Why do drugs stop working?

Why do drugs stop working? What role do clones play in becoming refractory to a drug? What are some other possible explanations for drug resistance?

That's a complicated series of questions. Great question. So relapse in myeloma in general, every patient has 2 to 6 different clones of myeloma that are percolating inside them at each time point from diagnosis and then onward. But at relapse, usually one clone is the predominant and that's what is causing the majority of the myeloma protein to show up in the blood.

You treat them, and that clone, if they respond, decreases. But another resistant clone starts to take priority and it's usually resistant to whatever the patient's currently receiving. You can see the myeloma proteins go up.

From the physician side, you don't know which clone was predominant before and is now causing trouble. You don't know. But on average, the clones that you have now are usually stronger and more resistant than the clones that predominated in the patient before.

So you usually can't go back to regimens that you've used before. And I never have successfully given a patient re-exposure to the exact same regimen and had a reasonable response out of it. You can certainly use components of an old regimen in combination with newer elements to try to get over the wall for a myeloma response, but never the exact same drug.

Why do plasma cells become triple or quadruple refractory to the treatments that we administer? We have triple-refractory, quadruple-refractory multiple myeloma patients, and it's not entirely clear why that is. So there are maybe theories that there is an immune escape of the tumor cells.

We have demonstrated these in frequent studies that the tumor cells are really smart. They know how to escape and don't respond any longer to any of those drugs, which led to the administration of triple therapy or now quadruple therapy, rather than monotherapy in the early stages of our experience. But there's also the theory that different clones—and not all the tumor cells or plasma cells, in this case, are created equal.

Some of them may be at a very, very low frequency and don't play a role at the first disease diagnostic or even first relapse or second relapse. But they may evolve and grow out over time with each treatment cycle or each treatment combination, so that the one cell that was not contributing to the disease in the early stage is now representing the majority of all tumor cells in the disease status.

So I would say the vast majority of myelomas, or myeloma patients, come in prior to any kind of treatment with multiple different tribes of myeloma, multiple different clones of myeloma from the very beginning. And they all arose from the original myeloma cell. But they all have different mutations, and they all have different resistances.

It's been very clear from studies that if you treat a myeloma patient, and you can actually look at all these different tribes, what will happen is some tribes will go away, other tribes will just sit there, and other tribes will actually grow. The resistance comes from the fact that multiple myeloma is truly multiple within a single patient.

What we are typically seeing is that it's not that myeloma at the very beginning is resistant to chemotherapy. In fact, the vast majority of our patients in this day and age actually respond very nicely to the initial set of chemotherapy. But there's a small population of myeloma clones that are, in fact, resistant to that initial therapy, and then they start to grow back.

That's the cause of the relapse. Then we treat with another set of drugs, and we can wipe out a big chunk of the myeloma. But again, there's a small subset of that myeloma, a small population that's also resistant to that chemotherapy, and they start to grow back. Over the course of time, what we develop is what we call acquired resistance.

It's not really resistance at the very beginning, but as the myeloma cells manage to survive the chemotherapy and become resistant to it, they actually build on top of each other and become more and more resistant to all sorts of therapies. Ultimately, I think that the major reason that most of our myeloma therapies fail is that the myeloma cells, over the course of five or six lines of therapy, have developed so much resistance that nothing works anymore on them.

Now that, in fact, is the interesting aspect of immunotherapy. Immunotherapy kills myeloma cells in a different way than chemotherapy. So despite the fact that a myeloma cell may be resistant to all kinds of chemotherapy, it has never faced an activated immune cell that's trying to kill it. So it's not resistant to the immune system.

This is why we've seen such dramatic responses with things like BCMA CAR-T cells. The myeloma cell is resistant to everything else but not resistant to the immune system, and the immune system is very effective in killing them.