Rationale for Immunotherapy in Multiple Myeloma

Transcript:Shaji Kumar, MD: Multiple myeloma is a malignancy of terminally differentiated plasma cells. It’s a very microenvironment-dependent disease, and most of the tumor cells typically live in the bone marrow with some of these cells also coming into the circulation as the disease progresses. Now, we know this disease, the multiple myeloma, actually progresses from a precancerous condition that we commonly refer to as monoclonal gammopathy of undetermined significance (MGUS). And, some patients also go through an intervening phase called smoldering multiple myeloma. A lot of different changes happen from the MGUS to myeloma in the tumor cell itself. But, we have also understood over the years that significant changes happen in the tumor microenvironment.

Now, these changes in the tumor microenvironment can involve a variety of different cell types, and also includes some changes, like increased blood vessel formation in the bone marrow. But one of the critical things that changes during the spectrum of progression are the changes in the immune system. We know that patients who are immune-suppressed are more likely to have this transition happen faster. We also know that as patients go from MGUS to myeloma, there is significant change in the immune system or in the ability of the immune system to control the tumor process.

The immunological systems, that the body already has, have the capability of controlling the disease, so it makes a very good disease model to see if immunotherapeutic approaches will work. Now, this has been tried for several decades now. There have been vaccine studies that have been done in the past. There have also been other dendritic cell approaches that have been tried in the past, both in combination with other treatments, as well as on their own. However, until now, there has not been any significant progress in terms of immunotherapy. In the past few years, I think we have made significant progress in terms of several different approaches to immunotherapy in multiple myeloma.

Peter Voorhees, MD: It’s been increasingly recognized that the immune system plays an important role in the development of a number of different cancers, and certainly that is the case with multiple myeloma. And, importantly, we do know that a number of different malignancies are capable of producing signals that are able to tamp down an immune response to the underlying disease. So there’s certainly a lot of interest in developing therapeutics that abrogate that particular pathway of inhibition of immune surveillance and reawaken the immune response to disease. That’s certainly a pathway of investigation that’s very important in multiple myeloma. The other branch of immunotherapy are the monoclonal antibodies. And monoclonal antibody technology is very useful in terms of targeting very specific antigens on the surface of cancer cells that may be unique or much more heavily expressed on the malignant cells compared to normal tissues, thereby making them not only effective, but very well tolerated as well.

Daratumumab is a monoclonal antibody that binds to a protein on the surface of plasma cells called, CD38. CD38 is heavily expressed on normal plasma cells, as well as malignant plasma cells, or multiple myeloma cells. It is expressed on other tissues of the body, as well, but at lower levels, and there’s significant specificity with regards to the daratumumab. Daratumumab binds to the surface of myeloma cells by engaging CD38, and elicits antibody-dependent cellular cytotoxicity. So, activated T-cells and natural killer cells will come in and mediate cell kill basically of these antibody-coated myeloma cells. In addition to that, it appears that cross-linking of CD38 on the surface of myeloma cells actually may lead to myeloma cell death, in and of itself.

Interestingly, and this was presented at the ASH meeting back in December of 2015, there is CD38 expression on myeloid-derived suppressor cells, on B regulatory cells and on T regulatory cells as well. So, you actually see depletion of these subsets of the immune cells with daratumumab therapy. And by virtue of suppression of these myeloid-derived suppressor cells, B regulatory and T regulatory, you actually see an increased number and activation status of T-cells, which helps elicit a more robust antibody-dependent cellular cytotoxicity. The antibody itself binds to the surface of the myeloma cells, and targets them for destruction by the immune system. And there are also indirect effects that allow the immune system to be activated in a more robust way.

Elotuzumab recognizes a protein on the surface of myeloma cells called, SLAMF7, also called, CS1. SLAMF7 is very specific to plasma cells, although it is also present on natural killer cells as well. And that’s also important with regards to its mechanism of action. The elotuzumab binds to the surface of both normal and malignant plasma cells, basically flagging them for destruction by the immune system. Now, in contrast to daratumumab, which does have single-agent activity in multiple myeloma, elotuzumab does not. So, it needs more than just the antibody to mediate its effect. The other thing that we see with elotuzumab is that it binds to the surface of natural killer cells, which express SLAMF7 and activate those natural killer cells. So not only is it binding to the surface of the myeloma cells, but it’s activating the natural killer cells, which will allow a more robust antibody-dependent cellular cytotoxicity. However, as a single agent, it did not have a significant activity with regards to reduction in tumor burden. Which is why it’s been paired up with the IMiDs, in particular, such as lenalidomide where you see very clear synergistic activity.

Transcript Edited for Clarity