The first portion of our program is we were going to talk about ensuring equitable care for minority patients with myeloma.

 

[00:06:10]

 

This is data that comes from Charmoun and colleagues that was published about 5 years ago, evaluating patients diagnosed from 2005 to 2014 through the National Cancer Database, looking at factors that were associated with improvement in survival.

 

This showed younger patients, those with fewer comorbidities, those living in a higher median economic area, and treatment in academic centers was associated with an improvement in overall survival for patients diagnosed with myeloma.

 

[00:06:42]

 

But what are the factors that affect treatment for patients with myeloma? And we can bucket these in several categories: patient-specific factors, disease factors, and socioeconomic factors, race, ethnicity, insurance availability, geographic location, socioeconomic status, and access to healthcare.

 

[00:07:02]

 

What we do know beyond that are, particularly for patients with myeloma, but all cancer patients, is the significant financial toxicity associated with treatment, not just the cost of the care, but the lack of employment income both for themselves many times, for their caregivers, time away, and all of those aspects factor in. The psychological and psychiatric aspects of this, their patient education aspects, support groups, care partner support, nutrition, sleep, and so many other aspects of care that we need to factor in for the treatment of our patients.

 

[00:07:40]

 

What are health disparities?

 

Health disparities are preventable differences in the burden of disease that we can address to achieve optimal health that are experienced by those that are socially disadvantaged. Health equity refers to individuals achieving their highest level of health through the elimination of these disparities in health and healthcare.

 

[00:08:02]

 

What are some of the drivers of these disparities?

 

You can see them listed here. Systemic racism, challenges within our healthcare system itself, social determinants of health. But the ones that we can impact upon, in particular delays in time to diagnosis, ensuring access to care, and ensuring that we have the diversity, the cultural sensitivity, and the communication of our healthcare professionals and our clinical trials such that they are reflective of the patient population that we are treating.

 

[00:08:36]

 

Some important facts are that Black patients have a longer time from their symptoms to diagnosis. They do not get to healthcare. It takes longer to make these diagnoses.

 

Black patients are about 5 years younger, on average, than White patients, but myeloma and MGUS are twice as common in Black patients as in Caucasians. They are also less likely to receive what are known as the 4 Ts, although it probably is the 3 Ts and a Q at this point in time: transplant, triplets, now quadruplets, which we will hear more about, clinical trials, and CAR T-cells.

 

Interestingly enough, there are biologic differences that studies are ongoing trying to sort out, but that oftentimes myeloma in Black patients has less high-risk disease than in others for reasons that are still being investigated, but survival in Black patients is about half what has been seen in White patients across the board. But if Black patients receive the same therapy, they achieve equal or better outcomes.

 

[00:09:39]

 

And we know this from several studies. And so, this is data that was published about 5 years ago looking at the CoMMPASS registry of 639 patients, looking at survival based on race, which you can see on your right-hand side of the slide, that across the board, White patients seem to do better, but with therapy with triplets, again, this is older data, there were comparable outcomes between Whites and Blacks. Again, evidence that if the comparable therapy is given, we can achieve the same or better outcomes for our patients.

 

[00:10:16]

 

This is data from the SEER database looking at the incidence rates of myeloma. It is, as noted before, more common, about twice as common in Blacks than Whites, but also the death rates are higher. Again, access to care, ensuring equitable care that patients get, can help eliminate this.

 

[00:10:36]

 

Unfortunately, there has been low enrollment of Black patients in myeloma clinical trials. This is data looking across diseases, lymphomas as well as myeloma, and only 4.5% of patients in the FDA review of myeloma trials were Black. This was performed about 5 years ago.

 

Increasing availability of trials improved access to novel therapies for underserved populations. They are more representative of the patient population with myeloma and help us to better identify molecular subgroups and potential differences in toxicities and side effects related to therapy.

 

[00:11:18]

 

How can we do this? How can we work on overcoming these disparities or reducing these disparities?

 

With regard to clinical trials, broadening our eligibility criteria, ensuring that our designs of trials encompass subtypes of disease that are common to Black patients, having diversity officers, reaching out to community partners and advocacy groups to try to increase enrollment in trials, ensuring that our staff have consistent education on differences in races, ethnicities, and values and culture systems so that we can better engage our patients that are there. Lots of efforts are going on here, but hopefully and with confidence that we can improve access to care for all patients with myeloma.

 

[00:12:08]

 

So if we segue now into evaluating and managing smoldering myeloma –

 

[00:12:14]

 

We will come back to our patient that we just talked about previously, a 58-year-old woman, no past medical history.

 

You can see her laboratories again here: white count of 4.3, hemoglobin 14.9, platelets of 252,000, serum-protein of 7 1⁄2, albumin of 4.8, and normal creatinine of 0.9, immunoglobulins are there with an IgG of 1436, an IgA of 42, an IgM of 49, an M-spike of 0.9, an elevated light chain ratio of 41, serum immunofixation showing IgG kappa, and urine immunofixation showing kappa light chains. 40% plasma cells, a 1q duplication on FISH, a 13q deletion, and no evidence of bone lesions.

 

[00:13:02]

 

And so this patient was diagnosed with smoldering myeloma, and the question now is: what would you recommend for treatment for this patient?

 

1. Daratumumab/bortezomib/lenalidomide/dexamethasone;
2. Lenalidomide, ± dexamethasone;
3. Daratumumab;
4. Watchful waiting; or
5. Enrollment in a clinical trial.

 

I think we will have a lively discussion about this as time goes on.

 

[00:13:52]

 

All right, so what are our diagnostic criteria for plasma cell disorders? And you may all be very familiar with this, but it is just good to remind ourselves that plasma cell disorders exist on a spectrum ranging from monoclonal gammopathy of undetermined significance on the right-most side of the slide, which is less than 10% clonal plasma cells and no evidence of myeloma-defining events.

 

Historically, the board's question, if you will, or the average answer is about a 1% per year risk of progression. And these patients, currently the recommendation is observation and making sure that we have excluded monoclonal gammopathies of clinical significance, which we will not talk about today, but those being neurologic, renal, and otherwise.

 

In the intermediate category is those patients who have been diagnosed with a more significant condition or smoldering myeloma. So a higher plasma cell percentage, typically in the 10-59% range, but again, no evidence of myeloma-defining events. These patients have a higher risk of progression, particularly, at least historically, in the first 5 years, but still over time, higher than those patients who fall into the monoclonal gammopathy of undetermined significance category. Currently, we have evidence, which we will go through to suggest treatment for patients with high-risk disease, but not those outside of clinical trials with lower-risk disease.

 

And then active myeloma, which we will discuss later, are patients who have evidence of at least 1 myeloma-defining event, and those are all patients that we do treat.

 

Summarized at the bottom of this slide, just for reference, are the SLiM-CRAB criteria, of which any of those would be considered a myeloma-defining event. So they are there for your reference.

 

[00:15:44]

 

Smoldering myeloma, the term was first coined almost 50 years ago by Drs. Kyle and Elvebak, when they recognized this population of patients that did not progress over time. Drs. Greipp and Kyle reviewed 334 cases diagnosed prior to 1974 and found that there were patients that did not develop myeloma over the observation period, and suggested at that point in time that the plasma cell labeling index might be helpful. That is not something we routinely use. But the term smoldering myeloma was officially adopted by the IMWG in 2003.

 

[00:16:25]

 

Unfortunately, there is a lack of consensus as to the true diagnostic criteria for this. There is the criteria typically used in the U.S., which you can see here on the right-hand side of the slide: greater than 10 but less than 60% plasma cells, and/or with presence of an M-protein greater than 3 g/dL or a urine M-spike greater than or equal to 500 mg, but again, no SLiM-CRAB criteria.

 

The Spanish criteria focus on the percentage of aberrant plasma cells and reduction of 1 or more of the uninvolved immunoglobulins and use slightly different criteria for the presence of protein in urine and serum, you can see.

 

[00:17:14]

 

The first models for progression of smoldering myeloma were established almost 20 years ago, and this slide may be familiar to many of you, but generally speaking, is where the suggestion, or where the evidence of increased risk of progression within the first 5 years. Now this lumped all smoldering patients together.

 

We now know, which we will go through, we can risk stratify these patients, and there are low- intermediate- and high-risk patients that are present, vs MGUS patients, which in general is about a 1% per year risk, although we can risk stratify those, but will not go through that today.

 

[00:17:50]

 

What are some of the models for risk stratification? So again, at the top of the slide is the Spanish model, looking at the percentage of aberrant plasma cells, reduction of normal immunoglobulins, and you can see that there are low-, intermediate-, and high-risk categories, and you can see the risk of progression for each of these categories with each of the different models.

 

The Mayo model in 2008 looked at the bone marrow plasma cells, the M-spike greater than or equal to 3, and the free light chain ratio that was abnormal. This has subsequently been modified to the 2/20/20 criteria, so that is an M-spike greater than 2 g/dL, greater than 20% plasma cells, and a free light chain ratio greater than 20 if it is capital lambda, or if it is lambda less than 0.05. This has also been further refined by the International Myeloma Working Group at the bottom, which takes into consideration the FISH abnormalities and further stratifies based on different breakpoints of plasma cell percentage in M-spike.

 

But all of these have a low-, intermediate-, and high-risk categories with increasing risk of progression over time.

 

[00:19:04]

 

And so the 2/20/20 criteria was further refined, as I mentioned previously, that included the genetic risk stratification as an additional potential point. And so there is low-, low-intermediate, intermediate-, and high-risk, and you can see the risk of progression goes up dramatically with patients, up to two thirds of them progressing, if they have 3 to 4 risk factors within a 2-year period.

 

[00:19:32]

 

And so these high-risk patients are where most of the efforts have been focused to see if we can change the natural history. And there have been trials, many of which we will go over, but certainly not all of them, with different paradigms. Do we give modest treatment with the goal of slowing progression, perhaps some of our newer treatments having an even greater impact, or aggressive treatment, perhaps with the desired goal of trying to stop myeloma from developing?

 

[00:20:04]

 

And so the first trials that were done, some of which are summarized here, were done in the era of older therapies focusing on bisphosphonates, melphalan, thalidomide. None of these trials showed improvements in survival.

 

[00:20:20]

 

The first trial that showed real benefit was the QUIRIDEX trial that was done with the Spanish myeloma group, where patients with high-risk smoldering myeloma were randomized to lenalidomide and dexamethasone vs observation.

 

And 9 cycles of treatment followed by maintenance vs observation. The groups were well balanced, and the primary endpoint was time to progression to symptomatic disease.

 

[00:20:48]

 

The biggest challenge here is there was not advanced imaging included in the criteria, and so likely patients with myeloma were randomized to both of these 2 arms, including observation treatment.

 

But what this trial did show was an improvement in progression-free and overall survival for patients. Although again, the impact of active myeloma that was placed in observation certainly limits the interpretation.

 

[00:21:18]

 

This was then followed by the ECOG trial looking at lenalidomide vs observation, taking out the steroids from this, and again, looking at progression-free survival in high-risk patients.

 

I should say the caveat is each of the eligibility criteria for these trials is a little bit different. And this trial, due to slow accrual, was amended to allow any abnormal light chain ratio for patients enrolling.

 

[00:21:42]

 

But this trial showed an improvement in progression-free survival, although not a difference in overall survival for patients receiving lenalidomide. And the 3-year progression-free survival was about 7% vs 32% for the observation arm.

 

[00:21:58]

 

But what we recently had is the AQUILA study, which has looked at daratumumab vs active monitoring in patients with high-risk smoldering myeloma. Again, the criteria are slightly different.

 

These are the European criteria that you can see summarized on the left-hand side of the slide, with the primary endpoint being looking at progression-free survival and long-term follow-up.

 

[00:22:22]

 

And what you can see here is that patients in the daratumumab arm, at 5 years of follow-up, 63% were progression-free, vs about 40% in the observation arm that is there.

 

[00:22:38]

 

These groups were balanced between that, but there were more high-risk patients in the active monitoring vs in the daratumumab, which you can see highlighted on the left-hand side of your slide here.

 

But looking at these based on the Mayo criteria, so again, that is not the criteria used to enroll, but about 40% were in the intermediate, and 44% in the high-risk category using the Mayo 2018 criteria.

 

[00:23:10]

 

This did show an improvement in overall survival, with 93% of patients receiving daratumumab alive at 5 years, vs 87% of those with active monitoring. And as noted on the first slide, this has led to the FDA approval of daratumumab for smoldering myeloma a little bit less than a month ago for patients with smoldering myeloma.

 

[00:23:34]

 

This is the safety data, well-tolerated. You can see that there were a little bit more in the way of infections with regard to respiratory infections, some diarrhea, arthralgias that you can see in the daratumumab-treated arm. But the most common adverse events were low-grade that is there.

 

6% of patients did discontinue due to adverse events.

 

[00:24:03]

 

Building upon this are ongoing phase III clinical trials, 1 of which is the DETER smoldering myeloma trial. This trial requires patients having been diagnosed within the last year before enrolling and having high-risk features.

 

Randomized to daratumumab lenalidomide dexamethasone vs lenalidomide dexamethasone. So there is not an observation arm in this trial. This trial is ongoing, and we will hope to have data soon.

 

[00:24:30]

 

There is also the ITHACA trial. Instead of daratumumab using isatuximab with lenalidomide and dexamethasone vs lenalidomide dexamethasone in high-risk myeloma. This is looking at those patients diagnosed within the last 5 years.

 

So a larger window of time for patients, which can lead to some degree of potential bias just if patients have remained smoldering in that period of time.

[00:24:58]

 

Looking at higher doses of therapy is the ASCENT trial. Looking at carfilzomib, lenalidomide, dexamethasone and daratumumab, so a quadruplet, followed by maintenance with a doublet. This has not shown a significant improvement in progression-free survival relative to more modest therapies. And certainly there are efforts ongoing looking at these, but I think that many would temper more towards less therapy rather than trying to give ablative type of treatment.

 

[00:25:38]

 

There is also the GEM-CESAR trial, which looked at the triplet KRd followed by a transplant followed by consolidation and maintenance with a doublet.

 

[00:25:49]

 

And again, this has not led to a resolution of myeloma or prevention from progression. So you can see here, unfortunately, patients, despite the intensive therapy, patients continue to progress to active myeloma with an overall survival in the study equivalent to less intensive interventions.

 

[00:26:08]

 

But what is really exciting, which I think you will hear throughout this presentation from all of us throughout ASH, are the role of T-cell engager therapies and the potential for these to have an impact. So T-cell engagers can potentially induce deep responses and reduce toxicity. The thought being also that the immune system may be healthier in earlier stages, and we can potentially circumvent toxicities related to more intensive regimens.

 

[00:26:38]

 

We just have early data on some of these regimens, and more will be forthcoming. Just a little bit from the first patients enrolled in the Immuno-PRISM study teclistamab in 12 high-risk patients had a 100% overall response rate. And in all of the evaluable patients they were MRD-negative at 10^-6.

 

Comparable safety and efficacy that has been seen in the relapsed and refractory population. This is ongoing with plans for additional bispecifics and others in other arms of the trial.

 

[00:27:12]

 

Also the linker trial looking at linvoseltamab in high-risk smoldering myeloma.

 

This data was updated most recently at the International Myeloma Workshop. This is a Phase I/II study for patients with high-risk diagnosed within the last 5 years, enrolled and receiving linvoseltamab. So this is a single-arm trial with the primary endpoints looking at complete response, MRD-negativity, and then secondary endpoints of overall response rate.

 

[00:27:48]

 

The data presented thus far shows a overall response rate of 100% of patients, with patients in the part 1 having deeper remissions as they have had longer amount of therapy, and all patients that were evaluable for MRD were negative at 10^-6. So very promising data on use of bispecifics.

 

[00:28:12]

 

And then also the CAR-PRISM study is just 1 of a few studies looking at using CAR T-cell therapy and smoldering myeloma. And so this data is early, 6 patients presented, high overall response rate, high MRD-negativity. Time will tell as we follow these patients further as to the durability of this and whether this really is promising therapy in this situation.

 

[00:28:39]

 

Just some of the additional trials that are open in high-risk smoldering myeloma, and I have broken these into categories. On the right-hand side of the slide, are the immunomodulatory drugs, CELMoDs, antibodies, and proteasome inhibitors, and you can see some of these summarized there. And on the left-hand side, the T-cell redirecting therapy and vaccine studies. So much more to come and a very exciting time for our patients.

 

[00:29:06]

 

Just sort of an algorithm to think through for how to manage smoldering myeloma. I think 1 of the most important things is to confirm the diagnosis and confirm that it truly is smoldering myeloma. Make sure that we get the advanced imaging studies in the form of PET scans and MRI scans to exclude active myeloma, all of which would need to be treated.

 

If you look through the diagram here, patients who have very high-risk smoldering myeloma with multiple high-risk features, some might go ahead and treat those patients. Certainly these would be people that we would want to enroll in a clinical trial or consider the use of daratumumab or lenalidomide regimens, but predominantly daratumumab, based on the recent AQUILA study. High-risk patients again enroll in clinical trials or consider therapy there.

 

If you do not, then follow closely with observation with laboratories at least every 2-3 months. Patients who fall in the standard risk criteria could certainly be enrolled in clinical trials but with follow-up every few months. If they evolve, then they would move over to a high-risk phenotype and the management that way.

 

And low-risk patients, again, we would observe these patients. We would not treat them at this point in time outside of a clinical trial.

 

[00:30:26]

 

This is just the most recent NCCN guidelines on the management of smoldering myeloma which you have available for your reference but again, dividing patients between low and high risk and the frequency of monitoring and assessment to ensure that you truly do have smoldering myeloma.

 

[00:30:43]

 

Some exciting abstracts to look for at this ASH meeting are summarized here. I call your attention to additional data from the AQUILA study that will be presented tomorrow afternoon from 16.00 to 18.00. There are posters tomorrow evening on racial disparities and socioeconomic differences and then Monday's poster session, we will have data on the teclistamab plus daratumumab combination from the REVIVE study. Dr Landgren and colleagues will present this. Importance of MRI in the diagnostic workup and the final results of the isatuximab-lenalidomide in high-risk smoldering myeloma.

 

[00:31:26]

 

So let us return to our case questions.

 

So again, our 58-year-old woman, I will not belabor you with all of the patient's details.

 

Again, they are summarized here, but this is a patient who has been diagnosed with smoldering myeloma.

 

[00:31:42]

 

Question 3: Using the IMWG 2/20/20 refined risk stratification model, would you consider treatment for this patient?

 

And the question here is using the IMWG 2/20/20 model, would you consider treatment for this patient?

 

1. No; she has low-risk smoldering myeloma;
2. No; she has intermediate-risk smoldering myeloma;
3. Yes; she has intermediate-risk and should consider treatment; and
4. Yes; she has high-risk smoldering myeloma and should consider treatment.

 

Great, so this patient does in fact fall into the high-risk smoldering myeloma category if we incorporate her genetic changes as well too, and so, we would consider treatment for this patient.

 

[00:32:58]

 

All right, again, she has 40% plasma cells, her light chain ratio is greater than 20 and she has high-risk genetic features, so she would fall into that category, and we would consider treatment for this patient.

 

All right, so I am going to turn the program over to Dr Rossi, and please send your questions in if you have them and we will get to them at the end.

 

[00:33:28]

 

Dr Adriana Rossi (Mount Sinai Hospital): Thank you so much. So thoroughly covered the precursors, now I have the pleasure of trying to sift through the data in the newly diagnosed, so not as ambiguous, we have a confirmed diagnosis, and here is our case.

 

[00:33:44]

 

A 77-year-old man with newly diagnosed symptomatic myeloma presented with fatigue and bone pain. Labs are remarkable for a hemoglobin of 9.8, the creatinine is 1.1, calcium 10.9, the M-protein is 3.2, and the free light chain ratio of 45. The bone marrow includes 40% plasma cells, and the imaging now has multiple lytic lesions. High-risk-sided genetics with a translocation 414 and a 1q and the patient, as so many of our patients do, has hypertension and a good performance status. So he is deemed ineligible for autologous stem cell transplant due to age but also patient preference. He is fit and not frail.

 

[00:34:34]

 

Question 5: Which frontline regimen would you recommend for this patient?

 

So which frontline regimen would you recommend for this patient?

 

1. Bortezomib + lenalidomide + dexamethasone;
2. VRd-lite, the dose attenuated version;
3. A CD38 monoclonal with lenalidomide and dexamethasone, either DRd or Ird; or
4. A CD38 monoclonal with bortezomib + lenalidomide + dexamethasone.

 

I like the trend, we are definitely moving towards quads. You have made my job quite easy.

 

[00:35:28]

 

Question 6: If this patient had an ECOG PS of 2 with mild renal impairment (CRCL 45 mL/min) and significant peripheral neuropathy due to diabetes, what treatment approach would you recommend?

 

Next question, changing the patient profile just a little bit.

 

What if the patient now has an ECOG performance status of 2, some mild renal impairment with a clearance of 45, and significant peripheral neuropathy due to diabetes? Which regimen would you recommend? Again the same similar concept:

 

1. Lenalidomide + Dex;
2. Bortezomib + lenalidomide + Dex;
3. VRd-lite;
4. The triplet of a CD38 with lenalidomide + dexamethasone; or
5. The quad of a CD38 + bortezomib + lenalidomide + dexamethasone.

 

Okay, high consensus in the room. I think this is a great way to start. So this may be a patient we would consider the triplet.

 

[00:36:34]

 

All right, so again, just to remind you, this is expected in 2025 to have over 36,000 new cases with over 12,000 deaths. And data back from 2022, we are approaching about 200,000 people living with myeloma in the United States. And while we are celebrating so many novel therapies and prognosis has significantly improved, we still have a median survival of about 11 years, which is great if you are diagnosed at 69, but for earlier, younger patients, I think we definitely would like that number to be bigger.

 

So we still do not consider it curable for most of our patients, but we do have an increasing armamentarium of therapeutic options.

 

[00:37:26]

 

So we have heard a little bit about the precursors. I will leave for Dr Martin the vast world of relapse, and we will focus really on that induction, that frontline therapy, which we still use the concept of transplant eligibility, not so much hopefully in planning that induction, but in the inclusion of a consolidation including transplant. So we will focus on either that continuous therapy or the induction consolidation maintenance portion to try to achieve that deeper and durable response for our patients.

 

[00:38:02]

 

And the goal of treatment really is to rapidly control the myeloma in order to prevent or reverse any disease-related complications, trying to obtain our deepest possible remission, expecting that to then translate into the longest remissions, and try to do that with minimum toxicity both in the long term and the short term, allowing for stem cell collection if desired.

 

[00:38:28]

 

So we spend a lot of time talking about high-risk, and what is it that we mean by that?

 

We are certainly familiar with the cytogenetic abnormalities, although, as we will see, we have recently updated that definition. Other laboratory factors like a high LDH, a high creatinine, but also incorporating clinical features such as extramedullary involvement, the presence of circulating plasma cells, age, and frailty into our decision. And what is getting more attention now is the functional high risk.

 

I think we are recognizing that despite these very promising, very powerful therapies, there are patients who remain either primary, refractory or relapse much sooner than expected. By definition we are using 18 months, but I think that time point can certainly change.

 

[00:39:21]

 

So here are the updated consensus from the IMS/IMWG just published this year.

 

We have delineated that deletion 17 has a cutoff of 20%, a p53 mutation with no threshold, the 1p32 either if it is biallelic or has a partner of 1q. Similarly, the IgA translocations, not so much on their own but with a 1p or 1q and still holding on to that high beta-2 as a high-risk feature.

 

[00:39:55]

 

And the revision of the ISS incorporating that 1q, I think, plays into this recognized importance and the evolving insights that we have on risk stratification for our patients, although, as we know, patients do not always follow the textbook.

 

[00:40:34]

 

I would like to spend some time focused on transplant candidates.

 

[00:40:19]

 

Pointing out that just the dynamic nature of the NCCN guidelines, the 2025, we had a single preferred regimen and 3 other regimens for this population. The updated, we now have 2 preferred regimens, both of them quads including an anti-CD38 with VRd, and we now have 4 other recommended. So while very helpful, as we increase the number of options, that can actually cause more confusion.

 

So we will look at how we got there.

 

[00:40:58]

 

I always start with SWOG the first time, as we heard earlier, triplets started really being defined. So that combination of an IMiD and proteasome inhibitor, I think, was recognized as the best thing we had back in 2020 and really has served as the backbone or the comparator arm for most of our upcoming data.

 

[00:41:20]

 

So CASSIOPEIA, using thalidomide, not lenalidomide, so not something we see often in the United States, but really establishing that addition of an anti-CD38 antibody to the backbone of a PI and IMiD, remembering that this study had 2 randomizations. So the first Dara-VTd vs VTd, and then a second randomization for maintenance. If we look at that first figure, we clearly see a benefit of the addition of the CD38 antibody, and in the curve we see that does translate to a PFS benefit.

 

But similarly, if we look at MRD-negativity in patients who received daratumumab, in the induction as well as maintenance, in the induction alone, maintenance alone, or neither, we see that if you receive it in 1 or the other, so the presence of that CD38 antibody is a benefit to not receiving it at all, but receiving it in both is the best.

 

[00:42:21]

 

And so a similar concept now using lenalidomide, comparing that addition of daratumumab to the VRd backbone in induction, consolidation, and maintenance. And here we start seeing MRD as a potential data set to help us decide on intensity of therapy.

 

[00:42:40]

 

As you probably know, we saw a significant PFS benefit and improvement in overall ability to attain an MRD-negative status either at 10^-5 or 10^-6. But I also think patients who are able to achieve that MRD down to 10^-6 really have almost exactly the same curve for a sustained below 10^-5. So the concept of sustained MRD-negativity starts to really come into play.

 

[00:43:12]

 

We have similar data using isatuximab, again to that VRd backbone both in induction and in maintenance. That was the Phase III HD7, but also the concept study. So patients receiving the Isa-KRd, so potentially our most powerful frontline quad, with a transplant or without, so broadening who we are speaking about, and then a consolidation of Isa-KRd with maintenance KR.

 

[00:43:42]

 

Interestingly, we certainly see a greater benefit for transplant-eligible patients. So while our transplant-ineligible are not considered, still see the benefit. This definitely starts to become an interesting combination, specifically for our transplant-eligible patients.

 

[00:44:01]

 

Similarly, the IsKia adding isatuximab to that KRd and transplant-eligible alone, induction, consolidation, and what is now called a light consolidation, so further therapy.

 

[00:44:14]

 

We see the ability to reach an MRD-negative state. Interestingly, seen in the so-called low-risk, right, zero high-risk features, 1 high-risk feature.

 

But what we are mostly recognizing as a troublesome population, those patients who have 2 or more high-risk features, are able to achieve that MRD-negativity, 10^-6, in a very, very disparate proportion. So isatuximab with the KRd potentially our best-yet option for these upfront transplant patients.

 

[00:44:52]

 

So what about transplant itself? I know they are transplant-eligible. Should we do it or not?

 

This is a question, you know, from the last century. We continue to have data showing benefit as far as PFS.

 

[00:45:08]

 

This was from the IFM, also seen in DETERMINATION, slightly different numbers, but similar, about 20% improvement in PFS.

 

[00:45:17]

 

But no overall survival benefit. So what do we do with that information?

 

[00:45:24]

 

Break it down a little bit further. One of the things that really comes out is the difference of the outcomes for standard-risk patients and those high-risk cytogenetics.

 

So despite the benefit seen with the addition of the transplant, patients with high-risk cytogenetics still reaching a median PFS of just over 50%.

 

[00:45:45]

 

Our most recent and potentially controversial data set come from the MIDAS data. Here, patients started with an Isa-KRd induction, and then their MRD status, so their ability to reach our deepest response, was used to stratify patients in so-called standard- vs high-risk, and then they were further divided with an Isa-KRd or Isa-KRd with 1 transplant in the high-risk, starting in the Isa-KRd with 1 transplant, comparing it to 2 transplants. And we will later see maintenance.

 

[00:46:20]

 

So not surprisingly, by definition, the induction patients in arm A and B, or those with standard risk, are able to achieve MRD-negativity in post-consolidation a little bit deeper, but we are still not seeing 15% of patients achieving that. And in the high-risk, really not that much of a benefit. Certainly, I think, taking away the tandem as a good option for our patients, especially in the U.S.

 

[00:46:51]

 

But part of the interesting is in the details, right? So when we break down MIDAS in that patient's post-induction and post-consolidation, the value of that deepening response that we see, we certainly see it with both arms A and B, but specifically looking at those patients with the translocation 11-14 vs not, so working towards using cytogenetics as potentially an ability to tailor treatments, I think it is interesting to see patients with the 11-14 translocation really did not have that impressive a response following induction, but they did have a greater deepening of response with the consolidation. So the dynamics and the biology of this disease is probably different and may require different monitoring.

 

[00:47:44]

 

Focusing on maintenance, so what do we do after these transplants? CASSIOPEIA really showed us that Dara vs observation. As we mentioned before, the Dara either in the induction, the consolidation, or both.

 

Certainly, both is better, but not receiving it, definitely the detriment and the outlier, I think highlighting the importance of monoclonal antibodies in the frontline therapy.

 

[00:48:12]

 

FORTE was the study using KRd ± a transplant followed by KR and R maintenance, and I include that just to show that in all populations, but especially in these high-risk, double-hit, potentially difficult-to-treat patients, a second agent and maintenance may be required or a minimum starting point for those patients.

 

[00:48:34]

 

And AURIGA, I think, our most recent using Dara-Len compared to Len alone in the maintenance setting.

 

[00:48:44]

 

Really showing a marked improvement. Again, the primary endpoint being that conversion to MRD-negativity more than doubled in the Dara-containing arm.

 

[00:48:56]

 

So if we switch a little bit, again, not to patients who cannot get a transplant, but where transplant is not planned.

 

[00:49:02]

 

We again, see a change in the NCCN guidelines for those patients called non-transplant candidates. We had 3 preferred regimens, 2 triplets and a quad, the quad being the Isatuximab VRd.

 

[00:49:18]

 

We now have the heading of transplant deferred or not indicated, so the evolution in how we are evaluating our patient population, but the preferred regimens now include 2 quads and a triplet. So every single preferred regimen includes an anti-CD38 monoclonal antibody, and 2 out of 3, specifically in patients under 80 who are not frail, a quad.

 

[00:49:46]

 

Despite having multiple different frailty scoring systems, most of us do not have the inclination resources to perform these on a regular basis.

 

There is data supporting their use both in clinical trials and in the real-world situation, but implementing them certainly has been tricky.

 

[00:50:06]

 

And we have great evidence for DRd, so addition of that monoclonal CD38 antibody, and now moving towards quads, which I think, as the polling showed, most of you are well aware.

 

[00:50:20]

 

But the addition of Dara to a VRd backbone in the transplant-ineligible, similar, again, to the transplant-eligible, just omitting that transplant consolidation and inclusion of the daratumumab in the maintenance setting.

 

[00:50:37]

 

We see the PFS, the curves are separating, and that separation is still growing at 54 months of follow-up, showing also a great benefit in achieving that MRD-negativity. It will be nice to see the sustained levels.

 

[00:50:55]

 

Similarly, IMROZ now using isatuximab with VRd and isatuximab Rd in the maintenance, so we now have four 6-week cycles compared to eight 3-week cycles, so very similar in duration and intensity.

 

[00:51:10]

 

And again, seeing median PFS not reached, but at 60 months, a marked increase in PFS for these patients, with that not only achieving but sustaining MRD-negativity in nearly half of them with the monoclonal.

 

[00:51:28]

 

Interestingly, the BENEFIT study, also looking at the addition of isatuximab to VRd, but this time the control arm omitting the proteasome inhibitor. So I think this study gives us 2 very valuable insights. One, it provides us data with the use of isatuximab-Len-Dex, so again, enforcing the utility of the anti-CD38, but now evaluating the contribution of the proteasome inhibitor, as so many of us are inclined to try to use a triplet in some of our older patients.

 

[00:52:04]

 

So impressively, not only achieving, but at 12 months and 18 months, that MRD-negative rate on the quad being markedly improved over the triplet. So while yes, there are patients who may not need the quad, I think it is important for us to consider the option of giving every patient our best therapeutic opportunity for a deep response and a longer remission.

 

[00:52:34]

 

Lastly, I wanted to touch on supportive care, which has also, I think, evolved over time.

 

[00:52:40]

 

And as most of our patients are now going to be exposed to quad therapy up front, and again, it is not quad forever, but starting with the quad and given the depth of responses, hopefully tapering off in time, we need to use antiviral prophylaxis for all anti-CD38 antibodies and all proteasome inhibitors, importance of anticoagulation in patients with IMiDs, and GI prophylaxis with our patients receiving steroids. And in addition, the bone-strengthening agents, which I think also have come a long way and should be a part of that treatment regimen.

 

[00:53:22]

 

As far as infection prophylaxis, we mentioned the viral prophylaxis with certain agents. Most bacterial infections, that risk is really early on, so consider levofloxacin in the appropriate setting. Many times, patients who may have high doses of steroids, I think the PJP and fungal infections, again, in the appropriate setup, I would prefer to lower those steroids and decrease that risk for most patients.

 

Remembering that COVID-19 and influenza, we do have antiviral therapies to, again, help the morbidity that comes with those infections in our patient population. The hypogamma, I think specifically in patients who have either a history of infections, either serious enough to bring them to the hospital or recurrently, requiring antibiotic support, not just the hypogamma alone. And the neutropenia, as I mentioned, in myeloma, we use very liberal use of GCSF to maintain them above, especially if that neutropenia is due to marrow involvement in the initial induction therapy.

 

[00:54:36]

 

So in conclusion, I think every time we see a patient, we have those 3 buckets. Even we saw in the smoldering, there are patient-related factors, mostly comorbidities, but also the non-medical, right? The caregiver support, the preferences, which in New York weigh heavily.

 

There are disease-related factors. Patients who present with particular organ involvement or extramedullary disease will tend to have different needs. And treatment-related factors, again, mitigating the toxicities of things that we use and more and more also, again, the requirement for visits.

 

[00:55:18]

 

So I think it is important to remember in our transplant-ineligible patients, as that line moves significantly in who needs 1 vs who should get 1, who may be able to forego. Quads really are the best option for most of these patients. There will always be exceptions.

 

We should be using techniques to assess frailty and not have a binary algorithm. The concept of combining mechanisms of action, we have seen this since the days of VRd-lite. Lower doses of more drugs tend to be more beneficial than trying to give fewer drug combinations. And again, the dose attenuations could really make our therapies much more tolerable.

 

[00:56:03]

 

And so we have so much data really supporting all different combinations. But the idea of the anti-CD38, an IMiD, and a proteasome inhibitor ± the transplant, supports the use of all of our therapeutic tools.

 

[00:56:22]

 

And really that focus on depth of response. MRD may not be a perfect test, but it is the best test we have to date. And regardless of therapeutic options, the curves, the separation in curves, and the association with a progression-free survival really are the metric we have for a rapid response.

 

[00:56:42]

 

And not only as a prognostic for PFS, but also for overall survival, which now will hopefully be a decade-long dataset if we wait for that.

 

[00:56:54]

 

And so, as the treatment therapy continues to evolve, I will leave to Dr Martin the more complicated side of things. I think, frontline, we seem to have a consensus.

 

[00:57:06]

 

So I would like to go back to our patient.

 

[00:57:09]

 

Remembering he is a 77-year-old with newly diagnosed myeloma, anemia with a hemoglobin of 9.8, an M-protein of 3.2, and a ratio of 45. 40% in the marrow with multiple lytic lesions on imaging. High-risk cytogenetics with a presence of a 414 and 1q. Hypertension and a good performance status.

 

[00:57:32]

 

Question 5: Which frontline regimen would you recommend for this patient?

 

So which frontline regimen would we recommend for this patient?

 

1. VRd;
2. VRd-lite;
3. DRd or Ird; or
4. The quad of D-VRd or I-VRd?

 

Excellent, 92%. We have got a few holdouts. Very good.

 

[00:58:08]

 

So again, hopefully I have shown you that with CEPHEUS and IMROZ, the addition of CD38 monoclonal antibodies to a triplet really show us considerable benefit. And remembering, these are not continuous quads. It is starting with a quad, getting them to a deep remission, and then adjusting the therapy as we need.

 

[00:58:32]

 

Question 6: If this patient had an ECOG PS of 2 with mild renal impairment (CrCl 45 mL/min) and significant peripheral neuropathy due to diabetes, what treatment approach would you recommend?

 

And again, if we now change his performance status to an ECOG of 2, give him some renal impairment, some peripheral neuropathy, would we now consider:

 

1. Rd;
2. VRd;
3. VRd-lite;
4. DRd or Ird; or
5. The quad of D-VRd or I-VRd.

 

Okay, not much changed. Thank you so much.

 

[00:59:16]

 

And the rationale, again, there are patients. I think the joy in treating myeloma is that there will never be an algorithm that this is how you treat. There will be patients who will need modifications from our data.

 

And I will now pass it on to Dr Martin.

 

[00:59:40]Dr Thomas Martin (UCSF Medical Center): Okay, good morning, everyone. In the next 30 minutes, I am going to talk about relapsed and refractory myeloma. And I will start off by saying there is no consensus in relapsed and refractory myeloma. There is not just 1 way to do it. And with each individual patient, it is a discussion with you and the patient on what is going to be their next and their next and their next therapy.

 

[01:00:01]

 

Question 7: A 78-yr-old patient with R/R MM has progressed after 2 PloT: bortezomib and lenalidomide. The patient is not a candidate for CAR T-cell therapy due to comorbidities, frailty, and logistical constraints. The patient has adequate renal function and no active ocular disease. Which of the following is an FDA-approved BCMA-targeted agent that could be an appropriate next-line therapy?

 

So we will start with a case.

 

A 78-year-old patient with relapsed/refractory myeloma has progressed after 2 prior lines of therapy, was exposed to bortezomib and lenalidomide. The patient is not a candidate for CAR T-cell therapy due to comorbidities, frailty, and logistical constraints. The patient has adequate renal function and no active ocular disease.

 

Which of the following is an FDA-approved BCMA-targeted agent that could be an appropriate next-line therapy? Go ahead and vote.

 

1. Elranatamab;
2. belantamab mafodotin;
3. Linvoseltamab; or
4. Talquetamab.

 

Okay, looks like we have quite a smattering of different votes. So we will see what comes up after my discussion.

 

[01:01:10]

 

So we have really had amazing success with immunotherapies and myeloma. And you know, I can talk for 2 hours on relapsed/refractory myeloma or longer. I am going to focus it really on the excitement that we have had in novel immunotherapies over the last 5 years or so.

 

belantamab mafodotin was the first approved drug for us back in 2020. But over the last 5 years, 6 additional agents have been approved. Two CAR T-cells and 4 bispecific antibodies. Mostly targeting BCMA, but also targeting another cell surface protein, and that is GPRC5D.

 

[01:01:46]

 

Now, as you know, these therapies have all been approved in the setting of the relapsed/refractory, the far right of this slide. In these really advanced patients, they have shown dramatic responses. Responses that really double the responses of our previous blockbuster agents.

 

We now have new blockbuster agents, right? And when we use them in the late-line setting and they work really well, we then move them to the earlier lines of therapy. And the goal in my mind is to everything as soon as possible and as quick as possible to frontline.

 

Frontline was easy when, as you just heard from Dr Rossi, it is not going to be easy going forward. It will be, next year it is going to be a different discussion. So we will see.

 

But we know that CAR T-cell therapy has now entered into the earlier-line space, and we will talk a little bit more about that. But the truth is, all these agents that we have, how should we deploy all these agents? In what combinations will be the best combinations, and what is the sequencing of these drugs? That is really going to be the fun over the next 5-10 years in terms of treatment of multiple myeloma.

 

[01:02:54]

 

Now, when we talk about relapsed/refractory myeloma, we always talk about attrition. That with each line of therapy, no matter if they are transplant-eligible or transplant-ineligible with each line of therapy, we lose patients for their ability to not go on to the next line of therapy because of comorbidities, because they just do not think they can handle the next line of therapy, etc. And that is a sad thing. So what it means is that we should be using, with each line of therapy, the best regimen at that time. And I usually say, right patient, right regimen, right time for these things.

 

Now the question becomes then, when we move these things to earlier lines of therapy, will some of these agents have curable potential. And I am going to bring up a new concept, and that concept is what I am calling the reverse attrition, okay? Would not it be glad to get to the reverse attrition?

 

What do I mean by that? That means they get these therapies in frontline and early relapse, and the reason they do not need subsequent therapy is because they have remained in remission for a prolonged period of time. We can aspire to try to get to reverse attrition.

 

[01:04:06]

 

Now the truth of the matter is, in terms of the number of patients that get to CAR T-cell therapy, it is quite low. We have to do better with getting patients to CAR T-cell therapy, but it is also true for bispecific antibody therapy. We had an initial question of how many in the room are from academia and how many are from the community, and we all have to come together as a group, learn how to use these agents, and use them both in academia and in the community.

 

These agents are going to be used throughout the myeloma treatment paradigm. Everybody has to learn how to use bispecific T-cell engagers in belantamab, etc. Now we know there are many different classes, right? We have proteasome inhibitors, we have IMiDs, we have monoclonal antibodies.

 

In the last 5 or 10 years, we have done a number of triplet vs doublet therapies, right? We have done CD38 plus KD vs KD. We have done CD38 plus pomalidomide and dexamethasone, and we have seen some very nice responses. We have seen PFSs, or responses of 85% or better, and responses upwards of 3 years. A little less for the pomalidomide-based regimens, but very good responses.

 

And that is our new benchmark in the relapsed/refractory, the early relapsed/refractory space. It is to try to get to 3 years or longer with the PFS of any next-generation regimen.

 

[01:05:32]

 

Now this is a simplified algorithm for late relapse. These are patients that have second or higher relapse. And when a patient is refractory to an IMiD or PI or anti-CD38 antibody, we then think about, okay, what is next? The way we sequence these things is different from patient to patient, but we try to change up the regimens.

 

I am not a person that somebody's on lenalidomide and Dex as maintenance, and they start to progress, that you just add in a third drug, right? That does not work. You have to switch the regimen.

 

And once they have had PIs and IMiDs, and you are getting to their third regimen or more, you know, we have other agents like cyclophosphamide. If they have not had carfilzomib, you could do carfilzomib cyclophosphamide or pomalidomide cyclophosphamide and Dex. Those are very good regimens.

 

On the right of this slide are what happens in our unmet need is when they are refractory to IMiDs, PIs, and CD38s and BCMA. That is our toughest population. Thankfully, in those patients, most of them have had 4 prior lines of therapy, and that is where bispecific T-cell engagers come into play. And most in those that are BCMA refractory, we go to GPRC5D.

 

There are other existing agents. We still have selinexor combinations. We have venetoclax combinations for patients that have 1114 translocation. And I tell people the last thing that we can try is bendamustine. We do not want to try it with any patient we are thinking about any T‑cell therapeutic, but it can be the last thing that we can try to see if they have a response to therapy.

 

[01:07:12]

 

When we overall think about factors that influence treatment selection, the most important thing in my mind is what they are refractory to. We are going to pick a class of agent that they are no longer refractory to that class of agent, so we are going to try to make a triplet and sometimes even a quadruplet in relapsed/refractory disease that we can use. And this is a discussion between you and the patient.

 

There are disease-related factors. There are patient-related factors. Can they get to the clinic? How much can they get to clinic for you to choose the regimen?

 

[01:07:42]

 

All right, so let us talk a little bit about the agents. I am going to talk about belantamab.

 

belantamab, you guys know, it is an antibody-drug conjugate. It works by several mechanisms. It blocks BCMA. It can cause ADCC, but it mainly works as an ADC. It gets internalized. The poison is basically taken off the antibody, and the MMAF toxin then causes myeloma cell death.

 

[01:08:08]

 

Now, we know that it was approved for use in 2020. It is based on a Phase II study in relapsed/refractory myeloma. It had a response rate of about 30%. It was pretty good. But then, unfortunately, the first Phase III trial, belantamab vs Pom-Dex, did not show statistically improvement in that study. It did not meet its statistical endpoints, and it was taken off the market.

 

It has had a rebirth. It has had a rebirth based on the DREAMM-7 and the DREAMM-8 studies. I am going to just go through the DREAMM-7 because this is the study that has resulted in a renewed FDA approval in the U.S., and this is a regimen that we hopefully all can start using.

 

The DREAMM-7 was belantamab methadone plus bortezomib and dexamethasone vs daratumumab plus bortezomib and dexamethasone. Again, this is patients that had greater than 1 prior line of therapy, no prior BCMA-directed therapy, not intolerant or refractory to bortezomib or daratumumab. They could have been exposed, but not intolerant or refractory. Eight cycles of Bela-Vd, 8 cycles of Dara-Vd, and then on to maintenance with just Bela and just Dara. So it truly is Bela vs Dara.

 

[01:09:22]

 

And to our surprise, the primary endpoint of PFS, we were all, I think, very surprised of the significance of the difference of Bela-Vd vs Dara-Vd. With a PFS now of 36.6 months, again, beats that 3-year PFS that I talked about a little bit earlier.

 

[01:09:39]

 

And if we look at overall response rates, very good overall response rates, over 80%. A quarter of the patients got to MRD-negativity. And the duration of response in responders was twice as much with Bela-Vd vs Dara-Vd.

 

[01:09:56]

 

And probably the kicker that really, I would say, caused the FDA to for sure approve this regimen was an improvement in overall survival with a hazard ratio of 0.58.

 

[01:10:10]

 

And based on this, belantamab is approved in patients that have 2 or more prior lines of therapy and exposure to an IMiD and a proteasome inhibitor. Now, we know there are safety issues. Mostly it is the keratopathy or keratitis that happens with this drug.

 

We do know how to manage this, right? If some patient gets keratopathy, you have to hold the drug, let it resolve, and then reinstitute the drug. You can reinstitute at a dose reduced from 2.5 to 1.9. And then you can actually also lengthen out the administration, maybe from every 3 weeks to every 8 weeks, etc. These, in my mind, belantamab is a combination, especially here, that we all will be able to use and should be using.

 

Two things to consider. One, once a patient is exposed to BCMA, the next line of BCMA may not actually work as well. So in patients that are CAR T-cell candidates or perhaps bispecific antibody candidates, maybe belantamab may not be the best option for them at this point in time. But there are plenty of patients that are not making it to the academic center for CAR T‑cell therapy, and are not making it to the academic center mostly to start bispecifics. That is why everybody in the room, everybody that is listening, everybody needs to be able to give bispecific therapy. But there are plenty of patients that this can be given safely, locally, and it is a very convenient regimen.

 

[01:11:40]

 

Okay, let us switch to CAR T-cell therapies.

 

[01:11:44]

 

And my disclosure is that I really actually favor CAR T-cell therapies for most therapies, and I will tell you why.

 

And you can see here in this slide, this is looking at approved CARs on the left, and some of the ones that are in clinical trials going from left to right, from BCMA to BCMA plus CD19, dual-targeted CARs to GPRC5D-targeted CARs. And they all show overall response rates that are over 90% in general. If we look at the original cilta-cel, the original CAR T-1, the original 97 patients, overall response rate was 98%.

 

And our PFS in 6 prior lines of therapy, this is not 1-3 prior lines, in 6 prior lines of therapy was 36 months, hit that 3-year benchmark.

 

[01:12:30]

 

And I think everybody knows that the data from cilta-cel just recently made, of course, the most reputable pamphlet that we have, or the most reputable article, the New York Times. And when it made the New York Times, the question was, do we now have a curative therapy for multiple myeloma?

 

So looking at 60-month follow-up, 5 years of follow-up, one-third of patients continue to be treatment and progression-free. It is at 5 years, okay? They have had nothing in 5 years, and they continue to be in remission.

 

Those patients, they cannot remember what it was like when they had myeloma. It is a new life for them, right? Is this cure? It is very possible that this is cure. Myeloma, we always say we have to follow them for 10 years, 15 years. But I say this is very encouraging data.

 

We should be referring more patients for CAR T-cell therapy. But the truth is, this is 6 prior lines of therapy. Can we do better? Can we get better than 50%? Can we get better than 75%?

 

[01:13:36]

 

And so 1 way that we can do this is to actually try to use it in an earlier line, in earlier lines of therapy.

 

We have 2 CARs that are now approved in earlier lines of therapy, ide-cel in 2-4 prior lines of therapy, and cilta-cel 1-3 prior lines of therapy. And this is based on the Phase III randomized KarMMa-3 study and the CARTITUDE-4 study. And I am going to focus mostly on CARTITUDE-4 because it was in, I think, an earlier line, 1-3 prior lines of therapy.

 

[01:14:04]

 

And in this study, the overall response rate in those patients, and this is intent-to-treat, was 85%. In the intent-to-treat PFS on the right, the 30-month PFS was 60%. If we look at the patients that actually received the CAR T-cell therapy and we look at CARTITUDE-4 vs CARTITUDE-1, there is a significantly higher curve of PFS, probably a third better.

 

And maybe, we will have to obviously follow, this is 30 months follow-up, we need, again, 60 months, we need 30 more months of follow-up to see, are we, we may be hitting the 50, maybe it is 50%, maybe it is better, who knows? We will see what it is at 60 months. But we do think it is even better in earlier-lines of therapy.

 

And this, hopefully, is going to show us again, just like in CARTITUDE-1, a plateau effect. Would not that be great?

 

[01:14:56]

 

Well, we have more CAR T-cells coming down the pipe. There are some issues with cilta-cel, there are some late toxicities, we will talk about that in a minute. But we have other CAR T‑cells that we are testing. This is data from the iMMagine-1, a Phase II study looking at anito-cel in the relapsed/refractory myeloma. At ASH, we are going to see an update of this data.

 

This, the special sauce of this, this is actually a synthetic peptide that is a binder of BCMA. There is a faster on-off rate on the binding of BCMA, and perhaps that actually keeps T-cells healthier for longer. It may also drop the toxicities, especially the late toxicities, as there has been no late neurologic toxicity seen yet with anito-cel, which is very interesting. There is not many patients treated, we need to see more.

 

[01:15:44]

 

But if we look at the overall response rate, very high, 97%, and the stringent CR is close to 70%. With CAR T-cell therapy, it is about stringent CR. If you do not get to see our stringent CR, you are going to relapse within 6 months.

 

Okay, so if your patient does not have MRD-negativity or stringent CR, they are going to relapse typically within 6 months' period of time. And that is the way CAR T-cell goes. I will say you are going to see data at this meeting about anito-cel, and maybe we will get our first PFS curve. That would be awesome, we will see. I invite you guys all to go to the abstract presentation, it will be really good.

 

[01:16:26]

 

Another CAR T-cell that actually targets a different target, GPRC5D, known as arlo-cel. And this is data that was initially presented by Susan Ball, this is ASH 2024. First-in-man study, a Phase I study. Again, in relapsed/refractory, more than 3 prior lines of therapy.

 

[01:16:45]

 

Looking at a very high overall response rate, over 85%, but in the target dose of 150 million, the response rate's over 90%. And on the right, you see the median PFS. And the median PFS did not differ on whether they were exposed to prior BCMA or not.

 

And the PFS is about 18 months. This is 1 of the best PFS that we see in prior BCMA-exposed therapy. And in my mind, it leads very nicely from that you can go from CAR to CAR.

 

The first question that patients ask me when they relapse after their CAR T-cell therapy, they say to me, "Can I get another CAR, Dr Martin?" Because of the 1-and-done strategy, or the 1-and-done component of CAR T-cell therapy.

 

[01:17:30]

 

Now, I am not going to talk much about toxicities to CAR T-cell therapy. I will say there are acute toxicities: there is CRS, there is ICANS, there are cytopenias, there are infections. These are mostly treated initially at the treatment center. We can treat these very well. We know how to treat these. These have not been problematic for us.

 

[01:17:50]

 

And in terms of late toxicities, as you know now, the FDA has approved for patients to leave the treatment center after just 2 weeks.

 

We do keep them at UCSF longer, usually 3-4 weeks. But just after 2 weeks, they can come back to the community. And you do have to worry about hypogammaglobulinemia, sometimes prolonged cytopenias, late infections, and late neurotoxicity.

 

This is happening in about 10%-15% of patients. This is cranial neuropathies, Parkinson-like syndromes, and then progressive peripheral neuropathies. Some can be bad, like Guillain-Barré. That is in a very low percentage, typically less than 1% of patients.

 

The community should work with the treatment center if they notice this. They may notice it. The community practitioners may notice this after the patient has left the treatment center. This occurs between 3 weeks to 3 months after the CAR T-cell therapy. The other toxicity is late gastrointestinal toxicity, and so significant diarrhea that all of a sudden just gets very bad in the post-CAR T-cell therapy should actually ring a bell that I need to call the treatment center and talk about management of IEC enterocolitis.

 

[01:19:02]So let us switch to bispecific antibodies.

 

[01:19:06]

 

As you know, we have 4 approved bispecifics, and we have 2, I think, that are in my mind that are on deck that hopefully will be approved in the not-so-distant future. Three right now that are approved that target BCMA, 1 that targets GPRC5D, and we have a new 1 that is going to target FCRH5, cevostamab, and then another BCMA-targeted the ABV383, etentamig, which that drug in my mind, it is possible.

 

Why do we need another 1? It is possible that it could actually be more convenient than some of the other ones. We will see.

 

There are a number of presentations on cevostamab and etentamig at ASH, and all of these, actually. I invite you to go to all of them. Real-world evidence for teclistamab and elranatamab and linvoseltamab, there are over 1,300 patients described in real-world evidence at this ASH. For talquetamab, there are over 1,100 real-world data presentations on that drug at this ASH. So it is a very busy ASH for bispecific antibodies.

 

[01:20:12]

 

I will just take you through a couple of the earlier data, and that is so for elranatamab, it was approved for use based on the Magnetismm‑3 study, looking at an overall response rate of about 61%.

 

In fact, when you look in the relapsed/refractory setting bispecific antibodies, in almost all the studies, one third of patients seem to be primary refractory. Why? We will talk about a little bit that at the end, but it may be that it is high soluble BCMA levels. It may be a T-cell health issue. Again, bringing it in earlier lines of therapy is going to be better.

 

[01:20:48]

 

Talquetamab, same thing, response rate somewhere in the high 60s to the low 70s with a PFS that ranges as a single agent of about 11 months.

 

[01:21:00]

 

And I will say, I am just going to say watch for ASH for data for cevostamab and etentamig. There are a bunch of studies. With these as initial agents, cevostamab treated with the use of sub-q administration of cevostamab, but also in combination with pomalidomide and dexamethasone.

 

And also with etentamig, you will see data in combination with pomalidomide and dexamethasone. We are going to go to combination therapies, no doubt with all these bispecific based therapies, right?

 

[01:21:36]

 

In terms of safety with bispecifics, you guys, I think everybody's aware of the signal. There is a safety signal in terms of infections, a high rate of infections. Patients get significant hypogammaglobulinemia. They need continuous IVIG therapy. They need IVIG therapy throughout their therapy with the bispecific engager. Perhaps the only 1 that does not need that is talquetamab.

 

The talquetamab often follows BCMA. So many patients are already hypogamma when they go on to talquetamab. So you often have to use IVIG, even with talquetamab. Talquetamab has less signal for infections, and perhaps that is a good bispecific to use in those patients that may have an increased risk for infection.

 

But it comes with some other toxicities, right? The nail toxicities, the mouth toxicities, the skin toxicities, which are manageable toxicities. Patients just need to know how to manage them and that they get better over time.

 

[01:22:36]

 

I will just say a few words on combinations of bispecifics.

 

[01:22:39]

 

So these are data that you will see updated data at ASH looking at linvoseltamab together with carfilzomib. Again, all of these bispecifics are going to be combined with our previous blockbusters, with proteasome inhibitors, and with immunomodulatory drugs.

 

[01:22:54]

 

And together, in combination in the relapsed/refractory setting with carfilzomib, very high overall response rates, anywhere between 90-100%. And you see the swim lane plot on the right showing some of these responses are actually quite durable.

 

[01:23:09]

 

We have also seen data from TRMM2, which is a combination of talquetamab with daratumumab and pomalidomide showing higher overall response rates. These are in patients that have more than 3 prior lines of therapy and exposures to the big 3 classes of medicines.

 

[01:23:24]

 

Again, very high response rates. In anti-CD38-naive patients, response rates as high as 100% and a very good PFS, closer to 15-18 months in a duration of response that is approaching just over 2 years, 26 months. So, very active, especially in combination.

 

[01:23:44]

 

Now, we have seen the combinations of the 2 talquetamab and teclistamab put together in the RedirecTT studies. In this 1, we actually also see a higher overall response rate, 80% and better in some subgroups of patients.

 

And you are going to see updated data at ASH for the RedirecTT study. Both RedirecTT in the relapsed/refractory myeloma, but also in the patients that have specifically, EMD.

 

[01:24:14]

 

It has been shown to have, in my mind, the best response rates in patients who have EMD.

 

It is now on the NCCN guidelines. We have actually had some success at UCSF in getting the combination of teclistamab and talquetamab to get insurers to actually pay for that combination, especially in patients that actually have extramedullary disease. And those that have true EMD, showing an overall response rate of 79%, actually pretty amazing.

 

[01:24:44]

 

And actually a median PFS of over 15 months. There are no other data like this in EMD for myeloma. We have to do better, of course, but this actually is the most potent combination for extramedullary disease.

 

[01:25:02]

 

Now, we also saw data at ASCO and EHA this year, looking at Phase I study of a trispecific antibody, the JNJ-5322, which is a BCMA, GPRC5D, CD3-targeted therapy.

 

And I will focus your attention at the middle of the slide, looking at the BCMA and GPRC5D-naive patient population, and looking at an overall response rate in 27 patients of 100%. I told you before that a third of patients, an individual treated just with Tec or Tal or any bispecific antibody, a third are refractory to therapy. Here, the overall response rate is 100%.

 

That is really pretty amazing. Maybe we do have to hit 2 targets at the same time. We will have to see how these data evolve over time, and you see the PFS curve that looks quite exciting.

 

And I think we are all very excited about what is going to happen with trispecifics. And there is other data at this ASH looking at trispecifics to CD38 and BCMA and CD3, and I invite you to go to those presentations.

 

[01:26:12]

 

But probably the biggest presentation, the biggest 1 at ASH, and for me, for this year, is going to be MajesTEC-3. And MajesTEC-3 is a multicenter randomized open-label Phase III trial. Patients with relapsed/refractory myeloma, 1-3 prior lines of therapy, with progressive disease on the most recent therapy, no prior treatment with a BCMA-targeted therapy, and not refractory to anti-CD38 antibody. And this was randomized to teclistamab plus daratumumab vs dealer's choice of either daratumumab-bortezomib index, Dara-Vd, or daratumumab plus pomalidomide-Dex, Dara-Pd.

 

This is going to be presented late-breaking. It is the last late-breaking abstract on Tuesday. It is last because they want to keep you here until the end. And in my mind, it is going to be the best presentation. I will not be here, but I will be online in San Francisco watching this. Patients are going to have to wait for me for this presentation.

 

This study was unblinded, right? In the control arm, the PFS was 18 months. The hazard ratio is 0.17. You can do the math. People have asked me, what would I be impressed with? I would be impressed with the PFS of 60 months. This is going to be better than 60 months.

 

If you do the math, it might be more than 90 months. We will have to see if it goes over time, right? But wow, this is again why everybody has to get into the scenario where they are using bispecifics in their clinic, especially in relapsed/refractory. We are going to have to look at that and compare that with other therapies like CAR T-cell therapy.

 

[01:27:52]

 

All right, so what to choose? ADCs, CAR T-cell therapies, or bispecifics? I say it is all of them. We choose all of them based on the individual patient. There are plenty of patients for each 1 of these drugs. And again, it is between you and the patient on which 1 is going to be the best 1 for them.

 

The only other teaser that I am going to throw out here, the big thing between ADCs and bispecifics and CAR T-cells, those 2 others are off-the-shelf. Also, in a late breaker, the first late breaker on Tuesday, you are going to hear the very first data at ASH of an in vivo CAR T‑cell therapy, an off-the-shelf CAR T-cell therapy.

 

Basically, the retroviral vector injected directly into the vein of a handful, just 1 handful of patients with relapsed/refractory myeloma, showing MRD-negativity. Again, an off-the-shelf CAR T-cell therapy. That potentially is a game-changer, and we will just have to see how that data evolves over the next 3-5 years. That is really exciting. It is a very exciting session, a late-breaking session for myeloma.

 

[01:29:06]

 

So why does treatment fail? Treatment fails because of bulky disease. Soluble BCMA are acting as a sink for some of these therapeutics. T-cell health is not good in patients that have had 5, 6, 7 prior lines of therapy. There may be tumor-related factors. There may be mutations. There may be deletions, etc. You are going to hear a lot more about us actually doing evaluations for mutations and deletions prior to starting these therapies, or starting a second BCMA, or a second GPRC5 therapy in patients that have relapsed/refractory disease. That comes next year.

 

[01:29:45]

 

Okay, in the last minute I am just going to tell you that basically we are all very excited also about the CELMoDs, iberdomide and mezigdomide. Why? It is based on this slide showing that compared to lenalidomide and pomalidomide, they provide better anti-myeloma effects, but they also provide the most immune stimulation. We think they are going to be the best synergistic combinations, both with some of our old drugs, as well as some of our new drugs.

 

[01:30:22]

 

Both of these drugs, Iber has been combined with a lot of our old drugs, showing better response rates in the relapsed/refractory setting. Iber has 2 EXCALIBER randomized Phase III trials that hopefully it will be approved in the not-so-distant future.

 

[01:30:37]

 

Mezigdomide also, you will see data from both Iber and Mezi at this ASH. Mezi in combination with a bispecific antibody, look out for that, which will be interesting. But mezigdomide has been combined with some of our standard medicines, showing again better overall response rates and also actually very good responses in EMD. It would be nice to see Mezi in combination with some of these bispecifics, etc.

 

[01:31:02]

 

With that, I will conclude, saying that it really is a time of great promise for immunotherapies and multiple myeloma, but we also have plenty of non-immunotherapies, and you really have to get experience with using all of these. The sequence that you use in individual patients really will depend on your experience, and it is an art, not a science, at this current time.

 

[01:31:25]

 

NCCN guidelines, actually, we need to add belantamab combination, belantamab-Vd to the NCCN guidelines, but they put you in, I think, the right space in terms of what things to think about when you are trying to choose.

 

If you cannot remember and you say, listen, I have got to look it up, look at the NCCN guidelines. They are actually pretty good to give you different options for patients that have relapsed/refractory myeloma.

 

[01:31:48]

 

Question 7: A 78-yr-old patient with R/R MM has progressed after 2 PloT: bortezomib and lenalidomide. The patient is not a candidate for CAR T-cell therapy due to comorbidities, frailty, and logistical constraints. The patient has adequate renal function and no active ocular disease. Which of the following is an FDA-approved BCMA-targeted agent that could be an appropriate next-line therapy?

 

Back to the case. We have a 78-year-old patient with relapsed/refractory myeloma, has progressed after 2 prior lines of therapy, bortezomib and lenalidomide, so having a PI and an IMiD. The patient's not a candidate for CAR T-cell therapy due to comorbidities, frailty, and logistical constraints. The patient has adequate renal function and no active ocular disease. So which of the following is an FDA-approved BCMA-targeted agent that could be an appropriate next-line therapy?

 

1. Elranatamab;
2. Belantamab mafodotin;
3. Linvoseltamab; or
4. Talquetamab.

 

Go ahead and vote again.

 

Okay, so wonderful. So as you guys know, the other 3 are basically bispecific antibodies, but right now, are 4 or more prior lines of therapy. So they are not actually available to this patient. So this patient with 2 prior lines of therapy, exposure to an IMiD-PI, belantamab mafodotin is the right choice here, and you guys did great.

 

So thank you very much for your attention. I think we will have a discussion.

 

[01:33:23]

 

Dr Huff: Okay, so we are just going to segue into a few discussion topics. I do not think we will hit all of these because they are quite needy discussion topics, but feel free to continue to submit your questions if you have them, and they will be forwarded on.

 

So I guess, Tom, which question would you like to tackle?

 

Dr Martin: So the top topic is actually a good one that we can all discuss. Bispecific antibodies, how do they differ? CAR T-cells, how do they differ, compare, and contrast with one another?

 

It is a really great question, and there are certainly differences in the way they are administered. Some of these are administered by subcutaneous injection, and then the CRS is going to happen within 48 hours, or those that are administered by IV administration in the CRS typically is going to be 24 hours.

 

Also the step-up dosing. Step-up dosing can be 2 or 3 step-up dosings, and also the monitoring after step-up dosing. For some, the monitoring is through the first full dose, and for some it is actually just after a couple step-up doses, and so that differs. For us, for me actually in San Francisco, it is more a pharmacy question than anything else because our pharmacists decide what we get.

 

In fact, so we get what our pharmacists tell us, and we get exposed to all of them, but we do have preferences, etc. I would say for people that are using these, you do not need all of these to have access. You have got to get comfortable with at least 1 or 2 of them, at least a BCMA-targeted one, and at least a GPRC5D-targeted one.

 

Get comfortable because these drugs, again, they are going to be used frontline, they are going to be used second-line, they are going to be used third-line, and it is going to be going through all these different combinations. Everybody's going to have to get accustomed to using these.

 

In terms of CAR T-cell therapies, I am going to ask Dr Rossi, what do you think of CAR Ts?

 

Dr Rossi: Yes, so just like you, I think the disclaimer is I am a big believer in CAR T, and we are mostly, I think, limited just by the access. So as far as ideal sequencing, CAR T should be the first therapeutic option, I think, for BCMA in 2025, 2026, but we cannot all get to it. So if a patient can go to CAR T, I think that would be the option first, mostly due to, again, the quality of T-cells.

 

But in the US, we do 2 approved BCMA products, and we have great datasets from the real world as we have expanded their use. So I think, again, giving us that flexibility to tailor the therapy to the patient. One of them, I think, cilta-cel is much more powerful, both in efficacy, but also in the toxicity. And we have the ide-cel, which is maybe a little less of both the efficacy and the side effects. So again, giving options to different patient populations at that time.

 

Dr Martin: Are you doing it in second-line? So somebody relapses on Len maintenance in their Len refractory, is it time for CAR T-cell therapy?

 

Dr Rossi: So I think that is the joy, and what made your topic so difficult is I would need a lot of other factors to play into it. So yes, I have my 35-year-old who is progressing within a year or 2, absolutely. I have someone who is 8 years on their Len maintenance and having a biochemical progression, maybe not.

 

So again, having it available so that for the right patient at the right time, I have the ability to use it.

 

Dr Martin: And I think there is quite a bit of controversy in that regard too, because you talked about functional high risk. And I am going to ask you another question later. What is functional high risk after a quad? How many years after a quad is functional high risk? But in functional high risk, we are all saying, yes, let us go on and let us treat them with CAR T-cell because they are functional high risk. Let us give them the best therapy.

 

Again, right patient, etc., right time, right therapy, right time. However, there is data that looks at standard-risk patients with cilta-cel. If you call out the standard-risk patients in the CARTITUDE-4 study, that PFS is close to the 75% level out more than 3 years.

 

So those are the patients that we actually might start to see a plateau that could be as high as 75%. It is that standard-risk population. It is always a difficult decision for me.

 

Carol, what do you do?

 

Dr Huff: I would say that I completely echo everything you are saying. And the only other piece I would say is that even in the older transplant data, those stage 1 patients, favorable risk actually benefited the most from the transplant as well. So I, too, at this point, I am probably more in the functional high risk in my second-line using ciltacabtagene for patients.

 

But I appreciate that I would like to see a little bit longer-term data to make sure that those patients are there. And as we get CAR T-cells with hopefully fewer potential side effects, it makes it an easier potential discussion. I would also say that it actually becomes a cost-effective therapy, even though there is a high cost associated with CAR T-cells.

 

If we actually have patients disease-free, both from a quality of life and overall cost, it becomes a cost-effective therapy as well, too. I would just also echo that bispecifics really are, and I know this is ASH, so it is a hematology meeting, and that is where our use is, but they are moving into the solid tumor realm. And so practices who have not yet gotten comfort will likely do so even more so as they move into the solid tumor realm.

 

But I very much echo getting comfortable with using at least a BCMA-targeted and a GPRC5D. There is not really a lot of value in having all of them initially. You need to get comfortable with the management and the oversight, but they are very effective therapies.

 

I guess I would ask the question back is, when do you change your frequency of your bispecifics for patients who are doing well?

 

Dr Martin: That actually is a really good question, and I think it does depend on response. And one third of patients do not respond, one third of patients basically progress in the next anywhere between Month 3 and Month 7 or 8 or 9, and then we have patients that actually do extremely well. For me, if their light chains are undetectable after cycle 3, then I am very comfortable with basically moving them to a less frequent dosing of their bispecific.

 

The M-protein, because of kinetics of M-protein half-life, the M-protein might not go away, and they are not in, quote-unquote, CR because the M-protein is still there. But if their light chains are undetectable, you know you have gotten rid of most of the plasma cells that are there, and I am very comfortable in moving it down at that point in time.

 

Dr Huff: What do you move it down to?

 

Dr Martin: So it is a stepwise fashion. For instance, for teclistamab, for me, it goes weekly. I think we often actually follow a little bit of the Dara mold in that we do weekly for 8-12 doses, and then it is every other week for 8-12 doses, and then it is monthly.

 

I will tell you, I have a bunch of 80-year-olds right now that are on either every 10-week or some even every 12-week dosing because they are doing fine, and they are enjoying life. Obviously, that is off-label, but it is very convenient.

 

Dr Huff: We have done the same, and people who are doing well, tolerating the therapy, staying in remission, not having to come in. It is off-label, but not having to re-dose escalate those patients so patients can do fine from a CRS perspective as well, too.

 

Dr Rossi: And I think you get the better longevity because we are not hiring out the T-cells at the same level, so absolutely.

 

Dr Martin: I will mention for everybody that soon, within the next week, the IMWG/IMF will have a website. It is a live website that will, you know, basically point people to the management of CAR T-cell therapies as well as bispecifics, and also give you kind of a blueprint of how to do it inpatient, how to do it outpatient, and it was put together mostly by the nursing board of the IMF, and we have 1 of the nursing board members that is in the back of the audience over there. She did a lot of the work for this, and it is actually going to be live guidelines.

 

We have published guidelines for CAR T-cells. There are many guidelines for CAR T-cells. There are many guidelines for bispecifics, but this will actually be a live site that we are going to change frequently depending on how things change. So, you know, I hope you can use that to your benefit.

 

So I want to ask you about functional high risk. So when should people be referring patients for potentially CAR T-cell therapy, especially now that quads really are what we are doing for frontline therapy?

 

Dr Huff: I would actually say at the time of relapse in that first-line so that patients can come be evaluated and also have the discussions. It is very difficult in my mind to outline every piece of a functional high risk, but we are all always happy to see those patients and engage them in those conversations.

 

Dr Rossi: Exactly, and I think exactly to your point earlier, right, if it works well in high-risk it would work well, even better in standard-risk. But I think it is so important, anybody who would be a candidate, to have that conversation start at the time of first relapse, even if it is to decide this is not the right time, but then that patient at least has that connection to the CAR T-center.

 

Dr Martin: Yes, absolutely. Early referral is what we need just to improve access. But I will go on record and say for me the functional high-risk, especially if they have had a quad, a transplant, and then maintenance. I am going to ask you about maintenance second. If they relapse within the first 3 years, that is functional high-risk. Those patients, you know, there is only maybe 10% or less that relapse in that first 3 years.

 

That patient's a bad patient, and that patient, I would say, is a good candidate potentially for CAR T-cell therapy at that point in time. Or when MajesTEC-3 is available, maybe that is more convenient for them. We will just have to see how that all goes.

 

Dr Huff: But I would say, as Adriana pointed out, someone who has had, unlikely to be a quad, but a triplet, a transplant, and maintenance lenalidomide, and is relapsing 7, 10 years later, that it is someone we would want to have a conversation with, but I would not personally put them in the functionally high-risk category, but certainly someone we would want to have a conversation with.

 

Dr Rossi: But that would be your potential cure, right? It would be. You had mentioned that 1 of the big differences is the transplant eligibility and CAR T eligibility. So I also think the so‑called transplant and eligible are ideal candidates because maybe that is the 1-and-done. They may not come back to need that next line, which I like your inverse.

 

Dr Huff: I will say I have a patient right now who did not want to do a stem cell transplant, ultimately had a second-line therapy, and went to CAR T-cell, and is in complete remission now, and doing great, and feeling well. Two months, 60 days later, back to work full-time.

 

Dr Martin: Yes, I think we all think the writing is on the wall for autologous transplant, that 5 years from now, we are on the stage, we are not really going to, I do not think, be presenting much data.

 

Speaking of that, MRD, do you guys follow MRD in your clinical world? Do you follow MRD? Does you make any decisions based on MRD?

 

Dr Rossi: Yes, I think 2 very different questions. We absolutely send MRD pretty much with any response marrow, but how to use that to inform a decision. It is not necessarily a real-time data point for us.

 

Dr Huff: I would agree. We send MRD, and we follow it. I will say, building on the DETERMINATION data, and patients who are MRD-negative after their initial therapy, and have more favorable disease, those are patients we will have a discussion about.

 

Do you do a transplant? Do you defer in a situation like that? But typically speaking, we are not yet making decisions based on changes in MRD at this point, although, worry if we start to see MRD rising.

 

How about you?

 

Dr Martin: Well, so Dr Wolf, who is in the audience here, basically taught us all from way back when that MRD is what guides therapy. And we would say that we do not use MRD to make any treatment decisions, but we actually have somebody that comes from Spain every summer and looks at our data year-to-year in terms of all the MRD data that we have. And probably 4 or 5 years ago now, he came and he said to us, you know about a third of the time you guys are making decisions based on MRD, even though we would say, no, we are not making any MRD decisions.

 

But yes, and a lot of the decision is that those people that are MRD-negative, and they have had Revlimid for a year or 2 years or 3 years, and they have a lot of Revlimid side effects, it is the easiest thing to stop their lenalidomide or stop the Revlimid. And if we look at a PFS curve, and this is obviously, this is post hoc, etc. If we look at that PFS curve of the people that we have changed our decision on MRD vs people that had MRD and we made no change whatsoever, that PFS curve is actually better.

 

So for us, we tap ourselves on the back and say, yes, we are doing good with MRD. But obviously we need it in randomized trials. I think the MIDAS trial will be something we need to follow up.

 

In the frontline setting, using bispecifics in the frontline, there will be data, a lot of data at ASH here, too. It is 100% MRD-negative. And if we are using MIDAS data to go forward, that means most of those patients are not going to get a transplant, right? We will just have to see how that evolves over time.

 

But yes, MRD, I think, is an important thing. If you are not also doing MRD, it is probably 1 of those things that everybody can do it because it is a bone marrow biopsy sample that is sent to Seattle to Adaptive at the current time. It is FDA-approved, basically, monitoring mechanism, unless you do local flow. And so that is something that people can do.

 

Dr Huff: And I would personally strongly advocate that it should be on the bone marrow, not the efforts to do it on peripheral blood, that the yield of that is much, much lower. I should say, just echoing, de-escalation of therapy based on MRD, I think, is definitely where things go when you see fluctuations in numbers. So I am excited and looking forward to more readouts of our trials in finite therapy, either discontinuation of therapy, de-escalation of therapy based on MRD-negativity.

 

Dr Rossi: I would just say not achieving, but sustained. I think that is the hard thing to do in upfront. You only have that 1 time point, so you do not have the sustainability of it. The other is in the US, we all have access to MRD testing. Maybe in the rest of the world, it may not be NGS, at least.

 

Dr Martin: It becomes more challenging. But I do want to comment on your comment too, and that is, completely agree. The peripheral blood MRD that patients are coming in with, it drives me a little crazy, because, and I will tell you that some of these patients, their light chains are 100. They are involved, light chains 100, and they are handing me a piece of paper that says their peripheral blood MRD was negative. I said, no, you are not negative because your light chains are still 100. So please, it is a bone marrow test. Until we really figure out the peripheral blood component of MRD, it is a bone marrow test at the current time.

 

How about mass spec? Does anybody use a mass spec for monitoring? Are you guys doing mass spec or mass fix?

 

Dr Rossi: Trying very much to get it. Work in progress. Work in progress.

 

[01:50:16]

 

Dr Huff: All right, how do we increase our trial enrollment? I will blend these things more. What can we do to increase clinical trial enrollment? What do you do to increase your clinical trial enrollment?

 

Dr Martin: Because I am obviously at an academic center, that is a main focus of our cancer center. It is really to look at our catchment area. I recommend that everybody looks at their catchment area.

 

So Anu Kumar at UCSF has done a map of our catchment center and has pulled out the zip codes of everybody that has received bispecific therapy at UCSF or CAR T-cell therapy at UCSF and has put it on the California map where we are getting and where we are not getting to. And we are trying to address with our cancer center, hey, there are several pockets in California where we know there are patients, and we are not getting any patients referred to us for that. We need to get to that.

 

It is difficult. We have to provide them with resources to actually get to us, and we also have to provide them with the data of why they need to get to us. One of the successes that we have had at UCSF is we have worked together with UC Fresno, and UC Fresno now is able to give bispecific antibodies, and they are actually just starting to give CAR T-cell therapies for non‑Hodgkin's lymphoma and then soon for myeloma.

 

And that actually is huge, where they actually took on the ability to get some of this done locally in their area, which is a far distance for patients. And anything that we can do, anything that we can help the local guys to get involved in and to be able to offer these to patients is really important.

 

Now, the truth is, you see, Fresno is a great referral to us for clinical trials. So if the patient does not qualify for a standard-of-care CAR T-cell or a standard-of-care bispecific, they then will refer them to us for that. So you make, you have to make relationships with your local practices, the community practices, and trying to get them involved also with the clinical trial enrollment.

 

Dr Huff: All right, I am just going to, unfortunately, we are not going to have time to get all of these questions that have come from the audience, but I will ask one. In transplant-eligible newly diagnosed patients, considering the MRD results of CASSIOPEIA and PERSEUS, is it time to question lenalidomide maintenance or just do daratumumab maintenance?

 

Dr Rossi: I will say in my practice, I do that, but mostly based on patient preference. I have a lot of patients who, if given the choice, to me the maintenance has to be part of the combination that got them to their remission, and I give them the option, and many of them will choose daratumumab easier than lenalidomide.

 

Dr Martin: I completely agree. And so, you know, I typically follow the protocol. There are, you know, there are some centers obviously in the U.S. that do quads transplant and then just Len maintenance and do not do the CD38, and we will not really have randomized data until the GMGHD7 study reads out. That was first presented at ASH in 2021. We still do not have the data from the maintenance component of that. Holy cow, that is actually how good we are doing.

 

Dr Rossi: It is such a good problem to have.

 

Dr Martin: It is a good problem to have, exactly. But so I do doublet. I do lenalidomide and daratumumab, and then I ask the patient which one, if we want to stop 1, which one do you think is more toxic, and would be less or more convenient for you, and I let the patient decide.

 

Dr Huff: As do we.