An Overview of Treatment Options Available for Patients with R/R MM

dr Joshua Richter: Welcome to this Cancer Network, Between The Lines program. The article presented today is “Guidelines for Use and Dosing of Selinexor in Multiple Myeloma in 2021”, consensus from the International Myeloma Foundation Expert Roundtable. my name is dr Joshua Richter, I am Associate Professor of Medicine at Tisch Cancer Institute Icahn School of Medicine at Mount Sinai and Director of Myeloma at Blavatnik Family Chelsea Medical Center at Mount Sinai. And I am pleased to introduce my colleague, Dr. Peter Forsberg, who I’ll talk to about it. Peter?

dr Peter Forsberg: Thanks, Josh. I’m Peter Forsberg, Associate Professor at the University of Colorado, where I direct our Myeloma Plasma Cell Disease program. So, why don’t we jump into the discussion of this commentary, which I believe is a synopsis of practical guidance on how to use Selinexor based on current evidence?

dr Joshua Richter: I think at the beginning we’re going to talk about where the sequencing data is or how we’re going to approach sequencing in myeloma. Over the past decade, more than a dozen therapies have been approved for this disease, and more are on the way. The listings of the NCCN guidelines are in alphabetical order and do not necessarily direct us to treating patients at the bedside. So, Peter, I’m going to ask you the hard questions in a moment. How do you go about sequencing our different options with someone with a recurring disease?

dr Peter Forsberg: Of course, I think it’s one of the more complex issues that we deal with very often in day-to-day practice. The NCCN guidelines are intended to help create a variety of options, but as you mentioned, they don’t provide many truly discrete hierarchical structurings of options for providers to guide through their practice. I think, like most people, I consider a variety of factors to make an appropriate treatment decision, because when we talk about relapsed refractory myeloma, we’re obviously talking about a very broad set of scenarios. So I think in these circumstances we always think of early relapse a little bit differently than late relapse, we might think of relapse in older and younger patients a little bit differently. But certainly things like what previous treatments patients have received, whether they have been exposed to those therapies or have progressed on those therapies, have developed refractory to a treatment, what tolerance they have had to prior treatments, what their response and stability of disease control are had with previous therapies. Aside from which comorbidities may be most pronounced, are there things we specifically want to avoid in certain patients because of a history of renal insufficiency or cardiovascular disease, or compromised bone marrow function? So, I think all of that matters, but I think there’s a little bit more diversity than we can really grasp even with these kinds of open-ended questions. So I think it’s still one of our more complex scenarios, even though most of us have some sort of guiding principles for the therapies that we’re going to apply more early in the disease course and later, partly based on approvals but also based on efficacy and tolerance profile.

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dr Joshua Richter: I can only agree with that. I think there are tons of debates, tons of studies going into this, but we don’t have a clear answer. I think a lot of us are using things like VRd, Dara VRd or KRd-like therapies early on. A lot of patients stay on some kind of maintenance therapy, either with or without a transplant, and then a lot of patients see progression in early lines, we’re still using a lot of Dara-based therapies or CD38 antibody-based therapies, things like Dara and isa/pomor Dara and isa/car early. Then, after going through the big food groups, IMiDs, PIs, and monoclonals, we reach for some of the newer MOAs like selinexor, like belantamab – mafodotin, which we’ve been looking at for a while, melflufen, although that’s not currently on the market, and are also now looking for things like CAR-Ts and biospecifics. And along those lines, I mentioned Selinexor as one of those therapies. I’m just wondering what your experiences have been with Selinexor. Are there specific patients or times that you bring selinexor into play?

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dr Peter Forsberg: I ​​think that’s a good question. I think as you mentioned the most common scenario is that we’re dealing with patients when they’re second line, when they’ve typically been on triplets or quadruplets, often with something like lenalidomide maintenance therapy. So you typically start in the second row with resistance to at least one drug and exposure to some of our core therapies. By the time patients entered second-line therapy, they usually had significant exposure to a CD38 monoclonal and probably one to two proteasome inhibitors and immunomodulatory agents. And I think at this point when you move into the 3rd to 4th line of therapy selinexor becomes a real consideration, it’s a therapy that has a different mechanism of action, it fits well together like I think we’re going to discuss a little , with other agents, this gives you a certain variety of options. And it may be available in an earlier line than some options like CAR-T or biospecifics in the very near future. So I think this is the time period and disease progression that I start to think about selinexor as an option. And consider what might be the best approach in terms of partners, dosage, and administration. But I think to talk about it, the best next step might be to get into the mechanism of action. It is unique compared to some other remedies we use.

dr Joshua Richter: Absolutely, let’s get straight to that. So, selinexor is a SINE, a selective inhibitor of nuclear export. What does that mean? And basically I call myself, at least as I conceptualize it, and I have to admit that I’m not a scientist, a chemotherapist, so I have to break it down to my level. Our body produces cancer cells 24 hours a day, and our body also has these mechanisms to kill cancer cells, we target cells for programmed cell death, apoptosis. But sometimes the cells don’t want to go through that and when you get a cell to undergo apoptosis you get a signal that travels to the nucleus and then in the nucleus you get a cascade of events, A, B, C, D, E, and this cascade leads to cell death. But the cancer cells get smart and say, “Wait a minute, I want to bypass this,” and the way to bypass that is to kick out part of that cascade, so let’s take C. Let’s kick C out of the nucleus , and it’s going to eject it out of the nucleus through these little holes in the nucleus called XP-L1 or exportance, and when it ejects it out of the nucleus, the cell is attacked for cell death, you get your A, your B, but um, it there is no C, so the cascade does not continue and the cell does not die and the cancer cell multiplies. What selinexor does is is a selective inhibitor of nuclear export, it blocks these XP-L1 channels and thus prevents the cancer cell from expelling part of this cascade and then ultimately the cell leads to death.

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dr Peter Forsberg: I ​​have to say I’ve never heard it described like that before, but I think that’s a great description, I think that’s a really down-to-earth, thoughtful way of discussing how this mechanism can be unique and who Disrupting the apoptosis bypass that cancer cells depend on. So definitely a unique mechanism that can both translate into a unique potency profile, but also have some impact on some of the toxicities and side effects that we are dealing with and working through.

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