Multiple Myeloma — An Interview with Dr Rafael Fonseca on Key Presentations from the 66th American Society of Hematology (ASH) Annual Meeting

Welcome to Oncology Today, key presentations from the ASH 2024 meeting on the management of multiple myeloma. This is medical oncologist, Dr. Neil Love. For this program, I met with Dr. Rafael Fonseca from the Mayo Clinic in Phoenix, Arizona. In addition to this interview, there's also a corresponding video program.

featuring Dr. Fonseca's slide presentation. To begin, I asked him about practical considerations in the use of bispecific antibodies in general medical oncology community-based clinics. We see this broadening of applications for bispecifics. As you know, we have it for small cell lung cancer, uveal melanoma, lymphoma, myeloma, and more coming.

I think the issue is mostly about logistics and convenience right now, but it builds on a general sense of confidence that the treatment centers need to have for the treatment of those patients. And I would say... Before I comment on tocilizumab, even if you don't necessarily think about your practice being able to sustain the prophylactic, if the center has access to the reactive tocilizumab,

most centers across the board, even in small cities, should be able to treat patients with bispecifics. Bispecifics are so well tolerated that in my mind, I don't think there's an upper age limit for any patient who can get a bispecific. And we're having conversations with patients in their 70s and 80s and patients who have severe comorbidities that, you know, we discuss with them by specifics as the next step. And once one gets the first few administrations and the step up dosing.

then the treatments are incredibly well-tolerated. You don't have to use, in the case of myeloma dexamethasone, and the patients can get the subcutaneous administration. So from a convenience and a tolerance perspective, they're wonderful drugs.

The main issue with bispecifics right now with, you know, their proper use is just the prevention of infections. And we can talk more about that and the proper replacement of intravenous immunoglobulin. Now, what about tocilizumab? In our center, we have actually used bispecific antibodies on an outpatient practice. So all of our patients start bispecifics. It's an outpatient. We're very fortunate that we have...

remote monitoring with our nursing teams. But honestly, I mean, with the era of technology that we're in and the multiple platforms that exist, I don't think that's going to be a niche. A lot of places can do that. And the monitoring is pretty simple, you know, just monitor for vital signs. and report if you have any of the following problems. So we have started doing that. We have not yet started the use of prophylactic tocilizumab.

And not a reflection of doubts of that being done. It's just, you know, something we're actively discussing. But we have the data I've shown from Dr. Kowalski. There's more data from Dr. van de Donk as well, too, that has shown that you significantly reduce. the risk of CRS. One of the criticisms is that the biggest reduction is of CRS grade one, but that's the most...

common form of CRS in the device specific. So then that would allow you to focus on those that perhaps need more attention. The CRS is great too. There are some questions, too, about efficacy. The preliminary data shows that there's similar efficacy, whether you use prophylactic tocilizumab or not. So hopefully as we get more data, that will expand.

But the real hope is that if more centers can treat, then the area under the curve of patients who get T-cell redirecting therapy is greatly expanded. no matter what, will remain a little bit nichey and have to be done in more specialized centers. But bispecifics don't have to. And it's very interesting. If you actually compare bispecifics to CAR-T,

Like the response rate MRDs is better with CAR T's than it is with bispecifics in the short term. But when you look at long term and you look at patients that have good responses with bispecifics, you know, patients who get a CR. those can be very long-lasting. And actually, the PFS of those, you know, those curves starts looking like a PFS of CAR-T. So it may be a future that either, you know, everyone has DOSI or...

States get TOSI delivered by drone, wherever you are, you always have access to TOSI. TOSI is part of the formulation of my specifics, you know, one of those three things. Interesting. So just to clarify, though, right now, since I guess Tosi hasn't come into standard practice to prevent... CRS. Are you saying that a doc could be okay giving a bispecific as long as they have access to an ER or tertiary center that has TOSI?

Yes, that's correct. I would say it's probably worth making sure that's the case to check in with your colleagues. But there's no reason why a community oncologist could not be given this if they have a relationship with a hospital that would say...

If my patient has this, please, you know, make sure you do that. I think, obviously, the treating doctor has to have that certainty because it's, you know, the responsibility as we think about the requirements for a safe administration of a bispecific, but it could be done. So we'll see how this evolves. But as long as you brought it up, again, from the point of view of the general medical oncologists in the community,

What are some of the post or the infective issues that come up with bispecific as well as with CAR-T? What kind of prophylactic antimicrobial strategies or immunoglobulin strategies?

should be used, and how do you approach vaccinations? Sure. Yeah, all great questions and very important. I would say the single most important thing of safe management to buy specifics, and CAR T's for that matter, will be the prevention of infections. Whenever you have an effective antimyeloma therapy, you run the risk of also eliminating normal late B cells and plasma cells. So humoral immunodeficiency should be expected with effective therapy.

It is a proverbial double-edged sword because the one side of the sword will kill the plasma cells that are malignant, but also the normal ones. And we see reliable hypogamma with patients who are getting this type of treatment. How we have gone about it is essentially by providing prophylaxis to all patients, and this is particularly important for patients who have IgG myeloma.

So you have an IgG myeloma, has a monoclonal protein of one gram, and then the total IgG is 1,200. That means the functional IgG is 200 only. Now... And historically, hematologists like me were trained to say, well, you know, you're going to monitor patients. And if they have recurrent infections, sinus pulmonary infections was the teaching, then you would give replacement therapy.

Now we are working actually with our colleagues in the Department of Immunology here at Mayo Clinic. So all of our patients were referred to immunology and we have allowed them to take charge of the replacement therapy. And their first reaction was, you know, you hematologists are very conservative about this. You should be more aggressive in replacement therapy. Because what they do is when they're replacing children who have primary hypogammaglobulinemia.

They say our decision is to replace or not. And if we replace, they go for a higher threshold. Our threshold used to be 400 for the IGG. And they say, no, we're going to go for 800 or 1,000 for replacement goals. So, you know, we're very happy we have that partnership. Not every center has it, but I would say that be very attentive to the replacement.

And lastly, I would say the empirical data in this very study show that if you do replace, you significantly decrease the risk of infection. In many of the clinical trials that looked at patients with bispecifics and also in CAR-Ts, most patients were not being replaced. You know, it was about 30% of patients. So not surprisingly, we see very high rates of infection.

Now, one of your questions is what kind of infections do you see, right? So I already alluded to the fact that if you kill late B cells and plasma cells, you're going to have hypogammaglobulinemia. But it turns out, too, that because these T-cells are being called to action all the time, so every time you give an injection of the bispecifics, they have to go and do their job.

We do see some infections as are seen with patients with T-cell immunodeficiency. So people have seen PJP, PML, and other adenoviral infections that can be seen with T-cell immunodeficiency. The field is moving towards the notion, and I think this will happen, of using less frequent administration of bispecifics. And this could be good in two ways. First, it could decrease the risk of infection.

But also there's a possibility that also decreases the risk of exhaustion. So actually the T cells may be more effective if we space out to buy specifics. And empirically, people are testing this to see if that's what we should be doing. But until then, many of the clinical practices are already spacing out by specifics as patients are able to reach very deep responses. In our own practice...

We provide prophylaxis with acyclobar, as is done, you know, for other intensive myeloma therapies, as well as trimethoprim, sulfametoxazole. We monitor levels of CD4 cells as well, too, for those patients. One can see, and it's true also with CAR-Ts, that there can be reactivation of CMB. It turns out most of the time it's low-level reactivation without clinical consequence. So it's not clear exactly that all these patients would need therapy, but it's just something to keep in mind.

And the unresolved question is vaccination because, you know, these patients also will suffer from some of the deficiencies. And I guess... People would say, well, they're more relevant now because we have seen some outbreaks of things like measles across the country. So it's a common question we get. One of the interesting things we have found...

is that some years ago we did a study because similar questions were happening. It was sort of a different time, but there were some outbreaks with measles. And we ask ourselves, okay, if you complete a stem cell transplant in the time of modern myeloma therapy, how many of these patients lose their protective antibodies?

The reality is very few. Most patients keep their immunity. So we don't know what's not the case for bispecifics. I think it's a safe presumption to say, and given what I just said before, that it's possible that they might lose immunity to some of those things. But the problem is if you're getting a bispecific, you probably are not going to mount a very strong immune response if you get a vaccination. So ideally, it would be before, perhaps after, or after they're stopped, if they are spaced.

And that leads me to the final thought. There's some people that are advocating for limited duration of therapy with bispecifics, which also may end up being a feasible approach. So, yeah, you see that throughout oncology, even in prostate cancers, intermittent therapy.

One thing, you know, sometimes, you know, kind of in the general medical oncology purview that we have, where we're seeing each, you know, every day is like a different tumor, and it may be a few months between programs. When I did this recent myeloma program, a bunch of things sort of hit me.

that were not new, but maybe it took me a longer time to process, and I kind of wonder whether that's true of other people. So I'm going to bring some of them up to you. I'm sure the myeloma community and investigators, this is old news, but... I don't know whether everybody appreciates. One of the things was that as I was watching the data for bispecifics, I mean, they really have pretty prolonged PFSs. And it also, as you were kind of alluding to, is kind of comparable to PFS and CAR-T.

Now, you know, it kind of gets into the issue of what comes first. And I know there's a great advantage of CAR-T in that it's a one and done. But I don't know. I kind of wonder whether we underestimate the impact, the long-term impact of just by specifics. Yeah, that's spot on. You know, the way I explain it is the outcomes after buy specifics are a little bit more binomial. Either you're going to do really well or it's just going to be a short-lived duration of benefit.

And we will usually know within a month if the patient is going to have a deep response. To expand a little bit on the durability, we've seen the long-term outcomes in the MAJESTIC-1 trial as well as the magnetism trials. Let's look at iranitamab, so the two bispecifics that we have approved in practice. And what they both show, if you have a complete response, it can be very long-lasting.

The numbers I keep in mind, two years out, somewhere between 60% and 80% of patients can remain without progression, which, as you mentioned, is comparable to what you can see with CAR-Ts. And I think for the time being, that will remain a strong debate because the question is, how do you sequence? Do you go with CAR-T or do you go with bispecific? As of now, they'll be writing sort of comment or where the crowd stands, their favor in Cartee, mostly because of that idea of the one and done.

And the CAR-Ts carry some baggage, you know, with some of those long-term toxicities. And they may be rare, but when they happen, they're serious, you know, including the delayed motor neuron toxicity, the gastrointestinal complications. you know, even secondary malignancies, which, you know, in the net sum, hands down, the Descartes are great treatments, but you have those risks.

but they're less so with the bispecifics. But then you have the lower immediate response to bispecifics. And lastly, we know that if you give a bispecific and later you have a CAR T, the results are going to be inferior for the CAR T. What seems to be coming through, too, is that if you give a CAR T first, the efficacy of a bispecific down the line is actually pretty good. So that may be actually the factor that decides how we sequence those things.

You know, if a patient, for whatever reason, cannot go through a CAR-T and are a good candidate for a buy specific, I think they shouldn't feel bad. It's a great option. I share with you a case we have of a person who's part of my clinical practice, and this patient had severe coronary disease. The patient really couldn't do anything but minimal activities. Emotions would give him chest pain.

And right or wrong, I said, you know, if we put this patient through our CAR T and get CRS and has 24 hours of CRS, I don't know what's going to happen. It's going to be very tricky on him. So we ended up going with that particular case with teclistimab. And now we're two years south and the patient's MRD negative is leaving his life. I'm filling out forms for this and that.

and has a level of control that we would normally only think of with a CAR-T. So I think it's an important part of the conversation that patients should have with their physicians. Reminds me of one of the... Most cited video interviews I've done with patients. We've done a bunch of interviews over the years with patients. One of my favorites that I like to bring up is...

a man who was on teclisimab, just as you said, had gotten treated about two years previously, was now cruising along doing great, and the day I interviewed him was the day that teclisimab was approved. Oh, wow, wonderful. Wonderful. Yes. Yeah, like clinical trials are not like they used to be. You know, people really can benefit from being in a clinical trial. So I always use him as the example. But anyhow, any thoughts about that?

I was just going to say, because you said the clinical trials, you know, in the old days, people used to think about phase one trials with low level response. Right, right, right. Altruistic participation. I mean, now the clinical trials that we're running in myeloma phase one oftentimes have expected response rates of 40% or higher. So the world has changed. It's quite different from when we were in training, right?

Yeah, I'd like to bring that up because about 30% of our audience has been in oncology less than five years, including a lot of fellows. And I don't think they necessarily realize exactly as you said. It wasn't that long ago, phase one studies were really chemo aversus.

chemo B or approved therapy A versus B or combinations. And now so many new exciting things. So another kind of revelation that I got that was kind of delayed, it took a little bit of time. relates to belantumab mafidotin. You can imagine how often we talk about antibody drug conjugates nowadays in almost every solid tumor and a lot of heme.

And, you know, I used to be kind of excited about apolantumab, and all of a sudden, like you say, it got pulled away. And then last summer, boom, these dream trials dropped in there. And I was just generally excited that, you know, there was a positive study or studies. People are interested in it. But it took me a while to realize that one of those dream trials compared Belantimab to DARA in combination. Correct? Correct. And the hazard...

You just showed a whole bunch of studies with Dara and Isituximab where you had great hazard rates under 5, but the hazard rates in that DREAM study for Belantimab versus Dara was like 0.5. Yeah. Yeah. So, you know, one of the questions I asked the team last week was, and of course, Dr. Dimopoulos has done a lot of research. As I said, are you? Does it look like, maybe, that Belantam is more effective indirectly than Dara or the anti-C38? And they both said, yeah. I mean, do you agree with that?

I agree with that. And I think particularly this is with Dream 7, which is Philanthema PD versus Dara PD. Which, by the way, I mentioned it in passing in my presentation, but it was a very courageous study going head-to-head against Dara, too. Absolutely. and still beating it. But I guess the stakes were high. I mean, they needed to have Bella be considered for coming back into the market.

So Bela, when it comes down to efficacy, is definitely more efficacious than Dara, based on what we know from DREAM7. It did have that huge handicap of the keratopathy, but now the dosing schedule... that is being proposed as much better as, you know, 1.9. In the Dream10 study that is testing Bella for frontline therapy in transplanting eligible patients, it's one dose every eight weeks. and then want those quarterly after the first six months. So, you know, it's very spaced out.

And most patients who have the keratopathy with that schedule are predicted to have mostly the ophthalmologic findings, but perhaps a little bit of bother, but not serious bother. So most patients can continue with their normal activities. That's definitely something to consider. Now, this is like sports, right? When we talk about the drugs in myeloma, the reason I use that word is you think something is good and then it comes and it's better.

Because one of the things that we should keep in mind too as well, that Bell is a great drug, but now by specifics as well, are you going to start knocking on that door? In fact, at the Ash meeting, The recent DASH meeting, we saw some early trials of bispecifics as part of frontline therapy. So things are constantly changing. Three years ago, the unquestionable bell of the bull had been daratumumab. And now here come all these other contenders.

So getting back to belantumab, first, you know, you referred to the keratopathy as being a huge problem. I don't know how much experience. I imagine you had a fair amount of experience when it was available or you might have had it on a trial. But first of all, I don't see much else than keratopathy, particularly in terms of quality of life issues, you tell me. And so globally, it seems like if you adjust the dose to keratopathy, as you say, it's a lot less of a problem. Sure.

And if you do that, there's not too much left that I see in terms of toxicity. So, I mean, I don't know what the right answer, and as you say, now the bisphysics are so exciting. But I also wonder, and you showed that, I think it was a Dream 10 ongoing. study, where again, in a combination, I think they're again comparing belantumab to DARA. So I'm looking for why isn't there belantumab plus anti-C to 38?

That's a great idea because, you know, and as he's been shown for my long, if something works, usually works better in combination. I think we have better clone coverage. I think those studies will have to be coming. They will have to be arranged for a combination of antibodies like that. And you're right. And what I mentioned with the keratopathy. I would say it was more of a problem, but I did mention already that I think these changes are pretty significant.

Back in the day, one of the things we experienced with Bela, which was seen at many centers, is that we would start patients with higher doses, more frequent. And then the patients had a more symptomatic carotopathy, and we had to stop treatment.

And then we would find out that six months later, the patients were still doing very well. It was somewhat surprising to many of us thinking, well, I'm going to have to stop. I don't want to see a progression. But no, we didn't see that. So we tend to have some durability too.

to those responses. So if those principles hold as we do this clinical trials, you can see how this will become part of earlier therapy. And like everything else, we learn how to best use it. Maybe there's going to be some other measures that can help. Prevent the keratopathy or it's just at such level that it doesn't become a major problem and has good acceptance by patients.

So given all that, I always like to say oncologists wake up in the morning, they check their phone to see what's been approved, and then they decide what they're going to do about it. So if you wake up tomorrow morning, and I don't know if it's even possible or when this might happen. that Belantamib is approved, or you could access it without any problem. Right now, how would you integrate it into your practice? Yeah, that's a great question.

I used the allusion in a recent talk about the musical chairs right now with all these drugs, because it all depends on what's happening with the other agents. First of all, I would cherish the fact of having Belanthamab in my toolbox. I personally have been moving more into the idea of supporting the use of cell-to-cell for that first relapse based on the data with Cardi24. I'll expand on that in a minute.

But then if that was the case, probably I could see myself using something that is not dependent on T cells after Celta cells. So it wouldn't be unheard of that I would think of. Maybe Belantimab could come for the second relapse. Alone or with something else? I would combine it like in Dream 7, so Belantimab PD probably in that patient population. But there's a lot of things that need to be explained there. One is, you know, why use seal to seal for that first relapse?

Well, I think we're learning if you take patients who are more fit, patients who have less explosive relapse, patients with lower burden of disease. And if we monitor them closely, you know, we're giving dexamethasone to patients who have a rise in their lymphocyte counts. And now we know that we have some of the antidotes that can be used for patients who are starting to develop symptoms of motor neuron toxicity. I feel a lot more confident about our use of these products in the first relapse.

Second of all, I think that we will move at some point to limited duration of maintenance in the frontline therapy with IMITS. such that hopefully pomalidomide will remain a very active drug for that next line of therapy whenever you need an image. So for that reason, I think it would be pretty reasonable to think about... you know, seal to seal and maybe Belanthema following that. And there's another important comment.

It seems like deletion of BCMA, which may be a mechanism of progression after CAR T's and bispecific antibodies, appears to be slightly less common with CAR T's than it is with bispecifics. And if that holds true, then, you know, something like bilantamab may work in that subsequent line of therapy. You could say, well, what are the other options? Another BCMA bispecific, it could be, you know, so that could be something else to consider.

Or could you consider a GPRC5D like talquetamab? And talquetamab is highly effective, but it carries its own baggage. You know, the issues with changes in taste and the dermatologic changes are of consequence to patients. Again, we can manage them better, but it's just part of what comes with that particular drug. So that may be a place where it would fit for me now. For me right now, the most exciting is that Dream 10.

Because I'm a little bit on a crusade right now to raise awareness about neuropathy with bortezoma. The benefit clinical trial that was used for transplant ineligible patients was a French study. They used bortezomib with VRD in patients who are transplanting eligible. They used bortezomib subcutaneous and weekly. And 50% of patients had peripheral neuropathy, and a quarter of patients had grade 3 or higher.

And when I'm working in my clinic, I always tell residents and fellows, you know, if a patient has been treated with bortezomib, I'll bet you we're going to start talking about neuropathy. And I tell them my least favorite story is, Dr.

You saved my life, but I still can't feel my feet. Is there something you have for neuropathy or I have special shoes or they're on gabapentin? So if with Bella, we can up the ante and have more efficacious treatment and yet avoid neuropathy, to me, that would be a major win.

So what about Bella and patients who are not candidates for CAR-T? That could be a very good option as well, too. And also, you know, for whatever reason, there's a patient that wouldn't have access or not a candidate for a bispecific. So I think there's going to be a lot of conversation, a lot of arguing back and forth as far as when do you position Bella for that first relapse. Now, if you were to use Bella for that first relapse...

The one potential implication is that you will decrease a fraction of patients that will respond to a subsequent TCL therapy, whether it's a CAR-T, whether that ineligibility is temporary or permanent. And that's just a compromise that will happen. And so I think that's something that we will have to try to quantify. I think we have to...

Start thinking more and more about the long-term effect of the sequencing of these therapies and what that means for the choices we make as far as what goes first and not. Yeah, it's so hard for people who don't see myeloma every day or don't see any particular thing every day to really get a grasp for the actual value and the benefit that patients experience. And again, it seems like...

To me, maybe we missed that the first time with Bella, and now we're kind of appreciating it more. One thing I just wanted to bring up, you mentioned Siltacel first line. Of course, you went through that data. I'm curious because you also talked about this other newer CAR-T therapy, AnitaCell, and the issue there, of course, with Siltacell, as you were talking about the delayed neurologic, the Parkinsonian things, et cetera, et cetera.

Right now, can you talk a little bit more granularly about what we're seeing with the needle cell? Is it enough patients for you to say, hey, this is definitely going to be different? And most importantly, where would you put it along the line in terms of silt to cell and eye to cell? Is it closer to silt to cell in terms of efficacy?

Sure. No, that's a great question. And I cannot answer precisely, but I would say from what we know right now, and that's with patients that will soon be adding to the hundreds, a need of sales seems to be highly efficacious. So when it comes down to... efficacy, I'd put it closer to sale to sale. And just for the audience, we know that...

continued output of the clinical trial data while not directly doing a comparison head-to-head between IdaCell and Siltacell. I think the consensus by most of the experts is that we have higher efficacy with Siltacell. But with efficacy also comes the toxicity and the toxicity of what's now called on-target off-tumor effects. And the late modern neuron toxicity would belong to that.

So that has not been reported with an E2 cell. So that's what really caught people's attention. And they haven't reported also peripheral neuropathies. Peripheral neuropathies, and I'll get to that in a second, have been seen in about 10% of patients being treated with seal to seal. We have seen them in our clinical practice. They're mostly reversible, but I think they're an indicator of what's happening with this on-target off-tumor effect.

I think the ultimate question is as follows. Is the lower or the absence of motor neuron toxicity with a needle cell a reflection of a better construct that somehow doesn't affect nervous tissue? Or could it be an early indicator of less power and then putting it more towards the IdaCell? Because modern neurotoxicity also was not common with IdaCell. And only time will tell.

I think it's going to be critically important to know the long-term duration of benefit with the need of cell, because just like we did a comparison, as I just did right now, between IdaCell and Siltacell. We know, for instance, that the indirect comparison of the trial shows a PFS of 12 versus 36 months. Real-world evidence is starting to trickle in. It shows longer duration of control with seal to seal.

So I hope that a needle cell has that efficacy. And if it has that efficacy and we still don't see the modern neurotoxicity, then the question would be, well, maybe it's one of two things. Again, the construct is better. or the management is better. Now, I am very encouraged by what we're seeing now with cell to cell. What I mean by that, early trials were showing motor neuron toxicity about 5% to patients. We all had patients in our practices.

Cartitude 4 reported this at 1%. And a recent real-world evidence report from, I think it was 15 centers with close to 250 patients came out at 2%. Now, in my recent practice, and we're doing, you know, in total, this is not only my alone, but we're doing about CAR T cells per month, about 10 of them. I have not seen peripheral nerve, you know, cranial nerve policies recently. So I wonder if it's a better approach on how we're managing now CAR-T. So...

One of my sayings now is the ideal patient for CAR-T is a patient that does not need bridging therapy. So, you know, we have better tools for monitoring relapse, and we know the patient for sure is going to relapse. Can we put them in a path for them to get the CAR-Ts? before there's bulky disease, before we incur a high risk of more extreme CRS and certainly ICANs.

You know, predictors for delayed more neurotoxicity include ICANs and the use of steroids, a little bit of age too matters. So if we get patients... better line up for CAR T, maybe that will decrease that risk of delayed more neurotoxicity. And as I mentioned before, now we monitor very closely the lymphocyte count. There's this notion that if a few days after administration...

of CLT cell, you start having a big spike on those lymphocytes. That seems to be a predictor of higher likelihood of modern neurotoxicity. Really interesting.

So I'm working my way back to the beginning of your talk with the upfront treatment, but I had so many questions about the last part of it, I couldn't resist it. One other thing I just wanted to bring up, you mentioned the teclistamab maintenance study. Sure. a fascinating idea. I'm curious where you see bispecifics heading in terms of maintenance therapy and whether or not we even need lenalidomide.

Okay, I like the way you phrased the last question. Do we need lenalidomide for maintenance? And going forward, the answer, maybe no. Lenalidomide, of course, was landmark because, you know, it's an oral... It could be used for a longer period of time. And in the context of where it was tested with at least three randomized trials and subsequently meta-analysis, it was proven beyond doubt that maintenance was better for patients.

But I think that concept is agnostic to the drug. So in other words, any drug that is good is going to work for maintenance as long as patients can stay on it. And now we see that, of course, with daratumumab, with the trials I mentioned. Why not? That could be seen maybe with, you know, syncopated or infrequent administration of Belanthamab. And that obviously takes you to the bispecific.

Could I see a future where bispecifics are integral for consolidation and maintenance? Yeah, I don't think it takes a lot of creativity to see that. In ALL, we have the clinical trial EA-1910, which is useful in a tumor map for maintenance after induction in ALL patients. And the study was frankly positive. But I think what was even more interesting and surprising in a positive way was that Dr. Litzow, when they...

They amended the study to allow blenotumumab treatment for patients who are MRD negative. And lo and behold, the study was positive in favor of blenotumumab administration. So I could see a parallel track for that to be done in myeloma as well, too, where even if you're MRD negative, you get a few doses of some bispecific. I've always...

Said tongue-in-cheek, if I was diagnosed with myeloma and I completed a stem cell transplant, even if the insurance wouldn't cover, I'd probably pull out my credit card and get a few doses. of a bispecific piece. I think it's very exciting to see what's happening with some of these drugs. And I hope that the trial that was presented by Dr. Samagni will lead to ultimate approval for this type of treatments.

There's a word of caution. Bispecifics are highly effective, and we love them, but they do have that risk of infection. So if one is to use a bispecific, and more so in the setting of maintenance, we don't want to create an undue toxicity that puts someone at risk. for a pneumonia or something that could be ultimately fatal. So it sounds like if you were a patient, you would want to get a transplant nowadays.

Well, I wouldn't say that I want to get a transplant because I know it's a tough thing. So I don't want any patient who would hear this to think I would enjoy that. But I have at least an intellectual commitment to think. The transplant is an important tool. And until we know better, I would still consider it in someone who would be deemed eligible.

I think I mentioned when you look at quads in the transplant ineligible, MRD is somewhere between 50% and 60%. Quads plus transplant, 70% to up to 80%. I think those differences may end up mattering. And when we see the longer-term survival for myeloma patients, almost always it's in patients who get a transplant. Does that mean that you're predicting it or that right now transplant will have a survival benefit?

I think so. I think it does. And, you know, much has been said about studies like the IFM 2009 or determination, and the statement usually goes like this. Well, you know, it improves PFS, but it doesn't improve survival. And I think that's wrong. I think it should be said it hasn't been shown yet to improve survival because if the trial is not designed for that, you cannot address the question. So I always weave in the comment of the absence of evidence is not evidence of absence.

the improvements that we have in overall survival in myeloma over the past many years, many of that comes with studies that haven't shown improvement in overall survival, but it all aggregates over time. Have you ever heard of Sir Richard Pito? Yes, of course. He was the first person I ever heard say that. Oh, the same statement? Yeah, I was literally about to quote him when you said that. He's the first person I remember hearing that.

He really was the one, I think, to me, who even brought in the whole issue of, you know... events and how to look at data and, you know, principles like you were just talking about. Anyhow, I'm sure you see that in your interviews with other colleagues, right? They say, well, it doesn't improve our survival. We cannot say that. No, no, I don't hear that from myeloma people. Actually, I hear people outside of myeloma bringing that up. Got it. You all.

100%. Nobody wavered at all. I've yet to find a myeloma investigator who was affected by that. They all say exactly the same thing as you do. So I want to get back to some of the things you brought up in the beginning that are really important and potentially practice changes.

And one, of course, is the paper, Kiela's study, I think it was called. looking at Dara and smoldering disease. Can you just sort of summarize the bottom line? I mean, it's kind of straightforward and maybe not that surprising, but... I'm sure whether or not it actually is practice changing. And specifically, if you could, or maybe you even are, how would you apply to your practice? Yeah.

I don't think it's practice changing now because we don't have the FDA approval. But once that comes, you're going to find that there is a split of opinions in the myeloma community as to whether it's practice changing or not.

I think that's the way to go. So I'll declare where I am and I'll try to explain some of the nuances. I think it's going to be very hard to make a blanket recommendation. Let's start with a caution. I mean, these trials are directed towards patients that have higher risk smoldering. And the bottom line of the trial was that if you give dartumumab, you delay and diminish the risk of progression of smoldering myeloma to active myeloma. Is that good?

Well, yeah, it depends how you frame that. You would say it's good because you're going to prevent complications. It's good because you could prevent progressive destruction of bone or renal failure, which can be enduring. The skeptics might say, well, you know, if you look at that KELA clinical trial, a lot of the progression were not that serious complications and patients could have been treated and then patients didn't get the best treatment sometimes after progression.

So if I were to follow my patient closely, maybe I could intervene if that is needed. Now, those in favor are going to argue, and rightfully so, said, well, that's what you say, but how good are we at following patients with smoldering myeloma? Are you really going to do it in your clinical practice? And the reality is many people are just lost. Patients come, they're seen once, twice, and they don't have more follow-up. And then the next encounter may be at the time of myeloma progression.

Where I think this is ultimately going to lead is in the continued identification of patients who clearly have either high risk of progression because the markers are such that you can make that determination. Or I think an even larger fraction of people in the hematology and myeloma community are going to be comfortable with saying, if I now have clear evidence the patient is progressing but hasn't progressed yet, then I should start treatment.

But then that brings a logical question that follows that statement, which would be, okay, you say you're going to start treatment. Why would you treat with DARA only? Why are you not going to treat them with four drugs? And that's a difficult question to address because if you already are committed to treatment, why not give the patient the full benefit of the doubt?

You might say, well, there are some patients where I don't want to expose them to all the toxicity. Maybe I'm going to do this and down the line I'll do something else. And you say, what I lose is, well, I lose maybe the efficacy of Dara down the line. It's not going to be the same. But I gain delayed progression and maybe my patient can be treated with something else down the line.

What you gain is just that. The patient may not progress for many more years, and they're happy, and maybe they complete a professional life without interruption or can conduct their daily activities. And sure enough, if they need treatment down the line, they can do that. Now, I myself... We'll be even more proactive in the idea of treating smoldering if I know I have a good backup for that active myeloma.

So if I think two years from now we might use bispecifics VRD combinations, I would say I don't care. I can sacrifice our tumor map knowing that in some patients I'm on a delayed progression quite a bit. I recently was asked to discuss this in a debate and I was asked to take the stance of wish and treat smoldering. And I looked at my practice and I said, I worked so hard on this topic that I actually convinced myself.

And what I said is I look at patients who have smoldering and I have treated, I have treated quite a few patients, but most of them when I see that they're progressing. So, you know, I guess another factor here could be patient involvement in the decision, since it is a difficult decision, and patients who want to be involved and have the ability to understand some of the nuances of treatment, that's always helpful.

Absolutely. Ultimately, I tell patients they are the boss and we're their consigliere, so we provide them advice, but they have to make the decision. But, you know, I've been thinking a little bit about this idea of, you know, the classic question of, you know, delaying PFS in various situations. And as I was looking at this study in mantle cell where the PFS was a 0.75 hazard rate. But it turned out to be like about a year difference.

And I was thinking, I wonder, like three or four years from now, maybe it'll make a year. Like, what's going to happen now compared to a year from now in mantle cell? Maybe, you know, the new drugs are going to move up, et cetera. So same thing in myeloma, even though the hazard... It may not be that great. You delay a couple of years. And like you said, all of a sudden you're getting treated with a bispecific.

first line. So another question in terms of upfront treatment. Again, I'm a simple person. I try to get practical issues, and there's so much data. You reviewed a lot of it, looking at quad therapy upfront. And I guess one sort of global 35,000-foot view of this situation is, what are the situations, if any, right now where you think anti-CD38 therapy should not be part of initial treatment?

I can't see a situation where I would not include a CE38 as part of treatment, salvo, I guess, someone having an anaphylactic reaction, a true anaphylactic reaction, or something that precludes them. Short of that, I don't think any patient should be treated with regimens that don't contain CD38. In fact, my three-step approach, I always start with the first one, which is the backbone of myeloma therapy should be... A C38 antibody plus Landex. And then the secondary steps are...

whether you do a transplant and whether you need to add a PI or not, but everyone should be getting that backbone. And I just can't imagine that there's a situation where I would do that. So for our audience, and to keep it simple, I would say... To me, VRD as such is dead. I think, as we have said, VAT is dead. I think VRD is the same. If you're going to use VRD, it must be used in combination with the antibody with those extremely rare exceptions that I mentioned.

So how about your algorithm for maintenance, particularly as it relates to anti-CD38, but also the use of MRD in making decisions? Well, that has changed. And you probably have heard me say before that I was adapting by MRD. And if it was MRD negative, maybe I would only give land maintenance. And if it was high risk or MRD positive, use Dara RD.

I think with the data that we have with Perseus, more and more I'm convinced that all patients should get DERA in the post-transplant setting. And even in other settings, even for the non-transplant eligible, a little bit longer duration of DERA. And interestingly, I'm hearing more and more from patients when the time comes to maybe talk about simplification of the regimens.

More and more patients are saying, I'd rather stop LEN than DERA because, you know, the safety profile and tolerance profile is so much more favorable for DERA over LEN that they say, I don't mind coming and driving once a month here, getting my shot, but you should take me off the pills. So the other sort of global question I have, given what you just said, is which...

anti-CD38 antibody. And from what I see up until now, that decision has really been dominated by the fact that one of them, specifically Dara, was available sub-Q. But as you point out, we're now starting to see... data with this device, one body device for subcu delivery of izatoximab. I'm curious, have you actually used this new device?

We have not. I have not participated in those clinical trials, but I'm very well aware of the device, and I think it's going to be a wonderful development. I think the choice of one versus the other has been quite a bit of familiarity. I think there's some contractual issues for certain networks that have used one or the other. As of now, I think you're going to have a hard time finding many myeloma people that would lean for one versus the other based on efficacy.

mechanism of action. We can see some differences, but I think it's fair to say that both are highly, highly effective. You know, the data of Imros, for instance, with this atoximab was very powerful. One of the statistics that I loved about that trial, when you look in the supplemental material in the publications, it's time to next treatment. I think time to next treatment showed that only about 20% of patients require change of therapy at five years.

You know, if you're 75 and you have an 80% chance of not requiring another line of therapy for five years, I think that's pretty good. That doesn't mean that's the end of the road. We still have a lot of other options, but that means you have a treatment that's keeping this under good control for a long time.

Absolutely. But again, getting back to choice, and I guess this is going to be not unlikely that this is going to happen if this sub-Q device for ESA comes into practice. Actually, Dr. Dimopoulos, who was on the... program we did last week has, you know, used advice. He showed it to us. He talked, he mentioned that his infusion nurses liked it. And I kind of am wondering, you know, of course, as you, you know, as we know, something becomes available first.

People get used to it and don't necessarily want to switch off it. But also, it looked like maybe there might be the potential at some point in time to either have infusions at home, either by the patient themselves, or maybe sending a nurse out to see the patient and do the on-body thing.

I don't know whether you can do that right now. I don't think so with those sub-Q DARA. But I know that probably patients who have real physical difficulties getting to clinic. But bottom line, are you expecting that if and when this sub-Q device... for ESA comes out, it's going to be kind of a coin flip? Or do you think maybe people are going to prefer this one body device?

You know, I don't know enough to really bet on that, so I'm going to say it's a coin flip right now, but I think the possibility that patients are treated at home is very tantalizing. You know, our center and others are exploring that. There's kind of an interesting story behind this too as well, which is the pharmacoeconomic and the business side.

Those things, I think, as our audience knows, you know, the bread and butter for oncologists comes from the therapy we administer. So people are happy to do that. But as long as you're part of that, you know, you don't want to. We don't. we don't make our living through the writing of clinical notes. So I think, and we also shouldn't commoditize the practice of oncology in the sense that, you know, you need to meet with patients, you need to gauge how they're doing and so forth.

So I think ultimately that's going to happen for many patients' treatment at home, but it has to be fully integrated with the treatment center.

So last question slash topic, you talked about a study looking at mesignamide. And I'm just kind of curious where you see cell mods heading. I feel like I've been hearing about them for so long. They sound so encouraging. You have ibertamide as well. What about these two unapproved agents? Do you expect them to be approved, and where do you think they're going to fit in? Yeah, no, it's...

It's still a little bit of an enigma and a puzzle of exactly how we're going to use them. I think there is no question that they're more efficacious than the current molecules that we have. And we know that from both the in vitro data as well as the data that's coming out clinically. They use some patients with prior exposure. And I think one of the most telling stories with this type of compounds is how the chemistry has evolved and the knowledge has evolved.

You can see very clearly how the doses we use represent that progress. So thalidomide, we started as high as 800 milligrams down to 200 later. REB, 25. two to four milligrams. And we're using even lower doses for the cell months because the binding is there. And I think if some of the complications that have seen with the image could be prevented, such could be secondary malignancies, which is one of the thoughts perhaps with the newer molecules might be better.

or even if just a loan on efficacy, they're better, the question has to be asked. I think the challenge is more one of... both development and commercial one, because I think there's going to be a lot of pressure and people are going to say, and pages might say, well, you have these drugs, why don't you use this first and then try that. But I'm excited with all the...

range of trials that we have going on with the cell mods to see how that works. It was very bizarre that with POM, we knew that, and still know that POM is better than LEN, but we always had to use LEN before, and then I used POM. So it seems like it's a story that is at risk of repeating itself that we might have to use foam before we use cell mods or something. So, Rafael, thank you so much. It's been a pleasure. I was kind of flashing, you know.

Along the way, you made the statement something about RVD is dead or something, or it's out, you know, and I was just flashing. I feel like the history of myeloma, I kind of... been talking to you about for years. I can remember when RVD was so exciting, you know, we talked about it. Now it's out the door, so to speak, but maybe not really, just added on to.

On its own, I think, for the most part, it's out the door. You know, I tell a lot of my colleagues at the global level that as they advocate for access to drugs... They might go to the payers and they might say exactly what you just said. Hey, you should be very happy. Now you have your RBD. It's like, yeah, but it's all generic. Now we need the DARA or the ISA RBD for my patients.

This concludes our program. Special thanks to Dr. Fonseca, and thank you for listening. This is Dr. Neil Love for Oncology Today. Key presentations at the ASH 2024 meeting on the management of multiple myeloma.