With that information, Omar, who do you think is the right patient for a BCMA [B-cell maturation antigen] bispecific like teclistamab?

: Everybody. No, I think the reality is as we’ve discussed, we have so many agents in the front line and first and second relapse that most patients end up becoming triple-class refractory earlier now in their disease course than what we were used to. We need some of these agents a bit in earlier lines of therapy, but right now where things are starting is, obviously with the CAR [chimeric antigen receptor] T approvals being in the 4 prior lines population, that’s a bit too far out for a lot of those patients. And unfortunately, because of lack of availability, many patients are either waiting or unable to make it to their CAR T infusion.

Then you have something like this, which I think splits the difference nicely. You’re seeing off-the-shelf capabilities, overall as a single agent, amazing responses in this heavily pretreated patient population. It seems to have manageable toxicity. Cytokine release syndrome [CRS] rates are lower. I think it could be primed for more widespread use compared to CAR T-cell therapies. I think that’s why we’re all so excited about it, and now seeing the PFS [progression-free survival] approaching close to a year, which is similar to what we saw with the original ide-cel [idecabtagene vicleucel] studies, at the RP2T [randomized phase 2 trial] dosing. I think that makes it a tough argument to go for something like that versus this is a lot easier.

The idecabtagene vicleucel queen is sitting right here.

: I think this is going to be the big question going forward. How are you going to choose between both that are simultaneously available? Is there one patient for whom you’re going to go in one-direction vs the other? I think it is important to acknowledge that the data we’re seeing with cilta-cel [ciltacabtagene autoleucel] looks, basically in terms of PFS, more than twice as good. There seem to be differences between the different CAR products. I think so far with bispecifics, perhaps we’re not seeing that as clearly yet, but I do think there’ll be some differentiating factors that’ll make us choose. There’s so much to still be learned about toxicities, and durability of responses in the real world, etc. But I do think this applies to a large majority of patients with myeloma, particularly as they get the other agents.

A perfect segue for Cristina, a lot to learn. We’ve heard about monotherapy. What can you tell us about combination strategies with bispecifics?

: Everybody is waiting for the combination because we tested this agent as a single agent and in a heavily pretreated population, and then we want to improve, we want to do better. The problem I have with these agents is that the responses are already amazing; it’s going to be tough to improve. There were a couple of presentations on combining. It makes sense, the mechanism of action between daratumumab, the anti-CD38 antibody, the immunomodulation, and the anti-BCMA, the bispecific. Some preliminary phase 1 data are showing that potentially you can improve the response. One of the abstracts by, I believe, [Paula] Rodriguez-Otero, [MD, PhD,] showed that in every pretreated population, because we’re still talking about 7 prior lines of therapy, their responses were a bit higher.

The Spanish group…they’re launching the MajesTEC-3 trial, where they are combining teclistamab with daratumumab vs the physician’s choice, and that is going to be very interesting. Now, it is going a little earlier because they can be refractory to daratumumab, and they have had to receive daratumumab more than 90 days prior. It will be a different population of patients. It is not the classic triple refractory, penta-exposed yes, but not necessarily refractory.

I think encouraging data, but it’s always hard with these single-arm studies to know what the combination is adding.

: But they are very interesting data. Rafael, you alluded to this, other targets besides BCMA. What else do you have to give us?

: A little disclaimer, it’s hard to discuss the study I’m going to talk about because you obviously have been the senior leader of that, but GPRC5D is another great target. I’m going to take a quick step back. I don’t think we should talk about BCMA-targeting agents, which means nothing. BCMA is just the anchor. We have ADCs [antibody-drug conjugates], we have bispecifics, and we have CAR T cells. I think there’s a real danger in people saying, “Oh, someone has had a BCMA.” Particularly I fear that at prior authorization, it’s a big rabbit hole to go into, but the point is BCMA is just a target. We need to think about the mechanism of action.

Taking it back to the monumental clinical trial, this was for talquetamab, which again targets this specific anchor. Interestingly, it’s also expressed in epidermal tissues. One of the things that is being understood is cutaneous nails and other forms of toxicity, which need to be considered; dysgeusia as well has been reported. But they report a very good level of response. At the weekly administration, which by the way is subcutaneous, there is a 70% response rate. At every other week, which is about twice the dosing, you have about a 60% response rate. It’s really active. About three-fourths of the patients get CRS, but mostly it’s grade 1 and 2. I can imagine a future where you get something like teclistamab, and if you progress, well, fortunately, we have talquetamab. I won’t mention the other agent because I think Dr Patel is going to talk about that, but we will have multiple lanes to approach patients in the future. To me, this is very exciting.

It’s good to have choices, and that’s a perfect segue to you, there’s even more than BCMA and GPRC [G protein-coupled receptor].

: Yes, cevostamab, I think with FCrH5, is another great target. I tell people we had CD19 envy for so long, and now they’re envious of us, because we have so many targets that we can go after, and it’s a great time to learn all of this. We know that’s another great target that’s in almost every patient; myeloma cells have a high antigen density of it. This is a bispecific with FCrH5 and CD3. They had patients who had prior anti-BCMA therapies, including bispecifics and ADCs, etc. The initial dosing was IV [intravenous], and it was every 3 weeks, which is a little different, and it’s fixed dosing. All the other bispecifics so far have been continuous dosing. I think a lot of people are excited to see what happens when you do fixed dosing.

What was really impressive was the response rates, even in the BCMA-exposed patients, different mechanism of action, but when they put them together, about 40% to 50% of patients still responded, which was nice to see. The next trial that they’re doing, they’re changing it up a bit where they’re giving subq [subcutaneous] cevostamab, because we know our patients love subq better than IV.I think it’s going to be every 4 weeks at 13 cycles. That’ll be really interesting to see.

Videos

Shifting toward the practical use of bispecific antibody teclistamab in RRMM, experts consider appropriate patient selection and investigational combination strategies. 

Teclistamab in RRMM: Patient Selection and Combining Therapies 

Let’s go to the bispecific antibodies. Rafael, do you want to tell us how these new compounds compare to what we just looked at?

: Yes, I think this is remarkable. At the ASH [American Society of Hematology] meeting I counted the number of agents, either bispecific or CAR [chimeric antigen receptor] T cells that are active, and there are about 15 of them. We have a tsunami of new options coming that depend on the activity of T cells as part of immunotherapy for multiple myeloma. For audience members who don’t know this, the bispecifics, what they do is they directly engage a T cell with a target cell, in this case, a multiple myeloma cell. Many of them target BCMA [B-cell maturation antigen], but we have other targets: GPRC5D, which we’re going to talk about, FcRH5, which is cevostamab; and even CS1 is being looked at. I think we have a plethora of options.

The nice thing about bispecifics, and I think there’s a lot of excitement behind this, is these are synthetic, off the shelf. We have options where we can see a patient in the morning, and the afternoon, the patient is either admitted or started on treatment. I think this will open a lot of new possibilities for patients. I know we have a slide with a summary of them. We’re going to talk about the details. I describe them to my patients; they’re like either matchmakers or double-sided Velcro. They bring together a T cell, which is always a bully, but a T cell on top of something else is going to attack it. That’s what we are able to achieve with the bispecifics. The results are remarkable. I know we’re going to go into the details, but I’m personally very excited about the practicalities of the bispecifics.

Krina, with that great introduction, you can tell us a little about the mechanism of action and update us on the MajesTEC-1study we heard about at ASCO [American Society of Clinical Oncology annual meeting]?

: Yes, teclistamab, one of our BCMA CAR Ts. We have other antigens, but we have lots of BCMA-targeted bispecifics first, and again, [it] takes the CD3, and the BCMA brings the T cells together, maybe gives them a bit of a fire under their butt, so they can kill the myeloma, but brings them closer in location. I think there were 94 patients or so presented, and the response rate was 63%, 64%. We saw previously [response rates] around 30%. To have a single agent that can hit double the response rate is pretty fantastic. Then, in terms of the duration of response, we actually have that now, we were all waiting for a bit longer follow-up, and it’s 18.4 months, and PFS [progression-free survival] of 11.3 months. It was much better than the 3 to 4 months for all the other patients, so almost 3 times longer now.

I think the bigger thing is, there are different adverse effects than what we are used to. We’ll talk more about it with the other CAR Ts, etc. But 72% of patients had CRS [cytokine release syndrome], but these are mostly all grade 1 or 2, and usually earlier in treatment, and then subside. I think there are new things we need to learn how to take care of, but it’s pretty fantastic that patients are doing really well with it. Then there are infections, of course, but I think it was great to see the PFS and duration of response follow-up this time.

I think one of the most eagerly awaited things was this PFS result. Because it’s the first bispecific, we’ve all been seeing those swimmer lane plots, waiting and waiting.

: Patients at up to 2 years were still going, but what’s the median?

Yes, finally. We’re going to come back to you. I know you love your CAR Ts.

It will be interesting to see what you think about that.

: That’s where we’re going to fight, but it’s OK.

But before we get to that, it is worth mentioning, one of the challenges. Luckily in the United States, we have an accelerated approval strategy, where if you have an unmet need, historically the benchmark was 20% to 30%, and you could get a new drug approval. But one of the challenges with accelerated approval is you don’t have a control arm, so what’s the context of this? I think here at this year’s ASCO, we had 2 efforts to look at that, one from Europe using the LocoMMotion study, and the other from the American side using the Flatiron [Health] database.

Basically, it was a study to try to compare these real-world patients on both sides of the Atlantic and using matching to try to—because we all know that these bispecific studies, even though less selective than CAR T, are still selective for pretty healthy patients. And when you factor all of those variables in, there was a statistically significant benefit. It’s striking, rarely is it the same on both sides of the Atlantic, but PFS and OS [overall survival] benefit was suggested based on this. I think the FDA usually likes these historical references for accelerated approval to put these drugs into context. I think especially important is that these are not cherry-picked CAR Ts. These are off the shelf, with sick patients. It was nice to see that.

Focusing on relapsed/refractory MM, expert panelists review data from MajesTEC-1 and consider how bispecific antibodies are impacting the treatment paradigm. 

BCMA-Targeting Bispecifics in RRMM: MajesTEC-1 Trial and Real-World Data for Teclistamab 

We now want to talk about relapsed myeloma and incorporating bispecific antibodies into the treatment. I think there’s tremendous excitement in myeloma about T-cell redirections. But just to set the stage a little bit about who these patients are, and before they’re coming to these bispecifics, we have a plethora of randomized phase 3s, all in high-impact 

 [medical journal] types of papers. And we have Rd [lenalidomide, dexamethasone] backbones. The problem with these is that most patients, as we said, are not going to be Len [lenalidomide] refractory. If we toss those out, we have a plethora of Vd [bortezomib, dexamethasone] backbone studies. These are great, but look at the progression-free survival [PFS] of the Vd control arm in pink; it’s 7 to 11 months. It’s hard to give twice-weekly bortezomib. Whether you intend to do fixed duration, like in the CASTOR [NCT02136134], or treatment to progression, patients don’t tolerate it and it’s not a great backbone on which to build. I think many of us have moved past that. Of course, the BELLINI study (NCT02755597) was really important for 11, 14, and had an unprecedented hazard ratio and PFS of 0.1 and an overall survival [OS] benefit, but not necessarily for all patients. Then we have the next generation Kd [carfilzomib, dexamethasone]-backbone studies, with really cool data for CANDOR (NCT03158688), IKEMA (NCT03275285) and K side dex [dexamethasone]. Now we’re seeing that the Kd-backbone is much better, 15 to 19 months, and on top of that, the addition of a CD38 is giving you a hazard ratio of around 0.6, which is really hard to do. Most importantly, we know that becoming Len refractory actually has shown an inferior prognosis. And we know from CANDOR already that Len refractory patients had a PFS of 28.1 months, which is not different from the overall population. Great backbone; PomDex [pomalidomide plus dexamethasone][is] obviously another option as well. These are slightly different. They’re usually a little more heavily treated and more Len refractory in the Kd studies that we saw. They’re only about a third of patients here, so much higher. The problem here is PomDex as a doublet [therapy] fares relatively poorly; 4 to 7 months. And then the addition of a third agent gives you better results. I think people have been very impressed with the Len refractory Kd, CD38 Kd-backbones. But once you’ve had all of those drugs, if you’re triple-class refractory or penta-drug refractory, bortezomib, carfilzomib, Len, Pom [pomalidomide] and CD38, then what do you do? You have a few choices; 96-hour infusion regimen, salvage transplant, celly, belantamab, melflufen of course came off the market, Iberdomide, with some encouraging data. But what you see here is that the response rate is about 20% to 30%, PFS, 3 to 4 months. And that’s what we were expecting historically.

Ajai Chari, MD provides an overview of treatment options in patients with multiple myeloma at first relapse and those with triple-refractory disease

RRMM: Treatment Options in Early Relapse and in Triple-Class Refractory MM

Rafael, I’m going to ask you a question, which I got from a community doctor when I was at a conference recently. They said: “I’ve been doing VRd [bortezomib, lenalidomide, dexamethasone] for all this time, and my patients aren’t dying. Why should I switch to DRd [daratumumab, lenalidomide, dexamethasone]?”

: That’s a great question. Familiarity is very powerful in this world, and that’s probably what happens. But we did a study that was presented at one of the oral sessions at ASH [annual meeting of the American Society of Hematology], and we asked ourselves, we have 2 regimens. As I mentioned, both had category 1 evidence. How do you choose between them? I will say that I personally have a concern with bortezomib and neuropathy. I always tell my worst stories; “Doctor, you saved my life but I still cannot feel my feet.” And even with subcutaneous weekly, it can happen. Given that we have these regimens, and they’re both perceived to be effective, how do we choose? We went about doing one of those simulations with real-world data, where we actually said, let’s look at the duration of therapy in first line, which could be with either a MAIA regimen or VRd or Rd [lenalidomide, dexamethasone]. Then, importantly, we did a sensitivity analysis with various levels of attrition because we know, and it’s been published by at least 4 papers, [there is] significant loss per line of therapy in the non-transplant-eligible patients. It can be as high as 50%. And the reason that’s important is because sometimes someone says, “Oh, drug A plus B is better than drug A.” Someone could say, “Hey, you need to show me drug A plus B is better than A followed by B.” But what they miss is that A followed by B divided by 2, if you have a 50% attrition. That’s very important. And then we use real-world data for the treatment of patients in the first relapse. If they were in MAIA, we assume it would be carfilzomib or pomalidomide. And if they weren’t RVd or Rd, it would be a daratumumab-containing combination. Everyone gets it. The only way to resolve this completely would be through a randomized phase 3 study, but that is several years out. SWOG [Cancer Research Network] has a study with some differences, but it’s addressing this question. But until then, what? And what we found is this: If you start with the MAIA regimen and follow up by current palm, you have a survival of about 9.1 years projected overall survival. And it’s about 2.5 years longer than if you start with SWOG and then go to a MAIA rescue. Is this definitive? No. But if you’re choosing between the 2 regimens, and with my added comment that you have the neuropathy-free regimen, that makes me think of the MAIA regimen as a preferred choice for our upfront.

I think a lot of people want that VRd light vs DRd study to be done. But unfortunately, by the time that is accrued and rolled and resulted, we have very exciting new agents that we’re going to talk about. Just to close this discussion, this is the take-home message slide, if you will, for the transplant-ineligible population.¼Again, the same kind of PFS [progression-free survival] graph on the left. We have the 777 on the left, with a hazard ratio of 0.74. RVd light, which is from our Boston colleagues, a very important study, but only 50 patients, single arm. VelC [bortezomib] or Dara [daratumumab] VMP vs VMP [bortezomib, melphalan, prednisone] has a ratio of 0.42, MAIA hazard of ratio 0.53 and finally IRD [ixazomib, lenalidomide, dexamethasone], 0.83. That was not statistically significant. I think the main question is really this RVd, MAIA, and I just want to call your attention to a few things. First, we’re not comparing the direct numbers. The Rd and MAIA’s PFS is actually very impressive, 34 months, as you pointed out. But what we’re comparing are the hazard ratios. What’s the value of adding bortezomib vs Dara?I think some of the devils are in the details. We want to highlight that the median age of 777 is only 63. I think many of us would not consider that to be a transplant-ineligible patient population. MAIA’s median age is 73. Next, there’s the ability to give the treatment as indicated. SWOG was twice-weekly bortezomib; who’s giving twice-weekly bortezomib to 73-year-olds? That is also not translatable to the patient in clinic. Last but not least, looking at the OS [overall survival] hazard ratio, 0.71 for the SWOG [trial] and 0.68, both are statistically significant. But look what happens to the hazard ratio for SWOG for the patients over 65, it’s not significant. And that’s the population we’re talking about. While we’re not trying to do direct cross-study comparisons, if you’re looking at the ability to give a drug as intended in the study to your older patients sitting in front of you in clinic and expecting that PFS and OS benefit, I think DRd is really hard to beat. And I think to close, it’s with 56-month follow-up, and we’ve still not reached a PFS median. That is a game changer for this population.

And that’s important; as Rafael mentioned, you may only get 1 shot with these patients.

 Take your best drug. Thank you for that great discussion.

Expert hematologist-oncologists home in on clinical trial data to consider which regimens are most appropriate for patients with transplant-ineligible NDMM. 

Selecting Optimal Therapy in Transplant-Ineligible NDMM and Key Takeaways

Cristina Gasparetto, MD, professor of medicine, Duke Cancer Institute, discusses how to manage keratopathy associated with treatment with belantamab mafodotin-blmf (Blenrep) in patients with multiple myeloma. 

It is important to reassure patients that ocular adverse effects, such as keratopathy, that are associated with belantamab mafodotin treatment, are not often permanent, according to Gasparetto. Frequent follow-ups with an ophthalmologist are needed to make appropriate adjustments and ensure that the patient can continue therapy for a prolonged period of time, Gasparetto adds.

Upon completion of belantamab mafodotin infusion, there is generally an improvement in ocular AEs, Gasparetto explains. Keratopathy may take a few months to improve, Gasparetto adds. Although these AEs cannot be prevented, they can effectively be managed through close collaboration with an ophthalmologist, Gasparetto concludes.

Cristina Gasparetto, MD, discusses how to manage keratopathy associated with treatment with belantamab mafodotin-blmf in patients with multiple myeloma. 

Cristina Gasparetto, MD, Duke University Medical Center

Articles

Teclistamab in RRMM: Patient Selection and Combining Therapies

BCMA-Targeting Bispecifics in RRMM: MajesTEC-1 Trial and Real-World Data for Teclistamab

RRMM: Treatment Options in Early Relapse and in Triple-Class Refractory MM

Selecting Optimal Therapy in Transplant-Ineligible NDMM and Key Takeaways

Dr. Gasparetto on Managing Keratopathy Associated With Belantamab Mafodotin in Myeloma