What are IMiDs and how do they work?

What are IMIDs and how do they work? IMIDs are immunomodulatory drugs. They're a class of drugs that are based on the first drug, it was called thalidomide, and was approved a while ago. Now there's a class of drugs that is based on the same structure of thalidomide, lenalidomide, and pomalidomide. Together they form the class of IMIDs, or immunomodulatory drugs. And these drugs are oral drugs that are a very important cornerstone of most of the regimens that we use to treat multiple myeloma, both upfront as well as in later lines of disease. And over time, by tweaking the structure of the drug, we have been able to develop more powerful compounds generally. And so we know very well from studies in the past that IMIDs have a direct effect on the and they sort of result in cell death and prevent the proliferation of myeloma cells. But very importantly, the fact why we call them immunomodulatory is the fact that they don't just have their effect on myeloma cells, but they act very importantly on cells that consist of the so-called immune microenvironment of multiple myeloma. In the bone marrow, so where the tumor is growing, there's a lot of other cells of the immune system as well. And we believe that they contribute or they can contribute to tumor killing. And IMIDs have an important effect on the cells of the immune microenvironment. More specifically, we know that they activate T cells and NK cells, natural killer cells, and both of these cells are known to be able to exert an anti-tumor effect. And I think that is part of the power of the immunomodulatory agents. These are immunomodulatory agents that have been used in the treatment of myeloma and have transformed them. The first drug was thalidomide. And interestingly, the mechanism of action of these drugs was unknown despite very significant clinical activity. It is now felt that the major action of these drugs is most likely through a combination of targeting the myeloma tumor cell itself, but most importantly also the tumor microenvironment. The targets that have been identified molecularly have been cereblon as well as some zinc finger proteins such as icaros and iolos that are present both in the myeloma cells as well as in T cells and other immune cells within the microenvironment. But how exactly these mechanisms affect everything is not really fully understood at this point. So IMIDs, of course, have a slightly controversial history prior to the discovery that they were effective in myeloma. Thalidomide was, as a lot of people know, initially used for morning sickness in pregnant women and obviously that had terrible teratogenic or birth defect effects. It was later actually realized that this compound could have a beneficial effect in myeloma and it was tested in that arena and had some efficacy. Thalidomide also has some nerve toxicity and causes somnolence. So its next generation agents, lenalidomide and pomalidomide, have less of these neurologic side effects and are very effective and better tolerated as well. As a class of drugs, these drugs target both the myeloma cell and also immune cells. What they do is they actually lead to the degradation of specific proteins. They're called the icaros proteins and those proteins that are degraded actually affect different processes in the myeloma cells that leads to the death of the myeloma cells than in the immune cells. In the immune cells, they actually lead to further activation of immune cells. And so in that sense, that's why they are called immunomodulatory drugs because they have this multiple immune effects where they lead to activation of natural killer cells and T cells that are thought to be important and part of the efficacy of these drugs. They can potentially be considered a form of immunotherapy. I think one of the challenges of that is that they are not necessarily clearly directed at the myeloma. It's perhaps more of a nonspecific immune activation. Some of it may be myeloma directed, some of it may not be. That is not very well understood, I think, at this point. Targeting the microenvironment, I think there's become a bigger appreciation for the fact that the way to eradicate myeloma is through direct killing of the tumor cell itself, but also of inhibition of the immunosuppressive mechanisms that exist within the bone marrow microenvironment and also activation of immune functions that exist within the bone marrow microenvironment. And so, for example, there are suppressive populations such as myeloid-derived suppressor cells, immunosuppressive factors such as VEGF or interleukin-6 or potentially even IL-17 that are known to inhibit the ability of the immune system to effectively kill myeloma. These are most likely downregulated by the use of IMIDS. And then there are T cells that are known to kill and able to kill myeloma that have been shown to be upregulated and to be able to kill more effectively when given or when exposed to a variety of IMIDS, linalytomide, lenalidomide and pomalidomide, as well as the newer IMIDS.