Smoldering myeloma remains contentious. The term was coined in 1978. And it was really this seminal paper that you can see on the left describing six patients only, all of whom had 10% plasma cells in a bone marrow and at least three grams per deciliter of a monoclonal protein and with a minimum of five years of follow-up, had not developed myeloma. And this – this was a – a paper that was so controversial that it took actually 33 more years for the IMWG to actually include smoldering myeloma as a real entity.

 

And everybody has probably seen the paper on the right showing what we all kind of have in our head that smoldering myeloma, different from MGUS, because there's 10% progression per year to actual myeloma. But of course, the funny thing has always been if you go out more than five or six years, that seems to flatten and now you have a 1% incidence a year matching MGUS.

 

Definition of SMM: Continued Debate

 

Now it's a pretty rare entity. You know, the incidence of myeloma is somewhere around six to seven in 100,000. This is much less than that. And the iSTOP study going on in Iceland just confirmed that the population incidence in people over age 40 is about 0.53%. We've had different definitions in – in the US versus Europe, everybody kind of agrees 10% plasma cells is what we should use.

 

But then how much monoclonal protein is really considered high? In the US, it's been three grams per deciliter in lots of monoclonal protein, whereas in Spain the focus has been more on these phenotypically aberrant plasma cells in the bone marrow that are lacking or dim for CD19, but have lots of CD56. And they were really the ones who first focused on immunoparesis, meaning low other immunoglobulin classes beyond what's involved.

 

And finally, they have always recognized IGA as perhaps something that is associated with a higher risk of progression for smoldering.

 

Models for Risk Stratification of SMM

 

Now we have these various risk classification systems listed here. There's the Spanish one, the original Mayo that was looking at that three grams and then the 2/20/20 comes in next as Mayo 2018. And finally, we have the IMWG refinement that adds in cytogenetic and FISH risk.

 

But one of the things to point out with these classification systems is that they were all shaped using an academic smoldering population. And I think it's pretty clear that patients referred to academic centers with smoldering myeloma may not be typical.

 

And this is underscored by the bar on the bottom, showing you that in that iSTOP myeloma study, patients referred – patients who were found to have smoldering myeloma with their countrywide screen, only 8% of them actually high – have high-risk smoldering myeloma, whereas in those academic populations, it ends up being about a third.

 

And I think, as many of you know as the 2/20/20 classification has ended up being the one that I think most people remember, because it's kind of easy.

 

QUIREDEX: Len/Dex Followed by Len Maintenance vs Observation in High-Risk SMM

 

Now in terms of treatment for smoldering myeloma, the first phase III study that showed a benefit. There were many previous studies that were done that didn't show any improvement or – or slowing down of progression to myeloma, but was the QUIREDEX study, 119 patients randomized to either lenalidomide for two years with dexamethasone or observation.

 

And you can see that these patients – the average age in the US of somebody with smoldering myeloma is 70. So these were a little bit younger patients. And they met the – these Spanish definition of smoldering myeloma.

 

QUIREDEX: Survival

 

Now this was really striking findings when first published in 2013. So progression-free survival had a hazard ratio of 0.24, big difference. And even the overall survival difference of 0.43. But lenalidomide and dexamethasone for high-risk smoldering was really never adopted, and probably for a couple of reasons, one of which is the study was always thought to probably include people with actual myeloma, since no advanced imaging was used.

 

And in addition, this – this study came out at a time that there was sort of some recognition of potential secondary primary malignancies associated with the use of autologous stem cell transplant and lenalidomide for actual myeloma, and I think that there was some concern about using lenalidomide in what was supposed to be completely asymptomatic patients.

 

And finally, some people really didn't want to – want to give dexamethasone. And it was unclear what the contribution was.

 

E3A06: Lenalidomide vs Observation in Patients With Asymptomatic Smoldering Myeloma

 

So next step was the E3A06 study from ECOG. This was a larger study and actually did require advanced imaging, which was a real plus. 182 patients in the randomized portion that was lenalidomide by itself until progression or observation.

 

Now, one of the problems with this study and interpretation in others is they had to open up the eligibility because of slow accrual. And so patients could be enrolled if they had 10% plasma cells and an altered FLC ratio at all altered, and they could have had smoldering myeloma for five years or less.

 

E3A06: Improvement in PFS, No Difference in Overall Survival

 

But again, they found that big PFS benefit at three years, PFS, meaning progression to myeloma, although in this study it was progression based on both biochemical and a myeloma defining event. No survival benefit. But the feeling was, is that the follow-up at three years was really not long enough to show that. And this study is going to be followed up soon in terms of whether there is some emerging differences.

 

Now, the quality of life didn't appear to be different between the two groups, but the average time on lenalidomide was only a couple of years, suggesting that maybe this was more difficult therapy for people to – to – to maintain.

 

E3A06: Subgroup Analysis of PFS

 

And subgroup analysis, this was not planned. But if you use that 20 – 2/20/20 risk stratification, you can see that really it was the high-risk people meeting that definition who really benefited. And one of the continued to be unexplained finding was that Black patients on this study didn't seem to benefit from lenalidomide.

 

Now, some of the other smoldering studies that – that I'm going to talk about do not have populations. They – they don't have very big non-white populations. So that finding remains unconfirmed.

 

CENTAURUS: Randomized Phase II Trial of Daratumumab Monotherapy for Intermediate-Risk or High-Risk SMM

 

Now, the CENTAURUS study was going on at about the same time. This was really a dose-finding study using daratumumab in smoldering myeloma, looking at a very, very abbreviated course of daratumumab up to many more months. And what they showed was both safety for the use of daratumumab in this population, but a suggestion that a longer course of daratumumab would be helpful.

 

AQUILA: Daratumumab vs Active Monitoring for High-Risk Smoldering Myeloma

 

And of course, this set the stage for the AQUILA trial, which it seems like a long time ago now, but this is only a year and a half ago that this study was presented at ASH in 2024, biggest study to-date for phase III treatment for smoldering myeloma.

 

Now, the high-risk definition is again different than – than some of these other studies because it included patients who had an IGA monoclonal protein. Patients who had immunoparesis only, altered FLC ratio, but it did include patients who had somewhere between 50% to 60% plasma cells in their bone marrow biopsy.

 

Pretty straightforward. Three years of daratumumab. I should point out, in the actual protocol, each of these doses was actually given with Solumedrol. That was the recommendation. So there are some steroids in there. And this was versus randomization to just active observation.

 

AQUILA: PFS and PD or Deaths by IRC

 

And I think you're all familiar with the five-year progression-free survival, 63% for those receiving daratumumab versus 40.8% for the observation.

 

Now, in this study, as - as I mentioned, the previous ECOG study was biochemical progression and a myeloma defining event. In this study, it was either-or, biochemical or a myeloma defining event. Most of the patients had biochemical progression, but there was a striking difference with a hazard ratio of 0.49.

 

AQUILA: Baseline Disease Characteristics and Disease Progression

 

And then if we look at who seems again to benefit, there's about a third of the patients in this study have high-risk smoldering myeloma by 20/2/20. A little bit more of those patients ended up in the observation arm.

 

AQUILA: IMWG Scoring System Subgroups PFS

 

But if we look at the analysis done in last year's ASH by Peter Voorhees, it is suggesting, first of all, that the high-risk patients are benefiting. The intermediate may also be benefiting here, which was something that was a little bit different. And still the low-risk doesn't seem like they are getting much advantage over treatment. But there is a rumor hazard that there may be some updates to this coming again as longer follow up occurs.

 

AQUILA: OS Benefit Potentially Driven by High-Risk SMM

 

There is this overall survival benefit favoring daratumumab intervention. The one – one criticism has been that the patients who ended up in observation getting myeloma treatment, only a minority, 17% had anti-CD38 therapy offered to them when they progressed, but that may be a reflection more of the time when the study was conducted.

 

AQUILA: Safety

 

Now the safety. I think this was what really led to the FDA approval in November. Very familiar to everybody who treats myeloma. So you see a little bit more respiratory infections using daratumumab. But in terms of other types of toxicities, really very easy to manage by and large.

 

Cross Trial Comparisons: QUIREDEX vs E3A06 vs AQUILA

 

Now, if you want to do cross comparisons for this therapy that is really not designed to cure smoldering myeloma, but basically to manage it and make it more MGUS-like, very similar in some aspects. Those high-risk definitions are a little bit different. And as I mentioned, this is a younger population on these trials, 64 median age. But suffice it to say that that we have now multiple phase III studies for this lower intensity approach.

 

GEM-CESAR: Curative Strategy for SMM

 

But what about if you think what we should do with smoldering myeloma is try to cure it? So there have been a number of phase II studies currently either underway or completed GEM-CESAR is the probably the biggest or – or most with the longest follow up. And this was a study basically myeloma therapy with carfilzomib/lenalidomide/dex induction, autologous stem cell transplant. More carfilzomib/lenalidomide/dex for two cycles and then a two-year maintenance with lenalidomide and dexamethasone.

 

GEM-CESAR: Survival

 

A couple things about this study. If you go back, the study was started before the 2014 revision of what myeloma is, is. So it includes about a third of patients who actually have myeloma. But there are a couple of things, I think, to notice here is that certainly patients and those that are in the red on the right who were MRD negative, seem to benefit more in terms of their time to biochemical progression. But there's no plateau here. These patients continue to relapse.

 

And another factor here, it's not shown on this slide is that six of these patients actually died from non-myeloma complications related to, in a couple of cases, secondary malignancies and also VTE. So again, you know, whether this is the right approach or not. This is the data.

 

ASCENT: Fixed-Duration Therapy With Car/Len/Dex-Dara for High-Risk Smoldering MM

 

In terms of other more intensive treatments, there's the ASCENT trial using carfilzomib/lenalidomide/dexamethasone/daratumumab for an intensive six months, a less intensive other six months, and then another 12 months of daratumumab and lenalidomide. This study was presented a couple of years ago, showing a progression-free survival of 89%, which is very similar to E3A06 using lenalidomide alone.

 

This study is going to be updated, I believe, maybe at this year's ASH, from what I have heard. And we'll see if – if it looks like there are a percentage of these patients who continue to do well.

 

Immuno-PRISM: Phase II Study of BsAbs in High-Risk SMM

 

And what about T-cell redirecting therapy for smoldering myeloma? Well, we are asking that question now too. Probably the – the oldest study, which is a couple of years, three years is the Immuno-PRISM study from Dana-Farber, where they took 12 patients and treated them with six months of teclistamab, 100% response rate, 100% MRD rate. However, this is again a – a kind of a mixture of – of risk in terms of their smoldering myeloma. Not everybody here is high-risk, but they – they have set the stage for this.

 

LINKER-SMM1: Linvoseltamab in HR-SMM

 

And of course, we came up last year with the LINKER study for smoldering myeloma. This is a larger study still. This was sort of preliminary results presented at the International Myeloma Society last fall.

 

Phase II LINKER-SMM1 Linvoseltamab in HR SMM: Primary Efficacy

 

Their response rate also pretty stunningly high. This is two years of linvoseltamab looking at – if you look at those patients who were evaluable for both response and MRD negativity, once again, it's 100%. And I think that, you know, the question is, is whether there is going to be a signal that this is maybe the way to go with longer follow up, which we don't have yet.

 

Many of you may know that here at this meeting, there was the ERASMM trial presented of elranatamab in 50 patients with smoldering myeloma who met the 20 – 20/2/20 definition of high-risk. Their response rate was 92% with 90% MRD negativity. Looked to be a pretty reasonable safety signal, but their follow-up was 14 months.

 

CAR-PRISM: Phase II Study of Ciltacabtagene Autoleucel (Cilta-Cel) in SMM

 

Of course, there's the CAR-PRISM trial that some of you may be aware of using ciltacabtagene autoleucel for the treatment of smoldering myeloma, and this was just presented at the AACR meeting as one of the plenary sessions and also just published. This is 20 patients, again, high-risk, but not the 20/2/20 definition of high-risk who underwent a cilta-cel CAR T procedure.

 

And there are a couple of things that came out of this that I think are important to mention. The response rate was there. It was 100%, as well as the MRD at 10 to the minus six 100%. But there were some toxicities seen. There was seven out of 20, 35% with neurotoxicity. This was non-ICANS neurotoxicity. And even though they tried to bring down the doses of the infused CAR T to try to limit this, four of the seven patients had a cranial nerve palsy but three had non-ICANS toxicity that has remained.

 

And I think it does bring up the question as to if you're taking an asymptomatic population, is this perhaps a direction that you want to go?

 

CAR-PRISM: Cilta-Cel in High-Risk SMM

 

This is showing you that basically what I just said.

 

Safety: Approved Bispecific Antibodies vs CAR T-Cell Therapy

 

And another thing that I just want to say about T-cell redirecting therapy of both kinds, either bispecific or CAR T for smoldering myeloma. This is actually a slide that Dr. Chari put together showing basically non-myeloma deaths on patients on bispecific and CAR T trials.

 

Now this is not newly diagnosed myeloma. And of course, these are heavily pre-treated patients. Some of this predates the widespread use of IVIG. But I think it is something to just remember that these therapies – these – these T-cell redirecting therapies do have significant side effects. And I think if we want to start applying them into completely asymptomatic patients, that is something to – to think about.

 

Utility of GWAS and Genomic Profiling

 

One of the things that probably is going to come up in the next couple of years is better defining the high-risk smoldering population. So GWAS or looking at SNPs. We think that we might be able to pick out patients who are clearly high-risk, but even more excitingly, maybe identify patients who should never get tested again.

 

Genomic IMWG Prognostic Score

 

This is something that we're hoping to see. This is a study from Francesco Maura looking at combination of genomic profiling at five different risk categories. If you combine that with 2/20/20, you can clearly see that there are patients who look like they absolutely need treatment for myeloma versus those who look like maybe they could get away with very little intervention.

 

NCCN: Recommendations for Patients With Smoldering Myeloma

 

This is our NCCN guidelines for smoldering myeloma. Always, always, we would like to recommend clinical trials as there's so much we don't understand yet about smoldering myeloma. But suffice it to say, I think people do support the idea of treating high-risk smoldering myeloma by 20/2/20, meaning two out of those three cat – three risks, two grams per deciliter of monoclonal protein, 20% plasma cells, FLC ratio above 20 of the involved versus uninvolved. And certainly either daratumumab or lenalidomide can be considered.

 

Additional Trials in HR-SMM

 

There are many, many trials underway. I think it's going to be a little bit difficult to sort through all of these, but I think not only do we want to look at efficacy, but – but also safety is going to be very important here.

 

DETER-SMM: Daratumumab/Lenalidomide/Dexamethasone vs Lenalidomide/Dexamethasone in High-Risk SMM

 

I just want to put in a plug for our ECOG study, which is the DETER smile – smoldering myeloma. This is a pure, pure, high-risk population. Within one year of diagnosis, they have to have 20/2/20 at least two high-risk features. And they get two years of therapy with either daratumumab, lenalidomide and dexamethasone or lenalidomide and dexamethasone as we don't think this group of patients should be observed any longer, but should be intervened upon.

 

Expert’s Algorithm for Managing Smoldering Myeloma

 

So this is just – I will not belabor this, but suffice it to say that there are still patients with smoldering myeloma who probably shouldn't be treated. Those are the low-risk individuals based on probably anybody's classification system. And over on the far left there, there are those individuals who may be able to be called out for myeloma style treatments. But again, clinical trial, if you have the option, is always preferred.

 

Conclusions

 

So finally, what I want to leave you with is that high-risk – or excuse me, low-risk smoldering myeloma can change to high-risk. So these patients should be followed over time. And we're still not 100% able to pick out who that's going to be.

 

And I think other than the therapies that we know have phase III data backing them up, everything else should be considered still investigational at this time.

 

ASCO 2026: Key Studies in SMM

 

I mentioned the ERASMM study.

 

Let's Revisit Our Case

 

Patient Case

 

And then finally, we're just going to go back to our case again.

 

Posttest 1

 

And this patient does in fact meet the criteria for high-risk smoldering myeloma, or I don't know if we're looking at the polling or – but in any case, yes, she has – she does meet the 20/2/20 high-risk. And it would be very reasonable to consider treating her with daratumumab or possibly lenalidomide if a trial is not available.

 

And I think that's the end of my time. Thank you.

 

MM Confirmed: What Are Next Steps for Optimal Treatment of NDMM?

 

Dr. Mark Schroeder (Washington University): Okay, on to newly diagnosed myeloma.

 

Let's Consider a Patient Case

 

We'll start again with the patient case.

 

Patient Case

 

A 77-year-old man is diagnosed with multiple myeloma. He has two high-risk cytogenetic features of translocation (4;14) and 1q, and is deemed not eligible for transplant because of his age and his preference.

 

Pretest 2

 

In this case of newly diagnosed myeloma, what frontline regimen would you recommend for this patient?

 

Okay. The majority choosing a quad induction regimen.

 

Interactive Case Discussion

 

One additional case.

 

Poll 4

 

Now we have a 60-year-old female, otherwise healthy and considered fit, newly diagnosed with myeloma as well with lytic bone disease and some fractures. Also has a high-risk 1q and a translocation (4;14) myeloma. Which regimen would you choose for this transplant-eligible patient with myeloma?

 

Okay. Most dara/bortezomib/len/dex and some with the carfilzomib/len/dex background – backbone, rather.

 

Evolution of Myeloma Staging Systems

 

So when we talk about risk stratification in myeloma, this summarizes the evolution of this staging system over the last – over 50 years now. More – more recently, we used the revised international staging system, and that's what's highlighted and used in the ongoing studies that I will highlight in this talk.

 

And the second revision of the ISS better stratifies risk in patients with myeloma. These staging systems incorporate clinical factors as well as cytogenetic factors.

 

What Do We Mean by “High Risk”?

 

In addition to the revised international staging system for myeloma and the cytogenetic abnormalities, clinical features also predict risk. A lot of the studies we’ll review exclude patients who've had plasma cell leukemia, which has recently been revised to include patients with over 5% circulating plasma cells.

 

Extramedullary leukemia – myeloma is worse prognosis. We'll talk a bit about how frailty impacts progression-free survival – survival in a couple trials. And then there's a class of patients that are considered functional high-risk where they don't respond to the first-line, or they progress rapidly after transplant within 18 or 24 months.

 

2024 IMS/IMWG Consensus on Defining High-Risk Myeloma

 

And recently, the IMWG and International Myeloma Society have come up with the high-risk definition in the age of quad therapy and revised what was previously considered high-risk if you had one cytogenetic abnormality by FISH. And now you can see in the boxes that to be high-risk by this consensus group staging, you have to have two factors: translocation of 14 with a 1q or 1p and just monoallelic loss of 1q or 1p is not enough. You have to have two, or you have to have a biallelic loss of 1p.

 

In addition, this new staging system incorporates next-generation sequencing. So now we have to send not only FISH on patients newly diagnosed with myeloma, but also sequencing to identify TP53 mutations which are associated with worse prognosis. The one laboratory parameter that remains in this revision is beta-two-microglobulin elevation.

 

Myeloma Treatment Paradigm

 

So our paradigm for myeloma in 2026 still involves stratifying patients into transplant-eligible and ineligible. There's a period of induction and potential consolidation and maintenance, whether you're transplant-eligible or ineligible. And our goals of treatment are to reduce the burden of disease, decrease the chance of complications, ideally, collect stem cells for somebody who's transplant-eligible.

 

And we want to lead to deep responses, and those deep responses are typically measured by MRD testing, which has been now approved as a surrogate endpoint for clinical trials in predicting progression-free survival. So the deeper the response, the better in treatment of newly diagnosed myeloma.

 

NDMM: Transplant-Eligible Patients

 

Let's review newly diagnosed transplant-eligible myeloma.

 

NCCN: Initial Therapy for Transplant-Eligible Patients With MM

 

In the following slides, I'll review studies that support the NCCN recommendations for treating newly diagnosed myeloma, as shown here.

 

Frontline Therapy for NDMM

 

To highlight, the take-home message is that as many answered in the initial poll, four-drug induction therapy is standard for newly diagnosed transplant-eligible myeloma. This includes an anti-CD38 monoclonal antibody, proteasome inhibitor, immunomodulatory drug and steroids. Of course, supportive care with antiviral prophylaxis, DVT prophylaxis, anti-infective or bacterial prophylaxis is sometimes considered in anti-resorptive therapy to prevent fractures.

 

CASSIOPEIA (Bortezomib/Thalidomide/Dexamethasone ± Dara) Update: MRD-Negativity Rates and PFS

 

The first study to support the incorporation of four drugs or quad induction therapy was CASSIOPEIA, which randomized patients to bortezomib/thalidomide/dexamethasone with or without daratumumab. This was before lenalidomide was approved in Europe, and this study has, as shown here, improved progression-free survival in those that get the quad induction and led to a deeper response, as shown post induction and consolidation with improvements in MRD negativity rate 10 to the minus five of 60%.

 

PERSEUS: Bor/Len/Dex ± Daratumumab in Transplant-Eligible NDMM

 

In follow-up to PERSEUS has been a phase II study called GRIFFIN – or in follow-up to CASSIOPEIA was the phase II study of GRIFFIN and now the phase III PERSEUS study, which I think many are familiar with, which was a large randomized study of daratumumab/bortezomib/len/dex compared to the triplet of bortezomib/len/dex.

 

Everybody on this study was transplant-eligible. The upper age limit was 70, and those patients going through transplant had additional cycles of consolidation, followed by maintenance with dara and lenalidomide. And this study was novel and incorporating an MRD-directed maintenance approach. In those that became MRD negative, daratumumab could be discontinued. And the primary end point was progression-free survival. The quad one out.

 

PERSEUS: PFS and MRD Negativity Rate

 

Progression-free survival was improved with bortezomib/len/dex. And MRD negativity rates in this population were upwards of 65% to 75% shown on the right. And 65% of patients also had sustained MRD negativity.

 

MASTER: PFS and OS

 

What about choice of proteasome inhibitor in the quad regimen? The MASTER study was a prospective study that used MRD-guided treatment and a backbone of carfilzomib with lenalidomide/dexamethasone and daratumumab.

 

Patients in this study were enriched for high-risk features. About 50% of the patients, compared to around 20% by our old criteria for high-risk were included in the MASTER study. They underwent induction in transplant, and then MRD was monitored. And if patients had MRD negativity and it was sustained, they could stop along this treatment.

 

So what they observed on the left is that patients with zero or one high-risk cytogenetic abnormality did very well. They had similar progression-free survival with quad induction. Two high-risk cytogenetic abnormalities had worse progression-free survival. And those patients with two high-risk cytogenetic abnormalities that became MRD negative and then stopped maintenance, ended up progressing sooner.

 

So the quad therapy of induction improved outcomes for those that had the one worst cytogenic – one high risk cytogenetic abnormality. But it was still a problem for those that had two risk cytogenetic abnormalities.

 

The table summarizes the three-year progression-free survival. If somebody has two high-risk cytogenetic abnormalities, as in our case, progression-free survival at three years using this four-drug induction is about 50%. A little bit better if they have sustained MRD negativity. And this supports the idea that in patients that do have newly defined high-risk myeloma, that continued maintenance is probably best for them.

 

Trials of Isatuximab Quadruplet Therapy in NDMM

 

Another trial supporting quad induction therapy now switches to the CD38 monoclonal antibody, isatuximab. There are several studies that support isatuximab and the quad regimen. GMMG-HD7 was a large phase III study, and part one of the study has been reported out. Patients were randomized isa/bortezomib/len/dex. And they went on to transplant. If they had less than a CR, they actually received two transplants. And unlike PERSEUS, they went directly on to maintenance therapy in this study. And at the maintenance point were randomized to either isa/len or len alone.

 

And then the second study I'll highlight is the GMMG-CONCEPT study, which enrolled all high-risk myeloma patients, had a four-drug induction with isa/carfilzomib/len/dex and patients were either deemed eligible or ineligible for transplant. They underwent further four-drug consolidation and three-drug maintenance with isa/carfilzomib/dex.

 

GMMG-HD7 (Part 1): PFS

 

What GMMG-HD7 showed is that progression-free survival again was improved, with the quad supporting that isatuximab is similar to daratumumab in terms of responses and progression-free survival. MRD negativity rate was 66% with the quad. This analysis would be for the maintenance part of the study, which is yet to be reported.

 

GMMG-CONCEPT: MRD Negativity Rate and Responses

 

GMMG-CONCEPT study enrolled again high-risk myeloma by the old definition of high-risk, showed that in patients that were high-risk, that MRD negativity rates after transplant for transplant-eligible patients were around 68%. For those that were otherwise deemed high-risk with the four-drug isa/carfilzomib/rev/dex regimen.

 

[00:36:11]

 

MIDAS: MRD-Driven Strategy Following Isa-Car/Len/Dex Induction in Transplant-Eligible NDMM

 

Two additional studies. One MIDAS and then another IsKia evaluated isatuximab. MIDAS study evaluated the role of isatuximab/carfilzomib/len/dex as initial induction, but then randomized patients after MRD testing from six cycles of induction therapy, and they stratified patients into a standard risk, which means that they had MRD negativity at 10 to the minus five after six cycles of induction or high-risk. So they had MRD greater than 10 to the minus five.

 

And what they observed on the right is that those patients that were MRD positive and randomized to a tandem transplant compared to single transplant had no improvement in deepening of MRD response from 10 to the minus fifth to greater than 10 to the minus sixth.

 

And in the standard risk group, they looked at again deepening of MRD response and showed that those that are MRD negative after six cycles of induction did not have a deepening of MRD response after transplant.

 

IsKia EMN24: Car/Len/Dex ± Isatuximab in Transplant-Eligible NDMM

 

IsKia is the most recent study, randomized phase III comparing isa/carfilzomib/len/dex to carfilzomib/len/dex. Again, patients who are less than 70, undergoing transplant.

 

IsKia EMN24: Post consolidation MRD Negativity by Cytogenetic Risk

 

MRD negativity was the primary outcome, and you can see here summarized that this is a highly potent regimen. MRD negativity rates, even with now what we define as high-risk myeloma to high-risk cytogenetic abnormalities obtained MRD negativity at 70% in this study, which was the primary outcome.

 

CASSIOPEIA Maintenance: Daratumumab vs Observation

 

Moving on to maintenance, which is an area I think that's a little bit controversial in myeloma currently. Revlimid certainly has support from multiple prospective studies for maintenance in myeloma. And I want to focus on the studies that I just reviewed, which all included a maintenance or a light consolidation type approach.

 

CASSIOPEIA randomized patients post-transplant to daratumumab or observation showed that daratumumab improved progression-free survival. And inclusion of daratumumab in the maintenance, improved progression-free survival, whether you had the quad induction or you had triplet.

 

Indirect Comparison of PFS: PERSEUS vs CASSIOPEIA

 

This recent analysis, indirectly comparing PERSEUS to CASSIOPEIA, suggested that the addition of lenalidomide improved progression-free survival. And then the two drugs, dara and len may improve progression-free survival more.

 

We have ongoing studies. The DRAMMATIC study to name it, is a randomized study comparing revlimid to dara/revlimid maintenance therapy after transplant and includes patients that receive quad induction. So that question whether dara and len is better than len or better than daratumumab alone hasn't yet to be answered.

 

AURIGA: Daratumumab/Lenalidomide vs Lenalidomide as Posttransplant Maintenance Therapy for NDMM

 

The AURIGA study enrolled patients who had undergone transplant but had not had any CD38 exposure and randomized them to daratumumab or lenalidomide.

 

AURIGA: MRD Negativity at 12 Mo and PFS

 

This study showed that MRD response is improved by the addition of daratumumab in somebody that has not seen a CD38 antibody prior to transplant, along with progression-free survival. So in this study, dara/len, if somebody has not been exposed to daratumumab pretransplant can improve responses and progression-free survival.

 

Efficacy of Induction Regimens in Transplant-Eligible Patients With NDMM

 

So this table summarizes the studies I discussed. The landmark of determination showing MRD negativity rates with triplet and transplant were around 50% before these more modern quad studies. And PERSEUS and IsKia and the GMMG studies support that response is deepened, progression-free survival is longer with quad therapy and newly diagnosed myeloma.

 

NDMM: Transplant-Ineligible Patients

 

So let's move on to transplant-ineligible patients.

 

NCCN: Initial Therapy for Transplant-Ineligible Patients With MM

 

Again, these are the NCCN guidelines for transplant-ineligible patients, and I'll highlight studies that support these recommendations.

 

Clinical Trials of Dara/Len/Dex vs Len/Dex in Transplant-Ineligible NDMM

 

The study that supported standard practice until recently for transplant-ineligible patients is the MAIA study, and also IFM had a randomized phase III study in patients who were transplant-ineligible. Of note, the MAIA study did not have an upper age limit, neither did IFM.

 

Both enrolled frail patients. MAIA about 50% of patients were frail. IFM specifically enrolled patients that were frail by a frailty score. And using dara/len/dex was superior in terms of progression-free survival and also MRD negativity rates were 30% with this regimen. So this was the standard practice to consider for somebody that was not transplant-eligible.

 

Impact of Frailty and Dexamethasone

 

In what we've learned from both MAIA and IFM is that frailty impacts prognosis. So again, MAIA didn't necessarily enroll just frail patients. But those that were frail had a worse progression-free survival, whether they were assigned to dara/len or – or len/dex. So frailty matters in terms of progression-free survival and survival in patients.

 

And the IFM specifically had dose-limited dexamethasone exposure. So in somebody that's frail, you could consider discontinuing dexamethasone after a couple cycles and continue len/dara with similar progression-free survival to dara/len/dex.

 

And at the bottom of this slide is a table that highlights that if somebody is – is not eligible for transplant but deemed fit, there is evidence through the GEM-2017FIT trial to support four-drug induction therapy with dara/carfilzomib/len/dex, leading to deep MRD negativity at 60% to 50%.

 

CEPHEUS: Daratumumab + Bortezomib + Lenalidomide + Dexamethasone in NDMM Without Planned Transplantation

 

And this study subsequently supports the evaluation of quad therapy for newly diagnosed transplant-ineligible myeloma. And I'll review those studies here now.

 

CEPHEUS compared dara/bortezomib/len/dex to bortezomib/len/dex. Eight cycles were given in patients who were newly diagnosed and up to the age of 80. The primary endpoint was MRD negativity, and maintenance therapy was continued until progression with dara and len/dex.

 

CEPHEUS: PFS and MRD Negativity Rate

 

CEPHEUS confirmed that quadruplet therapy improves progression-free survival in these patients in that MRD negativity rates were also improved.

 

IMROZ: Isatuximab + Bor/Len/Dex in Transplant-Ineligible NDMM

 

IMROZ substituted dara for isatuximab, so different CD38 monoclonal antibody. Again, randomized patients who were less than or equal to the age 80 – to age 80 and deemed transplant-ineligible.

 

Isatuximab is given as an IV formulation in this study and more frequently than typical regimen for daratumumab and continued until progression. Primary endpoint was progression-free survival for IMROZ, and the quad again beat the triplet in terms of progression-free survival.

 

IMROZ: PFS and MRD Negativity Rate

 

And MRD was also deepen as shown on the right of the slide.

 

BENEFIT: Isatuximab + Bor/Len/Dex in Transplant-Ineligible NDMM

 

And finally, you probably noted that the comparator was triplet with bortezomib/lenalidomide/dexamethasone in the last two studies. What if we compare to a regimen similar to MAIA, which was the standard? And this is where the BENEFIT study comes in, which evaluated isa/len/dex and bortezomib versus isa/len/dex.

 

And in the BENEFIT trial, they enrolled patients up to 79 years old or otherwise in – in reasonable fit shape. And the primary outcome, again, was MRD negativity after 18 months of therapy.

 

BENEFIT: MRD Negativity Rate and ORR in ITT Population

 

Benefit showed that MRD was improved with the quad. The results were immature, so PFS was not different between the arms yet.

 

Upfront Therapy for NDMM-TI Randomized Studies

 

So to summarize, the treatments we have for newly diagnosed myeloma that's transplant-ineligible with kind of landmark studies on the right. The SWOG-777 study showing a median progression-free survival of around 43 with triplet therapy. And our quadruplet therapy has improved progression-free survival, improved MRD negativity rates.

 

Key Takeaways

 

So the three key takeaways from this talk or the quad induction therapy should be considered for most patients with newly diagnosed myeloma. But you should consider incorporation of assessment of frailty to guide whether inclusion of a proteasome inhibitor in this quad is good for somebody who's not going to be transplant-eligible.

 

And we know that frailty assessment impacts progression-free survival and survival of patients with myeloma.

 

And finally, maintenance approach is prolonged progression-free survival, whether lenalidomide is – or dara/len is superior to lenalidomide or isa/len superior to len alone has yet to be determined.

 

ASCO 2026: Key Studies in Newly Diagnosed MM

 

Some studies and abstracts at ASCO for you to peruse and you may have already heard that – and I didn't include it here. But the PERSEUS study was updated yesterday in terms of stratifying patients into high-risk and showed that even in the new definition of high-risk, responses were still deepened by the quad.

 

Now, Let's Revisit Our Patient Case

 

So let's revisit the patient case.

 

Patient Case

 

We had a 77-year-old male with myeloma. He had two high-risk cytogenetic features, a (4;14) and a 1q and was transplant-ineligible.

 

Posttest 2

 

So which frontline regimen would you recommend for this patient now?

 

Okay. Pre and post, bortezomib/len/dex-lite. Okay. Completely. Okay. Majority improved.

 

Posttest 2: Rationale

 

Okay. So quad induction therapy supported by CEPHEUS and IMROZ and the BENEFIT study.

 

And that's it. I'll pass it off to Carol.

 

Updates on New Treatment Options for Previously Treated MM: Optimizing Therapy Sequencing in R/R MM

 

Dr. Huff: So thanks very much. We're going to go on a bit of a whirlwind tour through relapsed/refractory myeloma at this point in time. But we'll start off with a few cases and a question.

 

Patient Case

 

So the first is a 75-year-old woman who was diagnosed with myeloma in 2018. At that time, she received three-drug therapy with bortezomib/lenalidomide/dexamethasone, an autologous transplant, and lenalidomide maintenance therapy. She achieved a complete remission and maintained lenalidomide for eight years, but now is progressing through lenalidomide. She was referred for consideration of CAR T-cell therapy but has declined this treatment.

 

Pretest 3

 

And so the question here is what second-line treatment of those available would you recommend for this patient?

 

1. Belantamab plus bortezomib/dexamethasone;
2. Daratumumab/pomalidomide/dexamethasone;
3. Daratumumab/bortezomib/dexamethasone;
4. Pomalidomide/dexamethasone; or
5. Teclistamab/daratumumab.

 

Okay. Very good. We will come back to this question at the end after we go through some data.

 

Pretest 4

 

Our next question is ESA – ESO-T01 is a novel CAR T-cell therapy under development for the treatment of relapsed/refractory myeloma? Which of the following is the unique aspect of this therapy?

 

1. It employs a small D-domain for faster on/off activity;
2. Has two binding moieties on the chimeric antigen receptor;
3. Is generated in vivo without requiring ex vivo manufacturing; or
4. Targets GPRC5D.

 

Okay. Very good.

 

Patient Case

 

And our third question is a 79-year-old woman who's in her third cycle of belantamab/bortezomib/dexamethasone for relapsed/refractory myeloma. She complains of having blurry vision and has her scheduled ophthalmologic follow-up five days before her next scheduled dose of belantamab. The ophthalmologist notes that her visual acuity is now 20/40 from a baseline of 20/30, and she has superficial punctate corneal changes consistent with mild keratopathy.

 

Pretest 5

 

And the question is, which of the following is the most appropriate approach for the management of her belantamab with grade 1 mild ocular toxicity?

 

1. Proceed with treatment as planned;
2. Hold treatment until improvement to grade less than or equal to 1 and resume at the same dose;
3. Hold treatment until grade less than or equal to 1, and resume at a reduced dose; or
4. Permanently discontinue belantamab.

 

Okay. Very good. We will come back to this one as well too.

 

Novel Therapies in Multiple Myeloma

 

So not to belabor things. I think everyone here is very familiar with this, but really just looking at our timeline, in the last 11 years, we have had the approval of two monoclonal antibodies, two CAR T cells, one antibody drug conjugate and four bispecific T-cell engagers.

 

And the myriad of options that we have available at this point in time is quite large. We won't go through all of the data, but just to kind of set the stage for all of the wonderful options we have available for our patients at this point in time.

 

Relapsed Myeloma: Questions to Ask

 

But when a patient has recurrent myeloma at the time of first relapse, questions that we should ask ourselves are, first off, is this patient refractory to lenalidomide? And if so, are they a candidate for CAR T-cell therapy? And if so, refer that patient for CAR T-cell evaluation.

 

If they are – and I should also say CAR T cells would – excuse me. Clinical trials. If this patient is eligible for clinical trials, consider clinical trial enrolment as well too. If – if neither of these are options or not acceptable to the patient, certainly consider patient and disease-related factors in deciding your next line of therapy.

 

In second and subsequent relapses, again, ask ourselves the question whether this patient is a CAR T-cell candidate, and if so, make sure that that patient is evaluated. Are there clinical trials the patient is eligible for and obviously encourage them to enroll? And if those don't apply, consider what prior therapies, what the responses, tolerance and toxicities there were to help make the next treatment choice.

 

CAR T-Cell Therapies in Relapsed and R/R MM

 

So let's first talk about what we know about CAR T-cell therapy.

 

CARTITUDE-1: Cilta-cel in Patients With R/R MM

 

And again, you are probably all very familiar with the data from CARTITUDE-1 looking at ciltacabtagene in relapsed/refractory myeloma. This data was updated at ASCO last year, with the five-year data showing that a third of patients were treatment and progression-free five years after treatment.

 

This was a trial for patients who had had at least four prior lines of therapy. The median number of prior lines of therapy was six. These were patients who really had very little, if any, treatment options available with really remarkable response.

 

Phase III Data: Moving CAR T-Cell Therapies Earlier in R/R MM

 

And so this led to earlier phase trials looking at CAR T cells in earlier lines of therapy. And the two that I'll highlight here for you are the KarMMa-3 trial looking at idecabtagene in patients who had had two to four prior lines of therapy and were refractory to their last line of therapy, and CARTITUDE-4, looking at ciltacabtagene in patients who had had one to three prior lines of therapy and were refractory to lenalidomide.

 

You can see here the – the number of triple class refractory was higher in the idecabtagene trial. But you can see the overall response rates were 70 to 85% for patients in these trials, with median duration of response of about 14 months for idecabtagene and not reached that as of 30 months of follow-up for CARTITUDE-4.

 

CRS and neurotoxicity are the side effects that, again, you are all very well familiar with, with high rates, although much of it concentrated in the lower – lower grades 1 and 2, even for our CAR T cells.

 

KarMMa-3: PFS and Response

 

Looking at this data in a little more detail from the KarMMa-3 trial, you can look at the two different arms. These are patients who received idecabtagene as opposed to standard regimens. And you can see the median progression-free survival of 14 months for those receiving idecabtagene versus only 4.5 months for standard of care therapy and the higher overall response rates and duration of response on the right-hand side of the slide.

 

CARTITUDE-4: Efficacy Outcomes

 

Similarly, in CARTITUDE-4, similar findings. The patients who received CAR T-cell therapy with ciltacabtagene had a 30-month progression-free survival of 60% versus 26% for those receiving standard of care. And what you can see with longer follow-up on the left-hand side is those responses continue to deepen in the patients receiving ciltacabtagene with longer follow up, more patients in complete remission and deeper remissions over time.

 

You can see the hazard ratios at the bottom right-hand side of 0.29 for patients for progression – with progression-free survival for patients receiving ciltacabtagene versus standard of care.

 

iMMagine-1: Phase II Study of Anitocabtagene Autoleucel in R/R MM

 

What are our next CAR T-cell products? So the iMMagine-1 trial is a phase II study looking at anitocabtagene, which is also a BCMA CAR. But as you'll see in the top right-hand corner, a novel feature of this is that it has a D-domain, which is thought to have a faster on/off and hopefully lessen some of the toxicities that are seen.

 

This is the phase II trial for patients with relapsed/refractory disease with three or more prior lines of therapy. You can see the criteria there. Lymphodepleting therapy and infusion of idecabtagene – sorry, anitocabtagene and assessing response.

 

iMMagine-1: ORR and MRD Negativity

 

This is the data that was presented at EHA last year. A median follow-up of 13 months. An overall response rate of 97%, very high, and a median time to response of a month. 93% of these patients were MRD negative at 10 to the minus fifth. And this is undergoing review at this point in time at the FDA.

 

Investigational CAR T-Cell Therapies in R/R MM

 

What are some of our investigational CAR T-cell products? This is just a table summarizing several of these. Not all of them. I will call your attention to the second column. AZD0120 is a dual-targeting BCMA CD19 using the fasTCAR manufacturing process with a much shorter vein to vein times upwards of a few days, just to manufacture these.

 

In the third column – the third column is arlocabtagene targeting GPRC5D. And this data in – in phase I development, 87% overall response rate. And at this ASCO will be presentation updating on the phase III QUINTESSENTIAL-2 looking at arlocabtagene versus standard of care.

 

And then on the right-hand side is the first in vivo CAR T product, the ESO-T01 looking at a nanobody-directed lentiviral vector, allowing in vivo development of CAR T cells in a patient, so not requiring the ex vivo manufacturing processes allowing for direct injection into patients and early data is promising.

 

Holding Therapy, Bridging Therapy, and Lymphodepletion Chemotherapy in MM

 

Just as a description of what we need to think about is many times patients are progressing. And so consideration for holding therapy before we collect those cells to control the disease without jeopardizing the ability to collect cells. Once cells are collected for the current CAR Ts that we have, bridging therapy to control disease to allow time for manufacturing, and then lymphodepleting therapy associated with infusion of those CAR T cells.

 

CAR T-Cell Therapy: Acute Toxicities

 

Our acute toxicities are cytokine release and cytopenias, as well as ICANS and then immune effector cell-associated HLH syndromes and the management on the right-hand side of the slide, which again, you are all quite familiar with at this point.

 

CAR T-Cell Therapy: Delayed Toxicities

 

Delayed toxicities are typically managed when patients return away from the CAR T center back to their home oncology practice. And really those are being mindful of B-cell aplasia, hypogammaglobulinemia as well as prolonged cytopenias. And then as Natalie mentioned in – in other trials as well as in these, the long-term neurologic events and neurocognitive treatment-emergent adverse events to be managed as well as secondary malignancies that have been reported.

 

Management is on the right-hand side, but really important is management of infection and utilization of IVIG prophylactically and long-term, as well as antimicrobial agents, both in the acute period and longer term for patients with ongoing cytopenias.

 

Bispecific Antibodies in R/R Multiple Myeloma

 

So what about bispecifics in myeloma?

 

Bispecific Therapy Options for Multiple Myeloma

 

As I mentioned previously, we have four FDA-approved bispecifics at this point in time: three targeting BCMA, one targeting GPRC5D that are on this slide here. These are summarized here on this slide.

 

Efficacy of Bispecific Antibodies in R/R MM

 

The three BCMA, the approval trials listed here, MagnetisMM, MajesTEC and LINKER. These were patients who had had a median of five prior lines of therapy and an overall response rate of 60 to 70%, with median progression-free survival is anywhere from 11 to 17 months or more.

 

And GPRC5D, talquetamab, the MonumenTAL-1 trial, looking at two different dosing schedules weekly and every two weeks, with a median of five to six prior lines of therapy and median progression-free survival of 7.5 to 11 months.

 

Safety of Approved Bispecific Antibodies for Multiple Myeloma

 

This is the safety data, and I will call your attention to the cytokine release. The vast majority of these are grade 1 with low incidence of grade 2, low rates of ICANS and the unique side effects of on-target/off-tumor from GPRC5D targeting of talquetamab with dysgeusia, dry, mouth, dysphagia, ageusia as well as skin and hair and nail toxicities for management for patients.

 

Class Effect: Incidence of Infection With Bispecific Antibodies in MM

 

Infection though is really important and we've certainly gotten better. When these trials began, there was not universal inclusion of IVIG. And so infection rates are certainly higher in the initial trials. But any grade infection and infections can continue to persist even beyond the initial phases. Any grade infections anywhere from 60 to 75% and grade 3 infections anywhere from 20 to about 45%.

 

So it's important to make sure that we are vigilant and attentive that patients can continue to develop infections over time. And there are lots of efforts that are ongoing now to decrease the frequency of dosing, even considering discontinuation of these agents to help restore immunologic health and reduce these risks.

 

Bispecific Antibodies in R/R MM: Efficacy by Type of Prior Anti-BCMA Therapy

 

One of the questions, though, has to do with sequencing, and I really don't have time to present all of the data that we have here. But many of these later trials do allow patients who have had prior BCMA-targeted therapy. And what we can see based on this summary here, looking at data for teclistamab, elranatamab, linvoseltamab and talquetamab is that patients who’ve had prior BCMA-directed therapies still do respond to these agents.

 

The – the response rates are often a little bit lower, but they still do respond. And the longer duration away from these other therapies really does seem to matter. There is data that's being presented here at ASCO really suggesting that, which I think many of us believe that if a patient is a CAR T candidate, at least based on what we know now, we would prioritize CAR T over bispecifics rather than bispecific followed by CAR T for longer, better response and durability of those responses.

 

Select Ongoing Phase I/II Trials With Bispecific Antibodies in R/R Multiple Myeloma

 

So what are some of our ongoing phase I/II two trials of other targets? There is targeting FcRH5 with cevostamab, and then there is etentamig targeting BCMA as well too. The value here is that it has two BCMA binding domains and a faster on/off that – that hopefully is lessening the severity of infections and toxicity related to that.

 

It also is dosed less frequently on a monthly basis and – and flat dosing that you can see there.

 

Bispecific Antibody: Combination Therapy

 

So what about our bispecific combinations?

 

MajesTEC-3: Teclistamab + Daratumumab vs Daratumumab-Based Regimens in R/R Multiple Myeloma

 

So we will touch brief – we will touch on these. The MajesTEC-3 led to the approval of teclistamab with daratumumab. And this looked at teclistamab/daratumumab versus daratumumab in relapsed/refractory myeloma after one to three prior lines of therapy. This data was presented at ASH and then subsequently published and then approved.

 

MajesTEC-3: PFS

 

And what you can see here is the three-year, 83% progression-free survival for patients receiving daratumumab with teclistamab versus 30% receiving the standard of care regimen – the standard of care regimen on this arm. I should also point out that only about 5% of patients had had prior daratumumab in this combination arm that's there.

 

LINKER-MM2: Linvoseltamab + Carfilzomib in Patients With R/R MM

 

We also have the LINKER-MM2, looking at linvoseltamab with carfilzomib in relapsed/refractory myeloma. This is patients who have had three or more prior lines of therapy and were either triple class exposed or double refractory, received linvoseltamab for the first cycle, then combination therapy.

 

[01:04:17]

 

LINKER-MM2: Response

 

And what we can see here is a very high overall response rate, upwards of 100% in the 150 milligram arm with carfilzomib there, and overall response rates that you can see in the swimmer plot for patients, ongoing responses beyond 2.5 years and deepening over time.

 

TRIMM-2: Tal + Dara + Pom Cohort Antitumor Activity

 

From the TRIMM-2 trial just highlighting the talquetamab/daratumumab/pomalidomide cohort. These patients had, again, very high overall response rates, and patients could go on to this trial being refractory to daratumumab or to pomalidomide. And what you can see in the left-hand side of the slide is even patients who were daratumumab refractory had a 78% overall response rate, and those that were pomalidomide refractory had an 81% overall response rate.

 

And prior T-cell redirecting therapy also had an 82% overall response rate. Patients who were anti-CD38 naive or sensitive had 100% response rate.

 

And you can see on the right-hand side of the slide, the progression-free survival curves, looking at different dosing schedules for this, but very promising data here.

 

RedirecTT-1: Teclistamab Plus Talquetamab in R/R MM

 

And – and finally, the RedirecTT-1 trial looking at teclistamab and talquetamab in relapsed/refractory myeloma. This was a trial where patients had had a median of four prior lines of therapy and was enriched for patients with extramedullary disease. And the initial phase of the trial, about a third of the patients had extramedullary plasmacytomas. And you can see that there was an 80% overall response rate for patients at the recommended phase II dose, with over half the patients achieving a complete response.

 

RedirecTT-1: Talquetamab + Teclistamab Among Patients With True EMD

 

The second phase of this trial enrolled patients who had true extramedullary disease at least one lesion that was two centimeters and was not contiguous with bone. And this reported a 79% overall response rate in this patient population, significantly higher than what might be anticipated, pulling out this subgroup from other trials that are there.

 

The trial also allowed changing to monthly dosing after four cycles for patients who were in at least a very good partial remission and after six cycles for all patients. And almost 78% of patients did switch to monthly dosing and a median progression-free survival of about 15 months for patients and a 12-month projected progression-free survival of 61%.

 

You can see down in the bottom corner patients who had had prior T-cell redirecting therapy, either with anti-BCMA CAR T cells with FcRH5 bispecific antibodies or belantamab, and again, very high responses, very small numbers, but nevertheless very encouraging.

 

Phase I Study of Trispecific Antibody JNJ-5322 in R/R MM

 

The last in this section we will talk about is a phase I study looking at a trispecific antibody targeting both BCMA, GPRC5D, as well as CD3. And what you can see in the population of patients who were naive to both BCMA and GPRC5D on the three rightmost bars of the graph on the left-hand side is that the recommended phase II dose. There was 100% response rate of – at the recommended phase II for patients who were naive, but still 55% of patients who had been exposed previously did respond.

 

Antibody–Drug Conjugate: Belantamab Mafodotin

 

DREAMM-7: Belantamab Mafodotin + Bortezomib + Dex vs Daratumumab + Bortezomib + Dex in R/R MM

 

If we turn our attention to our antibody drug conjugate, belantamab mafodotin with bortezomib dexamethasone, the DREAMM-7 study. This was patients who had had one or more prior lines of therapy. They were randomized to belantamab with bortezomib/dexamethasone or daratumumab with bortezomib/dexamethasone for eight cycles, followed by ongoing therapy either with belantamab or daratumumab, and looked at progression-free survival.

 

DREAMM-7: PFS and OS

 

And this trial showed superiority for the belantamab/bortezomib/dexamethasone arm over daratumumab/bortezomib. And this led to FDA approval of belantamab for patients who had had at least two prior lines of therapy, including an immunomodulatory drug and a proteasome inhibitor. And you can see the – the three-year projected data on the right-hand side.

 

DREAMM-8: Progression-Free Survival

 

The DREAMM-8 study looked at pomalidomide with belantamab and dexamethasone versus pomalidomide/bortezomib/dexamethasone, and this did not lead to FDA approval. The FDA felt that there might be better dosing adjustments that are there. But nevertheless, you can see from this trial a significant improvement in progression-free survival with belantamab, with pomalidomide and dexamethasone versus the bortezomib/pomalidomide/dexamethasone.

 

DREAMM-7 and DREAMM-8: Ocular Toxicities

 

The ocular toxicities are – are the predominant side effect. They do occur in the vast majority of patients. And you can see in this trial, 80 to 90% of patients had some ocular toxicity, but the rates of discontinuation were low. And over 90% of patients recovered their vision with time. So they do resolve with dose reduction and/or delay and the median time is about 30 days to improvement.

 

Keratopathy and Visual Acuity Grading Scale Monitoring/Managing Bel-Maf–Induced Ocular Toxicities

 

This is the recommendation. So grade 1 keratopathy at the top, you would continue treatment. There is no need to make dose adjustments. But with grade 2, 3 or 4, the dose recommendations and the dose adjustments are listed here.

 

Select Ongoing Clinical Trials of BCMA-Targeted Therapies (ADC, CAR-T and BsAbs) in MM

 

These are just a selection of ongoing clinical trials of BCMA-targeted therapies in myeloma. And data will be forthcoming on these.

 

Novel Therapeutics: CELMoDs

 

Segueing into our last area, and that is of CELMoDs.

 

Chemical Structures and Relative Preclinical Properties of IMiDs, Iberdomide, and Mezigdomide

 

And so our immunomodulatory drugs, lenalidomide and pomalidomide, have really been some of our first game changers in myeloma. And now we have iberdomide and mezigdomide, which you can see their chemical structures on the right-hand side of the slide that have higher rates of cereblon bonding – binding and greater immune stimulation in synergy.

 

Select Data With Iberdomide in R/R MM

 

The – these are some select trials with iberdomide in relapsed/refractory myeloma, either the doublet iberdomide/dexamethasone or iberdomide/dexamethasone/daratumumab and then iberdomide/dexamethasone with bortezomib.

 

And you can see here, these are patients who have had two to three prior lines of therapy. On average, they've been have a median of four to six prior lines of therapy with overall response rates in the 40 to 50% of patients. And predominant toxicities are hematologic. Ongoing data in the phase three XCALIBER trial and relapsed/refractory disease is forthcoming.

 

Select Data With Mezigdomide in R/R MM

 

Selected trials with mezigdomide, again, doublet data with mezigdomide/dexamethasone or triplets with mezigdomide/daratumumab/dexamethasone or mezigdomide/elotuzumab/dexamethasone.

 

Again, these are pre-treated patients. In general, they are heavily pre-treated patients, particularly in the doublet trial, with a median of six prior lines of therapy but promising overall response rates anywhere from 40 to almost 80% of patients.

 

And so these trials are ongoing, as well as looking at teclistamab and mezigdomide in patients with relapsed/refractory myeloma.

 

NCCN: Treatment of R/R MM

 

These are the NCCN guidelines for relapsed/refractory disease, breaking this down into recommended regimens and useful in certain circumstances.

 

An Expert’s Approach to Relapsed MM

 

And I will just leave you with this diagram somewhat akin to what Natalie showed you for smoldering myeloma to try to help walk through options to consider for patients. Always, we would prefer clinical trials for patients who are eligible. But in the absence of that, looking at whether they are refractory to lenalidomide or not? How many prior lines of therapy? What they are – what their disease is refractory to, and helping to inpatient-centered care decide what would be next.

 

Patient Case

 

So if we go back to our cases, the first being a 75-year-old woman who was diagnosed in 2018. She received bortezomib/lenalidomide/dexamethasone, a transplant, and lenalidomide maintenance. Achieved a complete remission that lasted eight years and now is progressing through lenalidomide. She was referred for consideration of CAR T but declines this treatment.

 

Posttest 3

 

What second-line treatment would you recommend for this patient at this time?

 

Okay. So I can't see. It looks like we have about 77%. So – so the best answer here is in fact teclistamab/daratumumab for this patient at this point in time.

 

Posttest 3: Rationale

 

And this comes from the MajesTEC-3 trial showing superiority of this regimen in patients who had had one to three prior lines of therapy, superior even to option C, daratumumab/bortezomib/dexamethasone. The others are not approved for patients in second-line therapy.

 

Posttest 4

 

All right. ESO-T01 is a novel CAR T-cell therapy under development for treatment of relapsed/refractory myeloma. What is unique about this therapy?

 

1. Employs a small D-domain;
2. Has two binding moieties of their - on the chimeric antigen receptors;
3. Is generated in vivo without requiring ex vivo manufacturing; or
4. Targets GPRC5D.

 

All right. Yes. The correct answer here is it is generated in vivo and does not require ex vivo manufacturing.

 

Patient Case

 

All right. All right. Our next question is a 79-year-old woman in her third cycle of belantamab/bortezomib/dexamethasone for relapsed/refractory disease. She has blurred vision. She's seen her ophthalmologists within the 10 days that are required, and she has been found to have a slight decline in her visual acuity to 20 over 40.

 

Posttest 5

 

What is the most appropriate approach for patients who have belantamab-associated grade 1 ocular toxicity?

 

All right. Yes. The correct answer here is to proceed with treatment.

 

Posttest 5: Rationale

 

Grade 1 does not require dose reduction or holding.

 

Ensuring Equitable Care for Minority Patients With MM

 

All right. And just three last slides to just touch on and ensure that we have equitable care.

 

Call to Action—Facts About Black Patients and Myeloma

 

So patients – Black patients with myeloma generally are about five years younger than – than other patients and particularly Caucasians. MGUS and myeloma are twice as common in Black patients. And yet they're less likely to receive what are known as the four T's: transplant, triplets, trials and CAR T-cell therapy. And they're less likely to be diagnosed with high-risk disease.

 

And what I will show you is that they achieve equal or better outcomes when they receive the therapy.

 

Survival Outcomes by Race in Observational Study

 

And so this is data looking at the – the CoMMpass registry, looking at survival-based on race. And yet you can see that Black patients do not do as well as White patients. And yet if they received at the data that's available, triplets in transplant, they do equally well. And so we need to ensure that our patients all have access to all of the available therapies that's there.

 

Potential Solutions for Reducing Disparities

 

And I will just leave you with this. You can study this at a later time, but just some of the opportunities that we have to reduce the disparities in the treatment of our patients with myeloma.

 

Key Takeaways

 

And so just from key takeaways, BCMA and other targets are offering great promise. Targeting T cells with CAR T-cell therapy and bispecifics is now moving to earlier lines focusing on supportive care and really ensuring that we have access to novel agents. The future for relapsed myeloma is exploring alternate schedules, sequencing and combinations.

 

ASCO 2026: Key Studies in R/R MM

 

And I will just leave you with a few key abstracts that you may want to see or did see yesterday here at ASCO.

 

Hot Topics: Key Questions and Controversies

 

And I will segue into our next section. And we will have a conversation about some key controversies and discussion.

 

Interactive Discussion

 

So I'm going to come sit down. And I will let – I'll let Nathalie start. Which of the NCCN guideline updates are the most critical to implement right now?

 

Dr. Callander: Well, I think the hardest ones that we have, as you well know, being on the committee is in the relapsed area I think. It's – it's been a little bit hard to keep up with what's actually happening on the ground. And I think a lot of the trials that you very elegantly presented here are not addressing yet patients that we're going to see here in the US, that is double refractory after first-line of therapy. So patients who are lenalidomide and daratumumab refractory.

 

There are very few trials that – that look at that particular population. Most of them are either in relapsed dara unexposed. Or, you know, they – they are just have had transplant plus len. And so I think that's been something that just as a committee that we've been having a little bit of a hard time to keep up and try to make it relevant for those patients who are walking in the door.

 

Dr. Schroeder: Yeah, I – I think definitely bispecifics immunotherapies were recently implemented and those are having a large uptake in management of patients with myeloma. I think your recommendations in terms of considering CAR T is something that, that I would do at first relapse for patients. And I would consider CAR T in the – in the first relapse for most of my patients.

 

Dr. Huff: Yeah, I would agree. I think it's the – the rapidity with which patients we are moving things forward and then having the trials and the answers to really speak to the next line. You know, we are wonderfully adopting quadruplets and doublet, perhaps maintenance and then what to do after that. And – and we really don't have that data as yet.

 

So I think the other piece is that, you know, really trying to make the NCCN guidelines usable for people and really help guide things. And I know that we've – we've all been working very hard on that to try to make them user friendly and relevant for people.

 

So what do you think is going to change in the near future?

 

Dr. Callander: Well, I – I think that there's a couple of key trials that in the interest of time that nobody could present. I think we're certainly going to want to see what CARTITUDE-5 and CARTITUDE-6 look like. So these are trials that are comparing – CARTITUDE-5 even – even though it's a not even read out, still incorporates just a triplet lenalidomide/bortezomib/dex for patients who are not transplant-eligible and comparing that with CAR T.

 

I think that is going to be a big – a big trial to see whether autologous stem cell transplantation just gets axed permanently. That's obviously CARTITUDE-6.

 

So I think those are – are going to be very important. And I think we're also seeing in some of the studies presented at ASH a year ago, it seems like it's ancient history again, just using the incorporation of bispecifics upfront. And I think that those are potentially hugely practice changing.

 

Dr. Schroeder: Yeah, I – I agree. Incorporation of bispecifics in newly diagnosed myeloma patients in the high risk or the ultra-high risk, the newly defined high-risk patients incorporating CAR T-cell therapy. There's ongoing development of studies for high-risk patients to use CAR T post-transplant to consolidate transplant responses.

 

And so I think, yeah, immunotherapy moving early in the line is the next.

 

Dr. Huff: And I think even post CAR T, what – what else can we do? You know, what – are – are we going to do maintenance therapy? Are we going to add in other things? Are there able – ability to deepen responses if we don't see the depth that we want? So very good. All right. What about –

 

A Final Survey

 

All right. I guess you want – are you – I will advance these slides. Sorry.

 

Poll 5

 

Okay. So two quick polling questions and then we will get to some of your questions that are here. So do you plan to make any changes in your practice based on what you learned today?

 

1. Yes;
2. No; or
3. Uncertain.

 

Poll 6

 

All right. And then if you could please just take a moment to enter one key change you plan to make in your clinical practice based on your education today. That would be great.

 

Q&A

 

All right. So in your practice, Natalie, for smoldering myeloma, where does high-risk cytogenetics come into your management options?

 

Dr. Callander: They absolutely come into play and it's one of the IMWG risk stratification. It's certainly something that I look at and it's incorporated in the DETER-SMM trial. So I consider it as one of, you know, the four high-risk features that you can look at. So I – I definitely pay attention to that.

 

Dr. Huff: For those over 80, would you consider – how would you decide quadruplet therapy for those patients?

 

Dr. Huff: So there are validated frailty scores to use. It is, I think most patients that I see over 80 probably still get a triplet. And so it would be a person over the age of 80 that looks and performs like a 70-year-old that I would consider exposing to a proteasome inhibitor.

 

Dr. Callander: I just want to just give a shout out along those lines to the ECOG trial, EAA 181, which is looking at sort of the backwards quadruplet question. So patients get DRd, lenalidomide/dexamethasone/daratumumab for nine cycles upfront, and then they're randomized if they're MRD positive to the inclusion of bortezomib for another nine cycles, yes or no. And I think this is really a non-transplant. It is transplant deferred. This is a study that we've accrued a lot of patients on. I just put somebody on who's 82 this week.

 

I think that's a very important question to look at it on the back end. Are there patients who really don't even need it? So I – I – I think that's been a very good study.

 

Dr. Huff: Yeah, that'll be interesting to see, for sure. All right. Several of these are in the relapsed setting, but I may ask them to you all. So what – what schedule of belantamab do you all use? Every three to four weeks, every six to eight weeks, every eight to 12 weeks.

 

Dr. Schroeder: I have to confess, I don't use belantamab a lot.

 

Dr. Huff: Okay.

 

Dr. Callander: We've had belantamab around for a long time because we had some of the original DREAMM studies. It's – it’s a very useful drug. And if – if – we try to back off as soon as possible to usually 12 weeks even. And we've had a couple of patients on the extended use program that have had biannual injections and stayed in remission. So.

 

Dr. Huff: Yeah, I would say I try to back off as quickly as I can. I tend to use more of the other BCMA-targeting therapies, but we too had patients in the earlier trials and they – but I would say tend to be patients, probably more in the eight week schedule. I think it's really balancing between the – the toxicity and the efficacy of it. And so making sure that, you know, you still have your target in mind. But at the same token, trying to ensure that patients are able to quality of life aspects that are there.

 

All right. So the next question is what are the preferred therapies prior to BCMA CAR T apheresis that are not expected to risk the BCMA product being out of spec?

 

So I will – I will share my thoughts first. And feel free…

 

Dr. Callander: Oh, yeah.

 

Dr. Huff: And so we actually haven't had a lot of difficulty with BCMA products being out of spec. And there – there actually is some thought as to the – the rapidity with which the cells are collected and otherwise. But I think the thing you want to make sure the – the thought is reducing the amount of alkylating agents and multi-agent chemotherapy. So I personally don't use pace chemotherapy at this point in time, but reducing those aspects and trying very hard.

 

I do not use bispecifics before I try to collect the cells. I will use them as part of my bridging therapy, but not – I will use an alternative bispecific as part of bridging. So I try to get the disease well enough control that I can get the patient to a collection that's there.

 

Dr. Callander: Yeah. I think for, you know, whether you want to label it holding therapy or bridging therapy, I – you know, I think that the – the drug that has probably fallen off in use the most is bendamustine. I think people are very much staying away from that. But you sometimes do have patients who have very aggressive, bulky disease, and we will still give them cyclophosphamide-based regimens, whether it's carfilzomib/cyclophosphamide, which, you know, a couple of cycles or even one cycle can be enough to – to get a person able to go ahead and get CAR T collected.

 

Dr. Schroeder: Yeah. Unfortunately, not everybody can move quickly to CAR T at my center. So sometimes I'm recycling prior therapies to try and hold their disease that they haven't seen before. I do avoid alkylators. I try to avoid bispecific antibodies prior to pheresis.

 

Dr. Huff: All right. One of the questions here is why do we feel – why do I feel, why do we know that myeloma is different in Black people than in White people? And I don't think we fully know the answer to this. We do know that there – there tends to be more IgG myeloma in – in Black people than in White people.

 

But what we do know is that if we can give them therapy, they will do just as well as others. It's really access to – to care. But there have been a lot of efforts ongoing trying to look at genetic differences and aspects and really haven't fully teased all of this out at this point in time.

 

Dr. Huff: Yeah, I would agree with that. I mean, there seems to be a higher incidence of (11;14) translocations. In general, some – there seems to be a different kinetic response in terms of – of patients with (11;14) that ultimately do better, but they're slower sometimes. And then in just in terms of some of the GWAS studying that has been done, there seems to be some differences, but I would agree that I'm not sure that we completely understand it. There's the whole Duffy antigen question that's come up. But – but I think we still have a lot more to learn.

 

And I would 100% underscore what you're saying is it's access, access, access is probably the most changeable thing that we can do at this point.

 

Dr. Schroeder: Yeah, and I think the data that you showed, if you have access to therapy and transplant, outcomes are improved.

 

Dr. Huff: All right. The – the – the last question here is, will bispecific therapy be compared to CAR T cells in the near future?

 

Dr. Callander: Ooh.

 

Dr. Schroeder: Well, I mean people – they’re doing cross-trial comparisons with MajesTEC-3 in CAR T and progression-free survival head-to-head comparisons as opposed to using a bispecific to those CAR T.

 

Dr. Huff: I would envision that maybe the question, but I think that would be a hard trial to do because...

 

Dr. Callander: In the relapsed setting, maybe because of the starting point, like what are you going to make that getting on and how unstable are those patients going to be? I think that might be a little bit difficult, but I certainly think – I mean, there are – there are those out there who think that CAR T is just going to be a novelty and that it's all going to be bispecifics that that's what we're going to use it for. And I know there's absolutely people who have that opinion.

 

Dr. Huff: I think once they have greater adoption out in the community, they will – they will be much more widely utilized.

 

All right. Any parting comments?

 

Dr. Callander: Well, I think, you know, anybody who's come to ASCO in the last 10 years and comes to these myeloma sessions. I mean we have more and more and more and more things to discuss and more and more drugs. And I think the – the sequencing issue is probably one of the other big ones that you alluded to that we are still trying – we're really struggling, I think, with that, trying to figure out what you do.

 

You know, you nailed everything for the front line. I think everybody feels like you said, very comfortable. But it's now what are you doing second, third, fourth.

 

Dr. Schroeder: Right. Yeah. I mean, in – in newly diagnosed myeloma, I think quad is accepted. And as we move immunotherapies earlier, potentially transplant may be supplanted.

 

Thank You for Attending

 

Dr. Huff: All right. And I think, you know, as we get later lines of therapy, it's really continuing to try to – I didn't show this data. But you know, if you look across the world, there's a lot of attrition line after line. So really trying to give the very best therapy at each time, but making sure we have ongoing options available for our next line and trying to balance the efficacy, the risks, the benefits and patient-centered care and patient – you know, patient preference engagement in the process.