The Role of BCL-2 in Normal and Multiple Myeloma Cells

EP: 1.An Overview of Multiple Myeloma

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EP: 2.The Role of BCL-2 in Normal and Multiple Myeloma Cells

EP: 3.Venetoclax Monotherapy for the Treatment of Multiple Myeloma

EP: 4.Venetoclax plus Dexamethasone for Multiple Myeloma Treatment

EP: 5.Venetoclax for Multiple Myeloma: The Phase 3 BELLINI Trial

EP: 6.Venetoclax in Combination with Daratumumab for Multiple Myeloma Treatment

EP: 7.Venetoclax in Combination with Carfilzomib for Multiple Myeloma Treatment

EP: 8.Other Venetoclax-based Combination Regimens Being Evaluated in Multiple Myeloma

EP: 9.Other Investigational Agents Targeting BCL-2 Family Proteins for Multiple Myeloma Treatment

EP: 10.Where Does Inhibition of BCL-2 Family Proteins Fit into the Multiple Myeloma Treatment Landscape?

Jonathan Kaufman, MD: We are here today to talk about BCL-2, so the question I have for you, Shaji, is what’s the role of BCL-2 in normal cells?

Shaji Kumar, MD: It’s a family of proteins that play an important role in the apoptosis of cells. Apoptosis is a crucial process through which the body eliminates cells that have a variety of different damage, primarily damage to the underlying genetic material. The BCL-2 family of proteins are often referred to as “gatekeepers of death,” and is involved in this apoptotic pathway, particularly the intrinsic pathway, which is often triggered by intracellular events like DNA damage. BCL-2 is a very large group of proteins; there are almost 20 members in the BCL-2 family, and they are broadly grouped into those that are considered to allow the cells to survive, which includes BCL-2, or the major protein, BCL-XL, BCL-W, and MCL-1. There are pro-apoptotic proteins called BAX/BAK and BIM being some of the more important ones. They all tend to share one homologous domain, which is called BH domain. These proteins again appear to be those initial sensors that detect that there is something wrong going on in the cell, and initiate the apoptosis pathway, leading to cell death. It has been identified in playing a major role in survival of a variety of different cancer cells, including myeloma cells. As a result, the therapeutics targeting BCL-2 family proteins have been the focus of a lot of pharmaceutical research and academic research in order to come up with drugs that can interfere with something that is so fundamental that the thing can provide some degree of selective targeting of PUMA cells given that they are more dependent on BCL-2 family proteins for survival. Again, the conducts of myeloma has been shown to be quite important, and Jonathan, a lot of work has been done by your colleague at Emory, Dr Larry Boise. Maybe I will hand it over to you to talk about the role of BCL-2 family proteins in myeloma.

Jonathan Kaufman, MD: Thanks, Shaji. We know that cancer cells are very sick, and they have intrinsic pro-growth signals. Pro-growth signals aren’t inherently pro-apoptotic, and that’s why in order to live, the cancer cell — the myeloma cell in particular — must significantly up-regulate it’s anti-apoptotic proteins. The most common anti-apoptotic protein that prevents myeloma cells from dying is actually not BCL-2, but MCL-1. Probably somewhere around 80% to 85% of myeloma cells are kept alive by MCL-1. A fraction, maybe 15% to 20% of myeloma cells, are what we call co-dependent on BCL-2. What BCL-2 does, in this situation, is it takes up, it holds on to the BH3 protein BIM that you mentioned, and it prevents BIM from interacting with downstream pro-apoptotic proteins, then leading to apoptosis. What we found is that the group of patients that are most likely to have co-dependence on BCL-2 are those patients who harbor the t(11;14) translocation. Those t(11;14) patients are more likely to be co-dependent on BCL-2, and when we discover that codependency – when I say we, as you mentioned, this is primarily Dr Larry Boise in his lab — but we predicted that if we could find the medication that targeted BCL-2 that we should focus that medication on patients with (11;14) translocation. I think in a large part that led to all the work of venetoclax that we have been doing for coming on 10 years now. I guess that leads to the question of the study that you published several years ago, the phase I study looking at venetoclax in relapsed and refractory myeloma.

Shaji Kumar, MD: Thanks, Jonathan. Absolutely. I think there is a lot of work that has been going on in the context of venetoclax in multiple myeloma, or broadly, plasma cell disorders.

Transcript edited for clarity.