 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.

Videos

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.

Joshua Richter, MD, Tisch Cancer Center at Mount Sinai

Articles

Analysis of the BOSTON Trial

Evolving Treatment Options for Relapsed/Refractory Multiple Myeloma

Clinical Data for Selinexor Use in Myeloma

Newly Approved Regimens for Relapsed/Refractory Multiple Myeloma

Risk of Myeloma Relapse After Frontline Therapy