The Impact of Evolving Treatment Options in Multiple Myeloma, Part 8

Bruce A. Feinberg, DO: We started with how we got here and now we have had some of the realities of being here with the complexity of the day-to-day stuff like REMS and now we have the future. Joe, level-set us again. You mentioned one of the new agents just now as we were finishing that segment. Can we bucket what these new agents look like, so we have CD38, there is going to be more, but help us understand because as complex as it is, it’s not like it gets easier, it looks like it’s going to get even more so.

Joseph Mikhael, MD: Absolutely and there are lots of ways of giving the overview. I will keep it simple and try to put it this way. First of all, we have, if you will, next-generation drugs of the current main classes of drugs that we have now. Our 3 major classes of drugs are proteasome inhibitors, immunomodulatory drugs [IMiDs], and monoclonal antibodies. Historically, we have worked with bortezomib [Velcade], then we added carfilzomib [Kyprolis], and then ixazomib [Ninlaro]. For the IMiDs, initially we used thalidomide [Thalomid], then lenalidomide [Revlimid], and now pomalidomide [Pomalyst]. Lastly, in the monoclonal antibodies, we had daratumumab [Darzalex], elotuzumab [Empliciti], and recently we have added isatuximab [Sarclisa].

Those are sort of 1 pool. The second pool would now be entirely new mechanisms of action. We have introduced selinexor [Xpovio], which is an oral agent that blocks the expulsion of good tumor suppressors out of the nucleus, the XPO1 pathway, and it was used in triple class refractory myeloma but is now coming up earlier in combination. Following a similar pathway would be belantamab mafodotin [Blenrep], which we mentioned, which is a monoclonal antibody but also an antibody-drug conjugate. This is the first drug to target BCMA [B-cell maturation antigen], and then lastly old friend, new friend melphalan flufenamide [Pepaxto], or melflufen, which is a new delivery system of the melphalan alkylating drug that we have been using for 50 years in multiple myeloma. That’s the triple class refractory space that is still primarily used on their own, although I mentioned selinexor started to be used in combination. We expect the same in the other 2. Then the third and final category is the true new immunotherapies, which is at the top of the list right now, is CAR [chimeric antigen receptor] T-cell therapy. We have already had 1 approved in the form of ide-cel [idecabtagene vicleuce] a few months ago, and it’s likely we will have another one soon. Looking to the future and other immune approaches like using these bispecific antibodies, 1 that hooks on to the tumor and 1 that hooks on to a local T cell to engage it, so you don’t have to go through all the process of collecting T cells as we do now for CAR-T. It is changing every month. If we did this next month, I would be adding more to it, so it’s amazing that we have not only developed new versions of old drugs, we have come with a whole new mechanism of action and now new ways to leverage the immune system.

Bruce A. Feinberg, DO: Ryan, you’re at an institution [Winship Cancer Institute] that is a known myeloma center. How does it work with all this? You just had a clinical trial for every one of these and everyone is in a third salvage clinical trial. Once you have accrued one, do you just move on up to the next and keep moving through them? How are you adopting these? How are they seeing the light of day? Is there any of this that is going outside of a trial?

Ryan Haumschild, PharmD, MS, MBA: I think it’s a great question. We do accrue a lot in trials, I’ll be honest. One of the things we pride ourselves on is being the first to treat with innovative therapies and I think when we talk about some of those new BCMA agents a lot of those clinical trials were actually completed here at our institution [Winship Cancer Institute]. I think we got really great real-world data. A lot is going on. We are now figuring out CAR T-cell therapy and where that fits in, in terms of triaging patients through the relapse/refractory stage. I think that’s where a lot more of the innovations are coming in, with the relapse/refractory patient population. I will say when we think about some of these BCMA targeted therapies, they are starting to meet into our treatment right after someone had at least 4 lines of therapy, we are starting to include more now in our patient population, monitoring obviously for keratopathy but also really trying to continue our mission of treating it as a chronic disease and making sure we are extending lines of therapy.Then how do we start deciding between CAR T-cell therapy and some of these newer BCMA options? And where does selinexor come in even with side effects? I think in that relapse/refractory patient population is where it becomes a patient-specific conversation in terms of how can they tolerate the side effects, what is their fitness level for CAR T-cell therapy, or do we think they might be a great candidate to receive BCMA in an outpatient environment. That’s how the conversations are going right now.

It’s great for us because there is a lot of new therapies in that relapse/refractory patient population wherein the past it has been hard to treat patient populations, some of the patients would disband the therapy due to side effect management, so I am excited to see this. I think where we’re going to see it going is some of these relapse refractory medications joining with biospecifics and we’re going to see it moved in earlier lines of therapy. For us, what that means is we have a great standard of care options but now we also have other clinical trial options available for patients and we are actively enrolling in a lot of combinations between some of the medications right now.

Bruce A. Feinberg, DO: The low-risk patient is going to start with quadruplet and then go to transplant and then CAR-T, just so I understand how this is all going to work.

Ryan Haumschild, PharmD, MS, MBA: It’s a little more complex than that because once the patient has a response to D-VRd [daratumumab (Darzalex), bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone] then that’s great. If they have a response they can go to transplant again potentially, if they don’t you can use ixazomib, pomalidomide, and dexamethasone. It’s really patient specific, but I think once you transition past those 3 agents to your point there is a mix there as do they go to BCMA therapy for relapse/refractory and we use belantamab mafodotin, or do we use CAR-T? I think that’s where some patient-specific factors come in and then on top of that we are not doing it yet but I am really wondering where MRD [minimal residual disease] comes into play as you are that deep in the treatment. Not a perfect answer but I think that’s the general direction in where we are heading right now.

Bruce A. Feinberg, DO: I appreciate that because I am obviously pushing. Go ahead, Joe.

Joseph Mikhael, MD:: I was just going to say, to make it even more complicated we are doing clinical trials now where after induction therapy people are randomized to transplant or CAR-T, so there could be…

Bruce A. Feinberg, DO: That seems natural to me.

Joseph Mikhael, MD: Absolutely. There could be a time that we supplant the current transplant with one big whopping dose of melphalan to actually CAR-T upfront because we are seeing responses to CAR-T even though I mentioned all those drugs in parallel. Our response to CAR-T both in depth and duration of response is unprecedented in myeloma in those extremely heavily pretreated patients. It’s a step…

Bruce A. Feinberg, DO: What would you do earlier on?

Joseph Mikhael, MD: It can happen early on but we are testing that to see, and we are already seeing that it’s feasible and it may well give an even deeper more durable response. To add to your earlier point, the reason why I mentioned it here is one of the greatest benefits of CAR-T at least right now is the way we are giving it. It is really a 1 and done treatment. It may be particularly costly upfront but some of the great benefit that patients are receiving is that we are not generally giving maintenance therapy after CAR-T. They are in that drug-free zone and on my favorite drug: nada. And they love it, very compliant, the price is good, copay is excellent, side effect profile is good. I say this tongue-in-cheek but it is amazing to us how many of our patients now have been able to go 1, 2, maybe even more years on no therapy after CAR-T. That is a bit of a taste of maybe what the future of myeloma could look like.

Transcript Edited for Clarity