Targeting the Osteogenic Lineage as a Therapeutic Strategy in Multiple Myeloma
Peter Croucher
PhDGarvan Institute of Medical Research
Project Term: July 1, 2024 - June 30, 2027
Multiple myeloma causes devastating bone disease characterised by focal bone lesions and generalise bone loss, which leads to an increase in bone fractures. Current therapies only stop bones from getting worse so patients continue to suffer fractures. We discovered that inhibiting a molecule called sclerostin in mice increases bone and is much better than current treatments. In this program we will investigate whether inhibiting sclerostin is able to restore lost bone and reduce fractures in patients with myeloma.
Multiple myeloma is a blood cancer that grows in the bone marrow in the skeleton. Patients with multiple myeloma develop a devastating bone disease that is particularly painful. This bone disease results in a loss of bone which leads to bone fractures and an increase in mortality. Unfortunately, current therapies only stop further bone loss and prevent the skeleton from getting worst. A consequence of this is that patients continue to experience fractures. Indeed, 45% of patients receiving current therapies will experience new fractures. There is an urgent clinical need for treatments that restore lost bone and stop future fractures. To achieve this new therapies that make new bone to replace the bone that has been lost are needed. This requires drugs that tell osteoblasts, which are the cells that synthesize bone, to make more new bone. Until recently there have been no drugs to do this.
In addition to their role in making bone osteoblasts have another role. That role is to keep myeloma cells in dormant state. When myeloma cell are dormant they are resistant to myeloma treatments. When these dormant cells are woken up they grow and form more myeloma. This is part of the reason why myeloma can return following initial treatment. Since osteoblast cells are important in these two aspects of the disease if we develop drugs that change their behaviour they may have multiple benefits.
We have discovered a new molecule, called sclerostin, that is important in controlling osteoblasts. Blocking sclerostin in mice with myeloma made their bones stronger and made them resistant to fracture. A drug that inhibits sclerostin has recently been introduced to treat patients with osteoporosis. This drug has yet to be tested in patients with myeloma. Our discoveries in mice provides a new opportunity to test this osteoporosis drug in patients with myeloma. We are proposing to treat patients with myeloma with this new drug and determine whether:
- This osteoporosis drug increases osteoblasts and new bone formation in patients with myeloma.
- This drug increases bone mass and repairs bone defects in patients with myeloma.
- This drug changes dormant cells and myeloma burden in patients with myeloma.
We anticipate that this drug will stop the myeloma bone disease. We anticipate that this will restore lost bone, repair any bone defects and stop further fractures. We also anticipate that this drug may alter dormant myeloma cells and slow the development of myeloma. This program will establish a new paradigm in therapies that target osteoblasts in patients with multiple myeloma. This will pave the way for clinical trials in patients and speed up the introduction of these new drugs for patients.