Emerging Therapies in the Treatment of Multiple Myeloma

David S. Siegel, MD, PhD

Today, we are discussing therapies in development for multiple myeloma with David S. Siegel, MD, PhD, who is the chief of the division of multiple myeloma at the John Theurer Cancer Center, part of the Hackensack University Medical Center in New Jersey. Dr. Siegel recently gave a talk on this topic at the International Congress on Hematologic Malignancies that was held February 23–25 in Sunny Isles, Florida.

-Interviewed by Anna Azvolinsky 

Cancer Network: First, what are some of the therapies for relapsed multiple myeloma patients that are currently tested in clinical trials? Are any of these specifically targeting the biology of multiple myeloma?

Dr. Siegel: Yes, I think that we are fortunate that we understand the biology of myeloma better. I think the first drug that is in clinical trials for multiple myeloma that seems to be specific to a specific biology is a drug called venetoclax. It’s a drug that has been approved in other B-cell malignancies, but is particularly effective for a subset of myeloma patients with a particular genetic abnormality called a translocation 11;14. I think this is the first example of a drug that is going to specifically target a subset of myeloma patients that carry a particular biological feature. But most of the drugs that we use in myeloma, including the drugs in clinical trials, are aimed at the nature of the cell. The malignant cell in myeloma is a plasma cell or a preplasma cell, so the drugs that we use are not really directed at a specific mutation, but are directed at killing plasma cells.

We have a number of other drugs in clinical trials. One exciting new class are exemplified by a new drug called selinexor. And these are drugs that inhibit the movement of both proteins and genetic material from the nucleus of the cell to the cytoplasm of the cell, so from where the control center of the cell, the nucleus where all of the DNA is, that nucleus needs to communicate with the machinery of the cell which is in the outer part of the cell called the cytoplasm. And there are very specific pores between the nucleus and the cytoplasm that transfer information and materials back and forth. Selinexor is the first compound to inhibit that process and it turns out to be very effective, not just in myeloma, but in some other cancers as well. And the success of selinexor has led to the development of derivatives of selinexor. Even though selinexor itself is not yet approved, we are already working on the derivatives of that drug and I find those to be a very exciting class of drugs.

The list of possibilities is quite long, but I think another kind of process that is much more complicated has to do with a drug that we call CAR T cells and T cells are one of the many immune cells that we have, but these are cells that are capable of killing tumor cells. The problem is that it’s hard to get them to recognize the tumor cell and do that job. Quite cleverly, a scientist a number of years ago tried to put a gene into these cells that would encode a receptor that made these cells able to recognize a specific target. And so you can take T cells out of a patient, that are not directed against the myeloma, and when you take them out, you can put this special construct into the cell and these cells will, sort of miraculously now, express a receptor on their surface that allows them to bind the myeloma cell and kill the myeloma cells.

There is a new target that has been recognized in myeloma, B-cell maturation antigen (BCMA). You can take a gene that will create a receptor for BCMA on the surface of the T cells and now you have patients’ T cells to put back into patients that will recognize the cancerous myeloma cells and kill them very specifically. I think everyone is excited about that although it’s obviously a very complicated process.

That is just one of many kinds of things that are going on, but certainly reason to be quite hopeful, both as a care provider for patients with myeloma and more importantly, as a myeloma patient.

Cancer Network: And what are the notable trials or agents in development in the frontline setting?

Dr. Siegel: I think that the way things work in multiple myeloma is that drugs that have been shown to have activity in the more advanced myeloma patients, those who have relapsed more than once, those drugs slowly get moved forward. Some of the new drugs, drugs like daratumumab, the monoclonal antibody, is moving into the frontline setting.

And another very exciting new class of drugs that is being widely used in oncology in general, but now in myeloma, are a class of drugs called checkpoint inhibitors. And these are drugs that block the ability of the cancer cell to turn off the immune system. These drugs have shown activity in multiple myeloma and the studies that are going on right now are in patients with relapsed disease, which are very exciting studies, and these drugs are being moved into earlier stages of the disease and I think that the use of these kinds of drugs in the early stage of myeloma will lead us to potentially cure at least a subset of patients with myeloma. But the monoclonal antibodies are what is most ready for prime time right now.

Cancer Network: Lastly, what do you see as the major gap in care for patients with multiple myeloma, either subpopulations that are not that many trials ongoing or other issues where you think more attention is needed?

Dr. Siegel: I am not going to be unique in this opinion, but all of us I think recognize that high-risk myeloma patients, the subset of patients that carry certain genetic markers that predict for short remissions, are the area where we are most in need of development. Unfortunately, we have not yet developed therapies that are specific for them. And this is not for lack of trying. There is much work that is going on, but I think that is where we have failed the most badly.

The other area is that we sort of talk about myeloma as if it is one diagnosis, but in reality, it is many genetically diverse diseases that sort of look very similar superficially. But we are just starting to explore whether we can identify subsets of myeloma patients that are more appropriate for very specific therapies.

While we have developed many great drugs, we don't know which patients should really get which of those drugs. Carfilzomib may be very active and daratumumab may be very active, but they work better in some patients than they do in others and we just can’t recognize those patients before we start treatment. And the reverse is also true; we have patients who after stem cell transplant that have remissions that last 20 years. Well, if we could identify those patients and say, look, you have a stem cell transplant and you are likely to stay in remission for a very long time, it would save us much heartache on the patient’s side, of their dilemma of what therapy to chose and would certainly make the process of recommending one therapy over another much easier from the clinician’s perspective.

Cancer Network: Thank you so much for joining us today, Dr. Siegel.

Dr. Siegel: Thank you, it was my pleasure.