Treatments on the Horizon in Multiple Myeloma

A variety of treatments to counteract the bone-wasting effects of multiple myeloma are in development.

Osteolytic bone lesions are present in 70% to 80% of the 120,000 cases of multiple myeloma (MM) that occur worldwide each year. Often, the first sign of MM is a pathologic fracture—predominantly fractures of the spine, although other common sites include the femur, pelvis, rib, and humerus.

Because multiple myeloma is a disease that includes the pathogenic process of bone wasting, treatments that reduce its effect on bones are an area of drug discovery in MM. Although bisphosphonates have been used as a treatment mainstay in patients with MM, the utility of these agents is limited. Webb and Edwards reviewed some novel bone-targeting treatments in development for multiple myeloma in an April issue of The British Journal of Pharmacology.

One group of cells predominant in bone wasting syndromes are known as osteoclasts (the suffix “clast” in “osteoclast” refers to bone breakdown, whereas the suffix “blast” in “osteoblast” refers bone growth). In healthy individuals, the bone-wasting activity of osteoclasts is balanced by the bone-building activity of osteoblasts.

In MM, tumor cells stimulate the activity of osteoclasts and inhibit the activity of osteoblasts. Several pathways are involved in the dysregulation of osteoclast and osteoblast activity in MM. As scientists learn more about these pathways, they are finding new ways to help slow or even reverse bone wasting in MM.

The RANK/RANKL/OPG pathway

One pathway involved in osteoclast/osteoblast signaling is the RANK/RANKL/OPG pathway. The transmembrane RANK receptor resembles the tumor necrosis factor (TNF) receptor and is present on the surface of developing osteoclasts.

The ligand that corresponds with RANK—RANK ligand (RANKL)—binds with RANK on the surface of developing osteoclasts and stimulates osteoclast growth and development. To prevent overproduction of osteoclasts, a soluble receptor known as OPG binds with RANKL, preventing RANKL from simulating the growth of osteoclasts (see Figure).

Figure: The RANK/RANKL/OPG Pathway

In multiple myeloma, the body produces too much RANKL and too little OPG. As a result, RANKL stimulates the formation of osteoclasts, which ultimately leads to bone degeneration and breakdown.

Denosumab works by binding to RANKL, effectively performing the function of OPG, which prevents RANKL from binding to RANK and ultimately reduces the overproduction of osteoclasts. Phase II and III trials of denosumab in several types of bone cancer have demonstrated the product’s efficacy in improving bone mineral density.

Dickkopf-1

Another pathway involved in the bone disease associated with multiple myeloma is the Dickkopf-1 (Dkk1) pathway. In patients with multiple myeloma, Dkk1 reduces the proliferation of osteoblasts, which promotes bone formation. Evidence for this includes (1) high levels of Dkk1 in patients with osteolytic lesions, and (2) in vitro studies showing that Dkk1 blocks the differentiation of osteoblasts.

In an early trial utilizing a mouse model of multiple myeloma, mice were vaccinated with a drug based on Dkk1 DNA (known by the code name BHQ880). The vaccine was found to protect some mice from developing MM, reducing the tumor load, and slowing the growth of MM cells. Phase II clinical studies with BHQ880 indicate that it may reduce the likelihood of progressing from smoldering MM to full MM.

Dkk1 inhibits osteoblast formation by blocking a cell signaling pathway known as Wnt. Patients with bone disease not only have high levels of Dkk1, but also may have high levels of a compound known as sclerostin, which also blocks the Wnt signaling pathway. High levels of sclerostin have been observed in patients with myeloma and in patients with advanced bone diseases.

A monoclonal antibody that blocks the effect of sclerostin (code named AMG785 [romosozumab]) shows promising early results in animal studies conducted in mice and in more recent studies in humans. Romosozumab also has potential as a treatment for low bone density in postmenopausal women.

Activin A

Activin acts on the activin receptor-like kinase 4 (ALK4) receptor to induce activity of the Smad pathway. Dysregulation of the Smad pathway may play a role in the pathogenesis of primary bone tumors. Patients with MM have high levels of activin A in bone marrow plasma. In vitro studies indicate that activin A may prevent osteoblasts from differentiating.

A biologic fusion protein drug code named ACE011 (sotatercept) mediates activation of the JNK pathway, which inhibits production of activin A. In phase II studies, ACE011 reduced bone pain, reduced the risk of anemia, and reduced markers of bone resorption.

Proteasome Inhibitors

The proteasome pathway, which is controlled by activation of nuclear factor-kappa B (Nf-κB), has been targeted using the drug bortezomib. By inhibiting the activity of the proteasome, bortezomib prevents myeloma cells from secreting immunoglobulin G and other proteins. Bortezomib also promotes the differentiation of osteoblasts, helping bone formation.

The effect of bortezomib on bone growth may be mediated through interaction between the Nf-κB and RANK pathways through inhibition of the TRAF6 signaling pathway. Other studies show that bortezomib may reduce the bone-wasting effects of Dkk1.

In Summary

A variety of biochemical pathways are currently under investigation. Scientists are beginning to harness the understanding of these pathways to advance the treatment of multiple myeloma. Particularly exciting are the preliminary results with cancer vaccines.

However, these studies are also elucidating existing mechanisms of medications that are already available commercially (eg, bortezomib and denosumab). With many new drugs on the horizon in multiple myeloma, researchers are hopeful that further improvements in survival will be realized with new combinations of medications and treatment modalities.

Reference:

• Webb SL, Edwards CM. Novel therapeutic targets in myeloma bone disease [published online April 21, 2014]. Br J Pharmacol. 2014.