What treatments should be considered in bortezomib/velcade refractory patients at first relapse?

What treatments should be considered in bortezomib-refractory patients at first relapse?

Yeah. So the general principles, I guess, for relapse of a first-line, second-line refractory would be: what are the treatments that the patient has received previously? How did they tolerate those treatments? What kinds of comorbidities or side effects do the patients have? Neuropathy, cardiac side effects, renal dysfunction, or other issues that might play into these choices. Convenience, logistics, IV, subcutaneous dosing, oral drugs—is one preferable over the other?

So those are the broad principles in which we decide. And because we have so many drugs, I listed some of the treatment choices, and we use combinations. You can imagine that the permutations and combinations of different drugs would lead to ten or twelve different combinations that any doctor or patient can consider for their treatment.

For the specific example of somebody who is bortezomib-refractory, this means that they are on bortezomib and their disease is progressing, or their disease progressed very soon after getting their last dose of bortezomib. In those patients, obviously, you might not want to use a combination that has bortezomib in it because it would not make sense that the same drug would have any significant impact on the treatment.

So you are looking at other classes. For instance, if they've not had daratumumab or a CD38 antibody like isatuximab and daratumumab, you would want a combination with that. So what can you combine these drugs with? You can combine them with lenalidomide, again, if a patient has not had significant lenalidomide exposure, or pomalidomide, which is another immunomodulatory drug, or carfilzomib, which is a proteasome inhibitor like bortezomib but with a different mechanism of action.

So you have several choices: the two CD38 antibodies combined with either lenalidomide, pomalidomide, or carfilzomib. Similarly, you can make combinations of carfilzomib with lenalidomide, carfilzomib with pomalidomide. I think this highlights the number of choices we are faced with. The good news, I guess, is that these are all effective combinations. Starting with one combination does not preclude patients from getting others in the future.

You can go from one of these combinations to another one even if and when the disease comes back. I think, as I said, a consideration of side effects is important. Carfilzomib has somewhat higher cardiac side effects. Daratumumab lowers the immune system a little more maybe than other drugs, particularly in combinations. Lenalidomide and pomalidomide are oral. Some are IV, some are subcutaneous. I think those other factors, like logistics and convenience, might also factor in on how we decide which treatments to go with for relapsed myeloma.

It’s important to know what we mean by the difference between refractory and relapse. Let’s say you're on a drug—maybe you're on a three-drug combination, you're on Velcade, Revlimid, dexamethasone—and you've been treated with that for a year, and then the disease begins to come back. You are relapsing, and you are refractory to those drugs. It doesn't mean you're refractory to other drugs. It just means that you are refractory to those drugs.

So what you choose next will depend on what you've already had and what you're refractory to. You would generally choose drugs that the patient has never seen before, that the cancer has never seen before.

In this circumstance, if somebody has been on RVD and they relapse, then a common combination would have carfilzomib in it, which is another proteasome inhibitor like Velcade. But people respond to it even if they relapsed from Velcade. Maybe pomalidomide, because they've had Revlimid and they’re refractory to Revlimid. And then we always throw dexamethasone in, but we're trying to minimize that these days.

But a different situation would be if somebody had RVD, Revlimid, Velcade, and dex, then they get a transplant, and they're on Revlimid maintenance, and then they relapse while on Revlimid maintenance. They are relapsed, but they’re not refractory to Velcade, which they had a while back but weren’t on when they relapsed. They’re probably still going to respond to Velcade.

So they’ve relapsed, but they’re not refractory to Velcade. You might put Velcade into your next combination again and use it because they haven’t proven refractory to that drug. That’s the difference between relapsed and refractory and how we would choose drugs.

Patients who are refractory to bortezomib can go on a monoclonal antibody and IMiD combination such as Dara, Pom, Dex. They can go on a carfilzomib-based regimen. So, carfilzomib, Dara, Dex; carfilzomib, Pom, Dex. There are other treatments as well. You can use selinexor in those patients in combination with pomalidomide, or in combination with bortezomib.

You can use alkylating agents such as Cytoxan. It depends on what side effects you want to avoid and how quickly the disease is coming back.

On April 5th, 2024, the U.S. Food and Drug Administration approved CARVYKTI for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, and are refractory to lenalidomide.

To learn more about the drugs mentioned in this video, visit the link in the description.