What are some possible monoclonal antibodies and MAB combinations to consider at first relapse?

What are some possible monoclonal antibodies and monoclonal antibody combinations to consider at first relapse?

So I think there are two broad classes of targets for monoclonal antibodies. We have CD38 targeting monoclonal antibodies and SLAMF7. These are the two proteins that are present on myeloma cells. And we have antibodies, monoclonal antibodies, that are available to target both of these. For CD38, as I mentioned, you have daratumumab and isatuximab for SLAMF7. We have an antibody called elotuzumab. So those are the three US FDA-approved monoclonal antibodies for the treatment of multiple myeloma.

Now, each of these drugs can be combined with many of the other drugs we talked about: lenalidomide, pomalidomide, carfilzomib. So all of these are legitimate choices to combine. And again, how we decide which combination, I think, to some degree depends on what they have had in the past, preference, how active the disease is, and how quickly you want responses, etc. But all of these are reasonable choices. Combinations of all of these are reasonable choices.

The one consideration is that more and more overwhelming data would suggest that the combinations are better than one or two drugs. So we wouldn't use necessarily these antibodies by themselves unless there were specific reasons, side effects, or other reasons to use them. Largely, for first relapse, you're thinking about using a three-drug combination. So these antibodies with one of the other drugs from one of the other classes of drugs we talked about.

We have two CD38 monoclonal antibodies. One is daratumumab and the other is isatuximab. In my mind, they're kind of interchangeable in terms of efficacy. So at first relapse, I think the situation depends on what you're relapsing off of. I think if you've not been exposed to a CD38 monoclonal antibody, that's a great place to introduce that. What you pair that with, I think, will again depend on what you were on before.

In terms of daratumumab versus isatuximab, I think they're interchangeable. Some of the things that really go into that may be the schedule of how it's given or even the mode of administration. For example, daratumumab is available in an injection or subcu form, which can be really easy. There are some observation periods and ramp-up dosing, so it could mean a little more visits upfront in the clinic, but eventually, it's just a five-minute shot once a month. Versus a drug like isatuximab, where you still have to go in for infusions every two weeks. If you're getting a drug with isatuximab that is already an IV drug, for example, like carfilzomib, it may not be a big deal to just get two IV drugs at the same time.

So I think there are patient factors, and what treatments are being given in combination with them make a difference. We are looking into whether, if you don't respond to daratumumab, you will get any benefit from isatuximab, or if they’re interchangeable. We're not going to have head-to-head data that tells us that, but I think, again, I kind of use them interchangeably. So if you're not responding to a CD38 monoclonal antibody in general, it’s unlikely that you're going to respond to just a different formulation of it, so to speak.

If daratumumab was part of induction, could it be considered at first relapse? Who may still benefit?

For quite a number of years after daratumumab was approved, it was mainly used in the relapsed/refractory setting. Then with new data that's been coming along, more and more of us are using daratumumab as part of initial treatment for newly diagnosed myeloma, as part of, say, daratumumab with bortezomib, lenalidomide, and dexamethasone—so-called quadruplet treatments that are showing promise.

The question you're asking is, if somebody has already gotten daratumumab as a frontline treatment and then, say, two, four, or five years down the line, that disease is coming back, is it a consideration to give them more daratumumab then, or should we not be using daratumumab?

The honest answer is we don't fully understand or know. I would say that the one class of patients I would consider it for are patients who got initial induction but not continued maintenance with daratumumab. That’s daratumumab exposure, i.e., they've been exposed to daratumumab, but they're not refractory to it—that means that they did not progress on daratumumab—and the disease came back some years later. In those patients, I think it's reasonable to think that these patients can benefit from further antibody treatment, particularly CD38.

If it's a patient who has been on daratumumab throughout and while on daratumumab their disease progressed, I'd be less inclined to consider more daratumumab as part of their second-line treatment in that situation.

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