orthopedic surgery;
5. Prior administration of denosumab or bisphosphonates;
6. Patients with active bone metabolic diseases (Paget disease of bone, Cushing syndrome and hyperprolactinemia), rheumatoid arthritis, uncontrolled hyper/hypothyroidism or hyper/hypoparathyroidism;
7. Uncontrolled concurrent diseases, including but not limited to: symptomatic congestive heart failure, hypertension (blood pressure remains > 150/90 mmHg after standard therapy), unstable angina, arrhythmia requiring medication or instruments, history of myocardial infarction within 6 months, echocardiography showing left ventricular ejection fraction <50%;
8. Active bacterial or fungal infections requiring systemic treatment within 7 days before randomization;
9. Known infection with human immunodeficiency virus (HIV), active infection with Hepatitis B virus (positive hepatitis B surface antigen and positive HBV-DNA) or Hepatitis C virus(positive hepatitis C surface antigen and positive HCV-RNA);
10. Pregnancy (serum β-HCG positive) or lactation;

11. Use of any of the following anti-bone metabolism drugs within 6 months before enrollment:

    1. parathyroid hormonerelated peptides
    2. calcitonin
    3. osteoprotegerin
    4. mithramycin
    5. strontium ranelate
12. Known sensitivity to narlumosbart, denosumab, calcium or vitamin D;
13. Any other factors not suitable for participation in this study that in the opinion of the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Narlumosbart; 120 mg SC Q4W, up to 2 years.	Drug: Narlumosbart; Administered by subcutaneous injection once every 4 weeks.; Other Names: Narlumosbart Injection, JMT103
Active Comparator: Denosumab; 120 mg SC Q4W, up to 2 years.	Drug: Denosumab; Administered by subcutaneous injection once every 4 weeks.; Other Names: XGEVA®, AMG 162

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent change from baseline in urinary N-terminal telopeptide of type 1 collagen corrected for urinary creatinine (uNTx/uCr) at week 13	Compare narlumosbart and denosumab for percentage change in bone turnover marker (BTM) - urinary N-terminal telopeptide of type 1 collagen (uNTx) corrected for urinary creatinine (uCr) (uNTx/uCr from baseline to week 13)	From baseline to week 13

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The proportion of subjects with a change in uNTx/uCr greater than 65% from baseline to week 13	Compare narlumosbart and denosumab for the proportion of subjects with a change in uNTx/uCr greater than 65% from baseline to week 13 (uNTx/uCr from baseline to week 13 >65%)	From baseline to week 13
Time to first on-study skeletal related event	A skeletal-related event (SRE) is defined as one of the following: pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE	From baseline to 90 days after the last dose, up to approximately 30 months
Percentage of participants with an on-study SRE at different time points	A skeletal-related event (SRE) is defined as one of the following: pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression. Percentage of participants with an on-study SRE at 3, 6, 12, 18 and 24 months	Months 3, 6, 12, 18 and 24
Time to first and subsequent on-study SRE	Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. Time to a subsequent SRE is defined, similarly to the time to first on-study SRE, as the time interval from the randomization date to the date of a subsequent occurrence of on-study SRE, which had to be at least 21 days after the previous SRE.	From baseline to 90 days after the last dose, up to approximately 30 months
Percent changes of serum bone alkaline phosphatase (BALP) and serum C-terminal telopeptide of type 1 collagen (sCTX-I)	Compare the changes of BALP and sCTX-I from baseline to weeks 13	From baseline to week 13
Overall Survival	Overall survival was defined as the time interval (in days) from the randomization date to the date of death.	From baseline to 90 days after the last dose, up to approximately 30 months
Incidence and type of adverse events (AEs)	To identify the incidence and the type of AEs, including abnormalities in clinical, laboratory assessments, ECGs, echocardiography, vital sign assessments, and physical exams.	From the first dose finished to 28 days after the last dose

Collaborators and Investigators

• Sponsor: RenJi Hospital
• Collaborators: Shanghai JMT-Bio Inc.
• Investigators: Principal Investigator: Jian Hou, M.D., Renji Hospital

Publications and helpful links

General Publications

• Dhillon S. Narlumosbart: First Approval. Drugs. 2024 Jan;84(1):105-109. doi: 10.1007/s40265-023-01985-3.

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): April 30, 2027

Study Registration Dates

• First Submitted: March 10, 2024
• First Submitted That Met QC Criteria: March 14, 2024
• First Posted (Actual): March 18, 2024

Study Record Updates

• Last Update Posted (Actual): March 18, 2024
• Last Update Submitted That Met QC Criteria: March 14, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Musculoskeletal Diseases; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Bone Diseases; Physiological Effects of Drugs; Bone Density Conservation Agents; Denosumab
• Other Study ID Numbers: IIT-2024-0011

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No