Real World Health Care Blog

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Multiple Myeloma: A Rare and Complex Cancer

We continue our series on multiple myeloma with an interview with Gareth J. Morgan, MD, FRCP, FRCPath, PhD, professor of hematology and director of the Myeloma Institute at the University of Arkansas for Medical Sciences (UAMS). Dr. Morgan also serves as deputy director of the Winthrop P. Rockefeller Cancer Institute at UAMS.

Dr. Morgan is responsible for all clinical, research, and administrative operations at the Myeloma Institute, which is one of the largest programs in the world focused on the research and treatment of multiple myeloma and related diseases. Clinically, he directly oversees 8 physician specialists, 14 mid-level providers, and 7 hospitalists, all experts in the management of myeloma and related plasma cell diseases. He also manages 8 research teams, which represent an integrated program of the genetics and biology of myeloma.

Mechanisms of Malignant Transformation

Real World Health Care: What got you interested in the field of multiple myeloma and what keeps you inspired?

Dr. Gareth Morgan, University of Arkansas for Medical Sciences

Gareth Morgan: Scientifically, I saw the opportunity to exploit the transition of MGUS (monoclonal gammopathy of undetermined significance) to smoldering myeloma to multiple myeloma as a model to understand the mechanism that drives malignant transformation. I reasoned that if we understood these, we should be able to manipulate them therapeutically.

I continue to be inspired by the ability to translate the biology and genetics of myeloma into clinical practice, where better and less toxic treatments can and are being developed to help patients achieve better outcomes and increased survival. Patients are the true source of inspiration.

Myeloma Genome Project

RWHC: Tell us about your recent research work and its significance to the multiple myeloma patient community.

GM: This is an exciting time for the field of myeloma, and our research investigations have led to some exciting discoveries in the biology of myeloma based on the genetic variations within the human genome. With our colleagues in Europe, have identified eight new genetic variations that could be linked to an increased risk of developing myeloma.

We are also focused on developing a molecular classification of myeloma based on patient subgroups with distinct pathogenesis and clinical behavior. We have partnered with Celgene and the Dana–Farber Cancer Institute in establishing a global collaboration called the Myeloma Genome Project. The goal of this project is to compile and analyze the largest set of genomic and clinical data to design a molecular classification system to improve the diagnosis, prognosis and treatment of myeloma. Up to this point, we have collated the data that we already have, and now we are bringing other national and international investigators in to really form a global consortium. This data will help us identify patients who have distinct clinical outcomes, and allow us to take a stratified-risk approach to designing treatment strategies. This initiative could really lead the way in developing specific clinical trials for targeted treatments for patients in the future.

Personalized Medicine: The Future of Cancer Care

RWHC: What are the most promising new treatments for multiple myeloma? Are there any on the horizon that hold the possibility for a cure?

GM: I believe that stem cell transplantation remains the backbone of treatment for many patients, and we don’t want to move away from a strategy we know to be successful for many. So, we are now incorporating new treatments to increase cure rates and to give more patients higher and better responses overall. This involves moving away from the one-size-fits-all approach to a more directed, personalized one which includes the use of novel agents, immunotherapy, and targeted-based treatments.

Immunotherapy is one of the more exciting developments for patients with relapsed/refractory disease, and we are now looking at incorporating these agents into the newly diagnosed setting. Using different combinations of antibodies that address the different components of the immune system is going to be a really important way forward. In addition, the increased understanding of cancer genomics has given us a wealth of information about the biological processes involved in the initiation and development of myeloma cells, which has really powered the concept of developing targeted therapies directed at specific mutations at the molecular level. This approach, also known as personalized or precision medicine, clearly represents the future of cancer care.

Underlying Causes of Myeloma

RWHC: What are some of the biggest challenges facing multiple myeloma researchers?

GM: Some challenges myeloma researchers face include gaining a better understanding of the underlying causes of myeloma and designing prevention and early intervention strategies, as well as developing strategies to prevent precursor states of myeloma—MGUS (monoclonal gammopathy of undetermined significance) and smoldering myeloma—from developing into active multiple myeloma. Of course, funding remains one of the biggest challenges faced by researchers, and it probably always will be.

Increasing collaborations with university and industry partners provides an opportunity to gain access to much larger datasets and to develop clinical trials to help answer some of these important questions.

Overcoming Resistance to Multiple Myeloma Treatment

RWHC: What are some of the biggest challenges facing clinicians treating multiple myeloma patients?

GM: Over the last decade, we’ve seen an unprecedented improvement in multiple myeloma as novel agents and treatment combinations expand. Despite the vast improvement, there remains a proportion of patients who relapse and are more likely to have aggressive disease that is refractory to therapy. I think one of the challenges in myeloma is how do we treat and design strategies that can overcome treatment resistance for these high-risk patients to improve their long-term outcomes.

This challenge requires a change that focuses on the use of genetic analyses to segment myeloma at the molecular level to enhance risk segmentation to develop biologically-stratified treatment approaches. We are also exploring the use of imaging studies to recognize high-risk and DNA-based features. Collecting the sequencing and imaging data and analyzing it consistently provides a resource for the myeloma community that can continue to grow into the future.

Another important challenge facing clinicians is patient access to a myeloma specialist. Myeloma is a rare and complex cancer, so oncologists can’t use concepts developed for more common cancers, such as breast or colon, in myeloma. The key is having a focused strategy that is directed by a myeloma expert. Unfortunately, some patients don’t have access to a specialist because of location, insurance, or other financial restrictions. At the Myeloma Institute we incorporate a team approach, whereby our team of myeloma experts direct the treatment strategy and for practical purposes, patients can receive much of their treatment locally. So, if myeloma experts can partner with local oncologists who can then deliver some of the treatment, then it’s an ideal setting for patients, because they receive the benefit of a myeloma-specific strategy and risk stratification upfront, and in the long-term, they have the comfort and security of being close to home.

 

Multiple Myeloma & Cardiac Risk

Real World Health Care continues our series on multiple myeloma with a discussion about the cardiac effects of cancer treatment with Dr. Robert Frank Cornell.  Dr. Cornell is the clinical director of the plasma cell disorder program and the director of the plasma cell/lymphoma clinical trial research program at Vanderbilt University Medical Center.

Dr. Cornell’s research focuses on translational and early phase clinical trials for the treatment of multiple myeloma. He also conducts research and clinical trials for relapsed/refractory multiple myeloma and other plasma cell disorders. He also researches cardio-oncology to better understand the effects of chemotherapy on the heart and vascular system.

Effective Treatments Carry Risks

Real World Health Care: What initially intrigued you about the cardiac effects of cancer treatments?

Robert Frank Cornell, MD, Vanderbilt University Medical Center

Robert Frank Cornell: I was initially drawn to study cardio-oncology due to some cardiac toxicities observed with a drug used to treat myeloma called carfilzomib. While this drug was found to be very effective in treating myeloma, it had a small but definitive increased risk of cardiac toxicities including heart failure, arrhythmia, hypertension, coronary syndrome and rarely sudden cardiac death.

I continue to be inspired by researching cardiac toxicities because it is through our research efforts we have determined means to both predict patients at risk for cardiac toxicity and mitigate the severity of the effects in order for patients to continue to receive this effective therapy. As more drugs are developed, such as CAR T-cell therapies, there will be ongoing need to understand any potential cardiac risk associated with treatments with the goal of improved patient outcomes and quality of life.

Many Myeloma Patients Already at Risk

RWHC: Can you describe some of the common cardiac complications involved in multiple myeloma treatment?

RFC: Since the average age of diagnosis for myeloma is around 68 years, many patients already have risk factors for cardiac toxicities such as hypertension, hyperlipidemia, diabetes mellitus, obesity and kidney dysfunction. The addition of chemotherapy in this patient population increases the risk of possible cardiac complications.

One of the most common drugs used to treat myeloma is dexamethasone. This drug is a corticosteroid and can result in fluid retention and high blood pressure. Another treatment commonly used for myeloma is high dose melphalan followed by autologous hematopoietic cell transplantation (stem cell transplant). During the course of the transplantation process, patients are monitored for development of cardiac toxicities. It is not uncommon for patients to develop atrial fibrillation (a fib) or have an exacerbation of preexisting a fib during the course of transplant due to the added stress on the heart.

Carfilzomib, as mentioned above, also increases the risk as cardiac complications. The drug class of immunomodulatory/cereblon-binding agents including lenalidomide and pomalidomide increases the risk for thromboembolic events including deep vein thrombosis (clot in the deep veins of the leg) or pulmonary embolus (clot in the artery of the lung). While this is not a traditional cardiac complication, many cardiologists monitor for this since it is thought that the blood vascular system may play a role in the development of these.

The majority of other FDA approved treatments for myeloma have very low risk for cardiac toxicity such as the drug class of reversible proteasome inhibitors including bortezomib and Ixazomib (though there are case reports of cardiac problems with bortezomib) and monoclonal antibodies including elotuzumab and daratumumab.

Collaborative Care

RWHC: What sort of challenges do clinicians face when treating multiple myeloma patients in terms of minimizing cardiac complications?

RFC: The biggest challenge I see is how best to manage a patient considered to be at very high risk for cardiac complications during the course of treatment. This patient is identified according the medical history as already having a known history of cardiac difficulties. The best strategy to overcome this is with a collaborative cardiac and oncology effort to optimize the patient’s cardiac status prior to and during the course of treatment. This includes optimization of a patient’s blood pressure, cholesterol, diabetes, heart failure, rhythm control and volume status. Should cardiac problems arise during the course of treatment, then prompt evaluation by a cardiologist should be considered, particularly in high-risk patients.

Underlying Causes of Cardiac Complications

RWHC: How can researchers overcome the challenges they face when studying cardiac complications of cancer therapies?

RFC: One of the biggest challenging for the research of cardiac complications is the determination of the underlying cause for the cardiac complication. Since patients with myeloma already often have risk factors for cardiac events, it can be challenging determining if the cardiac event occurred from the treatment itself, from supportive care as part of the treatment such as intravenous fluids, or simply occurred by chance since the patient was at higher risk for cardiac complications regardless of treatment. The cardiac event may have also occurred due to a combination of these factors. To overcome this challenge, ongoing research and collaboration between hematology and cardiology are needed to better understand the cardiac complications, develop strategies to prevent or mitigate the events and optimize patients care and outcomes to both improve survival and quality of life.