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First and Second-Line Treatment Protocols for Multiple Myeloma

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Published on August 24, 2021

Multiple Myeloma Experts Explain the Treatment Classes

Listen in as Alfred Garfall, MD, and Edward Stadtmauer, MD, from Penn Medicine talk to host Cindy Chmielewski about the different classes of treatments that are available to individuals with multiple myeloma. This includes an overview of second-line treatments, therapies suitable for patients who have relapsed, and a discussion of whether an intensive first line of treatment is effective for long-term results.

Support for this series has been provided by Karyopharm Therapeutics. Patient Power maintains complete editorial control and is solely responsible for program content.


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Transcript | First and Second-Line Treatment Protocols for Multiple Myeloma

Cindy Chmielewski: And you must've read Margie's question because she wanted to know, should we be adding [daratumumab] (Darzalex) or Kyprolis (carfilzomib) up front to get that deeper remission? Or should we be saving that for later on, in relapse? Do we use it upfront, or do we wait later on? And Dr. Garfall, in a minute or two, can you answer that great debate?

What Is the Difference Between Using a Drug in a First-Line or Second-Line Setting?

Dr. Garfall: Yeah, that is the million-dollar question. And, you can come up conceptually with the reason why one or the other answer might be true. You could say on one hand that we need to beat these things over the head as hard and fast as we can and try to kill every last one of them in the first line of therapy and keep all those therapies going for as long as we possibly can. And then as we get more and more drug we shed 4, 5, 6 drugs and make these really intensive first-line therapies. And look, that's how the pediatricians have managed to cure acute lymphoblastic leukemia in 85% of kids. You know, it was by over the years as we get new drugs that are active [and] learn to combine them in safe ways as part of a really intensive first line of therapy.

On the other hand that is going to add up in terms of toxicity for patients, even these really well tolerated drugs, as we add more and more into the first line of therapy there is more toxicity and risk associated with that. And it's possible that you just get the same type of long-term outcome if you use them in more bite size combinations. If that Revlimid (lenalidomide), Velcade (bortezomib) and dexamethasone (Decadron) together can give you a really good response and 95% of initial patients, maybe just go with that for most patients and use daratumumab and Kyprolis in later lines of therapy. And you can tell oftentimes in the first month or two of therapy, whether maybe someone's not having the type of response that we'd like to see to Revlimid, Velcade, dexamethasone and then you can add in, daratumumab just to those patients. And so that, really, I think is the question. And as Ed mentioned, we've been through that story, comparing doublets and triplets. And so I think we now know from big clinical trials that is better in most patients to use a triplet, not just for the early response, but for the long-term outcome. And the question is, how far does that go? And I don't think we know for sure the answer quite yet.

Cindy Chmielewski: We still have studies and if we could get the next slide out, if Dr. Stadtmauer thought the last slide was busy, he's really not going to like the next slide. See, I told you, you were not going to like this one, but in a way it's exciting to me because it is so busy. Most of these drugs were not on the slide when I was diagnosed back in 2008. And we talked a little bit about the proteasome inhibitors and the image and the monoclonal antibodies. Can we just briefly talk a little bit about these newer mechanisms of action? Like what is selinexor (Xpovio) and can you just explain how that works and how's it different from the other ones and why should we be excited. In a minute Dr. Stadtmauer because we're really overtime, and we have to go to break.

Dr. Stadtmauer: I was hoping you were going to ask Al.

What Are the Protocols for Using New Treatments Like Monoclonal Antibodies?

Dr. Stadtmauer: Alright. So, we've talked about proteasome inhibitors, which are really key, and immunomodulatory agents. And as you can see, we have got three of each and each one's like a different generation. And what's really nice is that if one stops losing its activity frequently, the next generation will work for a subset of those patients. And in fact, one of the key thoughts when I have people who relapse their disease is different combinations of the same medicine sometimes that you've had in the past but giving them in different combinations can actually lead to nice responses because it's a synergy. So I think of each combination as a different drug, more so than each drug individually. And then we talked about the monoclonal antibody, the daratumumab that we were talking about, but there's two others. There's elotuzumab (Empliciti), and there's cetuximab (Erbitux).

They all are latching on to surface proteins on the abnormal cells. So those are the big three, proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies. But, the medical research hasn't stopped there, there's a whole bunch of other ways of doing it. And in fact, and this selinexor that you were talking about is one of the first in class, it's called a nuclear transport protein inhibitor. And it's really cool from, again, somebody who's been doing this for a long time, and took biology and molecular biology probably like 40 years ago. And all of that stuff that I learned in college has really been used to make all of these great drugs. And as you know, a cell has a nucleus and then around it is the cytoplasm, and the nucleus is where things are produced and what keeps the cell alive.

And then the cytoplasm does what's happening. Well, it turns out that, if you can stop... And there's stuff that builds up in these tumor cells and for tumor cells to live, they have to be able to metabolize and get rid of these waste products that build up. And a lot of these medicines, and selinexor is one of them, is it stops the release of the waste products. And so they just keep building up in the nucleus and the cell chokes on it and dies. And so, the selinexor pill was one of the first in class. And in fact, your doctor, Dr. Vogel was in charge of the development. He did the study that got this FDA approved, and it's a really cool medicine. And it's a first in class and I expect we're going to see lots of different... And again, by itself, it's probably not the answer to many things, but if you start combining it with other medicines, we see beautiful responses.

So, that's one of the newer medicines. There's that melphalan flufenamide (Pepaxto), or melflufen, which is sort of a weird targeted melphalan like medicine that was just FDA approved and seems to be causing responses even in people who have a lot of prior therapies. And of course, I don't know if we're going to spend… Are we going to talk more about CAR T-cells after this?

Cindy Chmielewski: Yeah, we'll talk more about that.

Dr. Stadtmauer: Well, I'm not going to say anything about that. What I was going to say though is, as you can see in that class of monoclonal antibodies, the elotuzumab, the daratumumab, what I call them are naked antibodies, or they're just the antibody by itself, latching onto the tumor cell and exploding it. But, now what we're doing is we're using the same targeting mechanism of an antibody, but we're making it even more potent. And one of those examples is the one that you have there, belantamab mafodotin or Blenrep, which is just an antibody just like Elo, just like Dara, it's directed against a thing called BCMA, the B cell maturation antigen. But in addition to being an antibody, it's got latched onto it some chemotherapy. And what I always say is it's like a scorpion, you drip it in, it finds its way to the myeloma cell and then injects just into the myeloma cell, this chemotherapy to explode the cell. And it's really remarkable. It's remarkable technology that has actually been put into a drug. And it's those really innovative new therapies that are the current subjects of investigation, or just starting to be FDA approved.

Cindy Chmielewski: That's what's exciting to me is all these new mechanisms of action like you were talking about, the antibody drug conjugates, and we don't even have time to even give CAR T-cell it's justification here. We'll probably need to do that after break. I mean because that's a whole new way.

Dr. Stadtmauer: And I'd figure we'll leave that for Al to talk about.

Cindy Chmielewski: Maybe we could answer a quick question. Can a person start maintenance therapy when they're in a very good partial remission or do they need to be in a full remission to start maintenance therapy? And what is the recommended and how long? Dr. Garfall, do I have to be in a complete remission? Or is it VGPR (Very Good Partial Response)?

Can a Multiple Myeloma Patient Start Maintenance Therapy During Partial Remission?

Dr. Garfall: How many hours do you have now?

Cindy Chmielewski: We only have 10 seconds. So, it's a yes or no.

Dr. Garfall: That's an easy one. So no, there's not a requisite response to start maintenance therapy. The idea of maintenance therapy is that you're already in a response. And while again, for research purposes, you might parse a partial response from a very good partial response. The main thing that we care about for our patients is whether the disease is under control, meaning whether or not it's growing and at the level it is, whatever level that is partial response, very good partial response, is it causing problems? And as long as the disease is at a level where it's not causing active problems and it's not growing, we're satisfied with maintaining that level of the disease. And so that's perfectly acceptable to start maintenance therapy in that condition. You don't need to go on additional therapy to get into a better response before starting maintenance therapy.

Cindy Chmielewski: Because that's what happened to me. I was just hoping that we did it the right way. So we did.