Kristie L. Kahl: What is myeloma and how does it develop?
Lee Greenberger: Myeloma is when a mutation occurs in certain types of blood cells. Normal blood cells are manufactured, and these are put out in hundreds of thousands of cells a day, they can either become white cells or non-white cells. The white cells are the lymphatic cells, go through a program development. At the end stage of development are plasma cells. These plasma cells can undergo mutations and if they undergo the right mutation, these plasma cells will become myeloma cells. The important thing about myeloma cells is that they will grow uncontrollably. Normally a plasma cell will make antibodies, function normally and grow at a certain rate. These myeloma cells will grow abnormally fast and will not function well, and they will begin to crowd out the normal cells. Not only will they not function correctly, but they will crowd out the normal cells, in addition to which the myeloma cells can actually circulate throughout the body and can compromise the kidney and the bones. So, patients might walk in saying, “I’m not feeling well, I’m weak. I have back pain.” And it turns out that it’s because the bones are being compromised.
Kristie L. Kahl: There is also smoldering myeloma, what is this and how is it different from active disease?
Lee Greenberger: There is actually three stages of myeloma: MGUS, which is an undetermined, early stage pre-myeloma; smoldering myeloma; and full-blown myeloma. This is basically three stages, and most patients, as we know, just go through all of the stages. However, many patients walk in and already have myeloma. So, they’ve got all the symptoms: the kidney compromise, the bone compromise and something called high-end protein in their myeloma cells.
The smoldering myeloma patients don’t have full blown myeloma, they have something called m-protein, which is a signature of myeloma cells, they basically just produce these proteins. It can go into the urine or the blood and we can analyze these. It has a low level of that. And those smoldering myeloma patients will basically not require treatment, at least, up until a year or two ago. When you look at smoldering myeloma patients, we can now actually divide these patients into low-grade disease and high-risk smoldering myeloma. We can do that by taking these cells out and asking, “Do they have certain mutations that will indicate that this disease is going to advance rapidly to full blown myeloma and also have a bad prognosis?” So, for example, high-risk smoldering myeloma patients, in about 50% of those patients in two years will progress to myeloma. MGUS is even lower grade disease and basically the watch-and-wait situation.
So, why do I break this down? You’re going to treat myeloma patients with chemotherapy and a whole variety of other therapies that are available. But now we are beginning to move those treatments back. There are treatments for relapsed disease to newly diagnosed myeloma patients to begin to treat high-risk myeloma patients, and there’s even therapies that we consider that we understand well enough and are approved by the FDA for relapsed disease. So, there is a lot of experience to treat even lower risk smoldering myeloma patients. That will being to roll the therapies back. So, smoldering myeloma looks like, in the future, is going to be considered “you’ve got myeloma, we can treat these,” because we have drugs that are capable of controlling the disease and we don’t have significant toxic side effects.
Kristie L. Kahl: What is minimal residual disease and how does it play a role as a biomarker?
Lee Greenberger: Minimal residual disease is basically an index of how many myeloma cells are there. It is basically a surrogate for that. So, how do we do that? You can take a sample of the bone marrow, a sample of the blood, and you can simply ask how many myeloma cells are there? Minimal residual disease basically defines how many cells are there. So, if you can see one out of a million cells, that’s basically low-level minimal residual disease or as low as we can define it. Typically myeloma patients will have obvious disease, but as you begin to treat those patients the number of myeloma cells will begin to go further and further down. You can use molecular methods to figure out how many cells are there.
When you say minimal residual disease, we can do this basically in two ways: Take the sample of the bone marrow and send it out to this fancy machine that basically can analyze for how many cells are there. It’s basically a very clever machine, and can pass these cells one at a time through a scanning device and can detect and count the number of cells that are myeloma cells. We can also do it by an analysis of mutations. We have machines that can look for mutations and look at the frequency of mutations, and that will tell us the frequency of that mutation. Those machines are capable of detecting very low level of disease, high sensitivity, to say whether the mutation in those cells exist or not.
It’s important because as the disease is reduced farther and farther, you can begin to say whether you’ve actually controlled the disease or not. So, minimal residual disease is a good sign when you are MRD-negative — that means that we can’t find the myeloma. That doesn’t mean that the myeloma is gone. We’ve now gone from the term MRD-negative to UMRD, which means undetectable minimal residual disease just because you can’t find one cell in a million doesn’t mean there’s one cell in 10 million. Disease has a nasty habit of returning. It may return in a year, it may return in 10 years, but you can’t say it’s completely gone even with MRD-negative.
Kristie L. Kahl: With relapsed/refractory disease, how has precision medicine come into play?
Lee Greenberger: Many of the drugs that we treat for myeloma — which by the way, are quite different than (treatment for) lymphoma – there are many particular drugs that we use. Some of these are cytotoxic agents, drugs that target the immune system and now, as we begin to understand what the mutations are in these cells, we have drugs that specifically can target these. One of the most effective ways of new drugs to treat myeloma are drugs that can attack the cell’s surface of the myeloma. In other words, myeloma cells have a very high expression of proteins on the surface. That happens to be CD38, and we have drugs that target CD38, which is called (Darzalex [daratumumab]) and is a monoclonal antibody that will basically bind to those cells and instruct the immune system to kill those cells. These can be helpful when used in combination with those cytotoxic agents, particularly use in myeloma. Those are good at causing minimal residual disease so patients can go into an undetectable MRD state in a high proportion and can control the disease. Prior to those drugs, we used to think that the overall survival rate was about five years in a newly diagnosed myeloma patient. We now think with those drugs, the thinking is you can go out about seven to 10 years. It can control the disease for a longer period.
There is also, of late, another marker on those cells called BCMA. Why is BCMA so important? Because we can instruct the immune cells to recognize BCMA on the myeloma cell’s surface. We have a variety of immune mechanisms, a monoclonal antibody directed at BCMA attached to a toxin, so it’s basically the guided missile approach. We now have something called BCMA CAR T, so you take the cells out of the patients, put in a gene that is specifically recognizes BCMA on the surface. Those T cells now home to the tumor cells, expand dramatically, kill the tumor cells. We also have bi-specific BCMA-directed therapy. We have a tumor cell that is expressing BCMA, you have T cells. You basically have a T cell engager called a bi-specific antibody that will recognize the T cells and the myeloma cells that have CD38 and BCMA on them and bring them together. Those have pretty dramatic effects…This is 20 years in the making.
I think patients should understand that it comes out of work of monoclonal antibodies, how to manufacture them, how to genetically engineer T cells, how to grow T cells outside the patients, how to genetically engineer those T cells, five or 10 years of clinical trials, and now finally another three years later after the drugs have been approved (for other indications), now effective therapies for myeloma. So, it’s really exciting time in myeloma with multiple treatment options.
Transcript Edited for Clarity