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).

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.

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.