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


Opening their discussion on relapsed/refractory multiple myeloma, Joshua Richter, MD and Peter Forsberg, MD review options for treatment sequencing, initiating treatment, and the mechanism of action for selinexor.

Dr. Joshua Richter: Welcome to this Cancer Network, Between The Lines program. Today's featured article is Guidelines for Use and Dosing of Selinexor in Multiple Myeloma in 2021, a consensus from the International Myeloma Foundation Expert Round Table. My name is Dr. Joshua Richter, I'm an Associate Professor of Medicine at the Tisch Cancer Institute Icahn School of Medicine at Mount Sinai, and the Director of Myeloma at the Blavatnik Family Chelsea Medical Center at Mount Sinai. And I am pleased to introduce my colleague who I'll be discussing this with, Dr. Peter Forsberg. Peter?

Dr. Peter Forsberg: Thanks, Josh. I'm Peter Forsberg, I'm an Associate Professor at the University of Colorado where I'm the lead on our myeloma plasma cell disorders program. So, why don't we jump into discussing this commentary which I think is a review for practical guidance around the use of selinexor based on current evidence?

Dr. Joshua Richter: So, kicking things off, I think we're going to talk about where the sequencing data is, or how we approach sequencing in myeloma. There have been more than a dozen approvals of therapy for this disease across the last decade, and more coming and on the way. The NCCN guidelines' listings are in alphabetical order, and it doesn't necessarily guide us in how to treat patients at the bedside. So, Peter, I'm going to ask you the hard questions right off the bat. In someone who has relapsed disease, how do you approach sequencing our different options?

Dr. Peter Forsberg: Obviously, I think it's one of the more complex issues that we deal with in very common day-to-day practice. NCCN guidelines are there to help create a variety of options, but as you mentioned, they don't give a lot of really discrete hierarchical structuring of options for providers to guide through their practice. I think, like most folks, I use a variety of factors to consider when deciding upon appropriate treatment because obviously when we say relapsed refractory myeloma we're talking about a very broad group of scenarios. So, I think in that circumstance, we're always considering early relapse a little bit differently than late relapse, we're thinking about relapse in older and younger patients potentially a little bit differently. But certainly, things like what prior treatments patients have had, whether they've been exposed, or developed progression on those therapies, developed refractoriness to treatment, what tolerance they've had of prior treatments, what response and stability of disease control they've had with prior therapies, as well as which comorbidities may be most pronounced. Are there things we specifically want to avoid in given patients given that they have a history of renal insufficiency or cardiovascular disease, or limited bone marrow function? So, I think all of those things kind of factor in, but I do think there's a little bit more diversity than we can really pin down too with these types of open-ended questions. So, I do think it represents one of our more complex scenarios still, even if most of us have some kind of guiding principles for the therapies we're more likely to use earlier in the disease course, and later, partly based around approvals but also based around efficacy and tolerability profile.

Dr. Joshua Richter: I couldn't agree more. I think there's tons of debate, tons of studies looking into this but we don't have any clear answer. I think a lot of us are, early on, up-front, using things like VRd, DARA-VRd, or KRd-like regimens. Many patients remain on some type of maintenance either with or without a transplant, and then a lot of patients see progression in early lines, we're using a lot of dara-based regimens still, or CD38 antibody-based regimens, things like dara and isa/pom, dara and isa/car early on. Then, after we've gone through the major food groups, we've gone through IMiDs, PIs, and monoclonals, we start reaching out for some of the newer MOAs like selinexor, like belantamab – mafodotin, for a while we were looking at melflufen, although that's not currently on the market, and now also looking for things like CAR-Ts and biospecifics. And following along those lines, I did mention selinexor as one of those therapies, I'm just wondering about your experience about when you bring selinexor, are there certain patients or times when you bring selinexor into the fray?

Dr. Peter Forsberg: I think it's a good question. I think that, as you mentioned, the most common scenario is that we're dealing with patients by the time they're in the second line they've usually been through a triplet or a quadruplet therapy, often with something like lenalidomide maintenance. So, you're usually starting in the second line with at least one agent refractoriness, and exposure to a couple of our core therapies. By the time patients have gone through second-line therapy, usually you had substantial exposure to a CD38 monoclonal and probably one to two proteasome inhibitors and immunomodulatory agents. And I think at that point when you're moving into the third to fourth line therapy is when selinexor becomes a real consideration, it's a therapy that has a different mechanism of action, it partners well, as I think we'll discuss a little bit, with other agents, that gives you some diversity of options. And it's potentially available at an earlier line than some options like CAR-T or biospecifics in the very near future might be. So, I do think that's the time period and disease course where I'm beginning to think about selinexor as an option. And considering what the best approach to it in terms of how to partner it, how to dose it, how to manage it, might be. But I guess, to talk about it, getting into the mechanism of action might be the best next step. It is a unique one in comparison to some of the other agents we use.

Dr. Joshua Richter: Absolutely, let's dive right into it. So, selinexor is a SINE, a selective inhibitor of nuclear export. So, what does that mean? And basically, at least the way I conceptualize it, and I have to admit I'm not a scientist, I call myself a chemotherapist, so I have to break it down to my level. Our body makes 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 undergo that, and when you trigger a cell to undergo apoptosis, you get a signal that travels to the nucleus, and then inside the nucleus, you get a cascade of events, A, B, C, D, E, and that cascade leads to cell death. But the cancer cells will get smart and they'll say, "Well, wait a minute, I want to get around that," and the way to get around that is to kick out one part of that cascade, so, let's take C. Let's kick C out of the nucleus, and it'll kick it out of the nucleus through these little holes in the nucleus called XPO1, or exportins, and when it kicks it out of the nucleus and the cell is targeted for cell death, you'll get your A, your B, but uh-uh, there's no C, so the cascade doesn't follow through and the cell does not die, and the cancer cell proliferates. What selinexor does, is it's a selective inhibitor of nuclear export, it blocks those XPO1 channels, so it prevents the cancer cell from kicking out part of that cascade, and then ultimately the cell will lead to death.

Dr. Peter Forsberg: I've got to say I've never heard it described quite that way, but I think that's a great description, I think that's a really down-to-earth, thoughtful, way to discuss how this mechanism may be unique and interrupt that evasion of apoptosis that cancer cells are so dependent on. So, definitely a unique mechanism that may translate into both a unique effectiveness profile, but also, may have some impact on some of the toxicities and side effects that we deal with and work through.

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