Researchers from the University of Athens and Penn State University have announced that in a study of newly diagnosed patients, elevated TIMP-1, a blood biomarker, correlated with more advanced multiple myeloma, poorer overall survival, and the presence of bone lesions.

TIMP-1 belongs to the family of “tissue inhibitors of metalloproteinases,” a group of proteins that help regulate bone turnover – the removal of old bone tissue (resorption) and the addition of new bone tissue (ossification). Through multiple molecular pathways, excess TIMP-1 may contribute to tumor development because it directly encourages cell growth and inhibits programmed cell death. TIMP-1 also encourages angiogenesis, the growth of blood vessels, which can fuel tumor advancement.

In the current study, researchers tested the TIMP-1 levels of 55 newly diagnosed myeloma patients who had not yet begun treatment. Although TIMP-1 levels naturally increase with age and are higher in post-menopausal women, 47 percent of the patients exhibited significantly elevated TIMP-1. In fact, the average level of myeloma patients’ TIMP-1 was more than double the amount in healthy controls (431.9 versus 201 ng/ml).

At diagnosis, each patient also received x-rays to determine the presence of osteolytic lesions, soft spots or holes in bones, that frequently accompany myeloma. Those patients with elevated TIMP-1 were far more likely to harbor bone lesions and small fractures, as well as demonstrate faster bone degradation. The study authors hypothesize that myeloma tumor cells may directly produce TIMP-1, and this excess TIMP-1 may be one of the critical factors responsible for myeloma-associated bone disease.

Elevated TIMP-1 was not only correlated with the presence of bone disease, but it was also associated with more advanced myeloma and shorter overall survival. At diagnosis, patients whose myeloma was classified as Stage 3 exhibited higher TIMP-1 levels than those classified in Stages 1 or 2.

Researchers followed the patients for an average of 2.5 years after the study, during which all patients received treatment with novel agents; the most common treatment was Velcade (bortezomib), followed by thalidomide (Thalomid ), and Revlimid (lenalidomide). Despite these treatments, however, patients who began the study with TIMP-1 levels above 431.9 ng/ml – that is, with levels higher than those of the average myeloma patient – experienced significantly shorter survival time. The elevated TIMP-1 patients experienced an average survival time of 32 months after diagnosis, compared to 62 months for the average or low-level TIMP-1 patients.

“Our study provides evidence, for the first time, that an increased pre-treatment serum level of TIMP-1 correlates with advanced myeloma and predicts for reduced survival,” state the study authors. “These results . . . strongly support the role of serum TIMP-1 as a potential predictive and prognostic biomarker for further study.”

For more information, please see the article in Leukemia Research (abstract).