Bone Turnover Biomarkers Are Useful In Monitoring Myeloma Bone Disease and As Early Predictor Biomarkers For Relapse Disease In Multiple Myeloma
Authors: Ting Kay Reen , Hameed Abdul , Brady Jennifer , Dowling Paul , Clarke Colin , Meiller Justine , Mitsiades Constantine S. , Richardson Paul G. , Anderson Kenneth C. , Clynes Martin , O'Gorman Peter 
Published: October 2019

Abstract

Background
Multiple myeloma is a plasma cell disorder characterised by bone marrow infiltration with clonal plasma cells that secrete monoclonal immunoglobulin which is detected in serum or urine samples. Bone disease is a well-known devastating complication. It has a significant impact to the quality of life and morbidity in multiple myeloma. The uncoupling effect of osteoblast and osteoclast activity is the major element in development of myeloma bone disease (MBD). Imaging techniques are used as the current standard method for detection of bony lesions. They have limitations as they cannot provide a real-time assessment of bone turnover. Early detection of relapse disease is crucial to allow preventative therapeutic intervention as it could significantly impact on quality of life.

Aims
Bone biomarkers such as C-terminal telopeptide of type 1 collagen (CTX-1) and procollagen type 1 N-propeptide (P1NP) can be used as an early predictor marker for MBD relapses and a monitor for MBD at different stages of the disease.

Methods
CTX-1 and P1NP were measured by chemiluminescent immunoassay on fasting plasma samples from 111 patients including newly diagnosed multiple myeloma (n=28), remission (n=34), relapses (n=22) and control (n=27). These were measured at regular intervals over a 30 month study period. Relapse disease was identified by conventional biomarkers like paraprotein and serum free light chains, and confirmed by imaging and bone marrow biopsy. In a subset of patients with disease relapse, the Mann-Whitney test was used to compare bone markers pre-relapse and at relapse.

Results
CTX-1 levels were significantly higher in newly diagnosed multiple myeloma compared to remission and control groups (p < 0.0001). In relapse group, CTX-1 rose significantly at the time of pre-relapse to relapse state (p=0.0001). A rise of ≥ 2.0 fold rise in the level of CTX-1 from remission to relapse disease was noted. The median time between the pre-relapse sample and relapse disease was 3 months (range 1-14 months). Most of them had new bone lesions at relapse. This proves that it has potential as an early predictor of relapse or progressive bone disease. A case showed CTX-1 level was the only biochemical parameter to rise significantly prior to relapse as compared to the other conventional biomarkers (ie. paraprotein and serum free light chain). As for P1NP, the rise in P1NP from pre-relapse to relapse was not significant (p=0.0810).

Conclusion
Osteoclast biomarker serum CTX-1 correlates accurately with the disease burden in newly diagnosed multiple myeloma patients as compared to the rest of the groups. It is a more sensitive early predictor of relapse/progressive disease than established biomarkers. It is a more robust marker than P1NP. The rise in P1NP goes against the theory that there is an uncoupling of bone turnover in MBD and requires further study. CTX-1 is more cost effective and accessible than imaging and should be used routinely when monitoring bone disease activity in multiple myeloma patients, facilitating early intervention when relapse occurs.

Disclosures:
No relevant conflicts of interest to declare.