Can you give a brief description of some of the challenges as it relates to the different prognoses for patients with their third relapse, fourth relapse, and fifth relapse and why with those differences—in terms of prognosis over time—it’s so important that we have some of these new options, specifically BCMA-targeted therapies, specifically CAR [chimeric antigen receptor] T-cell therapies and BiTEs [bispecific T-cell engaging antibodies] where you see the field evolving for these patients that have fewer options up to that point.

One of the things we see, at least in the United States, is that most patients don’t get beyond third or fourth relapse. Part of that is there’s a subgroup that does so well with the RVD [lenalidomide, bortezomib, dexamethasone] and daratumumab that they die 20 years later of something else. But for the unfortunate people who get to this position where the therapies have taken a toll on their marrow, they’ve taken a toll on their physical and emotional state. It’s not always easy to get levels of drugs into somebody that they can tolerate and that can control the disease. One of the big hopes of BCMA-targeted therapies is that they tend to have a little different adverse-effect profile from some other drugs.

As you said, we’re excited and hopeful about the realm of CAR Ts that we have approved; a number of them are on the way. There are two main classes. One is the bispecifics, of which there are a couple of exciting drugs, both BCMA-based bispecifics like teclistamab and then some other non-BCMA–based bispecifics like talquetamab and cevostamab that target GPRC5D and FCRH5, respectively. The cell mods, the next-generation IMiDs like iberdomide. The big challenge is going to be moving forward. Now that we have even more tools at our disposal, how do we optimally pick them? The way you said at the beginning is perfect. It’s so underestimated how individualized the approach needs to be for a specific patient. The biggest challenge is what to give when. What do you think?

You summarized that very well. Where are the different BCMA-targeted therapies going to fall out? The bispecifics are off the shelf. The CAR Ts requiring some bridging. [We need to have] some of these immunotherapies that target something other than BCMA, because within a year or 2 we’re all going to have many patients post-BCMA–targeted therapy. That’s going to be a new group of patients with a lot of different needs. The next year or 2 in myeloma is going to be about filling that space with compelling options. Ultimately, we’ll move some of these therapies earlier and aim, as we always do, for cures, which have been elusive, but hopefully we’re on the doorstep of being able to provide them for at least a subset of patients.

Any final things you want to bring up before we summarize and wrap up?

 No. You said it best in your most recent statement. Cure has been elusive, and there’s probably a small subset that we’re curing accidentally. Hopefully we cure more and more with intention with some of the drugs we have. Other than that, I thank everyone for tuning in.

It’s been a great pleasure for me. It’s always an opportunity to get to spend time with Dr Richter, a true expert in the field. I always like taking advantage of his wisdom. We were able to run through the landscape of relapse/refractory myeloma. We spent some time reviewing the newest anti-CD38 on the block, isatuximab, trying to figure out where we incorporate that. We talked about the benefits of daratumumab in combination with carfilzomib and the utilization of subcutaneous daratumumab. We spoke a fair amount about BCMA-targeted therapy, both the approved belantamab and the newest CAR T approach, as well as some forward-thinking discussion about bytes and newer CAR Ts to come. We mentioned melphalan as a novel alkylating agent and spent quite a bit of time on selinexor, both its initial approval and even more so in the BOSTON data, specifically highlighting the novel mechanism of action, the more tolerable adverse-effect profile with appropriate supportive care for patients who need a drug that works differently. I remain optimistic about the future for myeloma.

I really thank Dr Richter for his time and appreciate getting to do this with him. I hope that everybody enjoyed and learned something.

Videos

Key opinion leaders remark about recently approved therapies and exciting future treatment options for relapsed/refractory multiple myeloma. 

What’s Coming Next in Relapsed/Refractory Multiple Myeloma

We all confront patients who relapse, and then you have decisions to make in terms of what we’re going to use. I would say the average patient on first relapse has been exposed to some sort of triplet, a PI [proteasome inhibitor], an IMiD [immunomodulatory imide drug], and steroids. Some of them may have gotten a transplant. Many will be on some sort of maintenance. Nowadays some may have even had daratumumab as part of initial therapy. What factors do you consider when you’re looking at your relapse patients? Whether it’s aspects of their disease or aspects of their prior treatment, including whether they got daratumumab early. As you try to decide what to do next and maybe specifically, does mechanism of action play a role on some of those decisions?

 Absolutely. We always live by the mantra of the 3 determining factors: patient-related factors, treatment-related factors, and disease-related factors. The patient factors: Are they old, young, fit, or frail? Are there comorbidities? Disease-related factors; high risk cytogenetics, extramedullary disease, biochemical or aggressive relapse? The treatment factors: Do they have residual neuropathy from previous therapy? How did they respond or tolerate other therapies? This all gets mangled together, and we look through our own lens of how to interpret it. MOA [mechanism of action] plays a big role, and 1 of the biggest roles to me is the CD38 SLAMF7 conundrum that I wrestle with a little, that drugs like elotuzumab use NK [natural killer] cells to kill myeloma. NK cells express CD38. If you’re coming off a CD38 therapy like isatuximab or daratumumab, you have a reduced complement of NK cells, although they have a little more active profile. There are still fewer of them. I give elotuzumab prior to a CD38 if I can. Apart from that, it’s just thinking about all the factors we talked about. Do any big factors stand out in your mind?

I agree with that approach. I try to de-stress some of the decision-making with patients. I tell them it’s not this vs that; it’s now vs later. Whatever we decide we’re not going to use now goes into the follow-up group. I agree in terms of the struggles with elotuzumab. You almost have this use-it-or-lose-it thought in which you can try it late, but if it’s going to work, it’s more likely to work before daratumumab, but daratumumab is the more active monoclonal. In a high-risk aggressive relapse, you don’t want to play around with your less-good option. That’s a drug that takes a lot of wrestling. If you choose your best job first, and they’re coming off an IMiD and you want to switch classes, if there are adverse-effect–related reasons like neuropathy, GI [gastroenterology]–related problems with oral drugs, or access issues with medicines like carfilzomib. You did a good job summarizing it, and there’s a little creativity there. There’s no strict algorithm that we can broadcast. But there are no wrong decisions as long as you’re using highly active combinations because the other drugs are there for you should it not work out well.

 Let me throw out a loaded question. We’ve hinted at the notion of high-risk cytogenetics. But what about biologically high-risk patients who do well with induction? You put them on some type of maintenance with or without a prior transplant, and 6 months later they’re exploding. Do you have any approach? Is it time to bring in new mechanisms of action as opposed to just another generation IMiD or mAb [monoclonal antibody]? Is this a place for selinexor or belantamab?

That’s a really good question. I talk to my patients a lot about this because we all focus on the FISH [fluorescence in situ hybridization] and the genetics initially, and those are pretty good predictors of aggressivity of disease and time to relapse, etc. But as I sometimes explain to my patients, there’s no better predictor in terms of how things are going to go than how things go. If the disease relapses early or if it relapses aggressively, if there’s a clinical relapse that’s profound, the disease is telling you something. It’s telling you that it’s acting aggressively. Whether you can identify the genetics behind it or not, it’s acting aggressively. Sometimes for high-aggressive disease, high-turnover disease, you might want to incorporate alkylators or chemotherapy drugs that work for cells that are very actively dividing. Certainly, if you get less than ideal benefit from drugs like PIs and IMiDs, then you probably aren’t going to get gangbuster results simply by shifting other PIs and IMiDs. Not that you would never try it. None of these are never rules. But those are patients you may want to incorporate, or I might want to incorporate something different, whether it’s an alkylate or a combination or simply using drugs like selinexor or different mechanisms of action, different approaches. Maybe those are patients I would consider earlier for clinical trials that might be available to patients earlier in the course of their disease. I consider those patients’ high risk. I try to get appropriately aggressive with them to get the best-possible results. How about yourself? How do you deal with the clinically high risk?

 All the same ways. Early involvement in clinical trials. I say the same exact things to my patients, that people who do good do good, and those are really important statements to live by. I completely agree. If you’re biologically demonstrating that you’re not doing well on an IMiD, just bringing in a next-generation IMiD isn’t the answer. Or if you’re not doing well on a PI, another generation PI is not the answer. Those are the times where moving to drugs like selinexor are further up in the paradigm to give a mechanism of action that the disease is not used to.

One thing that’s interesting is what we’re seeing with the STOMP study. A lot of other ways that we can give the new MOA of the SINE—selective inhibitor of nuclear export, like selinexor—we can give them with other partners. STOMP is showing us combinations with pomalidomide and daratumumab and all the drugs that we already use. For patients who are getting PI, IMiD, or all these combinations up front in the early relapse, if they haven’t seen pomalidomide but they blew through the IMiD PI very quickly, that might be a patient for selinexor-pomalidomide-dexamethasone, which we’ve used in a couple of patients. For what it’s worth, that selinexor-pomalidomide-dexamethasone regimen has been our go-to in patients with leptomeningeal disease. For what it’s worth, we’re seeing more of this extramedullary disease. Both plasma cell leukemia, CNS [central nervous system] and both selinexor and pomalidomide cross the blood-brain barrier. For those 1-off patients who have that horrible issue, that’s where we’ve been approaching them with those selinexor-based combos.

That’s excellent advice. We don’t have a ton of drugs that have good CNS penetration. We treat systemic disease, and we’re all seeing more of those patients. That’s an excellent point. Selinexor is even being studied in primary brain tumors because of its good CNS penetration. That’s an excellent thing to bring up for a very desperate patient population.

Factors to consider when choosing the optimal treatment approach after the first relapse of multiple myeloma.

Considering Patient-, Treatment-, and Disease-Related Factors in Myeloma

 We did touch a little earlier on the IKEMA study: isatuximab, Kyprolis [carfilzomib], dexamethasone. I don’t know if you have any thoughts about daratumumab vs isatuximab. Are they interchangeable? Are there patients you would give DKD [daratumumab, carfilzomib, dexamethasone] or isatuximab–KD [carfilzomib, dexamethasone]? Just general top-line thoughts.

As we referenced earlier, it’s a little tricky when we don’t have data on 1 and then the other. We don’t know if either can be a backup plan for the other. Some of the things I factor in—certainly these patients get daratumumab first in my practice because daratumumab has been around longer. I wouldn’t bypass daratumumab. The question becomes where do you put isatuximab? The way I’ve done it, to this point in my practice, is that as a general rule I’ll use daratumumab re-treatment. If somebody has failed daratumumab and lenalidomide and they’re going on some other treatment and it’s months later, I have no qualms going to daratumumab and carfilzomib. The patients who I think of as isatuximab first as opposed to daratumumab re-treatment are ones whom the IV [intravenous] treatment doesn’t bother. Meaning they have access already, or it’s not an issue for them to sit in the treatment room. Or they’re getting carfilzomib, so they have IV access already. That’s been a plus for patients. I’m going to use carfilzomib, and I want to use a CD-38 and they’ve already been treated with daratumumab. I get the advantage of a slightly different mechanism, a slightly different epitope, and that’s been the cluster of patients for whom I’ve focused on isatuximab. It’s reasonable to use it in all re-treatments after a washout. But the ones with carfilzomib are who I’ve looked at. One final point is that some people try to make these cross-comparisons among these studies, and we both know that can be very perilous. You see control groups doing very differently across these studies so I try not to do that in terms of my decision-making. How about you?

 I struggle at figuring out where it fits in. I did start a patient on the isatuximab–KD [carfilzomib, dexamethasone] regimen within the last week. She is a little older. She got daratumumab -Revlimid [lenalidomide] as up-front therapy and was on a low dose of Revlimid [lenalidomide]. When COVID-19 hit, she didn’t want to be on a parenteral therapy. I put her on IRD [ixazomib, lenalidomide, dexamethasone]. She was on IRD [ixazomib, lenalidomide, dexamethasone] during COVID. She relapsed. She went on elotuzumab-pomalidomide for a while and then relapsed, and I wanted to give her a Kyprolis [carfilzomib]-based regimen. It had been more than 6 months, so I put her on isatuximab–KD [carfilzomib, dexamethasone] this week. Apart from her, it’s an ongoing struggle. You bring up 1 of the most important points is: You can’t compare trial to trial. It’s hard to say this 1 works better or this is a different AE [adverse event] profile. They’re a different group of patients. As both drugs spend more time in the clinic together, we’ll work our way through this as a community.

James Hoffman, MD, and Joshua Richter, MD, discuss the IKEMA study, the appropriate selection of therapy, and the differences between various options.

Selecting Appropriate Therapy for Patients With Relapsed/Refractory Multiple Myeloma

 One of the things we touched on briefly and that I was hoping we could spend a little time on is the BOSTON study, which received approval at the end of 2020. It used the selinexor–Velcade [bortezomib]–dexamethasone regimen, and I was wondering if you could give us a little granularity about the study and big takeaway points.

We talked about some of this earlier, but let’s dive a little deeper. Selinexor has been a topic of a lot of conversation. With the initial data, there was a lot of back and forth about the role of the drug and its approval. Once we got approval, there was a quick pivot to use it because there was a realization that it would be tough to give on the twice-a-week schedule that you referenced earlier. The BOSTON trial provides a template to use this drug in a way that’s effective, and a subset of patients will get some meaningful benefit. Another nice thing is that it seems you’ll know quickly who’s going to benefit and who’s not, so you don’t have to drag people through a lot of treatment to know who’s going to benefit.

Based on the mechanism of action, there are certainly going to be other partners who are explored, and that may offer some additional potential. The way this evolved with this drug and its approval and pivoting to this different dose and schedule is unique. But for patients who’ve failed the IMiD [immunomodulatory imide drug] class, carfilzomib-daratumumab, and maybe even 1 of the other drugs that we’ve mentioned up to this point—like belantamab and some alkylators—there aren’t a lot of drugs that can induce remissions. Here you have a drug that in this combination is not very onerous to give. I’m appreciative that I have it, and I certainly use it in this group of patients. How about yourself?

 There are a couple of arenas that selinexor has the ability to shine. One thing we’ve learned from the STORM study and some patients on the STOMP study is that there’s activity of selinexor in patients who have progressed beyond CAR [chimeric antigen receptor] T-cell therapies. Although most myeloma centers like ours [the Tisch Cancer Institute at Mount Sinai], and other people I’ve spoken to haven’t yet given the commercial Abecma [idecabtagene vicleucel], we’re certainly going to in the coming months. Unfortunately, those people will eventually relapse, so it’s nice to know there are some data out there about drugs that work post CAR T.

In terms of using it earlier, it’s a more select group of patients. One of the nice things that was in the final publication in 

 and that was presented last year at ASCO [American Society of Clinical Oncology Annual Meeting] is some of the subset analysis from the BOSTON trial, looking at patients who are older, with some renal dysfunction and high-risk cytogenetics. That’s the grouping of patients we see in clinic, and there was an advantage there of the triplet. One of the big things for me, a lot of these studies have shown us and as you pointed out perfectly, is that 100 mg is too much. Maybe a person needs 80 or 60 mg. But we’ve all moved into this realm in which it’s better to give a dose-adjusted triplet than a full-dose doublet in an older, frailer patient to get those multiple mechanisms of action. Especially for people with high-risk disease, we give a selinexor-like drug. The other thing is for people who have lymphoma-like disease, there’s a good role because selinexor also has FDA approval in diffuse large B-cell lymphoma.

That’s a good point. For those watching this, there’s plenty you can read about some of the discussions related to this trial and the control grouping Velcade [bortezomib]–dexamethasone and what kind of bar that was to hurdle in patients that previously received Velcade [bortezomib]. I would say that there’s not much controversy. This dose in schedule is reasonable. It’s doable, and there’s a subset of patients—some of our sickest and most difficult to treat—that can have meaningful benefit. I certainly place it firmly in the group of usable drugs. I’m happy that we have it. You’ll get a somewhat wider array of opinions about how eagerly you reach for it from the cupboard, so to speak, and where you place it in order. As we get more information and time goes by and we incorporate CAR T, some of that will get sorted out easier.

Another thing that you brought up a couple of times is that there has been a real lead on this is in terms of managing the adverse effects and monitoring patients on selinexor with Velcade [bortezomib]. You mentioned the supportive care medicines that you use, and some of these patients are coming weekly for the Velcade [bortezomib]. Is there anything else that you do in terms of monitoring these patients or informing patients before they start?

 Absolutely. Apart from the GI [gastrointestinal] issues, there are 2 other things we try to keep on top of. One is that there’s some hyponatremia that we see with the drug. Most of it isn’t hugely clinically significant, but patients often come in with a sodium of 129, 128 mEq/L. We tell them to keep a bag of chips on hand. This way they can have a nice salt-heavy diet if we need to make that up. The other thing is that it can suppress your counts. More specifically, selinexor has a tropism for the megakaryocytes. One of the things we’re seeing—we see this more with the late-stage selinexor usage as opposed to early relapse usage—is thrombocytopenia. If you reach for it in the first 1 to 3 lines, you’re not going to have this as much. But if you use it the way we mostly use it toward the end of the road, patients seem to get hit hard platelet-wise, and we’ve really embraced the usage of TPO [thyroid peroxidase] mimetics for those advanced patients who have burned-out marrows or have heavy marrow burden. Mostly using romiplostim, if you look at the Epocrates guidelines, you start at 1 µg/kg and week by week ramp up to a max dose of 10 µg/kg. We’ve escalated quickly in some of these patients, giving them 5 µg/kg in 1 week and 10 µg/kg the next week to keep the platelets up, so we can keep them on schedule with drug and get them over the hump. Do you have any other tips to add?

No. That sounds great. I know we use some romiplostim even in patients on the STORM study. That’s good advice with a rapid ramp-up. That’s something I haven’t done, but it’s reasonable. I probably will start to do that after this discussion.

Experts in the field of multiple myeloma discuss the BOSTON trial, the study design, and the benefits of using selinexor in a patient after CAR T-cell therapy.

Analysis of the BOSTON Trial

 We’ll see if we agree on this one. We’ve got to find some controversy here, perhaps. I’m always, and I would imagine you’re the same way, we’re seeing lots of patients with myeloma all the time, some of them in circumstances where options are limited. I like having options. I like having the ability to be a little creative with new drugs and trying to get people better despite sometimes tall odds. I’m happy that we have melflufen [melphalan flufenamide] as an option. The challenges for me is we all know that alkylators work, and we use them in the treatment of our patients. This is a drug where, it allows you to use melphalan [flufenamide] in a novel way where you can get higher intracellular levels, specifically intratumoral levels, and at least in a test tube preclinically, get higher cell kill. The challenge for me, at least as it relates to these data, is it’s hard to know how much this adds to alkylators or even drugs like melphalan [flufenamide] itself, which are older and cheaper. It has a place. I’m interested to see as we get more data if this is a more expensive melphalan [flufenamide] that has a cooler mechanism of action, or whether it’s a true advance. I’m curious to hear what you think about all of that.

 The drug was only approved around 2 months ago, and we only got it on our formulary about a week and a half ago, so I’ve only written [a prescription] for it once. The one big issue with the drug now is that you need a central venous catheter to give it. For the patient, I put a port-a-cath in in anticipation of this drug, and then I explained that if this one doesn’t work, we can use that central access for later. There are ongoing studies. The PORT study is looking to, hopefully by the end of the year, we can start to give this peripherally. I don’t know the answer yet. I am hopeful that the science pans out and this is a better version of melphalan [flufenamide], but I think your skepticism is extremely well founded. We don’t know yet if this is just melphalan [flufenamide] in a new bow, or this is something really different. It needs to get out into the clinic more for us to really see.

: Got it. I know that we’re all very excited about the new world of immunotherapies with CAR Ts [chimeric antigen receptor T-cell therapies] and BiTEs [bispecific T-cell engagers], and a lot of us in the field are hopeful that there’ll be a migration in that direction even earlier in therapy. And we’re all excited to get the first approval this year for commercial CAR T within the myeloma space, after we’ve had commercial approvals in the lymphoma and leukemia space, specifically with ide-cel [idecabtagene vicleucel]. I know that you have active clinical trials up there in this arena. I’m curious to hear your take on how this first commercial approval for CAR T in myeloma is going to impact your management and where you’re going to look to use it.

: I’m excited about the approval. Because this is a new technology, we haven’t been able to give our first commercial Abecma [idecabtagene vicleucel] treatment just yet. As opposed to a new pill that gets approved, you turn the machines on the day you get approved, you ship the pill, with this there are a lot of inner workings both at the company and internally to make sure cells get shipped in the right way. Hopefully we’ll be getting our first patient on at the end of May, early June. For approval, you must have had at least 4 prior lines [of therapy]. There are a number of patients we have sitting in our clinics right now, you and I probably share a lot of these, who are not eligible for a clinical trial, not for a truly horrible reason, but because of the way trials are written. People who have low grade other malignancies, diagnoses like a stage I breast cancer last year that they were cured from; they’re excluded from trials. They have a creatinine level of 2.5 [mg/dL] and they’re excluded from trials. One of the things that I’m excited about is being able to provide this type of therapy for a patient who is not extremely sick but was otherwise not fitting criteria for trials. It’s going to bring a lot of those patients into the world, and we’re going to learn a lot more from it. What are your thoughts?

 I agree completely. We also haven’t been able to give it, I’m hoping in the not-too-distant future. It’s nice to have a commercial option because as you mentioned there are a lot of hoops to jump through to get patients on clinical trials, and sometimes you miss it by a couple of platelets, and it can be very frustrating. This is going to be a great option. Certainly, you can see some really deep remissions and patients who have been heavily pretreated, and there can be some durability there. I’m hopeful over time we’re going to see even more durability as the CAR Ts evolve and we get some newer options, and perhaps maybe we treat some patients earlier in their disease when the disease is a little more sensitive. But after you’ve been through 4 lines of therapy, we don’t have a lot of one-and-done treatments that can get some deep and somewhat durable benefit. I’m looking forward to being able to prescribe it at UM [University of Miami Sylvester Cancer Center]. I know a lot of patients out there are eagerly looking for CAR T options. It’s been a real hot topic in the clinic for quite some time, and it’s nice that at least we have one that’s going to be prescriptible in short order.

Drs Hoffman and Richter discuss a promising new treatment for patients with relapsed/refractory multiple myeloma who are not eligible for a clinical trial after 4 lines of therapy. 

Evolving Treatment Options for Relapsed/Refractory Multiple Myeloma 

: The last couple of years have seen this explosion not only of the pipeline of myeloma drugs, but drugs that have obtained FDA approval. And the buzzword around myeloma lately is BCMA [B-cell maturation antigen]; BCMA-targeted antibody-drug conjugates, bifunctional antibodies, CAR Ts [chimeric antigen receptor T-cell therapies]. Now that we have one of these in the clinic, belantamab mafodotin, I was wondering if you could tell us a little bit about it and how you use it in your clinic.

 Yes, belantamab is a drug where you have a monoclonal antibody connected to a cytotoxic, and the target on the myeloma, as you referenced, is BCMA. It’s the first foray into BCMA-targeted therapy, the first approved, an off-the-shelf drug, fairly convenient schedule, given every 3 weeks. It’s been nice to have this. Some of the challenges are, certainly from an [adverse] effect profile, the eye toxicity, keratopathy, is clinically relevant. And it’s tethered to the need to get eye examinations before every single treatment, so you have to in practice have a protocol in place to ensure that gets done appropriately, because these patients will get some keratopathy. The degree of keratopathy, how clinically impactful, will determine whether you dose adjust. It’s a good drug; it certainly can work. Some responses will be deep. To me, one of the challenges is we’re all so excited, we’ll talk in a second about CAR T. But we’re all so excited about BCMA-targeted therapies, and at least in my estimation, this may not be the most effective BCMA-targeted therapy and the least toxic that we get a chance to use. So you have to think before you use this drug, is someone eligible for a trial with BCMA-targeted therapy that this is going to exclude them from? Or are you going to maybe miss a chance to give a more potent BCMA-targeted therapy over time? I’ve definitely used it in multiply relapsed patients who are not trial eligible who need therapy, who can’t wait around for commercial CAR T, etc, and have anecdotally have had some good results, and, again, have had to navigate this eye toxicity on a regular basis. How about you in your practice?

: Again, one of the wonderful things about this is that so far you and I are practicing essentially identically. I have been using this for people who are not eligible for trial because I agree that pound for pound some of the other BCMA therapies that are coming out are probably better. The one thing I think about in the back of my head is the other modalities, the BiTEs [bispecific T-cell engagers] and the CAR Ts, especially in someone who’s been extremely heavily pretreated, they may not have the most robust T cells. And the benefit of this is that it doesn’t use the T cells to kill myeloma as much as the others. But again, it’s really for those patients more toward the end. I’m excited that, like all drugs in myeloma, it’s approved as a single agent, and there are some interesting trials coming down the pike, especially trials like DREAMM-6, which is combining this with Velcade [bortezomib]. I agree the BCMA landscape’s going to become extremely complicated, and we’re going to have to pick the right patient for a drug like this, but it’s definitely nice to have that in our armamentarium.

: That’s an excellent point in terms of not relying on the immune system. And again, I agree with everything you said. Another new drug with a novel mechanism of action that I know you’re very familiar with is selinexor. Initially it was approved with dexamethasone as part of the STORM study and then more recently with data from the BOSTON study in combination with bortezomib. I’m curious in terms of how you’re using selinexor, how you’re mitigating toxicity, and what your thoughts are in terms of where it fits in the landscape of relapsed myeloma.

: Absolutely. I’m excited to have selinexor approved now almost 2 years ago. But one of the great things is every time we get a new drug in myeloma or a new mechanism of action, we don’t just get 1 drug, we get many different potential combinations. The BOSTON regimen of SVd [selinexor, bortezomib, dexamethasone] has been great, and the reason I like it so much is that most patients in the US get Velcade as part of their upfront therapy: VRd [bortezomib, lenalidomide, dexamethasone], CyBorD, [cyclophosphamide, bortezomib, dexamethasone], dara/RVd [daratumumab/lenalidomide, bortezomib, dexamethasone], if you’re in a fancy center like one of ours. But Velcade’s not used as commonly in the relapsed setting. We use a lot of dara [daratumumab] and Kyprolis [carfilzomib], and I find a lot of patients are still Velcade-sensitive in kind of the mid relapse. The benefit of this regimen is that it brings back in Velcade, which many patients do quite well with up front, and can do well with again. It’s given once weekly here at a dose of 100 mg as opposed to the original STORM study, which was 80 mg twice a week. Selinexor is tolerated much better if you give it once a week at 100 mg as opposed to twice a week at 80 mg. We use a lot of odd drugs to help prevent symptoms. The 2 biggest ones are Varubi, which is rolapitant. It’s basically similar to Emend, except it has fewer drug-drug interactions with selinexor than Emend does. It’s 180 mg every 2 weeks orally. And for patients who have issues or we think may have issues, there’s olanzapine, old-fashioned Zyprexa, doses ranging from about 2.5 to 7.5 mg. With these approaches, we’ve had a much better ability to use prophylaxis and prevent toxicity with selinexor. I have a number of patients on this type of regimen for years doing well, because some patients don’t respond as well to the IMiDs [immunomodulatory imide drugs], but respond much better to the SINEs [selective inhibitors of nuclear export]. How about you?

: I agree generally. We kind of copied your supportive-care regimen from a patient we once shared in terms of the Varubi. We’ve sometimes struggled to get Varubi for patients, and when that happens, we use Emend, like you referenced. We’ll use this since patients are coming in for their Velcade anyway. They’re in the treatment room. I would agree with you that it was a huge advance from the STORM study, which the benefit/risk was somewhat marginal, and it allows us to get this drug that has a novel mechanism of action and can work for people for whom the classic classes of medicines have stopped working in a way that’s much more tolerable. It’s become a little tricky when you have all of these options after patients have failed the IMiDs, the PIs [proteasome inhibitors], and the monoclonals, where you fit this in. But it certainly has a place, and I have seen it work well for patients who had limited options. There’s a fair amount of supportive care, following counts, etc, and we can dose reduce from 100 mg, and some patients still get good efficacy and find a happy place in terms of [adverse] effects. I was a little more dubious of the drug based on the STORM trial, but in this combination, it is much more tolerable and can be beneficial for some patients.

Experts in treating multiple myeloma discuss the trials that led to the approval of selinexor with bortezomib and dexamethasone, and which patient population would benefit from treatment, as well as the dosing, safety, and efficacy. 


Clinical Data for Selinexor Use in Myeloma 

: Both of us have taken advantage of and been excited about a lot of the advances and new drugs that have been coming for myeloma and some that we’re anticipating in the near future. I wanted to talk through some of these with you for the purposes of this presentation, specifically isatuximab as a new monoclonal antibody in combination with pomalidomide and carfilzomib. Certainly, the CD38 antibody daratumumab is something that we’ve used for years. I’m curious what you think about the addition of isatuximab and what some of the recent data have shown us.

 It’s been exciting, yet another tool in our tool belt. As you pointed out, CD38 monoclonals have become as crucial to the management of myeloma as Rituxan [rituximab] has to the management of non-Hodgkin lymphoma. And with the recent ICARIA and IKEMA data, ICARIA being isa/pom/dex [isatuximab, pomalidomide,dexamethasone] and IKEMA being isa/car/dex, [isatuximab, carfilzomib, dexamethasone] we have yet 2 more triplet options in the relapsed setting. Both are extremely active regimens, and both have shown excellent activity in Revlimid [lenalidomide]-refractory patients, which most patients in the US progress on Revlimid in the front line. One of the big questions I’m facing, and I want to hear your thoughts as well, is where do isatuximab-based regimens fit after dara [daratumumab]? We’re using at our institution a 6-month washout, so if you got dara/rev/dex [daratumumab, lenalidomide, dexamethasone] early on, and you got another regimen in between, and around 6 months have passed, then we say, well, CD38 has probably re-expressed itself on those plasma cells, and that may be a good time to bring in isatuximab with a different partner than they’ve had before. I’d definitely love to hear your thoughts on it.

: Those are all good points. For me, one of the challenges is, as you hinted at, we don’t have data on isatuximab after daratumumab, and we live in a daratumumab world, where patients are getting exposed on relapse, and some of them now with initial therapy. Certainly it would be nice to know or have some real data on what the response rates are going to be with isatuximab vs retreatment with daratumumab and some of these combinations. Isatuximab has some advantages and disadvantages. It’s IV [intravenous] as opposed to subQ [subcutaneous], which we’ll talk a little about with dara [daratumumab] coming up. There are some cost savings with isatuximab vs daratumumab. I haven’t used isatuximab a lot because I am comfortable reusing daratumumab, but I would say that in patients previously treated with dara[daratumumab] like you said, with a washout period and for whom I’m going to be using carfilzomib, which requires an IV anyway, to me that’s a group of patients for whom it’s very reasonable to use isatuximab as opposed to daratumumab, a slightly different epitope, slightly different mechanism. That’s been the one small patient population where I’ve focused on myself.

 One of the things you brought up in talking is the incorporation of subcutaneous daratumumab, and I want to hear how that’s impacted your practice and any tips or tricks for anyone.

 As soon as we could, we migrated most of our patients over to subcutaneous dara, [daratumumab], and I would say at this point, 95%-plus of our newly treated patients with dara [daratumumab] are getting the subQ formulation. We have rather good evidence that it’s noninferior to the IV form, and patients appreciate being in and out of the treatment room quickly, and not having to get IV access. For me, it’s been tremendous from a patient convenience perspective. These patients don’t want to spend any more time than they need to in the treatment room. At this point we only have a handful of people who are continuing on the IV for their own preferences. What about you guys up in New York?

 Exactly the same. The only few people who remain on it were the people who’ve been doing so well for years on the IV, they just don’t want to switch. Like when the pharmacy changes generic, they just don’t want to. But exactly the same. We’ve switched almost everyone over to subQ. Almost every new patient we start on subQ. One thing we do is, for the first time they get subQ dara, [daratumumab] especially if they’ve never had dara [daratumumab] before, we monitor them for 3 hours post-subcutaneous injection in the clinic, monitoring for infusion-related reactions. But again, the rates are relatively low, and once we know they tolerate it, exactly like you said, they come in, they get their injection, and they can leave much quicker.

 We do that exactly the same way. It’s nice to see we’re doing things the same, less controversy here. All of us have been comfortable for quite some time using daratumumab combinations, certainly combinations with IMiDs [immunomodulatory imide drugs] with nice synergy, in combination with bortezomib, and then more recently we have validation that it’s a good combination with the irreversible proteasome inhibitor [PI] carfilzomib. I’m curious what you think about the daratumumab, carfilzomib combination and how you might’ve incorporated that into your practice.

 Absolutely. The DKd [daratumumab, carfilzomib, dexamethasone] regimen has become a huge bonus for us in that a lot of patients now, whether you’re transplant eligible or ineligible, most people end up remaining on Revlimid as some type of maintenance. And unfortunately, every now and again we see patients with explosive relapses, extramedullary disease, renal failure, things like that. The benefit of DKd [daratumumab, carfilzomib, dexamethasone] is that it’s all parenteral, so you can give it immediately if someone shows up to the emergency department or to the clinic in extremis with a huge relapse. And especially for people who don’t do as well on Revlimid maintenance, where just biologically IMiDs don’t seem to be getting the job done, switching over to a CD38 PI has been great for those types of relapses.

 Yes, I agree completely. Certainly, some of our patients who we want to switch from the IMiD to a PI and they have a background neuropathy or didn’t have a great time with bortezomib early on, carfilzomib offers the ability to give a very potent proteasome inhibitor without neuropathy. I feel the same way, and I look to use it in the same patients, lenalidomide-refractory. In somewhat rapid disease progression, I also think it’s an excellent combination.

Key opinion leaders discuss newly approved agents and their impact on treatment decisions for relapsed/refractory multiple myeloma.

Newly Approved Regimens for Relapsed/Refractory Multiple Myeloma

 My name is James Hoffman, and I’m assistant professor of clinical medicine at the Sylvester Cancer Center at the University of Miami, Florida, and my clinical and research focus is on plasma cell diseases, such as multiple myeloma and amyloidosis.

: My name is Dr Joshua Richter. I’m an assistant professor of medicine at the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai in New York, New York, and the director of myeloma at the Blavatnik Family Chelsea Medical Center at Mount Sinai. And just like Dr Hoffman, my research and clinical focus is on plasma cell dyscrasias, mostly in multiple myeloma.

 The two of us are going to be discussing relapsed/refractory multiple myeloma today, and to get us started, Dr Richter, when it comes to predicting patients’ risk of relapse after initial therapy, what factors or variables do you focus on in terms of making that prediction?

 One of the things we classically look at is cytogenetic risk factors, looking for high-risk cytogenetic or FISH [fluorescence in situ hybridization] lesions like 17p deletions, 1q additions, and then a number of other presenting factors, such as extramedullary disease or initial presentation with renal dysfunction. We all note that even patients who present with renal dysfunction that gets better quickly, we get a flavor that their myeloma can affect their kidneys and has the potential to be more aggressive down the line. Those are some of the main areas I look for. Anything else?

 I agree completely: aggressiveness of presentation, initial genetics, and the pattern of their initial presentation, whether it was an aggressive presentation or more subtle. Yes, I agree completely with that approach.

 Along those lines, throwing it back to you, once you are treating these patients initially, how do you monitor or how often do you monitor with blood work or imaging, and what’s your trigger to change therapy?

: These are important questions, and obviously we individualize this for patients based on some of the factors we mentioned, such as what kind of risks they have. But I would say as kind of a standard, we check a full myeloma panel of blood work generally monthly. We don’t really need to check urine laboratory results all that often, so it’s primarily blood work. Certainly, if patients present with new symptoms despite blood work that looks reassuring, we will scan patients in those circumstances, looking for radiologic progression. Then in terms of when we initiate treatment, we all see some patients that can have slow serologic progression but don’t have any clinical progression, and some of those patients can be monitored for quite a bit before initiating therapy. For rapidly rising paraprotein or for any clinical relapse, we would always change therapy. What about you with the same question?

 I agree completely. It always amazes me how different patients can behave in terms of their relapse. We all follow the IMWG [International Myeloma Working Group] criteria for progressive disease, if the M [monoclonal] spike increases by an absolute of 0.5 g/dL in at least 25%, but exactly like you mentioned, we have people who go over a course of years, from 0.1 to 0.2 to 0.3 g/dL. I have a number of patients, as I’m sure you do, who have technically fit the criteria for progression, but they have no symptoms, the rate has been very slow, and we monitor them. One of the things that’s always in discussion with the IMWG is to include rate of progression or kinetics.

 Perfect, yes, and some of those same rules probably apply to patients with smoldering myeloma who we’re monitoring and trying to figure out when to pull the trigger, and none of us can emphasize enough how individualized treatment approaches need to be for patients. They can be widely different.

Myeloma experts, Drs James Hoffman and Joshua Richter, discuss the factors that increase a patient’s risk of relapse after frontline treatment for multiple myeloma.

James Hoffman, MD, University of Miami Sylvester Cancer Center

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