Results of a recent Greek study show that high levels of the protein sclerostin in the blood are associated with advanced disease and poor bone formation in multiple myeloma patients.

In addition, the results indicate that Velcade may be effective in reducing sclerostin levels in myeloma patients.

“Our study has shown that sclerostin is increased in myeloma patients, and together with the [laboratory] data presented at the last ASH meeting, suggests that sclerostin inhibits the function of [bone-building cells] in myeloma,” said Dr. Evangelos Terpos of the Alexandra General Hospital in Athens, Greece, and lead author of the study.

“Based on [our results], antibodies against sclerostin may be given in Phase 1 studies in the treatment of multiple myeloma. That is, I think, the major contribution of [our study],” he added.

Dr. Ken Shain of the Moffitt Cancer Center in Tampa, Florida, who was not involved in the study, agreed that the results would help to identify antibodies and other potential agents for the treatment of bone disease in multiple myeloma.

“[This study may help to] increase the number of agents we can use against bone disease in myeloma,” said Dr. Shain.

“If [targeting sclerostin] leads to improvements in current bone disease or prevents bone disease from occurring, we are going to be better off. The more therapeutic options we have, the better off myeloma patients will be in the long run,” he added.

Nearly 80 percent of myeloma patients have evidence of bone loss when they are first diagnosed with myeloma, and bone disease ^[1] is one of the most challenging complications of myeloma.

In multiple myeloma, bone disease occurs because of an imbalance between bone-building cells (osteoblasts) and bone-destroying cells (osteoclasts).
Specifically, bone-destroying cells are favored over bone-building cells in myeloma patients because proteins called “Wnt inhibitors” interfere with the pathways involved in the functioning of bone-building cells.

One such Wnt inhibitor, DKK-1, is considered a promising target for new myeloma bone disease treatments (see related Beacon ^[2] news).

Sclerostin is another Wnt inhibitor that is produced by mature bone cells and inhibits bone formation. In recent years, elevated sclerostin levels have been found in patients with osteoporosis and other bone diseases not related to myeloma.

There is not much concrete information, however, about the role of sclerostin in multiple myeloma.

According to Dr. Shain, it is important to determine whether myeloma cells directly cause the increased production of sclerostin in myeloma patients.

“[We need to determine] if sclerostin is truly a [cause] of bone disease in multiple myeloma or just a marker of bone disease. If sclerostin is not actively causing bone disease, then it is not an appropriate target [for therapy],” commented Dr. Shain.

Results of recent laboratory studies have suggested that myeloma cells may be directly involved in the production of sclerostin.

One study showed an increase in sclerostin production when bone marrow cells were placed in the same environment as human myeloma cells. This suggests that the interaction between myeloma cells and bone marrow cells results in elevated sclerostin levels, contributing to bone disease in myeloma patients.

Another study revealed that myeloma cells cause sclerostin-producing bone cells to die, and that sclerostin is released into the blood when these bone cells are destroyed.

In the current study, Greek researchers investigated the role of sclerostin in myeloma patients and explored whether clinical observations would be in line with the recent laboratory data.

The study included 224 participants: 157 newly diagnosed multiple myeloma patients, 25 relapsed multiple myeloma patients, 21 patients with monoclonal gammopathy of undetermined significance (MGUS), and 21 healthy individuals. The median age of the study participants was 68 years.

The newly diagnosed myeloma patients received a median of three lines of therapy during the course of the study. Eighty-seven percent of these patients received conventional chemotherapy as first-line therapy, and the remaining 13 percent of patients received treatment with different combinations of novel agents. In addition, 21 percent of patients received a stem cell transplant.

The relapsed myeloma patients had previously received between one and three lines of therapy. All relapsed myeloma patients received four cycles of Velcade ^[3] (bortezomib) monotherapy during the course of the study.

Blood samples were collected from the newly diagnosed myeloma patients and the MGUS patients one week from diagnosis. Blood samples were also collected from the relapsed myeloma patients, once on the first day of treatment with Velcade and once near the end of treatment.

The study authors found that the newly diagnosed myeloma patients had higher levels of sclerostin than the MGUS patients and the healthy participants in the trial.

Moreover, patients who had either advanced bone disease or fractures at diagnosis had higher sclerostin levels compared to all other patients.

In addition, patients with more advanced stages of multiple myeloma also had higher sclerostin levels than patients with less advanced stages of myeloma.

The median overall survival time for newly diagnosed patients was 48 months. Patients with high sclerostin levels had significantly shorter overall survival times than patients with lower sclerostin levels (27 months versus 98 months).

Forty-four percent of the relapsed myeloma patients responded to Velcade monotherapy, including 8 percent who achieved a total response.

Sclerostin levels decreased in patients who responded to Velcade as well as those who did not respond to Velcade (47 percent and 51 percent, respectively).  According to the study authors, this may be a sign that Velcade can reverse bone formation abnormalities in myeloma.

For more information, please see the full article in the International Journal of Cancer ^[4] (abstract).