A: Large pelvic lesion prior to treatment B: Remineralization following multi-agent treatment with stem cell transplant

Donghoon Yoon, Ph.D., in his lab where his focus is on the factors and mechanisms of bone metabolism in myeloma

Bone disease is a hallmark of myeloma, affecting up to 90 percent of patients. An unexplained fracture or bone pain can be the first sign that something is not right and often leads patients to seek medical attention.

Bone lesions are present in about 70 percent of myeloma patients at diagnosis, with the most commonly involved sites being the skull, spine, rib cage and pelvis. Almost 50 percent of newly diagnosed patients will develop a fracture during the first year following diagnosis and about 65 percent of newly diagnosed patients will develop a fracture at some point during the course of their disease.

Like all human tissue, bone is continually changing — it is not static. In a healthy individual, there is a balance between destruction of old bone and development of new bone. That balance ensures that bones are strong, maintain proper density, and have the capacity to heal if injured. In patients with myeloma, the normal process of bone remodeling is off kilter. The rate of resorption of old cells outpaces production of new cells, resulting in a net loss of bone mass.

More specifically, osteoclasts continually resorb damaged bone, which is replaced by new bone made by osteoblasts. Either directly or through complex interactions with the bone marrow microenvironment, myeloma cells stimulate the bone resorptive activity of osteoclasts and suppress the bone-forming activity of osteoblasts.

As a result of altered bone remodeling, myeloma patients typically develop osteoporosis and lytic lesions — holes that give the affected bones a Swiss-cheese-type look — that can lead to painful fractures and related complications, including spinal cord compression and hypercalcemia (excess calcium in the blood that can cause confusion). Bone loss is often more prevalent at sites populated by myeloma cells and is more pronounced in older patients.

Compromised bone health can have devastating effects on a patient’s quality of life, said Maurizio Zangari, M.D., professor in the UAMS College of Medicine and director of bone disease research at the Myeloma Institute.

“Almost all of our patients are at increased risk for long bone fractures or vertebral collapse,” Zangari said. “We want to minimize further bone loss and stimulate bone growth so that patients can resume adequate mobility, and, in the case of vertebral lesions, we want to be able to prevent further collapse.”

Most myeloma patients at the institute, including those with no detectable bone lesions and those with myeloma-related osteopenia or osteoporosis, receive bisphosphonates — usually a monthly infusion of zoledronic acid (Zometa) — as a routine part of their treatment. Bisphosphonates inhibit osteoclasts and are effective at reducing the incidence of bone fractures. However, they can negatively affect the kidneys, so renal function must be closely monitored, especially in patients with established kidney problems. If a patient’s vitamin D level is low, a supplement might be indicated to support bone health and maximize the effectiveness of the bisphosphonate.

Assessment of bone disease is done via magnetic resonance imaging (MRI), bone density exams (DEXA) and positron emission tomography (PET) scans. The Myeloma Institute has a wealth of data from these tests conducted over many years. The data document bone disease progression and improvements based on specific treatments, which in turn help our doctors determine optimal treatments and the timing of treatments.

Proteasome inhibitors, such as bortezomib and carfilzomib, have proven effective for improving bone remodeling since they both inhibit bone resorption and promote bone formation. Zangari and Larry Suva, Ph.D., formerly with the Department of Orthopaedic Surgery in the UAMS College of Medicine, conducted a review of clinical studies focused on bone disease – “The effects of proteasome inhibitors on bone remodeling in multiple myeloma,” published in 2016 in the journal Bone.

The majority of those studies demonstrated that treatment with bortezomib (Velcade) is associated with an increase in the levels of biomarkers associated with bone formation, such as serum bone alkaline phosphatase, and a reduction in the levels of biomarkers associated with bone resorption. Similarly, carfilzomib has been shown to stimulate osteoblasts (bone-forming cells) in myeloma patients.

Of particular interest is the relationship between the anti-myeloma activity of proteasome inhibitors and the presence of serum parathyroid hormone (PTH). Zangari reported preliminary evidence indicating that high spiking levels of PTH in bone marrow are associated with better response to bortezomib treatment (“Parathyroid hormone receptor mediates the anti-myeloma effect of proteasome inhibitors,” published in 2014 in Bone). This information was also supported by gene arrays done on bone marrow biopsy specimens. Zangari and his research team are investigating the correlation between the PTH system and proteasome inhibitors, as the findings could shed light on potential targeted treatment strategies.

A more recent study by Zangari and colleagues, reported in “Extensive remineralization of large pelvic lytic lesions following total therapy treatment in patients with multiple myeloma,” published in February 2017 in Journal of Bone and Mineral Research, was initiated after observing unexpected radiological improvement in pelvic CT assessment in a Myeloma Institute patient treated in one of the institute’s total therapy protocols.

The patient presented with a pathological fracture of the acetabulum (the socket of the hipbone) and large lytic lesions in the pelvis. Following multi-agent treatment, including bortezomib, as part of the total therapy regimen, CT imaging revealed significant remineralization of the lesions.

Zangari’s retrospective analysis of 62 patients treated with combination therapy demonstrated a significant percentage — 43 percent — of remineralization of large pelvic lytic lesions. The data indicate that lytic lesions, at least in the pelvis, retain the capacity for remineralization, which bodes well for restoring patients’ activity levels.

“These findings are very positive and give us the basis for further research,” Zangari said.

When surgery is required, Zangari and other Myeloma Institute physicians call upon specialists at UAMS who understand the complexities of myeloma. Corey Montgomery, M.D., and Richard Nicholas, M.D., in the Department of Orthopaedic Surgery specialize in oncology. They see about 26 new myeloma referrals, resulting in about 20 procedures — mostly on the long bones — per year.  T. Glenn Pait, M.D., professor in the UAMS College of Medicine Departments of Neurosurgery and Orthopaedic Surgery, operates on the spine. He typically receives two referrals per week and performs spine surgery 20 times per year on myeloma patients. Vertebral collapse is treated by the UAMS interventional radiology team. The most common procedure for myeloma patients, kyphoplasty, involves the creation of space between vertebral bodies and injection of a filler to maintain the space.

“We are very fortunate to have such skilled experts who can provide surgical care for our patients,” Zangari said. “They help us improve patients’ quality of life, and they operate with both compassion and a keen understanding of the myeloma disease process.”

In addition to a current clinical trial (see page 8) Zangari anticipates future studies that focus on bone-forming agents, such as PTH, and the introduction of antibodies against sclerostin (a substance that inhibits bone resorption). “Our goals are to provide treatment based on a thorough understanding of bone disease processes and to give patients the best possible quality of life,” he said.