Do individuals become refractory to a given drug or an entire class of drugs?

Do individuals become refractory to a given drug or an entire class of drugs?

So there are many medications that we use in multiple myeloma. And as a principle, when the myeloma in an individual patient learns to grow on a specific medication, we deem that myeloma refractory to that medication, and the value of going back to that medication is somewhat limited. Sometimes, in certain combinations, you can kind of recapture some benefit. But in general, that medicine no longer works for that patient's myeloma.

However, myeloma medicines are varied. There are certain key categories of medication. There are the immunomodulators, like lenalidomide and pomalidomide. There are the proteasome inhibitors like bortezomib and carfilzomib. And we know that if a patient is refractory to an agent within a specific category, like refractory to lenalidomide, which is also called REVLIMID, they can still do very well with a newer drug called Pomalidomide or POMALYST.

So being refractory to a drug does not mean you're refractory to a category of drug. And again, sometimes patients can have a relapse on an individual medication, but then combinations, even incorporating that same medication, can still be effective. So there's no absolute rule here. Although, again, once a patient is refractory to a certain medication, the benefit of that specific medicine, not the class, becomes limited.

Although there is some cross-resistance among classes on the same drug, for the most part, we assume if you are refractory to a drug, you are not necessarily refractory to all the drugs in that class. That works in somewhat of a hierarchical way. There's not a lot of evidence to support that. But what the evidence allows us to state is, for example, in general, if you are refractory to a first generation of a class, you still can respond to a second or third generation.

The same is not true the other way around. So we know, for instance, many patients who have become refractory to Bortezomib (Velcade) can respond to carfilzomib. This same is probably not true the other way around, although it hasn't been properly addressed. We know for a fact that patients who become refractory to lenalidomide (REVLIMID) can and actually are likely to respond to Pomalidomide (POMALYST), particularly when used in combination with a third agent, in particular if that agent is a monoclonal antibody.

If a patient progressed on one immunomodulatory drug, is it possible to respond to another?

Yes. Each and every image from REVLIMID onwards. So if you have REVLIMID-resistant disease, you've been on REVLIMID and dexamethasone, and it's not working, and you're exposed to POMALYST and dexamethasone, you have about a 30% response rate. If you're resistant to POMALYST and dexamethasone and you get iberdomide and dexamethasone, you have about a 30% response rate.

So each one of these improvements in efficacy, with a slight upgrade in mechanism of action, will lead to clinical responses.

If a patient progresses on one proteasome inhibitor, is it possible to respond to another?

Yes, there are some caveats in that it's less likely for a patient to respond to a proteasome inhibitor where dose is very important. So the cumulative intensity of the proteasome inhibitor makes all the difference. Ixazomib is the weakest proteasome inhibitor. Then comes Velcade, and then comes carfilzomib.

At certain doses of carfilzomib, you expect a lot more efficacy than the standard 1.3 milligrams per meter squared of Velcade subcutaneously, which is a whole lot more than 2 to 4 milligrams of Ninlaro weekly. So at each level, you have a different effectiveness of each proteasome inhibitor. If you're getting 70 milligrams per meter squared of carfilzomib once weekly, and then you want to go to 3 milligrams of Ninlaro and think that that will salvage you, that's not going to work. So as long as you're increasing the dose intensity, you have a chance of getting some effect.

If a patient progresses on one monoclonal antibody, is it possible to respond to another?

I am not aware of any patient who has become refractory to a Darzalex-based regimen and then responded to an Isatuximab-based regimen. But on any of those clinical trials, where any patient has been treated with Isatuximab and then gone to Darzalex or Darzalex to Isatuximab, I'm not aware that anyone's been salvaged effectively with a different CD38 antibody.

That's not the case, and it's much more difficult to figure out with a CS1 or SLAMF7 antibody, Elotuzumab, because Elotuzumab is always given with an IMiD and dexamethasone. You can certainly have a response, and we've seen that with Elotuzumab, IMiD, and dexamethasone after failing on a Darzalex-based combination.

So those are not clearly cross-resistant. But the number of patients who respond to Elotuzumab effectively in the relapsed setting is pretty darn small.

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