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.