What are some possible monoclonal antibodies combinations to consider at first relapse in multiple myeloma? (daratumumab, isatuximab, elotuzumab)

What are some possible monoclonal antibody combinations to consider at first relapse in multiple myeloma?

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 in 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 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 and, preference, how active the disease is. How quickly do 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 three the combination of better than 1 or 2 drugs. So we wouldn't use necessarily these antibodies by themselves unless there were specific reasons, side effects, 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 on one of the other classes of drugs we talked about.

We have two CD38 monoclonal antibodies. One is daratumumab and the other is isatuximab. And you know, in my mind they're kind of interchangeable in terms of efficacy. So at first relapse, I think again, I think this situation depends on what you're relapsing off of. I think if you've not been exposed to a CD38 monoclonal antibody, it's the it's a great place to introduce that. What you pair that with I think will again depend on what you were on before. Daratumumab versus isatuximab, I think interchangeable. Some of the things that really go into that may be the schedule of how it's given, even the mode of administration.

So for example, daratumumab is available in an injection, a subq form, which can be really easy because you know, there are some observation periods and there's a ramp up dosing. So it could be a little bit more visits upfront in the clinic, but eventually it's just a five minute shot once a month. Versus a drug like isatuximab, which you have to still 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 may be not be a big deal to just get two IV drugs at the same time. So I think that there's again, patient factors, what the treatments are being kind of given in combination with them make a difference.

Sarclisa (isatuximab) is currently FDA approved for intravenous infusion in combination with other drugs for treating multiple myeloma, subcutaneous administration of Sarclisa via an on body delivery system is currently under investigation and is not yet FDA approved. Studies are exploring the potential benefits of subcutaneous Sarclisa delivered through an on body delivery system, suggesting potential for improved patient convenience, reduced clinic time, and comparable efficacy and safety to IV administration. A phase three trial indicated non-inferiority of subcutaneous Sarclisa delivered by the on body delivery system compared to IV Sarclisa, supporting the potential of this delivery method without compromising patient outcomes.

If a patient is refractory to daratumumab, could isatuximab be considered? Sometimes we do do that. But oftentimes you wind up switching to partner drug as well. So if you're refractory to a daratumumab based combination then let's say you were on a dara rev based combination. You might switch to isatuximab carfilzomib combination. So it's difficult to say whether it's the carfilzomib doing the work, or isatuximab doing the work. I think they're more similar than different. So, It wouldn't be the sort of the top choice of, medications that I would pursue. I would probably, focus in on other modalities in that scenario.

We are looking into, if you don't respond to daratumumab are you going to get any benefit from isatuximab are they interchangeable? And again, you know, we're not going to have head to head data or anything that tells us that that looks at that. But I think that, again, I kind of use them interchangeably. And so if you're not responding to a CD38 monoclonal antibody in general, unlikely that you're going to respond just to a different, you know, formulation of it, so to speak.

If daratumumab was part of induction, could it be considered at first relapse in which patients would benefit from it? More and more although you know, for for quite a number of years after dara was approved, it was mainly used in the relapsed refractory setting. And 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 quadruplets, treatments that are showing promise.

So the question you're asking is if somebody has already gotten daratumumab in the front line treatment and then say, two, 4 or 5 years down the line, the 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 no, I would say that the one class of patients I would consider certainly is 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. 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 treatments targeting CD38.

If it's a patient who has been on daratumumab throughout and while on daratumumab, their disease progress, I'd be less inclined to consider, you know, more daratumumab as part of their second line treatment in that situation. These days it should be fairly standard for individuals to receive anti CD38, treatment approaches in the first line setting. So, either daratumumab. Revlimid, Velcade, dexamethasone or daratumumab or isatuximab, carfilzomiab, Revlimid, dexamethasone. And then a subgroup of individuals should probably be getting these in the maintenance setting as well.

So at relapse it really just depends. What have you been exposed to in the past. If you are not have not yet been exposed to the anti CD38 monoclonal antibodies, then a combination with anti CD38 directed monoclonal antibody is appropriate together with pomalyst or with carfilzomib. If you have been exposed to those elotuzumab, pomalidomide combination is probably a reasonable approach or elotuzumab lenalidomide combination.

If you're on lenalidomide only and you know, in my practice approach there is if you have biochemical progression that seems relatively indolent, then elotuzumab with lenalidomide, seems to be, quite efficacious and very, very well tolerated. Daratumumab and isatuximab, anti CD38 antibodies are now moving into frontline therapy. So those quad combinations of anti CD38 plus Revlimid, Velcade, dexamethasone are very commonly being used. And those combinations are very effective. They do show higher response rates than the Rvd triplet. And they show deeper responses. And the current data suggests that when done in sequence with autologous stem cell transplant and maintenance therapy, there's very good outcomes.

What we don't know is whether using, dara or isatuximab in the frontline setting then negates their use later. So for example, if somebody is on, revlimid maintenance only after they have their transplant. So it may be years before they need another line of therapy. Can we still use, an anti CD38 monoclonal antibody in that setting? That's really an unanswered question. We don't know. I think there needs to be, more research into the application of anti CD38 after people who have had revlimid maintenance only from their frontline therapy.

Now, the flip side, obviously, if somebody is getting a CD38 or CD38 combo as maintenance and they relapse, then that negates the utility of of a CD38 antibody in that setting. So what are the other alternatives? Well, there's a couple, in the second line, people forget about elotuzumab, which is the anti SLAMF7 antibody. And unfortunately the available data suggests that is less effective if it's delivered after anti CD38 therapy. But it is not ineffective. So there is a subset of patients who respond well to elotuzumab even if they've recently had an anti CD38 antibody. So that's one option. And that would have to be given in combination with an IMiD drug such as pomalidomide for example.

In addition to that there's BCMA antibody drug conjugate. This is belantamab mafodotin, which is in the process of applying for re approval in the United States. And I believe it's already available in Europe again. And so this is a potential option if it is approved in second line therapy. But that's a big issue. So we'll have to see about that.

And other therapies are available for patients and second line therapy. But then we're getting into either second or third generation proteasome inhibitors such as carfilzomib or CAR T-cells which are cilta-cel not approved in second line therapy. There's a lot of interest in novel monoclonal antibody targets. Many of them do not directly target the myeloma cells, but rather, help to do things like activate NK cells or activate antigen presenting cells to promote an immune response. But those are still in clinical trial, so we're not, unfortunately, those aren't available for general use.