Treating Patients With Multiple Myeloma in the VA
Moderator
João Ascensão, MD, PhD, is a professor in the Department of Medicine and Immunology at George Washington University School of Medicine and chief hematologist and chairman of the R&D Committee at the Washington DC VA Medical Center, both in Washington, DC. He is also a clinical professor of medicine at Uniformed Services University in Bethesda, Maryland. In 2015 Dr. Ascensão served as president of the Association of VA Hematology/Oncology (AVAHO).
Panelists
Thomas R. Chauncey, MD, PhD, is an associate professor of medicine and oncology at the University of Washington, and an associate member of the Fred Hutchinson Cancer Research Center. Dr. Chauncey is director of the Marrow Transplant Unit at the VA Puget Sound Health Care System, all in Seattle.
Sean Cosgriff, PharmD, BCOP, is the hematology/oncology clinical specialist at the VA Portland Health Care System and affiliate faculty at Oregon State and Pacific University, both in Portland, Oregon. In 2014 Dr. Cosgriff served as AVAHO president.
Paulette Mehta, MD, MPH, is a professor of hematology/oncology at the University of Arkansas and a physician at the Central Arkansas Veterans Healthcare System, both in Little Rock. In 2010, Dr. Mehta served as AVAHO president.
G. David Roodman, MD, PhD, is the Kenneth Wiseman professor of medicine and director of the hematology/oncology department at Indiana University School of Medicine. Dr. Roodman is also a staff physician at the Roudebush VA Hospital Healthcare System in Indianapolis.
Nikhil C. Munshi, MD, is a professor of medicine at Harvard Medical School and Dana-Farber Cancer Institute, both in Boston, Massachusetts. Dr. Munshi is also a staff physician at the VA Boston Healthcare System at the Jamaica Plain Campus.
Dr. Ascensão. What’s interesting is that there are some DoD specimens (most of it is serology is my understanding), but we may be able to get other material. Having predisease tissue and watching as the patient develops MGUS, smoldering MM, or MM would allow us to see whether there were already mutational changes in the individual even before Agent Orange exposure or, perhaps, was a result of the exposure.
Dr. Mehta. If we could do that, we could even develop protocols to prevent progression of disease. We could imagine a day when we can see the first event occurring and do something to prevent the progression to MGUS and then to smoldering and overt myeloma. Now, we’re in a particularly good position having a national network to propose this type of national bank.
Dr. Ascensão. We have some advantages as a group with a high prevalence of African American patients, as Dr. Munshi mentioned. And we have the biologic components of pathogenesis with Agent Orange. I think it’s something we can afford. Dr. Roodman, what do people in the field need to know about the biology of myeloma that’s going to help them?
Dr. Roodman. People still don’t understand some of the mechanisms underlying support of myeloma growth by the microenvironment. There are multiple targets that have been examined, and none of them work especially well except for what we already use, proteasome antagonists and immunomodulatory agents. In terms of the biology of myeloma bone disease, healing myeloma bone lesions is still a major issue that needs to be addressed. The question is how to do that. I have a VA grant to look at that question and other groups are actively studying the problem.
How particular myeloma clones become dominant is still a wide-open question. Some researchers are pursuing how the microenvironment selectively allows more aggressive clones to become dominant. Currently, the major research focus is on intrinsic changes in the myeloma cell but the microenvironment may also be contributing to the process.
Relapse
Dr. Ascensão. Years ago, people who relapsed, relapsed with bone disease, which may not be necessarily how people are relapsing these days. We are seeing testicular relapses, hepatic relapses, or pulmonary relapses in individuals who are exposed to some of the new agents. There may be interesting developments in terms of interactions in the hepatocellular microenvironment component and the myeloma cells at that level.
Dr. Roodman. These types of relapses are by myeloma cells that can grow independent of the bone marrow micro-environment and these myeloma cells are behaving more like a lymphoma than a myeloma. Several groups have been studying these types of relapses and are examining the expression of adhesion molecules and loss of expression of adhesion molecules to understand why the myeloma cells aren’t anchored in the marrow. This is just my opinion, but we really need to decide on something that could be done within the VA and ask questions similar to the 2 VA clinical trials Dr. Munshi developed. Those were doable in the VA, and we were able to get support for these trials. I think we have to ask questions that allow us to take advantage of the unique features of the VA patient population.
Dr. Chauncey. I would offer a comment from the clinical perspective. You mentioned that this is an observation with newer therapies, and it’s certainly been an observation in the marrow transplantation setting that the pattern of relapse changes. As treatments become more effective, the pattern of relapse can change. When we first started performing autologous transplantation, the pattern of relapse changed from the chemotherapy used at the time. When we started performing allogeneic transplantation, and to the extent that we use that option, we see a different pattern of relapse with substantially more extramedullary disease. This is really a polyclonal or oligoclonal disease, and as different clones evolve over time, whether it’s immunologically mediated or cytotoxic suppression of the initially dominant clone, you see clonal evolution with a different clinical presentation.
Immune System
Dr. Ascensão. Dr. Munshi, what do you think about the immunologic aspects of the disease in terms of its evolution?
Dr. Munshi. They are both aspects of the impact of myeloma on the immune system as Dr. Chauncey mentioned with progression similar to what Dr. Roodman described in the bone, but with greater impact on immune functions. With both pro- and antifunctions you get more TH17 responses, increased T regulatory cell responses, but also more microenvironmental immune cells change.
The second effect is that the immune cell also affects the myeloma growth. For example, proinflammatory cytokine produce interleukin (IL)6, IL17, IL21, and IL23 that affect myeloma or provide myeloma cell growth and signaling mechanism. Also, the PDC (plasmacytoid dendritic cell) is one of the best bone marrow components that induces and supports myeloma growth. With progression, some of these microenvironmental elements actually play a greater role in having the disease function or progress growth more aggressively than otherwise.
The second important aspect that comes into the picture in the immune and bone marrow microenvironment is the role of selecting the clone. There are literally hundreds of clones in a given patient. Certain clones would be supported preferentially by the immune cells, and in some cases, these aggressive clones become independent and grow without the need of support. That’s when they end up becoming extramedullary disease, which also determines how the myeloma cell is growing with these molecular changes.
Dr. Mehta. Another point of evidence for the immune system dysregulation in allowing growth of myeloma is the impact of some of the new trials. So the KEYSTONE 023 trial, for example, showed that pembrolizumab, the programmed death 1 protein (PD1) inhibitor, helped to prevent progression of disease and actually increased survival. The CAR T [chimeric antigen receptor T-cell] studies, some of which were presented at ASH [American Society of Hematology annual meeting] last December, also are beginning to show promise, almost as well as in chronic lymphocytic leukemia. We could look at the therapeutic response as an indicator of biologic pathogenesis and say, “likely the immune system is a major determinant.”
Standard of Therapy
Dr. Ascensão. The Spanish group published some interesting data on high-risk MGUS and smoldering MM. What do you as investigators and clinicians look at to make a diagnosis of MGUS, and what kind of test would you do in order to separate these different groups? How would you define current standard of therapy, and do you assign specific therapies for specific groups of patients?
Dr. Munshi. The current standard is a 3-drug regimen in the U.S. The most common 3-drug regimen that we all usually use, definitely in younger people, but also in older people with some dose modification, was a proteasome inhibitor and immunomodulator with dexamethasone—commonly lenalidomide, bortezomib, and dexamethasone (RVD). One can use carfilzomib also. Now we are beginning to switch to ixazomib, an oral proteasome inhibitor, and it can become an all-oral regimen that could be very convenient. We will have a VA study utilizing a similar agent to make an all-oral regimen for treatment.
