We are reporting from the 2022 ASH Annual Meeting!

Get ready, because we are presenting the top news presented each day during the meeting—and soon we’ll speak with Dr. Ryotaro Nakamura on data related to graft-vs-host disease, and Dr. Joshua Brody on the latest in non-Hodgkin lymphoma.

Welcome to OncLive News Network! I’m Gina Mauro.

In the phase 3 TRANSFORM trial, treatment with lisocabtagene maraleucel led to a statistically significant and clinically meaningful improvements in event-free survival, complete response rate, and progression-free survival in the second-line setting for patients with relapsed/refractory large B-cell lymphoma.

Mosunetuzumab continued to elicit durable responses in patients with relapsed/refractory follicular lymphoma, and showed higher response rates, duration of response, progression-free survival, and time to next therapy compared with patients’ last prior therapy. The encouraging data were from an updated analysis of a phase 2 trial.

In younger patients with mantle cell lymphoma, adding ibrutinib during induction and as maintenance therapy with or without autologous stem cell transplant showed strong efficacy signals and an acceptable safety profile in the randomized TRIANGLE trial. While more follow-up is needed to clarify the role of transplant with ibrutinib-containing regimens, the current data already support the use of frontline ibrutinib in this patient population.

A new CD19-directed CAR-T cell therapy, called rapcabtagene autoleucel, demonstrated distinct cellular kinetics, efficacy, and a manageable safety profile. In patients with relapsed/refractory diffuse large B-cell lymphoma in updated findings of a phase 1 study.

Finally, in multiple myeloma, mezigdomide, a novel cereblon E3 ligase modulator, showed promising efficacy in combination with dexamethasone in patients with triple-class refractory disease. The objective response rate was nearly 40%, and was 50% in those who received anti-BCMA therapy.

Please be sure to check out more of our coverage from the 2022 ASH Annual Meeting at OncLive.com.

That’s all for today. Tomorrow, we will sit down virtually with Dr. Catherine Coombs for updates in chronic lymphocytic leukemia, Dr. Nelli Bejanyan on the latest in graft-vs-host disease, and Dr. Aaron Gerds on new data in myeloproliferative neoplasms.

Thank you for watching OncLive News Network: On Location, I’m Gina Mauro.

Videos

In this episode, OncLive® speaks with Dr. Noopur Raje on developments in multiple myeloma, Dr. Ryotaro Nakamura on data related to graft-vs-host disease, and Dr. Joshua Brody on the latest in non-Hodgkin lymphoma.  

Unpacking Data in Multiple Myeloma, Non-Hodgkin Lymphoma, and GVHD: Drs Noopur Raje, Joshua Brody, and Ryotaro Nakamura

Let’s close with the question of pros and cons of CAR T, antibody-drug conjugates, and BiTEs [bispecific T-cell engagers]. Let’s assume that these are probably going to move earlier in treatment into an early relapsed settings. Why would you choose 1 over the other?

Well, everybody here probably has the same thoughts, that as these agents get moved up earlier, we’re all very interested to see some of the earlier data, like KarMMa-3, when you are offering CAR [chimeric antigen receptor] T-[cell therapy] after only a couple of therapies. If you start seeing patients and then have durable responses for years, that’s going to be fairly persuasive. The question is whether we’ll be able to do 1 sequential BCMA therapy after another and then what sequence should you do this in.

We’re going to ignore cost right now because, of course, this is not cheap. Noopur, what do you think? Where are we going to use these?

 I think they’re all going to move earlier and earlier. Some of the things we’ve talked about—in terms of disadvantages of taking 4 to 6 weeks to produce, etc, are going to go away. We are going to be able to do it earlier, without having to worry about things like a bridging therapy. We have to think about sequencing some of these BCMA targets, because 1 of the good things about CAR T cells is it’s 1 and done. If we are able to see a durability of response, in my mind, that’s going to be a huge benefit for our patients. On the other hand, as we bring them earlier, if we don’t see a remission duration that is long lasting, and we’ve got to pull back with some of these other agents, then it’s an open area, and we will be talking about sequencing some of these BCMA-targeted approaches.

Tom, if you had a patient today who had 3 or 4 prior therapies, and if all 3 were available, would you have a preference for antibody-drug conjugate over a BiTE? We’ll take CAR T out of the equation for now.

 The bispecific antibodies are going to be extremely potent for all these patients. It’s going to be moved to front line in early relapse quite quickly. These response rates are 80%, 90%. It’s amazing, actually. I would prefer that bispecific.

 I agree with Tom in general. For a triple-class refractory patient, if I had the choice between an AC [antibody-drug conjugate] and a bispecific BCMA target, I would lean toward the bispecific. If I had a patient with significant cardiopulmonary disease who I was concerned may not tolerate cytokine release syndrome, I might gravitate toward the antibody-drug conjugate in that scenario. Otherwise, most patients would get the bispecific antibodies. I have a similar level of enthusiasm as Tom does. If the response rates, the durability of those responses are similar to what we’re seeing with CAR T cells, that’s a game changer. Although Noopur is right: Patients enjoy that treatment-free interval. That’s 1 of the most valuable things for them after going through CAR T-cell therapy.

There you have it, folks. Everybody is very excited about BCMA-targeted therapy. We have numerous, probably over a dozen agents in the clinic right now being studied who will probably transform how we treat myeloma. Lots to learn and lots of work to be done to figure out where we’re going to use them most effectively and most cost effectively as well.

I thank the panelists for their time today. It’s been a great discussion. We’ve covered a lot of ground quite quickly. With that, I’d like to thank you all for this, Dr Callander, Dr Martin, Dr Raje, and Dr Voorhees. And thank you to our viewing audience. We hope you found this 

® discussion to be useful and informative.

Future of BCMA-Targeted Therapies in Multiple Myeloma

I want to review the data for bispecific antibodies, or BiTEs—slightly different technologies, but we’ll lump them together for today. Peter, you’ve had some experience with some of these. Do you want to talk us through that?

 Sure. At LCI [Levine Cancer Institute in Charlotte, North Carolina], we’ve been involved in the phase 1 Janssen study of teclistamab. This is a BCMA-targeted bispecific antibody. This is a 2-pronged antibody, as I describe it. One prong of the antibody binds to BCMA on the surface of plasma cells. The other prong of the antibody binds CD3 on T cells and activates T cells, basically creates an immune synapse between the T cell and the myeloma cell, and engages that T cell to destroy the myeloma cell—the blinatumomab, if you will, of multiple myeloma.

There are several different products out there. There’s AMG 420, which was the first proof of concept of BiTEs in this specific space. The problem with AMG 420 was that it had to be administered as a 4-week continuous infusion, much like blinatumomab must be administered. These next-generation BCMA bispecifics have a longer half-life and can be dosed less frequently. In the teclistamab phase 1, the bispecific antibody was administered with step-up dosing during the first week and then weekly therapeutic dosing thereafter. My colleague presented this data at ASCO [American Society of Clinical Oncology Annual Meeting]. At the higher-dose level that they looked at with the IV [intravenous] formulation, they’re seeing response rates at this point of 67%—granted, with a very small number of patients, 12. But the patients I’ve treated on these things have very refractory disease and extramedullary involvement, and I’m seeing really quite impressive responses and durable responses with this agent.

 That seems to be a common theme to all the BiTEs. We have many of them in clinical trials, at least 6. Not to pick on anyone specific, but Tom, at ASH [American Society of Hematology Annual Meeting] you presented on a different one from a different company. Tell us about the results of that, and the toxicity.

 We have been part of the Celgene trial for their bispecific T-cell engager. And it was presented by Dr [Luciano] Costa at ASH. They did a first-in-human dose-escalation trial, then they treated 9 patients at what they believe is going to be the dose. They took to an expansion and then to a phase 2, which is a step-up dose of 6 to 10 mg, and then some patients at 10 mg. There were 9 patients treated at that higher dose, who had 8 of 9 responders. And 5 of those people are MRD [minimal residual disease] negative. It’s pretty impressive, actually—a response rate of almost 90% for these 9 patients.

I have a few patients on it. When patients get on it, it appears durable. The big question, in the waterfall plot that was shown at ASCO for teclistamab, there were patients out 19 months. Most of the patients who were out 12 months were still continuing in response. The question is, will it be as good as the CARs or not? We’re all really looking forward to seeing those data. This might be easier.

The problem is, it does require a hospital stay. The toxicity is the cytokine release syndrome, or CRS. It requires a hospital stay for the first dose and every step-up dose, because you might activate more T cells each time. But after you’re done with the step-up dosing and the first real dose and then the T cells, there is essentially no CRS. Patients may need to be hospitalized once, twice, or 3 times before they can continue, but then can continue in the outpatient clinic thereafter.

The neurotoxicity is also similar, but much less—less than 10% neurotoxicity. You still do see some cytopenias. About a third of the patients do get cytopenias. But as you said earlier, this is a really heavily pretreated population. Maybe it’ll be less if we do it in less heavily pretreated patients. Of all the agents, these are my favorite.

 We’ve used a couple of these agents targeting different companies, different agents. My impression is they’re a lot less toxic than CAR [chimeric antigen receptor] T cells, and I suspect they could probably be delivered safely as an outpatient from the majority of patients, particularly if you had some home monitoring system you could use. Also, to go back to CAR T, for some of those products on the horizon, they may not require hospitalization for everybody, at least initially. The other thing I’ve been a bit concerned about is unlike CAR T, at least in my experience, the remission duration has not been as long. The people do progress more quickly, at least in my short experience. This is something you have to pay attention to. But off the shelf, you don’t have to wait. There are good high response rates, and obviously this is going to be a very important addition to our therapy.

Bispecific Antibodies for Multiple Myeloma

 Peter, do you see any difference between them that strikes you that is worth calling out at this point? Or are they all still too early to see?

It’s too early to know. The overall response rates in all of them are obviously quite high. Depth of response is quite good. Median duration of follow-up remains quite short, and it’s important to recognize that this depth of response in a lot of these patients continues to deepen over time. I have [treated] patients for 1 to 2 years who are finally getting into complete remission. We have to wait in order to see any meaningful differences between the products.

 I agree with what Noopur [Raje] and Pete have said. One issue that has come up in our experience is that the manufacturing time can be daunting for patients. That doesn’t sound like a long time, 3 or 4 weeks. But there is this issue of patients falling apart during that interim and you are unable to get them to transplant. A lot of the trials are restrictive in what you can give patients, unfortunately. I’m not sure it makes a big difference what you’re trying to do in terms of this bridging. We should try anything. But that’s still a hurdle. Going back to other BCMA [B-cell maturation antigen]–targeted therapies, that is a disadvantage, that you just cannot immediately give it to an ill patient.

 We’ve been lucky at UCSF [Helen Diller Family Comprehensive Cancer Center] because we’ve had all the products in clinical trial. I agree with everybody that there’s no real difference at the current time. We’ve been very excited over the overall response rate. But a couple of limitations: 1, patients must come to the licensed cellular therapies place, like the transplant center. And that’s going to be a problem for a lot of patients. This isn’t going to be for everybody, unfortunately. It’s probably going to be less than half the people who are going to be referred for CAR [chimeric antigen receptor] T-cell therapy because they have to come into the transplant center.

Then we’re all excited about the response rate. But the disappointment is, for most people, the relapsing. Relapses continue to occur 1 year down the road, 2 years down the road, 3 years down the road. That’s a stark contrast to lymphoma, where if they’re in remission for 6 months, they tend to be in remission forever, which is troublesome. I wonder what the advisers think. For me, the problem is, are these guys all going to need maintenance after the CAR? We just haven’t addressed that situation at the current time. They’re going to need something else other than just a CAR.

In fairness to the products, these are the worst of the worst patients in terms of the number of prior therapies and what their natural history would be. To me it’s quite miraculous that some of these patients pick up their bed and walk and have their first complete remission that lasts, even if it lasts for only a year, it’s often better than what the alternative was going to be.

 One of the most exciting things that we’re all going to be dealing with is, what about re-treating people with a different BCMA-targeted therapy. We use a drug conjugate after a CAR T, or can you use a BiTE [bispecific T-cell engager] before a CAR T? A lot of the trials are set up, so answering those questions now is quite limited. But we’re all going to try that. There are persuasive data that BCMA could be downregulated at the time of a CAR T relapse but comes back very quickly, particularly in people who have quite proliferative myeloma.

Differentiating among CAR T Products for Multiple Myeloma

Let’s discuss our favorite topic of CAR T-cells, Noopur has the most experience of all of us in using CAR T. Do you want to just give us a lay of the land, Noopur? Where are we at with these, and what’s your impression as we’ve get more experience?

: We were waiting on cellular therapy for myeloma and we now finally have them. We have several different products. All of them in the myeloma space are targeting the same protein, BCMA. And there are different products out there, including one from Janssen, one from Juno, one from bluebird, and one from Celgene. And the big differences are the way they are creating the CAR. All of them are using a very similar post-stimulatory domain, which is 41BB. And this is required for T-cell expansion. CAR T-cells, unlike what people really talked about with bela and maybe the BiTEs, which we will talk about later, this is not off-the-shelf. This requires collecting cells from patients, getting those cells back to whoever is producing the CAR, and from collecting the cells to creating the CAR T-cells, it can take anywhere between 3 and 4 weeks right now. And then once those CARs have been generated, we get the patients back. And they do need to be hospitalized, at least for right now.

This might change in the future. We’ll have to wait and see. But most patients will receive some conditioning chemotherapy, and we typically use a combination of Cytoxan with fludarabine, and following 3 days of that, 2 days of rest, and then you give back these CAR T-cells to patients. The most important toxicities associated with cellular therapy are twofold. One is neurotoxicity, and the second one being cytokine-release syndrome. And these occur because of the CAR T-cells being active. Once the CAR T-cells finds your treatment cell, they destroy the tumor cell, produce a lot of cytokines, and that results in cytokine release syndrome. And the second one, neurotoxicity, which is less well understood, is again because of the CAR T-cells and whether or not it’s because of crossing the blood-brain barrier or whether or not it’s because of some of these acute-phase reactants, it’s still not completely clear.

The most important thing we’ve learned from CAR T-cell technology in the last couple of years is the fact that they work. We can generate them in very end-stage myeloma patients. They work with extremely high response rates, north of 80% in whichever clinical trial you look at. And it’s manageable toxicity. Most of the toxicity we’ve seen is cytokine release syndrome. And we’ve been able to manage that quite well. And we’ve seen very little in the way of neurotoxicity with these cellular products. It’s a really exciting space. We’re just at the beginning of cellular therapy in myeloma. And at least the initial look at this has been quite encouraging. The data looks quite exciting.

Development of CAR T Cells in Multiple Myeloma

Let’s start with belantamab. If you’ve had some experience with the drug, please describe in detail what the DREAMM-2 trial has taught us.

 We are fortunate to participate in the DREAMM-2 study. This was a large phase 2 trial looking at patients who were on at least 3 lines of therapy and had to be daratumumab refractory. Using this as a single agent, every-3-weeks IV [intravenous] administration, that’s very quick, with no steroids and patients liked that. The study was able to show that the response rate was about 33%. Two different dose levels were examined; 2½ mg is the dose we’re using. Many people have probably heard about the biggest toxicity. There’s some thrombocytopenia, which is quite manageable. But there is some keratopathy as well. Patients can develop dry, blurry, and irritated eyes. And that seems to be manageable in that, once the drug is stopped for a period of time, these resolve. In most cases, at least in our experience, the drug can be restarted. But we saw some very nice responses, including some sustained CRs [complete responses] using that drug. The research presented at ASCO [American Society of Clinical Oncology Annual Meeting] that Noopur talked about is combining this drug with Velcade, where that seemed to push the response rate up to almost 75%. But that’s a very small study and is just getting off the ground.

 We’ve been using it in the expanded-access program. We’ve put close to 10 patients on the expanded access. I have also been very impressed with the ease of administration, which is once every 3 weeks. We have a good ophthalmology group, so for us, it’s very easy for the patients to go to an ophthalmologist. They look at the surface of the eye. They tell us everything is OK. Patients can then get dosed with their next or subsequent dose. For us, it’s been convenient. We haven’t had a significant toxicity that wasn’t reversible.

What percentage of patients get this corneal toxicity, Tom, either from the study or your own experience?

 Upward of 70% of patients can have some corneal toxicity. And close to half the patients either have to hold the dose or have to dose reduce. It’s a significant number, and they have to be watched closely in terms of the ocular stuff.

 To be clear, 70% of patients had corneal findings on ophthalmologic examination. Not everybody had symptoms of those corneal findings, although dry eye, photophobia, and blurred vision were common adverse effects. Because of that, as Tom mentioned, there were a lot of dose holds and dose reductions. It’s going to be important to better understand why this is happening, to explore alternative dose schedules and other potential preventive strategies to mitigate this particular problem, because if it wasn’t for the corneal toxicity, this is a very easy agent to give.

 There was a substudy done looking at the use of steroid eye drops to prevent the keratopathy. Unfortunately, that did not seem to be helpful. But Pete’s right. The secret is probably going to be a change in the dosing schedule or maybe building in some positives, because the half-life of this drug is pretty long.

My experience with this class of drugs—antibody-drug conjugates, targeted BCMA [B-cell maturation antigen]—is that the high toxicity can be quite difficult for patients at times. In at least some of the patients I treated, it took quite a long time for the symptoms to resolve after they stopped the drug. What I found interesting, and I guess other people have seen, is that the response persisted.

Even though they were off the drug for quite a long time—and surprisingly so, in my experience, given the stage of disease the patients had—they would be coming 3 three months later. And I’d go, “Wow, you’re still in complete remission [CR]. That’s amazing.” Have others had that experience?

 Yes, absolutely. I had a patient who had a 6-month dose hold because of keratopathy and was absolutely stable. She wasn’t in a CR, but she had a deep PR [partial response] with an M-spike [monoclonal protein] that just sat there at 0.2 for 6 months.

 The median duration of response in the updated ASCO [American Society of Clinical Oncology Annual Meeting] presentation is 11 months, which is long compared with, for example, selinexor-dexamethasone from the STORM trial, where the median duration of response was about 4½ months. For those patients who respond, they respond very well in spite of those dose holds.

The other thing I noticed was the responses were quite deep. I had a couple of people go into complete remission, which was kind of surprising. It’s definitely a drug to watch. I think you’re right. This issue that the responses can be quite durable—and the half-life of the antibody, of course, is quite long—suggests maybe that, to me at least, the dosing schedule is something to look at rather than stopping and starting. Just have a longer time between treatments if they start to develop problems. Is that logical or illogical? What do people think?

 The combination we’re going to use it in, right? It’s probably not going to be most effective just as a single agent. We probably can use it in a lower dose like we’re talking about with selinexor, in combination with another agent. It’s a race to figure out which one is going to be the best combination.

 Noopur, where are you going to use this drug? At what stage of disease?

 Obviously, BCMA targets are all very exciting. The benefit of belantamab mafodotin is the fact that it is an off-the-shelf antibody. There is no processing. There is no waiting. And the toxicity, outside the ocular toxicity, is very manageable, completely outpatient. Given that we are already using daratumumab at the onset, at the final diagnosis, patients are all going to be daratumumab exposed at first and second relapse. All BCMA targets are going to come on earlier and earlier in their lines of treatment. Second and third line is where we’re going to use it. Just to put things into context, Natalie mentioned the response rate of belantamab mafodotin as a single agent. If you go back to the CD38 antibodies, single-agent CD38 antibodies had a similar response rate. It falls into that same category as a single-agent monoclonal antibody.

Yes, that’s absolutely true. Tom, where do you think you’re going to use it? We should be clear that right now, it’s got a specific FDA approval. Could you speak to that and then say where you think we’ll go in the future.

 I think it’ll get FDA approval in the triple-class refractory or the data exposed. I will point out, though, in the daratumumab-sensitive people, the single-agent activity was 60%. It wasn’t 30%. It was 60%. In the same patients daratumumab and isatuximab were used and got about a 25%, 30% response rate. This got a 60% response rate. This is a quite active agent. And of the BCMA agents, it’s the only 1 that’s not going to require hospitalization. All the other BCMA agents being tested nowadays will require some form of hospital stay. The off-the-shelf nature to it and the ability of the private practice doctor to give this drug—it’s going to be used a lot. This has a bright future, in my mind.

 Yes, you’re right, although I do worry about this corneal issue in terms of whether that will limit its uptake a little, particularly if you have other choices in early relapse. That may be something we have to continue to work on with the company.

Using Antibody-Drug Conjugates in Multiple Myeloma

 Let’s talk about the most exciting target we have in myeloma today, which is BCMA [B-cell maturation antigen] and how we can approach targeting that. Nooper, you’ve been quite involved in some of the drug therapies that are targeting BCMA. What is BCMA, and why do we care?

 BCMA is 1 of the most exciting targets that we’ve discovered in the last few years. 

 stands for B-cell maturation antigen. It is a protein that is expressed on all plasma cells. It’s present on all patients with multiple myeloma. Over the years, we’ve begun to appreciate that you don’t even need to measure BCMA levels, because all plasma cells will have that. This is a tumor-specific target, and going after this makes a lot of sense. We have a lot of different approaches to targeting BCMA. There’s conjugated monoclonal antibodies, which are in clinical trials. The 1 that is in development is belantamab mafodotin. This is a conjugated monoclonal antibody targeting BCMA, and there were nice data on the DREAMM trials presented at this year’s ASCO [American Society of Clinical Oncology Annual Meeting]. There are other strategies, such as BiTEs, which stands for bispecific T-cell engagers. These are also off-the-shelf monoclonal antibodies that target the same protein, and while doing so, they also activate your T cells and can bring the T cells to the tumor and can cause immune T-cell killing of the tumor itself. The most exciting space or the most data we have using BCMA as a target is the cellular therapy world, which is CAR [chimeric antigen receptor] T cells, again directed toward BCMA.

BCMA-Targeted Therapies in Multiple Myeloma

 Let’s discuss venetoclax, which has taken us by storm in the last year or 2. Tom, you were an early adopter of venetoclax. Tell us about your experience. What do you think of the BELLINI clinical trial? Maybe you could describe what that is.

 Venetoclax is an inhibitor of BCL2. We started using it in relapsed/refractory before selinexor was approved. We could get it in some patients by compassionate use. We had about a 20% response rate with venetoclax plus dexamethasone with people who were triple-class refractory. But what was found by several investigators is that those patients who have the 11;14 translocation likely have overexpression of the BCL2 pathway. But those people are exquisitely sensitive to this BCL2 inhibitor, and they had a really nice response. A phase 2 was done, randomized bortezomib–BCL2 inhibitor–venetoclax and dexamethasone vs bortezomib and dexamethasone, showing a benefit in people with 1 to 3 prior lines of therapy, all comers. That instigated the BELLINI trial, which was a phase 3 randomized trial, in patients with 1 to 3 prior lines of therapy. And patients are randomized to the triplet vs the doublet of bortezomib and dexamethasone. What we found is that the triplet actually was more toxic. In fact, there was higher mortality. It was updated at ASCO [American Society of Clinical Oncology Annual Meeting] this year by Dr Shaji Kumar showing that that toxicity still persists, that there were more GI [gastrointestinal] toxicities, more infections, and there was some cardiac toxicity in the triplet vs the doublet. In that study was a subset of patients who had the 11;14 translocations. Those patients had exquisite responses. The overall response rate was well over 90%. After 2 or 3 years, these patients remained in remission PFS [progression-free survival]. That curve is an impressive curve in the 11;14s. It’s going to be a great drug for the patients who have the translocation at 11;14. But for everybody else right now, they’re probably not going to move forward in that direction.

 Thank you, Tom. Natalie, are you using it in clinical practice yet?

 We would have, we have had a lot of trouble getting payers to approve it, even with the presence of 11;14. That’s been the biggest hurdle. We’ve had a couple of patients who were treated through the VA [Veterans Affairs Medical Center], where they’ve had nice responses again. This is going to be a drug for the 11;14. Unfortunately, because of the BELLINI trial results, it’s put a damper on a lot of the research that we’d all like to see done. Hopefully, there’s going to be recognition that there are patients who benefit from this. But it’s put the brakes on a lot of things.

 Peter, last word to you before we move on to something different?

: I agree that in 11;14-translocated, in 

-high patients, it’s a very active agent. We’ll see it eventually get approval there. I do want to give a quick shout-out to the daratumumab-venetoclax-dexamethasone data that presented at ASH [American Society of Hematology Congress] in December. The overall response rate was over 90%, and every single patient was either a VGPR [very good partial remission] or CR [complete response]. Granted, they were small numbers.

 Yes, I must say, I’ve used quite a lot of venetoclax, and these are very impressive results in the 11;14 population, as you’ve all said. Unlike Natalie, we seem to be able to get it quite easily, at least until a couple of months ago. I don’t know if that’s changed. For the folks watching, if you have an 11;14 translocated patient—first, test for it, because you won’t know unless you do the test. Second, a lot of the commercial labs aren’t running 11;14 testing. You have to be careful that they’re actually measuring it. And if you do find somebody with that, it’s a drug to consider as a single agent or in combination.

BELLINI Trial; Venetoclax-Vd in Multiple Myeloma

 New drugs are coming out. Let’s begin with selinexor, which has been approved by the FDA, so it is available. There are recent updates from the BOSTON study with the combination of selinexor with Velcade. Does anybody who participated in that want to comment?

 The STORM data were what got selinexor approved. The nice thing about the BOSTON trial is that they have used bortezomib on a weekly schedule, in a subcutaneous way. It’s more of a real-world way of using bortezomib. The other thing they’ve done with the selinexor in this combination is they’ve used weekly dosing of selinexor, although at 100 mg, so that’s something we can argue about. They did see a benefit in terms of a progression-free survival of a little over 4 months. This is hopefully going to get the drug finally approved. As far as selinexor is concerned, most of us still worry about the toxicity associated with selinexor. Depending on what your partner drug is going to be, it’s important to dose-modify selinexor so that it’s well tolerated, and patients can stay on medication.

 Let’s describe selinexor, for those of you who may not be familiar with it. It’s an orally delivered agent. It has a novel target, which is exportin, a protein that shuttles things from the nucleus to the cytoplasm and back. But it can be blocked by this drug, so it’s a completely novel mechanism of action. It is approved by the FDA as a single agent in heavily pretreated patients. They were called penta-refractory, 5 prior regimens with a response rate of about 26%. In this BOSTON trial that we’ve just described, was a randomized phase 3 trial of bortezomib-dexamethasone vs bortezomib-dexamethasone and selinexor. It was mostly done in Europe, because the control arm wasn’t that attractive in the United States. But as Noopur just pointed out, there was about a 4-month progression-free survival advantage.

 This was a logical way for them to get regulatory approvals in earlier relapse. Given the fact that we have other proteasome-inhibitor-based triplets that we’ve already talked about: daratumumab-carfilzomib-dexamethasone, soon to be isatuximab-carfilzomib-dexamethasone, pomalidomide-bortezomib-dexamethasone. In a similar patient population, just given the adverse-effect profile that Noopur alluded to, I don’t think we’re going to be using this a lot in this particular clinical scenario.

 Tom, what do you think? How are you going to be using it?

 We’ve reserved the use at the current time in the penta-refractory scenario where we don’t have anything left. We don’t have a clinical trial slot for a patient, and we don’t have any other therapeutic options. We have tried it, and it’s a tough drug to give. There’s no doubt about it. You have to be very diligent about checking their electrolytes, giving them fluids, giving them antinausea medicines, checking in with the patients. But you do get some patients who you wouldn’t believe you’d get a response to. It’s reasonable to try in patients, either in the combination of bortezomib-selinexor-dexamethasone, or just selinexor and dexamethasone. Give them a cycle and 4 weeks. Make sure they get through it OK. If they have a response, you can continue. But it is, in general, a lot more work than all the other regimens.

 In fairness to the drug, when it was dropped to weekly dosing, as Noopur described in the BOSTON trial, it apparently looked like it was quite a bit better tolerated, right?

 We’ve been participating in what’s called the STOMP trial, which has partnered selinexor with a lot of different agents. And we’ve been very impressed with 2 combinations in relapsed/refractory patients: carfilzomib with selinexor and dexamethasone. That has had a good response rate, as well as daratumumab and selinexor. We learned with other oral drugs, you get more drug in patients with lower doses. And we’ve been aggressive at cutting the doses. Then patients can stay on. As Tom said, in some of these very refractory patients, there have been some dynamite responses. We just don’t have a biomarker for it to say who’s going to be the person who responds, unfortunately. But there are some people I’ve treated who have really benefited.

BOSTON Study; SVd in Relapsed/Refractory Multiple Myeloma

 I’m surprised nobody mentioned daratumumab with bortezomib earlier. That hasn’t even been brought up as an option in a lenalidomide-refractory patient. Noopur, I’ll pick on you again. Why not use that?

 Well, part of the reason for not using that is that most of our patients have been exposed to bortezomib already up front. The issues around toxicity of bortezomib for long-term use is something we’ve talked about, the neuropathy specifically. If you look at the old data with bortezomib-daratumumab, although it was a positive trial, the data were not that impressive. In the CANDOR and the IKEMA studies, the data look much better. We tend to use carfilzomib at the time of relapse now. That might change with more people using KRd [carfilzomib, lenalidomide, dexamethasone] up front. But for right now, the go-to proteasome inhibitor seems to be carfilzomib at the time of first relapse.

 Many of you mentioned using pomalidomide. Tom, why not just use lenalidomide again? I gave the case where somebody was progressing on it, so I made it easy. But if you had lenalidomide and stopped it, would you use pomalidomide at relapse, or would you go back and use lenalidomide again?

 If there’s been a significant 6- to 12-month break, and they’re truly not refractory to lenalidomide, it’s acceptable to give that a try, as long as they didn’t have toxicity to the lenalidomide. Pomalidomide is tolerated a little better than lenalidomide. I prefer it when they do have relapse. I tend to do that even if they’ve been off lenalidomide for a while.

 It’s been my experience that there may be more neutropenia, where I don’t know if it’s compared with lenalidomide. But when you use pomalidomide with daratumumab, for example, that can be a bit of a challenge. Anybody else want to comment?

 Yes, I agree with what Tom says. A lot of people who are on long-term lenalidomide hate the GI [gastrointestinal] adverse effects: chronic surprise diarrhea and things like that. Pomalidomide really doesn’t seem to have that. A lot of patients appreciate that. If I have a patient who’s had a long-term response on lenalidomide maintenance after a transplant and then stopped maintenance, and they start to have a biochemical relapse, those are people I will give lenalidomide again to.

 Most of us want to use the most active drug. Pomalyst is certainly more active than lenalidomide. Now we have the new CELMoDs [CRBN modulating agents]. The worry used to be, what are you going to do next? We have really active CELMoDs coming down the pike. So I would go to pomalidomide.

 A CELMoD is a third-generation version of thalidomide-lenalidomide-pomalidomide, with maybe some slightly different biological effects. But there are some very potent ones out there in clinical trials. Iberdomide is the 1 we’ve heard the most about, showing some activity even in people who’ve failed pomalidomide. Pomalidomide sounds like a good choice. What else have you combined it with, Natalie?

 Based on the OPTIMISMM trial, we use some Velcade. I know you mentioned that people aren’t using Velcade. We will give pomalidomide with Velcade, typically in a person who hasn’t had previous neuropathy. One of the regimens that we’ve used in older people, and I don’t know if other people have done this, is an old [Antonio] Palumbo regimen: pomalidomide with oral cyclophosphamide and prednisone, which is a triplet regimen you can give older patients. It’s very well tolerated.

 The data with elotuzumab-pomalidomide-dexamethasone are quite good. There’s a clear difference in overall response and a very significant difference in median progression-free survival with the addition of the elotuzumab. As Tom alluded to before, the toxicity profile of elotuzumab is quite favorable. The challenge with elotuzumab-pomalidomide-dexamethasone is that it’s unclear what its activity is and what its role is going to be in a post-CD38 antibody world, which is where most of us are using it. Anecdotally, my experience with elotuzumab-pomalidomide-dexamethasone in daratumumab-refractory patients has been suboptimal.

 We’ve concluded that pomalidomide can be combined with a number of different drugs. It seems to be the IMiD [immunomodulatory imide drug] of choice at relapse among the group, and it’s pretty active and certainly a good choice in this situation.

Lenalidomide-Refractory Multiple Myeloma

 It sounds like more and more of our patients might start getting daratumumab up front as part of their induction therapy, particularly those who are not so fit. For patients on daratumumab in the past, would you use it again, or would you switch to cetuximab?

 It depends on the length of administration when you give it for induction in maintenance-based therapy. For the GRIFFIN trial, Peter said that daratumumab is stopped at 2 years and then patients continue lenalidomide. They may be on lenalidomide for 2, 3, or 4 more years before they have disease relapse. In that scenario, those patients are for sure, in my mind, CD38 sensitive. For this patient, I would be fine putting them on isatuximab plus pomalidomide. I’d probably put them on daratumumab plus pomalidomide. If they were on a CD38 when they progressed and when they relapsed, then going from 1 CD38 to the other is not going to be an effective strategy, so I wouldn’t recommend that.

 I agree completely with what he’s saying.

 It’s very reasonable. [Winship Cancer Institute of] Emory [University] has presented data about going back and using daratumumab specifically with carfilzomib in people who previously even progressed on daratumumab. They still had a response rate that was respectable in the sort of 27%, 28% range. I would agree with Tom that somebody who’s progressing very quickly on an anti-CD38 antibody probably isn’t going to benefit from either.

 I want to challenge you all on your choice. We’ve talked about using pomalidomide in a lenalidomide-refractory.But there are a couple of trials now suggesting that you can combine carfilzomib with daratumumab and have an IMiD [immunomodulatory imide drug]–sparing regimen in those patients. I’m going to go with the person I think is least likely to think that, which is Noopur.

Sorry. I like that combination, Keith. The carfilzomib-daratumumab combination is great. The initial challenge was giving 2 IV [intravenous] drugs, the duration of the treatment when we started split-dose daratumumab. Just this past week, we’ve started using subcutaneous daratumumab as well. That makes it even more convenient. In patients who have very aggressive disease and where you want really good responses quickly, I have absolutely used carfilzomib and daratumumab. The data looked quite good.

 I want to make sure we recognize that at the European Hematology Association [Congress] that Phillipe Moreau presented data from isatuximab, also with carfilzomib, the IKEMA trial.

With the IKEMA trial, there was a significant advantage to the triplet isatuximab plus carfilzomib and dexamethasone versus the doublet carfilzomib-dexamethasone. The hazard ratio is quite low, 0.5. That was the best hazard ratio for an isatuximab study. It looked very promising too. But I agree with you. That is a great regimen for the patients who have lenalidomide-refractory disease.

Just to add, there is a subset of patients who just don’t do well on an IMiD. In that patient population, this combination is actually useful.

 Or they can’t get access to an IMiD for financial reasons or insurance problems.

 We have 2 big trials now: the CANDOR study, which was carfilzomib and daratumumab vs carfilzomib and dexamethasone alone; and the study that Tom just mentioned from Dr Moreau presented of isatuximab, carfilzomib, and dexamethasone vs carfilzomib-dexamethasone. Both positive studies for progression-free survival, both show reasonable tolerability. One thing is they both use carfilzomib, in the conventional way, which is somewhat inconvenient for patients. Many people are still using twice-weekly carfilzomib, and many are using weekly dosing.

: I’m using weekly carfilzomib exclusively at this point. When using it with daratumumab, I use the 70 mg/m2 weekly dose.

 Have you had any challenges with that in terms of toxicity?

 There isn’t any significant difference in toxicity relative to the twice-weekly. The ARROW study would support that.

 We use weekly carfilzomib most often at 56 than 70 mg/m2. You know, the ARROW study obviously is out there. But we only use twice a week if a study requires it.

 The dosing of carfilzomib depends on the backbone. If it’s cyclophosphamide or daratumumab based, I use the 70 mg/m2. But if it’s IMiD based, I’ll use a 56 mg/m2 weekly dose.

 What we’re saying in summary is that there are alternatives for lenalidomide-refractory or intolerant patients, which combine 2 of our most active drugs, an anti-CD30 antibody with a very active proteasome inhibitor.

Daratumumab With Carfilzomib in Frontline Multiple Myeloma

How about the treatment of patients with relapsed or refractory myeloma, can you provide some key updates on recent data and practice patterns? Tom, let me start with you. What principles do you use when you’re selecting your relapse therapy or subsequent therapy after induction?

 There are 3 things that I consider. First is, what are their current and residual toxicities or comorbidities that I must worry about when choosing the regimen? The second is what have they been on in the past and what they may be either refractory to or what I think they may be most sensitive to. And then the third, which is part of the patient’s part of this, is convenience, is which one, can they come to the center relatively easily to get a subcutaneous injection or to get an IV [intravenous] medication? That’s how I choose it. If there’s a fourth thing, it’s how they present. If they present aggressive, then I know I have to choose a regimen that’s going to provide a substantial improvement in their aggressive disease.

 In terms of your thinking around the course that you’re going to pursue with that patient, is a second transplant on your radar? Or are you committing to long-term use of a relapse regimen?

 I’m not a big fan of second transplants right out of the gate in first and second relapse. Some of the salvage regimens that we have provide a significant progression-free survival [PFS] advantage, without having to use a transplant. For me, it’s a triplet-based regimen and not a transplant at that time.

 Peter, let’s assume our patient has had what we just all described as standard of care, which is VRd [bortezomib, lenalidomide, dexamethasone], transplant, and lenalidomide maintenance. Now they’re progressing on lenalidomide. What are you doing for those patients? What’s your choice of regimen, assuming that they’re eligible to come into the hospital and everything else?

 The 2 regimens that are the most attractive in this situation would be daratumumab, pomalidomide, dexamethasone, and daratumumab, carfilzomib, dexamethasone, given the biologic rationale of incorporating an IMiD [immunomodulatory drug]with a monoclonal antibody. A lot of us gravitate toward the daratumumab, pomalidomide, dexamethasone triplet over the daratumumab, carfilzomib, dexamethasone triplet. It would be very interesting to do a randomized trial of this exact patient population comparing the two. I think that they would both perform very well.

 You’re sticking with an IMiD, even though they’ve just progressed on lenalidomide.

 We have good data that pomalidomide has activity in lenalidomide-refractory patients, even when they’ve become refractory in their most recent line of therapy.

 That would be pomalidomide, dexamethasone doublet in patients with lenalidomide refractory disease, whether the lenalidomide refractoriness is on the most recent therapy or previous, there is a benefit to pomalidomide, dexamethasone in that situation.

 I want to highlight Pete’s trial for Alliance. That’s going to be interesting when those results come out. He’s looking specifically at patients progressing on lenalidomide maintenance and then randomizing them to pomalidomide, dexamethasone versus pomalidomide, ixazomib, dexamethasone. Those results will be interesting as to whether they can show a triplet is the better move at that point. And these are patients who largely have indolent relapses more or less, biochemical type?

 Yes. This is biochemical progression and with a crossover.

 I do put a lot of patients on Pete’s trials. Ones with the biochemical progression. Most of us would turn to a pomalidomide-based regimen because the data do suggest that it does work in lenalidomide-refractory patients. The partner to the pomalidomide is largely dictated by the nature of the relapse. If we have somebody with high-risk features, aggressive relapse, that’s where I would reach out to the carfilzomib, pomalidomide, dexamethasone combination. And if not, then you could choose between pomalidomide, daratumumab, dexamethasone, which is an effective treatment. And more of those indolent relapses is where I would use Pete’s Alliance trial.

 I do think there’s a lot of regimens that can be used with pomalidomide, dexamethasone as a backbone. We’ve shown many studies. There’s also elotuzumab with pomalidomide, dexamethasone. And sometimes we choose that in patients who may be frailer. The infusion reaction rate is only 10%, which is great. It’s a well-tolerated drug. And the other thing I’ll mention is isatuximab. The other CD38 that now is approved for use is isatuximab, together with pomalidomide and dexamethasone. And if you look at the subset of patients who are lenalidomide-refractory in a subgroup analysis, they still do well on the isatuximab, pomalidomide, dexamethasone versus pomalidomide, dexamethasone. The triplet does better than the doublet. 

 For the audience to keep up with us here, isatuximab is another monoclonal antibody targeting a CD38, a second-in-class drug that resembles daratumumab. Tom, you’ve used both of them quite a lot. Do you have any suggestion that one might be better than the other, or there are any advantages to one over the other? They both seem to be quite active.

 Yes, they’ve both been used in the refractory setting as single agents, together with lenalidomide, together with pomalidomide, bortezomib, and carfilzomib. If you compare all the studies, they’re very similar in terms of overall response rates and PFS. They work very similarly and probably have the same overall activity.

 Which one would you choose, and if so, why, if you had all things being equal in your patient?

 Just approved also is subcutaneous dosing of daratumumab. The convenience of subcutaneous dosing, the 5-minute dose, I think is going to be a win-win for infusion centers like ours that are very busy, and also for patients who don’t want to sit in the chair for 2 or 3 hours to get their IV infusion. For me, subcutaneous injection is going to win out.

 Your center did a lot more with subcutaneous daratumumab. Are you using that routinely now?

 We’re in the process of getting it on our outpatient formulary. We don’t have access to it yet. But we’re hopeful as long as the economics make sense that we’ll get this on our formulary, and we’ll start converting patients to subcutaneous daratumumab in every situation we can.

Management of Relapsed/Refractory Multiple Myeloma

 That takes us to the question of consolidation and maintenance, and we just have a few minutes here. Peter, what’s your approach to maintenance today? What drugs, for how long, and low versus high risk. Where are you at with that?

 For most patients, lenalidomide is the standard of care. It has a role both in standard-risk patients as well as high-risk patients. The MRC 11 trial showed us that lenalidomide maintenance is active in patients who have the 4;14 translocation as well as deletion 17p. Lenalidomide, and until disease progression for now until a study tells us otherwise, because the CALGB and MRC 11 trial showed a survival advantage post-transplant with the use of lenalidomide maintenance therapy until disease progression. As far as single-agent proteasome inhibitor maintenance, there are no good randomized data supporting that for patients with deletion 17p or the 4;14 translocation. I have gravitated, based on the experience from the Emory [University] group, and now we’ve got my colleague’s S1211 trial looking at RVd [lenalidomide, bortezomib, dexamethasone] induction therapy, followed by prolonged lenalidomide/bortezomib maintenance therapy in high-risk patients with a very respectable median progression-free survival that came out of that study. I have gravitated toward lenalidomide/bortezomib combination maintenance for patients with high-risk disease.

: Just for high-risk, but not for your low-risk patients?

: Natalie, what’s your approach right now? We accept lenalidomide for everybody?

 I go with Pete, lenalidomide for standard risk, VRd [lenalidomide, bortezomib, dexamethasone] for high risk.

 We cut it out quickly. It modulates some [adverse] effects, sometimes some of the cytopenias. But at some starting dose of dexamethasone, but not 40 [mg].

 I know you’re big fans of lenalidomide in Boston. Are you using bortezomib as well?

 High-risk patients, add bortezomib, change to ixazomib if they have neuropathy.

: Noopur, how long for? There was all this debate that Paul wants to treat forever, and most of us are like, no, 2 or 3 years is probably enough torture.

 I continue forever unless they have toxicity that precludes them from being on it.

: Tom, could you talk to the role, since you’re doing MRD [minimal residual disease] testing, do you use any consolidation if it’s still positive?

 We don’t use any consolidation. But for the high-risk patients, I’m different. If it’s a high-risk patient who is MRD-positive at 3 months, based on our tests, I’m going KR [carfilzomib, lenalidomide] plus or minus D [dexamethasone] as the maintenance strategy, vis-à-vis the MMRC study. K [carfilzomib] is my preferred maintenance strategy for the high risk. And for standard risk, I am just with lenalidomide.

: What we were doing before I left the Mayo [Clinic], was more aggressive. I was using lenalidomide and bortezomib in almost everybody. More and more are turning to daratumumab if they were MRD-positive, which I find many of my patients are still MRD-positive post-transplant. And I got the notion that daratumumab, even though it’s not really approved yet in this setting, as a consolidation to try and get to MRD negativity was worth a shot. That’s where I was leading. Outside of the United States, of course, many of these things are not feasible at all. And lenalidomide will be the standard of care, as you’ve all said, for everybody, time-limited or forever, and then the use of bortezomib, perhaps, in the higher-risk patients. In Europe, a second transplant is commonly employed. Is anybody doing second autotransplants for their high-risk patients? Natalie, I’ll pick on you because you’re kind of the transplant-avid person here.

 We haven’t, just because I think we were swayed initially by the BMT CTN 0702 [trial]. It released the early data that didn’t show benefit for tandem or consolidation. They updated their data at ASCO [the American Society of Clinical Oncology annual meeting], which is interesting, looking at not just intention to treat, but who received the tandem. They were able to show a benefit for tandem, particularly for high-risk patients. Speaking again to the MRD issue, they also showed that there was a significant benefit for long-term lenalidomide in terms of maintaining MRD negativity. And I thought those were interesting data.

 We’re not at this point. A second look at the StaMINA trial was a bit of cherry-picking, to be honest with you. They are taking the patients who went through the 2 transplants, which are probably the fittest patients. In the absence of randomization of that specific subgroup of patients, you can’t say anything one way or the other. I’ve gravitated away from the 2 transplants.

 One thing we should highlight here, we keep talking about a second transplant benefiting the high-risk patient population. Remember, including the FORTE trial, including the StaMINA trial, the maintenance did not include a proteasome inhibitor. It was lenalidomide alone. And that’s why it’s hard to put it into practice, because that’s what we typically do for our high-risk patients.

Maintenance Therapy Approaches in Multiple Myeloma

 Since you brought up MRD, or minimal residual disease, monitoring, let’s take a quick poll of each of you, are you using it, and at what point would you measure it first?

 We’ve had a huge debate on this institutionally. We’re doing it by consensus post-transplant. What we’re not doing is using a single result, like Pete says, to determine ending treatment unless somebody’s on a clinical trial. Patients are asking for it. Many people are not sure what you do with it. Maybe 90 days post-transplant isn’t the right point to test it. It should be at a year later on. That’s a possibility.

 I don’t routinely do it in my practice. And that’s largely because we’re not making any treatment-related decisions. The 1 subset of patients where I do look at MRD is the high-risk patient population. There are enough data now. We’ve been talking about transplant here, but it doesn’t matter how you do that MRD-negativity. If you can sustain it with the maintenance that we do in the United States, I do think we ask the question on transplant now. As of right now, only high-risk patients.

We routinely do it. When patients achieve a CR [complete response], whether it’s pretransplant, 3 months post-transplant, or a year post-transplant, we do MRD testing routinely. That is our clinical practice. We try not to make any clinical decisions based on it. But our goal is to get to MRD negative specifically for the high-risk patients. And for other patients, it’s still our hope that we can get there.

 Tom, if you’re not making any decisions, why bother doing it? That doesn’t make much sense.

If you have sustained MRD negativity, and you have toxicity, the clinical decisions that we’re making, somebody has a year of sustained MRD negativity and then has neuropathy or has GI [gastrointestinal] toxicity, it’s a lot easier to take them off their medicine. When we look back at our data and say, are we really not making decisions, about a third of the time, we are making a change based on the MRD.

At the Mayo [Clinic], I know that my colleagues were quite insistent that we do MRD testing at day 100. To me, this was totally illogical, because it wasn’t going to change what we did. But that’s what they were doing. I was a bit like you, Natalie. I was waiting till there was a decision point to be made, like Tom said. Maybe they’re getting toxicity from maintenance, and you’re probably looking for an excuse to take them off if they’re MRD negative on a couple of occasions.

Or alternatively, if it was a young patient, and they still have quite a high reading, despite a normal bone marrow and a negative blood test. Then, it does beg the question of whether one should escalate therapy in that patient.

MRD Monitoring in Multiple Myeloma

:We have seen trials now from Spain, one from the United States, and Birmingham, suggesting that transplant might not be required so frequently anymore, and particularly if you’re using these 4-drug regimens together, such as carfilzomib, lenalidomide, dexamethasone, and daratumumab, or as we just talked, VRd [bortezomib, lenalidomide, dexamethasone]/daratumumab. What do people think about that? Is transplant still with us? And if so, for how long? What do you think?

The FORTE trial randomized patients to KRd [carfilzomib, lenalidomide, dexamethasone] 12 cycles, versus KRd [carfilzomib, lenalidomide, dexamethasone] 8 cycles, plus a single autologous transplant. In that study, the people who were not high risk did well whether they received a transplant or not. KRd [carfilzomib, lenalidomide, dexamethasone] in that setting might be enough, and you might not need to do an autologous transplant. However, in the high-risk population, it still was a benefit.

 We’re involved in a trial called the MASTER trial, which involves giving KRd [carfilzomib, lenalidomide, dexamethasone]/daratumumab.It’s also an MRD [minimal residual disease]-driven trial. And this has about 112 patients accrued at 6 different institutions. We can tell that the MRD negativity rate goes up, even with a 4-drug regimen, post-transplant. And it’s substantial. If we end up using MRD as a surrogate end point or to limit therapy, that’ll be very interesting. I have to put myself in the protransplant camp, it does provide benefit to patients. I am interested to see about long-term data with FORTE.

: This is [Luciano] Costa’s, [MD,] presentation of the trial right?

: That’s the one I meant from Birmingham. In that trial, they all get transplanted? Is that right?

 They can be transplant-ineligible. That’s allowed. But the majority of patients have gone on to transplant.

: The jury’s still out for the time being. People are still transplanting. Peter, is that the case with you?

 Yes, I would say so. And going back to the FORTE trial, the transplant arm did have a higher proportion of patients with sustained MRD negativity. And sustained MRD negativity is more important than MRD negativity in 1 point in time.

The Role of Transplant in Multiple Myeloma

 Let’s talk about 4-drug regimens if we’re looking toward the future. Peter, since you’re the lead investigator on the GRIFFIN clinical trial, can you tell the audience what the trial is all about and what you found?

 This was a randomized phase 2 study looking at the addition of daratumumab into the RVd [lenalidomide, bortezomib, dexamethasone] backbone for transplant-eligible myeloma patients. They received 4 cycles of RVd [lenalidomide, bortezomib, dexamethasone] induction, transplant, 2 cycles of post-transplant RVd [lenalidomide, bortezomib, dexamethasone] consolidation, and then went on to lend maintenance until disease progression. The dara arm received daratumumab, both with induction and consolidation, as well as the first 2 years of maintenance therapy. And what we found up to this point is that by the end of consolidation therapy, the stringent CR [complete response] rates and the CR and nonstringent CR rates are better when you add daratumumab into the RVd [lenalidomide, bortezomib, dexamethasone] backbone. We’ve also shown an increased rate of MRD [minimal residual disease] negativity with the addition of daratumumab as well. At this point, with close to 2 years of median follow-up, progression-free survival is very good and similar between the 2 arms of the trial. We have yet to see a progression-free survival advantage with the addition of daratumumab. But we clearly have shown an improvement in the depth of response.

 Tom, are you using 4-drug cocktails yet?

 Unfortunately, we’re not able to do that because of insurance purposes. I think we are going to all move to 4-drug regimens—especially in the transplant-eligible population—and that we’re going to get a very deep remission in 3 to 4 cycles and then go right to transplant, just like what’s done in the GRIFFIN study. That’s the wave of the future, to try to get an even deeper response using 4-drug regimens quicker. But right now, we can’t do it just from insurance purposes.

 When you say that, there are FDA-approved regimens that contain 4 drugs from the ALCYONE trial and I think CASSIOPEIA too. For the audience, these drugs are using melphalan or thalidomide as 1 of the 4 drugs. Is it across all 4 drug combinations or just the 1 that Peter talked about?

: That’s a great question. In terms of the ALCYONE trial, using melphalan as a front-line therapy induction is certainly in a transplant-ineligible population. In the MAIA study with a three-drug, it looks more impressive than a four-drug regimen using melphalan and bortezomib instead of lenalidomide. I would still go with the three-drug with dara as front-line.

In terms of thalidomide as part of the therapy, I don’t think I’ve used thalidomide since maybe 2004 or 2005. And I’m not ready to go back.

: Anybody better able to use four drugs, and are you?And if so, in who?

 We’ve only used it in trials. Right now we are holding back and seeing, one of the things that we noticed in some of the trials--and I don’t know if the other panelists have--is that at least our impression in some of the dara-containing regimens that there’s a more difficulty with stem-cell collection. I don’t know if other people have noticed that, but it just seems sometimes we’re taking more time to collect stem cells.

: I’ve seen some data on that which seems to suggest their yields are lower, but still quite adequate for transplant most of the time.

 There’s a higher rate of use of combination with GCSF for mobilization. And as long as you’re doing that, the stem cell yields are similar. They’re a little lower, but it’s not a clinically significant difference. And time to engraftment is the same. But if you do go beyond four cycles of four-drug therapy, whether it’s RBd/dara or KRd/dara, you’re potentially asking for trouble.I would collect after four cycles.

: That’s an excellent point to make. Noopur, what’s happening in Boston? Are you moving to four drugs?

 Not quite. We’re doing that in the context of clinical trials, for a lot of the reasons which all of the panelists have mentioned. But I just want to point one thing out there. We are all using four-drug regimens. And sure, four-drug regimens are going to show us a depth of response. I think what we need to start doing is using that depth of response to really tailor therapy in these four-drug regimens, because along with deep responses comes two things, both real toxicity to our patients and financial toxicity as well.

: I have had a bad experience. When I was still at Mayo Clinic, we started using four drugs for younger, higher risk patients. I didn’t find it easy. The infection rate and other complications in my early experience was high. We do need to approach with a little bit of conservatism and wait for final results from Peter’s work.

Treating Transplant-Eligible and -Ineligible MM

 Noopur, tell us about the MAIA trial. What about using a regimen that doesn’t contain a proteasome inhibitor? What’s your thinking about that?

 The MAIA trial is the best data that we’ve seen. And it’s 1 of the largest trials in the newly diagnosed space. This is for transplant-ineligible patient population. There are slight differences between this and the ENDURANCE trial. The ENDURANCE trial was supposed to be a transplant-deferred patient population. Having said that, a lot of patients on the ENDURANCE trial ended up getting a transplant. It’s hard to compare this with the MAIA study. The MAIA study was clearly a patient population that all of us see in our practice. These were above the age of 65 years old or not transplant eligible, for whatever reason. And it was close to 1500 patients, so 1 of the largest trials for multiple myeloma in the newly diagnosed space.

The other interesting thing about the MAIA study was it was the first time where they did sort of dose-modify both the dexamethasone and the lenalidomide based on patients’ creatinine clearance, which is something we have to deal with in the real world. They included patients who had slightly softer creatine clearances, which typically has not been done previously in a lot of clinical trials. For all those reasons, the MAIA trial is a practice-changing trial. In the transplant-ineligible patient population, the combination of Rd [lenalidomide, dexamethasone] with daratumumab is a reasonable and a good option for our patients who are transplant ineligible.

 If I’m hearing you right, it’s the VRd [bortezomib, lenalidomide, dexamethasone] for younger patients and dara-Rd [daratumumab, lenalidomide, dexamethasone] for less fit or elderly patients? Is that correct?

 That’s right. But also, for the younger, high-risk patient population, I would consider KRd [carfilzomib, lenalidomide, dexamethasone].

 Carfilzomib, lenalidomide, dex [dexamethasone] for high-risk, young; bortezomib, lenalidomide, dex [dexamethasone] for most people; and for the frail, daratumumab, lenalidomide, dex dexamethasone. Does anybody disagree with that algorithm?

 I wouldn’t necessarily restrict dara-len-dex [daratumumab, lenalidomide, dexamethasone] to frail patients. I think older patients with standard-risk cytogenetic profiles are good candidates for that approach.

 I would agree with that. For the very frail, I still consider a doublet at times, particularly if they can’t get to clinic very often, Rd [lenalidomide, dexamethasone] still has some pretty good responses in that population in particular—as Noopur said about dosing for creatinine clearance.

 The only thing for the MAIA patient population is that high-risk patients don’t seem to do that well with the monoclonal antibody and Rd [lenalidomide, dexamethasone]. There’s room for RVd [lenalidomide, bortezomib, dexamethasone] light, so bortezomib is given in a weekly schedule for patients who are older and have high-risk cytogenetics.

 Fair enough. We have to move on for time here. What about our patients with renal failure? How does that change the equation, Peter?

 These patients in acute renal failure are oftentimes in the hospital when they’re first diagnosed. You have rapid access to cyclophosphamide-bortezomib-dexamethasone in that situation. You don’t have to worry about renal modifications with that particular regimen. Starting with CyBorD [cyclophosphamide, bortezomib, dexamethasone] in that particular patient population is very appropriate.

But what we tend to do more and more now, since we do have comparisons to, say, CyBorD [cyclophosphamide, bortezomib, dexamethasone] versus VTd [bortezomib, thalidomide, dexamethasone], and now we have KCd [carfilzomib, cyclophosphamide, dexamethasone] versus KRd [carfilzomib, lenalidomide, dexamethasone]. And we do see improved depth of response with the IMiD [immunomodulatory imide drug]–proteasome inhibitor [PI] triplets. What we’re typically doing with cycle 2 and beyond is we’re converting to IMiD-PI-dex [dexamethasone] and just modifying the len [lenalidomide] dose, depending on where their renal function ultimately stabilizes.

Noopur Raje, MD, Massachusetts General Hospital

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