Quality of life for patients is a top priority at the Myeloma Institute. Our team is committed to providing a comprehensive, holistic experience, including effective disease management and emotional support for patients, family members and caregivers. We believe that patients should be able to live their lives as fully as possible with minimal side effects from treatment.
Bone disease is a significant complication of myeloma that affects a majority of patients. In this issue we describe how we are exploring ways to combat bone disease and give patients improved, pain-free mobility. Our researchers, in collaboration with colleagues in other specialties, such as orthopaedics and radiology, are investigating the nuances of bone remodeling at the cellular level.
Also in this issue are two patient stories that attest to living life fully with a high quality of life. We are continually inspired by the perseverance and inner strength of our patients.
Our steadfast mission is to provide the highest level of comprehensive care for the best outcomes and optimal living, while researching new methods of targeted treatment that lead to cure.
Cheers and kind regards,
Gareth Morgan, M.D., Ph.D
Director, UAMS Myeloma Institute
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.
Carolina Schinke, M.D., assistant professor, conducts research that leads to development of new clinical trials.
Bone disease is a major issue for the majority of multiple myeloma patients. Lytic lesions, fractures and collapse of vertebra in the spine — primary causes of pain and debilitation — can significantly compromise quality of life.
Clinical treatment for myeloma includes a focus on minimizing the effects of bone disease, preventing progression of bone destruction, and taking measures to increase healthy bone development.
With the goal of identifying the most effective treatments for optimal outcomes both now and in the future, clinical treatment is sometimes provided through clinical trials. The Myeloma Institute has always emphasized the importance of well-designed clinical trials so that patients can benefit from innovative and cutting-edge care.
“Phase II Prospective Evaluation of Bone Remodeling During Ixazomib Treatment,” a clinical trial at the Myeloma Institute under the direction of Maurizio Zangari, M.D., director of myeloma bone disease research, is intended to evaluate the effect of Ixazomib on inducing osteoblast activation in patients with relapsed/refractory myeloma. Ixazomib is a proteasome inhibitor — a drug that blocks the action of proteasomes, which are large protein complexes that help destroy other cellular proteins when they are no longer needed. Osteoblasts are cells that create new bone.
“The study is specifically investigating the effectiveness of Ixazomib as a single agent without other drugs,” Zangari said.
Ixazomib was approved by the U.S. Food and Drug Administration (FDA) in November 2015, under the brand name Ninlaro, as the first oral proteasome inhibitor to be used in combination with Revlimid (lenalidomide) and dexamethasone, a type of corticosteroid.
The safety and efficacy of Ninlaro had earlier been demonstrated in an international, randomized, double–blind clinical trial of 722 patients whose myeloma had relapsed or did not respond to previous treatment. (In a double-blind study neither the patients nor the investigators know which patients are in the test and control groups.) Ninlaro was granted priority review status by the FDA, a designation that is given to applications for drugs that, if approved, would be a significant improvement in safety or effectiveness in the treatment of a serious condition.
Zangari is hopeful that analysis of the trial data will yield positive results. “It would be a boon for patients to only have to take one drug that is administered orally instead of intravenously. The goal is to minimize side effects of multiple drugs, simplify how the drug is taken, and obtain an excellent outcome,” he said.
The estimated completion date for the trial is September 2017.
About Clinical Trials
Clinical trials — research studies that involve people — provide a mechanism for testing new treatments in a safe, structured manner and gleaning data that enables statistically valid analysis. They are key to making progress against cancer and complications associated with cancer and making sure that patients have access to the most effective care.
Clinical trials are the final step in a long process that begins with research in a laboratory. Before any new treatment or drug is used with people in clinical trials, researchers work for many years to understand its effects on cancer cells in the lab to try to figure out the side effects it may cause.
Clinical trials involve a series of phases, with each phase designed to answer a specific research question. If a new treatment is successful in one phase, it proceeds to the next phase for further testing. During the early phases (phases 1 and 2), researchers determine whether a new treatment is safe, what its side effects are, the optimal dosage, and whether the treatment has a clear-cut benefit, such as slowing tumor growth.
In the later phase (phase 3), researchers study whether the treatment works better than current standard therapy and they compare the safety of the new treatment to the safety of current treatments. Phase 3 trials enroll large numbers of patients to ensure efficacy and continue monitoring patients for adverse effects. Phase 4 trials look at long-term safety and effectiveness after a new treatment has been approved by the FDA and is on the market.
• Phase I trials enroll a small number of patients, usually 15
• Phase II trials, with a focus on determining effectiveness of the new drug or treatment, typically enroll about 100 patients.
• Phase III trials can enroll from 100 to several thousand patients, especially in the case of trials conducted at multiple sites.
Clinical trials go through a highly prescribed approval process before they are cleared to enroll patients. There are numerous regulatory steps along the way, all designed to ensure the scientific integrity and patient safety of the proposed treatment(s). The overall goal is to have the potential benefits outweigh the possible risks for clinical trial participants. Multiple oversight committees, including an institutional review board (IRB), which is charged with protecting the rights and welfare of human subjects, make sure that federal, institutional, and ethical guidelines are followed by principal investigators and research staff.
The UAMS IRB has been accredited by the Association for the Accreditation of Human Research Protection Programs (AAHRPP) since 2005. An independent, non-profit accrediting body, AAHRPP ensures that human research protection programs meet rigorous standards. Accredited organizations must provide evidence — through policies, procedures and practices — of their commitment to scientifically and ethically sound research. >>
Nathan Petty, director of clinical trials and regulatory affairs at the Myeloma Institute, describes the process of bringing a clinical trial from idea inception to patient enrollment as a highly disciplined path.
“The process demands great attention to detail and understanding of local and federal regulations. In order to successfully execute a clinical trial, one must understand how to implement and adhere to the regulatory requirements throughout the clinical research process,” Petty said. “It can take months to get a clinical trial to the point that patients can be consented and enrolled on study.”
Once patients are enrolled, clinical research assistants coordinate with research nurses and doctors to carefully monitor patient compliance to the protocol and record treatment progress, response to treatment and adverse reactions, if any.
“Everything must be documented. Every ‘t’ must be crossed and every ‘i’ dotted,” Petty said. Petty oversees a staff of more than 45 including research nurses, regulatory specialists, clinical research assistants, finance administrators and specimen procurement staff.
Successful treatments for cancer, including myeloma, are in large part the result of clinical trials. With a solid infrastructure for clinical trials operations, the Myeloma Institute has made tremendous progress over the decades in developing effective therapies aimed at curing myeloma and improving quality of life.
“If we can simplify treatments and enable patients to live fuller lives, we are indeed making progress,” Zangari said.
Bobbie Rainey receiving a post-surgery exam by orthopaedic surgeon Corey Montgomery, M.D.
Bobbie Rainey from Gould, Arkansas, came to the Myeloma Institute in September of 2010. She was experiencing pain all over her body, especially her lower back, legs and arms, in addition to other symptoms of myeloma.
Due to a persistent bone lesion in the humerus (a long bone of the upper arm that extends from the shoulder to the elbow) that put her at risk for fracture, Rainey’s Myeloma Institute physician, Maurizio Zangari, M.D., sent her in 2015 to UAMS orthopaedic surgeon Corey Montgomery, M.D., who performed open reduction internal fixation, known as ORIF, with wires and cement.
The result for Rainey was markedly improved quality of life: “Less pain in my arm and I didn’t have to be protective of it.”
She said that Montgomery was a true partner in her care.
“He’s a wonderful spiritual physician, he made me feel very comfortable, I had all the confidence in him. Having the surgery and entrusting Dr. Montgomery to perform it was the best thing I could have done.”
While multiple myeloma is the primary disease treated at the Myeloma Institute, other plasma cell neoplasms are also the focus of our research and treatment regimens.
What is a Plasma Cell Neoplasm?
A neoplasm is an abnormal mass of tissue that results when cells divide more than they should or do not die when they should.
A plasma cell neoplasm is a disease in which the body makes too many plasma cells.
Plasma cells develop from B lymphocytes (B cells), a type of white blood cell that is made in the bone marrow. Normally, when bacteria or viruses enter the body, some of the B cells change into plasma cells. The plasma cells make antibodies to fight bacteria and viruses and to stop infection and disease.
In plasma cell neoplasms, the abnormal plasma cells form tumors in the bones or soft tissues of the body. The plasma cells also make an antibody protein (M protein) that is not needed by the body and does not help fight infection. These antibody proteins can cause the blood to thicken or can damage the kidneys.
Neoplasms and plasma cell neoplasms can be benign (not cancer) or malignant (cancer).
Monoclonal gammopathy of undetermined significance (MGUS) is a benign plasma cell neoplasm. Malignant plasma cell neoplasms include plasmacytoma, multiple myeloma, Waldenstrom macroglobulinemia and amyloidosis.
Monoclonal Gammopathy of Undetermined Significance (MGUS)
In MGUS, less than 10 percent of the bone marrow is made up of abnormal plasma cells. The abnormal plasma cells make M protein, which is sometimes found during a routine blood or urine test. In most patients, the amount of M protein stays the same and there are no symptoms or health problems.
In some patients, MGUS may later become a more serious condition, such as amyloidosis, or cause problems with the kidneys, heart or nerves. MGUS can also become multiple myeloma, Waldenstrom macroglobulinemia or chronic lymphocytic leukemia.
A plasmacytoma forms when the abnormal plasma cells are in one place and form one tumor. There are two types of plasmacytoma.
• In an isolated plasmacytoma of bone, one plasma cell tumor is found in the bone. Less than 10 percent of the bone marrow is made up of plasma cells and there are no other signs of cancer. Over time, plasmacytoma of the bone often becomes multiple myeloma.
• In extramedullary plasmacytoma, one plasma cell tumor is found in soft tissue but not in the bone or the bone marrow. Extramedullary plasmacytomas commonly form in tissues of the throat, tonsil and paranasal sinuses.
Plasmacytoma of bone can cause pain or broken bones. In soft tissue, the tumor may press on nearby areas and cause pain or other problems (for example, difficulty swallowing).
In multiple myeloma, abnormal plasma cells build up in the bone marrow and form tumors in many bones of the body. These tumors may keep the bone marrow from making enough healthy blood cells. Normally, the bone marrow makes stem cells — immature cells — that become three types of mature blood cells:
• Red blood cells that carry oxygen and other substances to all tissues of the body
• White blood cells that fight infection and disease
• Platelets that form blood clots to help prevent bleeding
As the number of myeloma cells increases, fewer red blood cells, white blood cells and platelets are made. In addition, the myeloma cells can damage and weaken the bone and cause hypercalcemia (too much calcium in the blood), which can cause confusion and damage organs.
Sometimes multiple myeloma does not cause any signs or symptoms. This is called smoldering multiple myeloma. Smoldering multiple myeloma needs close monitoring since it can become multiple myeloma.
In Waldenstrom macroglobulinemia, abnormal plasma cells build up in the bone marrow, lymph nodes and spleen. They make too much M protein, which causes the blood to become thick. The lymph nodes, liver and spleen may become swollen. The thickened blood may cause problems with blood flow in small blood vessels.
Multiple myeloma and other plasma cell neoplasms may cause amyloidosis. Amyloidosis occurs when antibody proteins stick together in peripheral nerves and organs such as the kidney and heart. This can cause the nerves and organs to become stiff and unable to function properly.
POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, Skin changes) is a rare, multi system condition associated with plasma cell neoplasms. It is characterized by overproduction of plasma cells, which can cause damage to the nerves, liver and spleen, diabetes or thyroid problems, and skin rashes.
Castleman disease is a rare disease of the lymph nodes and related tissues that results from the overgrowth of benign cells in the body’s lymphatic system (the tissues and organs that produce, store and carry white blood cells that fight infections and other diseases).
In unicentric Castleman disease, only one group of lymph nodes in one part of the body — usually the chest or abdomen — is affected.
In multicentric Castleman disease, many groups of lymph nodes and lymphoid tissue throughout the body are affected and the immune system is weakened. Castleman disease involving plasma cells tends to be multicentric. Patients with multicentric Castleman disease are at increased risk of developing lymphoma.
Source: National Cancer Institute
Bi-allelic inactivation is more prevalent at relapse in multiple myeloma, identifying RB1 as an independent prognostic marker
A new publication in Blood Cancer Journal 24 February 2017, PMID: 28234347
Primary Authors: Shweta Chavan, Ph.D., and Brian Walker, Ph.D.
Targeted gene sequencing was conducted on 578 cases of plasma cell neoplasms, including monoclonal gammopathy of undermined significance (MGUS), smoldering myeloma and myeloma, in order to identify prognostic markers and treatment targets. A clinically certified, commercially available gene profiling panel, FoundationOneHeme – known as F1H – was used. The F1H test is aimed at identifying genetic abnormalities for which targeted treatments are available. Out of the 578 cases, 331, or 64 percent, were found to have potentially targetable alterations. The study also confirmed an important role for bi-allelic inactivation of key genes in myeloma at relapse and that loss of one of those genes, RB1, is an independent prognostic marker.
An allele is a variant form of a gene. Some genes have a variety of different forms, which are located at the same position, or genetic locus, on a chromosome. Humans are called diploid organisms because they have two alleles at each genetic locus, with one allele inherited from each parent.
The RB1 gene provides instructions for making a protein called pRB. This protein acts as a tumor suppressor, which means that it regulates cell growth and keeps cells from dividing too fast or in an uncontrolled way.
Extensive remineralization of large pelvic lytic lesions following total therapy treatment in patients with multiple myeloma
A new publication in Journal of Bone and Mineral Research
27 February 2017, PMID: 28240368
Primary Authors: Meera Mohan, M.D., and Maurizio Zangari, M.D.
Bone lesions — caused by the imbalances between bone formation and bone resorption — are a hallmark of multiple myeloma bone disease. Patients with bone lesions of the pelvis are at increased risk for fracture and related complications and frequently require surgical intervention. After observing unexpected radiological improvement in a patient whose treatment included the proteasome inhibitor bortezomib, a retrospective analysis of 62 patients treated with combination therapy was conducted. Forty-three percent of the patients experienced remineralization of the pelvic lesions. The study showed that significant mineral deposition in large pelvic lesions can be re-established in a significant proportion of myeloma patients treated on one of the Myeloma Institute’s multi-agent regimens. These findings can impact future quality-of-life treatment strategies.
A proteasome inhibitor is a drug that blocks the action of proteasomes — large protein complexes that help destroy other cellular proteins when they are no longer needed.