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Published on July 30, 2021
An Overview of Multiple Myeloma Treatment Options
In this excerpt from a recent Dinner with the Docs program, hosted in partnership with Mount Sinai Cancer Center, Patient Power co-founder and patient advocate Andrew Schorr talks to two experts about first-line treatments for multiple myeloma, combination therapies, and treatments on the horizon. They also discuss the lack of diversity in the treatment landscape and how to overcome structural barriers. Shambavi Richard, MD, is an Assistant Professor of Medicine in Hematology and Medical Oncology at the Icahn School of Medicine at Mount Sinai. Josh Harris, MD, is a Hematologist-Medical Oncologist at New York Cancer & Blood Specialists. Keep watching to learn more.
Support for this series has been provided by Karyopharm Therapeutics. Patient Power maintains complete editorial control and is solely responsible for program content.
Transcript | Multiple Myeloma Treatment Overview
Andrew Schorr: Okay. And would you call out, what would you say is the most common first-line treatment? Denise was asking, what’s sort of recommended generally?
Dr. Richard: One of the most common combinations that I use for frontline therapy is this combination called VRd. "V" stands for Velcade or bortezomib, and "R" stands for Revlimid or lenalidomide. "D" stands for dexamethasone. That's a very standard upfront induction regimen for myeloma. There are some instances where you may tweak that, alter it slightly. For instance, some patients present with a renal insufficiency, in that case, maybe you don't want to use the len, upfront, and you want to maybe substitute the cyclophosphamide. That's a very common alternative to VRd called VCd or CyBorD, depending on what institution or who is talking to you about this combination of medications. And now the quart therapy is starting to come to the fore. We have some studies now substantiating that a daratumumab (Darzalex) added to a standard of care regimen, like the VRd, these quads are actually showing some really great responses as well.
Andrew Schorr: Okay. So, Dr. Harris, that means some people might take some pills and they also might have some infusion. Like, daratumumab is infused. And you could have infused Velcade or Kyprolis, carfilzomib, or you could have an oral proteasome inhibitor, right? And then the lenalidomide is a pill. So, there could be a combination, right?
Dr. Harris: Correct. It's a combination and even most notably with daratumumab, which traditionally was a very long initial infusion. As of recent approximately months ago or so there was a subcutaneous form which makes it a lot easier as far as delivery and treatment time for patients. So, it's a combination between them, but there's a lot of neat things about each individual therapy.
Andrew Schorr: Okay. A little bit about mechanism of action. So, for instance, we have two things I want to particularly ask about. Selinexor (Xpovio), my understanding is that works not on the surface of the cell, but actually goes into the cell, and then also maybe you'd come in on BCMA. What is BCMA? But let's talk about going into the cell. We hit the surface of the cell and now we're going inside the cell, right?
Dr. Richard: So selinexor has a very interesting mechanism of action. It's unique. There is no other drug like it on this entire slide. It's called an XPO1 inhibitor. So Exportin 1 is a kind of transport protein that works to transport certain things out of the nucleus, into the cytoplasm, and in doing that, that particular compound, that particular molecule loses its efficacy. Let's say there is a tumor suppressor protein. The job of the tumor suppressor protein is to stop a tumor from happening to put it simply. It works best inside the nucleus, so if something comes along and takes this out of where it should be and puts it out in a place that it shouldn't be like in the cytoplasm, it just loses its efficacy. XPO1 inhibitors like selinexor come into the picture, drag it back into the nucleus, retains it there so that it starts becoming effective again.
So that's one simple way to explain that that's how selinexor acts. It does the same for certain other oncogenes, you know, proteins that actually promote a tumor. So again, if they are moved out into the cytoplasm, they start transcribing the mRNA and starting to develop all these cancer proteins, but if you retain them in the nucleus, then they don't have an opportunity to do that.
Andrew Schorr: Okay. Now, another new drug is this Pepaxto, or melphalan flufenamide. And my understanding is that's delivering melphalan, which has been around for a long time, in a much more targeted way. Is that right?
Dr. Richard: Yeah. So, they work with certain enzymes, aminopeptidases, to actually target and internalize into the cell, so it's very targeted. One of the issues with melphalan when we've been using it for decades now, and it's like the drug for transplant, but as anyone who's had a transplant will know, aside from killing the tumor, it does a bunch of other things. It drops your blood counts, it causes GI toxicity, it causes mucositis. It does all of these things so there's a limit to how much melphalan you can give without causing some other off target issue. Melflufen is — the way it works is it internalizes into the target cell so that its activity is more focused on that cell. We'll see how well now it can be used. It's been newly approved and there's a lot of studies trying it in various combinations.
Andrew Schorr: Okay. And Dr. Harris, so BCMA, so we have this drug Blenrep (belantamab mafodotin), and so that operates in a different way. BCMA is a target on the myeloma cell, right?
Dr. Harris: Correct. It's a B cell mechanism antigen where it's combined with a T cell type of therapy, and that in itself, after infusion is targeted to the actual CAR T-cell, Chimeric Antigen Receptor for T cell has been the new wave of a lot of myeloma therapies, and just as a recent approval, it showed remarkable responses, upwards [of], I think it was 76% or so, which was an overall response rate that was remarkable from that standpoint.
Andrew Schorr: Dr. Richard, so with adding CAR T, where are most people going to be? Will most people get to this newly approved, but much more advanced therapy? And I mean, advanced down the road CAR T, or are they going to be with this group may be more at the top, the groups, the four groups at the top, or maybe adding Blenrep? In other words, can these work for quite a long time, do you think now?
Dr. Richard: So as in any new drug approval in myeloma, we start with that patient who's had everything else, 6, 7, 10, 12 lines of therapy, and then we try this new thing. One of the wonderful things about CAR T is in that kind of patient, it has kind of proven its worth in that we're able to put remissions for, put patients in remissions for many, many months at this point, without needing any additional therapy. Which itself is like a big plus because most myeloma patients tend to stay on some drug or the other for long periods of time. So having that good holiday that lasts for maybe a year or two is a big plus.
So then what happens is then we start moving it earlier and earlier into the therapy to find out how best can we use it, and we are in this learning phase now with CAR T. So, there are various different trials going on for patients who are high-risk, which is one of the most difficult group of patients to treat. Patients who have failed very quickly after an autologous transplant for high-risk patients, as a randomized versus an autologous transplant and trying to figure out exactly where it fits into this whole milieu of myeloma treatment, is where we are in research with CAR T.
Andrew Schorr: So in the New York area, having grown up there, I know there is a great diversity, ethnic diversity, and Dr. Harris, I want to ask you, among in this diversity of the New York Metro area, does myeloma affect different populations differently? Or does it show... Or do people get access to care later? Or what are the concerns you have about diversity in myeloma?
Dr. Harris: Well, I think the latter of that really kind of points to it as far as the access to care and depending on where you reside, I think that that also creates a little bit of a barrier as far as when patients are able to get the care or recognize. Fortunately, being a community oncologist, a lot of what we do is pretty much out in the community. We make the referrals, so Dr. Richard or so, but I think a lot of it is making sure that some of these communities, which may not have a lot of the resources really have exposures and access to have the appropriate workups and establish a diagnosis. You know, from that standpoint, I think that with time, things are steadily improving, but I can speak for within the African American population, it definitely is one in which some of the demographics or some of the localities may be a little difficult to access. And because of that, that does end up having patients present with later stages of disease or misdiagnosis.
Andrew Schorr: So, Dr. Harris, what we've been hearing between you and Dr. Richard in discussing sort of the complexity in myeloma today, is this really what binds you with a sub-specialist like Dr. Richard? How do you have your patients out there on Long Island get optimal care? What do you tweak? How long do you do maintenance? Is that the kind of dialogue that goes on?
Dr. Harris: That's the bulk of the dialogue and thank goodness for people like Dr. Richard who is there to support. The beauty of oncology and everything that we do in the community setting is that things change so rapidly, so it's really nice to have the opportunity and the coordination between the programs, things like autologous stem cell transplant. Unfortunately, we can't do here as a local community-based practice so it's, I think hand in hand, when it comes to delivering care like that, there's been many patients that get very intensive therapy in the city, go to either clinical trials or whatever have you in that particular setting, and then when they are finished with their induction therapy, autologous transplant, or CAR T, we monitor for cytopenias, or we monitor just to make sure that the patients are doing it. It's much easier to do that closer to home, so I think that the most important thing is to understand that, I think good care in many facets really deserves to be as close to home as possible when feasible. And I think that that's an important part.