Michael Tveden Gundesen

Treatment and Monitoring of the Bone Disease in Multiple Myeloma Patients

Multiple Myeloma (MM) is an incurable hematological cancer which originates from malignant transformation and uncontrolled proliferation of plasma cells in the bone marrow. It is the hematological malignancy associated with the highest morbidity of all hematological cancers with a more than double risk of disability pension in a Danish setting, compared to e.g. acute leukemia or aggressive lymphoma. This high morbidity is primarily caused by severe bone destruction which causes bone fractures, pain and occasionally also neurological deficits.

At diagnosis 70% of patients have pathological bone structure. MM alters the microenviroment preventing bone healing and inducing bone loss. Treatment of the cancer may temporally halt the bone loss but for yet unknown reasons bone healing is almost never observed. Bone loss thus accumulates with each relapse. Treatment with high dose bisphosphonates may reduce the rate of bone degradation but prolonged treatment causes the jaw to dissolve. In addition the bone damage MM results in suppression of normal immune system, bone marrow failure, hypercalcemia and kidney damage.

Aim and methods

This project aim to improve the severely reduced life quality of myeloma patients caused by fractures and bone pain. We plan to do this in 3 ways.

1) Investigating, in a clinical trials in humans, if a new compound causes the bone to heal up in the time points where the cancer is in remission

2) Investigate the best way to monitor the bone disease over time

3) Investigate new ways of monitoring possible bone healing in MM In the first part we will investigate bone healing in MM. Bone healing is traditionally not seen in MM. but there are promising signs that the drug group called proteasome inhibitors, given time, may allow bone healing in MM. Traditionally these cannot be used for a longer period of time due to administration issues and side effects but a new proteasome inhibitor called Ninlaro is taken orally and is well tolerated opening the possibility of bone healing in MM which could be a breakthrough in treatment. We will investigate bone healing over a 2-year period during Ninlaro treatment.

In the second part we will investigate how to best monitor bone disease by comparing X-ray to CT-scans in MM to investigate the advantages and disadvantages of each modality. Earlier studies indicate that CT-scans identify bone lesions that cannot be seen in conventional radiography, are fast and more convenient for patients, but some lesions in the skeleton can be missed due to limitation in view. In the study we will follow MM patients over 2 years with both CT and X-ray and bone markers.

In the third part we will investigate how to best monitor bone healing. Most imaging techniques evaluate present bone damage. A more dynamic way to monitor ongoing bone damage is by use of markers of bone resorption and formation. Bone markers are small molecules that are released into the blood as bone remodeling is ongoing and can give a dynamic picture of bone formation or degradation. NaF-PET is an imaging technology that may offer dynamic information on bone formation. The NaF tracer is injected intravenously and rapidly binds to the bone matrix reflects synthesis of new bone matrix in the skeleton.

Feasibility and collaboration

These areas will be investigated in 2 major studies running at the hematological department at OUH called the MAGNOLIA protocol and the BONE protocol. The first project is a collaboration between all Danish and Norwegian departments of hematology, the project is initiated and maintained from Odense University Hospital. The second project is a collaboration between the department of hematology, department of nuclear medicine, the department of radiology, the department of pathology, and the department of biochemistry all at OUH.

The PhD student has research experience and has published earlier both within and outside of hematology. The supervisors are all expert in their fields. The main supervisor has extensive experience in the field of MM and has published many papers on bone disease and monitoring in MM but has only supervised one previous Ph.D. student. To compensate for this the professor in hematology, who has supervised numerous Ph.D. students is co-supervising the project.

Impact

This study could have a profound and imminent impact in the treatment in MM. If we find a way to reverse the ongoing and excessive bone loss in MM, it would be of tremendous importance to all the patients. Furthermore, improved monitoring of bone disease could result in a more targeted and individual tailored treatment preventing unnecessary overtreatment with an increased risk of side effects but also allow a more timely treatment before new fracture occur. We sincerely hope the OUH PhD fund will help to conduct this study since it may have a profound impact on the treatment of severely ill patients.