Short summary

Patient with multiple myeloma are randomised to recieve zoledronic acid for either 2 years or four year. 

Primary endpoint is time to progressive bone disease in the two cohorts.

Secondary endpoints are: To compare the incidence of bone healing, to compare the overall survival, to compare the incidence of BON, to compare the development in QoL, to compare the development in the bone markers CTX-I, PINP, bALP, and TRAP5b, and to compare conventional radiography compared to low-dose CT.     

Rationale

The purpose of this study is three-fold.

1. To determine the optimal time period to continue treatment with high-dose intravenous bisphosphonates in patients with multiple myeloma.

High-dose bisphosphonate has been used for treatment of cancer induced bone disease for many years. Bisphosphonates reduce the risk of pathological fractures, pain and improves patients' quality of life (QOL). However, it has been discovered that treatment beyond 2-3 years may result in a serious side effect, called, osteonecrosis of the jaw. This is seen in 5 to 10 percent of patients, most often following a tooth extraction. A recommended standard of care has therefore been to discontinue bisphosphonate treatment after two years. Unfortunately,   patients will experience continued bone loss due to the cancer. There is a long-term biological efficacy of bisphosphonates, but the bone protective effect diminishes when treatment is discontinued. Due to advances in medical cancer treatment, patients now live longer which highlights the need to offer long-term bone protection under optimal conditions for normal physical functioning, thereby, giving patients the best QOL possible.  Thus, there is an increasing need to examine whether we should stop treatment after two years in order to avoid osteonecrosis of the jaw, or if we should continue treatment to avoid progressive bone disease.     

2. To investigate if development of bone lesions can be predicted by using sequential measurements of bone markers in serum, potentially allowing individualised patient tailored initiation, termination and re-initiation of treatment.

In all cancers, bone disease is evaluated using different imaging techniques. Regardless of modality, they all identify bone loss that has already occurred. A different way to evaluate and monitor ongoing changes in bone mass is to measure markers of bone resorption and bone formation. These markers are small, specific protein molecules that are released into the bloodstream, as bone remodelling takes place. The hypothesis is that changes in bone marker levels precede actual loss of bone. Thereby, in the future, it may be possible to tailor treatment in the individual patient, and initiate treatment before irreversible bone damage takes place and then stop treatment when it is no longer needed. Multiple myeloma is the cancer disease where bone destruction occurs most often. Therefore, it is the optimal disease to test this hypothesis, before it is applied to more common cancer disease, such as mamma and prostate cancer.   

3. To determine if low-dose CT should replace conventional radiography as the chosen imaging method when evaluating bone disease in multiple myeloma patients.     

Conventional radiography remains the recommended gold standard when evaluating bone disease in multiple myeloma. However, we do know that a substantial amount of bone mass has to be lost before it is visible to this modality. It has been shown that low-dose CT, which has a better resolution, identifies more lytic bone lesions that conventional radiographs, therefore, low dose CT will probably be able to detect bone disease at a more early stage and thus allow more early intervention. The reason that low-dose CT is still not the recommended modality is probably because   no existing studies have documented its superiority in management of myeloma patients. For instance, we do not know if minor changes observed by low dose CT will ever develop into clinically relevant disease. An obvious benefit of using low dose CT, instead of conventional radiography, is that low dose CT is rapid and much more convenient for patients.   

Description of the cohort

Adult patients with newly diagnosed Multiple Myeloma will be included at diagnosis, treated for two years with zoledronic acid, and then randomised to either stop treatment or to continue treatment for another two years.

Data and biological material

QoL, conventional x-rays, bone CT scans and blood sample for bone marker measurement.

Collaborating researchers and departments

Heamatological departments in Denmark, Norway and Sweden.