Current and Emerging Therapeutic Approaches for Multiple Myeloma (MM) — Robert Z Orlowski, MD, PhD

DR ORLOWSKI: Thank you very much for the invitation to provide this overview of some of the exciting developments in multiple myeloma based in part on abstracts that were presented at the 2024 American Society of Hematology, many of which have now been published in the peer-reviewed literature. My name is Bob Orlowski. I'm the Florence Maude Thomas Cancer Research Professor at MD Anderson, serving as the Deputy Chair and the Vice Chair for translational research in multiple myeloma.

From an overview perspective, I think we can start with the earlier lines and then move to more advanced disease. And it doesn't get too much earlier than smoldering multiple myeloma. I'm sure all of you know that for right now we don't yet have anything approved for the smoldering setting. And it's definitely an area where we can improve upon. Because many of these people, especially if they're at high risk of progression, can develop bone lesions, anemia, renal failure and yet up to now the standard of care is still a watchful waiting approach, which, of course, is quite frustrating for patients as well as for providers.

So we did see a study presented at first the International Myeloma Symposium and then at ASH and now has been published in the New England Journal. Athanasios Dimopoulos was the first author and this was a study looking at smoldering patients who were randomized to receive either watchful waiting, also called active monitoring, or to daratumumab as a single agent and then monitored moving forward. In terms of progression-free survival, which was the primary endpoint, patients who got daratumumab had a lesser likelihood of progressing to symptomatic disease. You can see from the graph that there is a nice separation of the curves in favor of daratumumab and that separation really begins to happen very early in the trial and then seems to actually enlarge over time. And although the overall survival data were not yet mature, it did look like there was a trend beginning to favor the daratumumab arm. So based on these data, we're hopeful that we will later this year get an approval from the FDA to have dara available for smoldering myeloma. Probably this will be for high-risk smoldering according to the IMWG 2/20/20 system where the 2 means more than 2 g/dL M-protein, one of the 20s is more than 20% bone marrow involvement and the other 20 is an involved to uninvolved free light chain ratio of at least 20. Any 2 of those puts you into the high-risk setting and dara again will hopefully be the first agent approved. We also expect that there will be other combinations available down the road including anti-CD38 antibodies either dara or isatuximab with lenalidomide and dexamethasone.

And in terms of the toxicity profile, for those of you that have used daratumumab, there really were not any surprising findings. The group that were randomized to dara had a little bit more fatigue and some risk of upper respiratory infections, but otherwise it was a very well tolerated therapy with a relatively low incidence of serious adverse events.

Moving from smoldering now to newly diagnosed myeloma and, of course, for symptomatic patients, we still divide people up into those who are transplant eligible, and we'll start with that group, versus folks who are transplant ineligible, who we'll get to in one of the subsequent slides. The first study that really was very interesting came from the German study group looking at these transplant eligible patients and randomized them to get either one of the current standards of care at that time, which was RVd or lenalidomide with bortezomib and dexamethasone, versus the addition of isatuximab, an anti-CD38 antibody. And this trial looked at both progression-free survival as well as minimal residual disease negativity. This was a large study and you can see from the graph that the isa-RVd group in the purple color had a better progression-free survival than did the folks who got just the triplet RVd in the red color. And MRD wise what was interesting here is that if you were able to achieve MRD negativity, whether it was on RVd or on isa-RVd, you did better than if you did not achieve MRD negativity, which, of course, is expected. Less cancer is always going to be better than more cancer. But the interesting thing is, of course, that with isa there were more patients that achieved MRD negativity with the quadruplet than was the case with the triplet.

One of the interesting things now in terms of MRD testing is, are there other approaches that we can use besides just bone marrow evaluations? We can do MRD either with what's called next generation flow cytometry, which is good for about 1 in 10⁵ cells or we can do it based on sequencing with the typically used clonoSEQ assay, which gets you down to about 1 in 10⁶ cells that can be detected. But, of course, bone marrows are not that easy on patients and it would be interesting to have an even more convenient way. One approach that we think is coming is to do mass spectrometry on the peripheral blood, which would allow us to do serial assays and be more sensitive than approaches relying on just the immunofixation of the serum. But there was an analysis presented at ASH from the PERSEUS study, which was dara/RVd versus RVd where they looked at circulating tumor cells. We know from past studies that patients can have low levels of circulating myeloma cells that can be detected in the peripheral blood and the interesting thing about that kind of assay is that not only can you detect how much tumor there is but in some cases some of the assays allow you to do molecular testing on those cells. So you get an evaluation not just of disease burden but of the biology of the disease as well.

So in the analysis that was presented at ASH, there were a couple of things that were interesting. In the top graph, what you can see is that higher levels of circulating tumor cells were associated with a more rapid progression to the next line of therapy, which is to be expected. And people with very low levels of circulating tumor cells did better. The second analysis that I thought was particularly interesting is that they looked at whether this was an independent prognostic risk factor compared to molecular risk as well as ISS stage and they did actually confirm that the percentage of circulating tumor cells was an independent risk. So hopefully this is something that will be available moving forward where we can, first of all with greater sensitivity, detect how much myeloma is left and also maybe make some decisions in the future about treatment. For example, people with more circulating tumor cells may need more therapy compared with people that have fewer circulating tumor cells.

There also were studies looking at the value of the circulating tumor cells in the setting of getting quadruplet versus triplet therapy and also high risk versus standard risk. In terms of the risk profile, essentially having low levels of circulating tumor dells was beneficial whether you had standard risk or high risk but the difference was particularly important in the molecularly high-risk patients.

Moving on to the CEPHEUS study, which was dara/VRd versus VRd in transplant ineligible patients. This was an attempt to show that quadruplet therapy could be effective and safe in this transplant-ineligible population. We know, of course, from previous studies that have been presented that this is true for transplant eligible patients. Here in CEPHEUS, again focusing on transplant ineligible newly diagnosed myeloma, really the main exclusion to keep in mind is that most of these patients would not have been in the frail category, but they were randomized to get either the triplet or the quadruplet. And as you probably would expect from the transplant eligible population, in the ineligible patients the quadruplet did better in terms of progression-free survival. And minimal residual disease negativity was higher with the quadruplet. This was true at 10^-5, at 10^-6 and there also was a better rate of sustained MRD negativity. Sustained MRD negativity means that on at least 2 consecutive measurements patients were MRD-negative and as you would imagine people who have sustained MRD negativity do better than people who have MRD negativity just at a single timepoint.

The other trial that really I think informs what we do for transplant ineligible patients was the IMROZ study, which also looked at VRd as the control arm and compared it to isatuximab/VRd. Here the quadruplet again was superior with a hazard ratio of 0.6, which means a 40% reduction in the risk of progression. Full disclosure — I was one of the authors and investigators on this study so the data are exciting and hopefully will change what we do in transplant ineligible patients. And MRD negativity again was better with the quadruplet than was the case with the triplet both in the entire patient population as well as in those with complete response. And the sustained MRD negativity rate was almost double. So this is really what you want to try to achieve in patients is this MRD negativity that is sustained over time. And the adverse events were pretty much what you would expect with an anti-CD38 antibody.

In addition to IMROZ, there was an interesting study, which is in some ways a complement, and this was called the BENEFIT trial. In this study, the control arm was isatuximab with len/dex and the experimental arm was isa/VRd. So it's another test of a quadruplet in transplant ineligible patients but the difference here is that one arm had bortezomib and the other arm did not so it really asks the question, are proteosome inhibitors still important in transplant ineligible newly diagnosed patients? This was an almost 270 patient study by the time you got to the randomization and you can see that the overall response rate was better for the quadruplet and the very good partial response rate as well as complete response rate was better if you got the 4 drugs. In fact, the CR rate was almost double, which I think is really important and does show you that for transplant ineligible patients adding that fourth drug in the form of a proteosome inhibitor can be really helpful and MRD negativity was better at both 10^-5 as well as 10^-6. And if you look at the forest plot there you can see that the quad was better in almost all of the subgroups including men and woman, younger ineligible patients versus, how shall we say, more mature patients and in standard risk as well as molecularly high-risk patients.

For people that have had a transplant after prior therapy, for many years lenalidomide as a single agent has been the standard of care for maintenance especially if people are standard risk molecularly. We did see data at ASH that are now published from the AURIGA study and in this trial patients, after transplant, who still were MRD-positive, were randomized to get either len alone or they got dara plus len in combination and then were monitored for progression-free survival. Pretty large study with several hundred patients that were enrolled and the dara/len arm, which is in the red curve on the right, did show a better progression-free survival compared with just len alone in the green arm. So again, if you're MRD-positive still after transplant, it does suggest that the combination is going to be better than len alone. And we do hope soon to have data from a SWOG study that finished enrollment earlier this year that looked at len versus len/dara as a maintenance although it took all-comers. So you could be either MRD-negative after transplant or MRD-positive. It may still be a couple of years before we know but that will really be the last question to ask in the maintenance setting. And I do think that definitely for MRD-positive patients you should consider the combination and, potentially based on the SWOG study, maybe even for MRD-negative patients as well.

From a side-effect perspective, dara and len was pretty well tolerated and, of course, MRD-negative patients were able to do better than patients who still stayed MRD-positive despite the maintenance that they were on.

Another interesting aspect is MRD 1 year after stem cell transplant. And one of the studies that looked at this and had been presented at ASH was later published in the Journal of Clinical Oncology. One of the things that they looked at is if you are MRD negative at 1 year after transplant, does that translate into better outcomes? And as you might imagine, the answer is, yes, in terms of progression-free survival as well as overall survival. Another question that often comes up in this area is, well, if you have MRD data, what should you do about it, especially if you're MRD-positive? So they did an interesting analysis, which is that they looked at the patients who were MRD-positive but then converted to MRD-negative and whether their outcomes were different than the people who stayed MRD-negative throughout. And the interesting thing there is that both on PFS as well as OS, it looked like the people who converted to MRD-negative from a previous positive did as well as the people who were negative to begin with. And that really gives you the impetus to say not just is the MRD data important prognostically, but it may also support your treating the positive patients a little bit more aggressively so that they can achieve MRD negativity.

Moving now to the relapsed and refractory space there are a number of study updates that we've been able to see recently. And one was an update of the IKEMA study. With IKEMA you probably remember that the control arm was carfilzomib with dexamethasone or Kd and the experimental arm was isatuximab with Kd or IKd. And the early results of that showed a strong benefit for progression-free survival and also a trend towards a better overall survival. Towards the end of last year, we saw a publication of the OS analysis, the final overall survival data. And again, progression-free survival maintained a strong advantage for the triplet. But now the overall survival advantage, although there was still a trend that favored the triplet, the data now did not quite reach statistical significance. You can see the hazard ratio of 0.855, which means about a 15%, 1 to 5 percent, reduction in risk of progression or death, which didn't quite meet the 0.05 p-value although the trend was there at 0.18. I still think this is a very valuable regimen with a PFS that's over 3 years and the fact that the OS now is not as positive is really just an indicator of how successful we are at salvaging patients with the next line of therapy if they do progress.

Interestingly, there was a similar analysis published of the ICARIA study. This was pomalidomide and dex versus isatuximab, pomalidomide and dexamethasone. On average, this was a later line of therapy patient population because they had to be refractory to lenalidomide. And here again progression-free survival was substantially better for the triplet and the early data showed an OS advantage. And the final analysis also confirmed an OS advantage with a 0.776 hazard ratio, which is almost a 25% reduction in risk of progression and about an 8-month difference in the overall survival. So definitely something to consider with isatuximab.

And I think we'll also go into upcoming data that we'll see about subcutaneous administration of isa. Right now, isatuximab is only approved through an intravenous route. But there was a press announcement, and I think we're hoping to see this at ASCO in just a few weeks, of data from the IRAKLIA study. And this was a trial of a triplet versus a triplet where everybody got isatuximab with pom and dex but one arm got the isa given intravenously whereas the other arm got it subcutaneously, which is through what's called an on-body delivery system. So this is a device, which is put on the patient's body by a nurse, and then the injection occurs automatically. And after the injection, the patient can simply take this device off and discard it so it's something that I think all of us are really looking forward to. And this study met its primary endpoint and hopefully as well we'll see the data as I mentioned at ASCO. This was again a noninferiority study and hopefully will lead to the approval of this on-body delivery system.

Moving now to therapies that maybe aren't yet FDA approved but we hope soon will be. All of us are used to using lenalidomide and pomalidomide in particular. There is a new generation of cereblon binding drugs that are in development. The 2 main ones for myeloma are iberdomide and mezigdomide. These are drugs that were actually rationally designed to better bind cereblon more tightly. And in preclinical studies they seemed to be better than the older generation like len and pom in terms of their antimyeloma efficacy as well as their immune modulation. So we have an update that was presented at ASH of a couple of combinations. One was mezigdomide with carfilzomib/dex. The other is mezigdomide with bortezomib/dex. Both of these, by the way, are now in Phase III trials so hopefully you will have access to them and if you have patients that need novel therapies, I would definitely recommend these. But with either mezi and carfilzomib/dex or with mezi and bortezomib/dex, you can see that these were patients that had a median of 1 to 3 prior lines of therapy including a lot of patients with stem cell transplant. Many of them had prior proteosome inhibitors and almost all of them had prior immunomodulatory drugs. And yet they still had with these combinations really nice median progression-free survivals that were at least a year to 18 months potentially and really I think promising data.

Also correlative studies that have been done in some of these trials show that these drugs appear to be able to reverse T-cell exhaustion. So that's exciting because if we use a CAR-T or in particular if we use a T-cell engager, then oftentimes patients will develop exhausted T cells, which may limit what options you have in the next line of therapy. For example, if you use 1 T-cell engager and the patient progresses and they have exhausted T cells, a second T-cell engager against a different target may not work as well. But we have data from again preclinical correlative studies showing that iberdomide and mezigdomide may be able to reverse that T-cell exhaustion. And so that may ultimately allow us to do one T-cell engager. If they progress, move to an iber or mezi combination both for clinical efficacy and to overcome T-cell exhaustion. And then if they progress after that, switch back to a T-cell engager against a different target. For example, BCMA T cell engager, mezi combo and GPRC5D T-cell engager in that sequence of therapies.

So I think those were some of the highlights of ASH in recent publications in myeloma. Some of these will inform your practice now and hopefully many more will be available for you down the road as we try to get to that cure for myeloma. And thank you very much again for the opportunity to review all of this for you.

Chimeric Antigen Receptor (CAR) T-Cell Therapy, Bispecific Antibodies and Antibody-Drug Conjugates (ADCs) — Meletios-Athanasios (Thanos) C Dimopoulos, MD

PROF DIMOPOULOS: Hello, I’m Thanos Dimopoulos. I work at the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine in Athens, Greece, and I will present an update regarding immune therapies for the treatment of multiple myeloma, focusing primarily on CAR T-cell therapy, bispecific antibodies and antibody-drug conjugates.

Recently we had an update of the CARTITUDE-4 trial. In this study the cilta-cel product was compared to standard of care in patients with relapsed/refractory myeloma at early phases of the disease, 1 to 3 prior lines of therapy.

In this particular study we have now long-term follow up data, which indicates that there is a continuous improvement of progression-free survival in favor of the cilta-cel product. Furthermore, this progression-free survival advantage translated into overall survival as well.

Another CAR T-cell product is the ide-cel, and we have similar study, the KarMMA-3 study, which compared the activity of this product versus standard of care in patients who had received 2 to 4 prior lines of therapy, and recently we had long-term outcome of these patients. There was a progression-free survival advantage in favor of the ide-cel product. However, there was no obvious survival advantage, and this was explained by the crossover design of the study. A significant number of patients who progressed on standard of care were subsequently crossed over at the time of relapse to the ide-cel product.

Another very interesting CAR T-cell is the anito-cel, and we have preliminary efficacy data for this anti-BCMA CAR T-cell therapy in relapsed and refractory myeloma. In this initial study we have patients who have been heavily pretreated, many patients were pentarefractory, many patients have received high-dose therapy, and the interest of this product is that there was not only a very high response rate, with complete responses exceeding 60%, with high levels of MRD negativity, but also with low rates of side effects that we see with the use of CAR T-cells.

For example, the rate of cytokine release syndrome was 1 or less in almost all the patients. There were no ICANS, and there were no delayed non-ICANS neurotoxicities. And the potential explanation of neurotoxicity advantage of anito-cel is maybe thanks to its D-domain binder, which helps the therapy quickly release from the BCMA target and could help the product eliminate myeloma cells without severe immunotoxicity. So this is a very interesting compound that warrants further follow-up.

There is a significant interest to develop CAR T-cells that have a different target from anti-BCMA because we know that we have now many products that target BCMA, not only CAR T-cells, bispecifics, but also antibody drug conjugates. So it is of significant clinical importance to identify other targets. One of them is GPRC5D-targeted chimeric antigen receptor T-cell therapy, and this is particular of interest in patients who have been previously treated with an anti-BCMA-directed therapy.

Flow analysis have identified 20 unique B-cell clusters with significant differences between responders and nonresponders. The appropriate dose for this product was identified as 150 times 10⁶ CAR T-cells, and this was the maximum tolerated dose. Furthermore, 75% of patients who were previously treated with anti-BCMA responded to this product.

So this is a very interesting approach, and as I mentioned, we are in need of CAR T-cells that have a different target so that we can apply them to patients who have been previously treated with anti-BCMA therapy.

Moving now to bispecific monoclonal antibodies, we know that there are already 3 of them commercially available for the treatment of our patients with relapsed/refractory myeloma, teclistamab, talquetamab, and elranatamab. The approval of teclistamab was based on a large Phase I/Phase II study, the MajesTEC-1 study, and this study now has the longest follow-up of a bispecific monoclonal antibody with a median of 30 months. Teclistamab continues to demonstrate deep and durable responses, including in patients who transition to less frequent dosing.

And we can see a very high response rate, and also we can see that the median duration of response for responding patients was 24 months, and it has not been reached for patients who achieved a complete response or better. Furthermore, with longer follow-up of teclistamab there were no new safety concerns. Of course we know that with all bispecific monoclonal antibodies we now administer immunoglobulins either intravenously or subcutaneously when the level of serum IgG is less than 400, and this has significantly improved the tolerability and has reduced the rate of infections with bispecific monoclonal antibodies.

Another important and approved bispecific monoclonal antibody is elranatamab, which again has been administered to several patients with triple-class exposed relapsed/refractory myeloma. And we have here the long-term follow up of the MagnetisMM-3 trial, which included a large number of patients and confirmed the activity of elranatamab in patients with triple class-exposed myeloma.

With 32 months after last patient and median follow up of about 3 years elranatamab was given at a dose of 76 mg every week, and in responding patients then the treatment was given every 2 weeks, and if response continued for 6 months or more it was given every 4 weeks. The projected overall survival is 3 years. It is important to note that following switch from every 2 weeks to every 4 weeks 96% of the patients maintained their response for 6 months or more, and the incidence of Grade 3 and 4 infections decreased significantly. Thus, with bispecific monoclonal antibodies it is important to decrease the frequency of administration for responding patients and also to administer immunoglobulins in order to reduce the well-known immunosuppression. Furthermore, of course these patients are being treated with prophylactic antibiotics, antivirals, and antifungal agents.

Talquetamab is the third bispecific monoclonal antibody which is approved for the treatment of multiple myeloma. It has a different target, a non-BCMA target, and also we have the long-term follow-up of MonumenTAL-1, which is a study that led to the approval of this agent. In this particular study a very large number of patients were treated either on a lower dose given weekly or at a higher dose given every 2 weeks.

The overall response rate was about 70%, and also we noted, and this is very important, that patients who had received a prior CAR T-cell, anti-BCMA CAR T-cell and relapsed had a 70% probability to respond to talquetamab. And also, patients who were pretreated with an anti-BCMA bispecific had a 58% chance to respond to talquetamab. The response rate to extramedullary disease was about 50%. We also noted that the every-2-week dosing was better — had a better duration of response than every-week dosing, especially in patients who were naïve to prior anti-BCMA therapies.

Because teclistamab and talquetamab have different targets there has been the study, a Phase IB/II study, the RedirecTT study, which has evaluated the combination of these 2 bispecific monoclonal antibodies who have different targets. This study established that the administration of talquetamab at a dose of 0.8 mg/kg and teclistamab at a dose of 3 mg/kg every other week was the recommended Phase II dose. At this recommended dose we noted a response in 80% of the patients. Furthermore, and more importantly, we saw a response of 60% in patients with extramedullary plasmacytomas, and we know that this is a hard-to-treat condition in patients with advanced myeloma. And also, at 18 months 82% of patients with extramedullary plasmacytomas were free of progression.

And with appropriate measures, such as with salt and soda rinses, glucocorticoid rinses, we’re able to mitigate to a significant degree the taste disorder, which is caused by talquetamab. So this is an important study that of course requires further follow up in the future, and I would like to stress again the significant activity in patients with extramedullary plasmacytoma and the durability of these responses.

Another new bispecific monoclonal antibody is linvoseltamab. This agent is being given intravenously, so the advantage of the intravenous administration is that it requires a shorter hospitalization because CRS is occurring earlier. So the intravenous administration is associated with an earlier occurrence of CRS and then subsequent shorter administration.

In this particular study linvoseltamab was given at increasing doses, and in responding patients it was given every 2 weeks, and then after several months it was given on a monthly basis. And this is, of course, important for patients’ convenience. At 21 months objective responses were documented in 70% of the patients. The median duration of response was 29 months, and the median overall survival was 31 months. There was a response in patients who had high BCMA expression and also with less frequent administration, every 4 weeks. There was a decreased risk for infection, so there was a favorable safety profile of this particular agent.

Moving now to antibody drug conjugates, we know that belantamab mafodotin is an antibody drug conjugate that targets BCMA. After this link with BCMA it delivers a payload in the anterior of the cell and has multiple modes of action. In the DREAMM-8 study there was a comparison between a standard regimen, which is bortezomib, pomalidomide, and dexamethasone, versus the combination of belantamab mafodotin with pomalidomide and dexamethasone. The target population was patients who have been pretreated with lenalidomide, so this was an inclusion criteria, and I believe this is a very important because now almost all patients with myeloma are being pretreated with lenalidomide. And also in this trial patients with prior exposure to daratumumab were also included, so this is a study which addressed real-world patients with multiple myeloma. The primary endpoint was progression-free survival with key secondary endpoints of response rate, overall survival, duration of response and of course tolerability.

In this particular study, the majority of the patients were lenalidomide resistant, but also about one quarter of the patients were previously treated with daratumumab. There was a significant improvement of progression-free survival in favor of the combination of belantamab with pomalidomide and dexamethasone versus PVd.

The adverse events of interest indicated that there was no significant difference between the rate of myelosuppression. Of course, with belantamab mafodotin we expect some ocular toxicity, which is usually — usually consists of keratopathy of various degrees. However, clinically significant ocular side effects that may affect the daily activity of the patients occurred in approximately one third of them. And these side effects resolved completely upon holding the drug and starting at a lower dose.

Another important study is the DREAMM-7 trial. In this particular trial there was a head-to-head comparison between daratumumab and belantamab mafodotin. Both of these drugs were combined with bortezomib and dexamethasone. Again, the primary endpoint was progression-free survival and secondary endpoints MRD negativity, overall survival and duration of response.

The patients that were included were typical of those with myeloma. Several of them have high-risk cytogenetics. About one half of these patients had received previously lenalidomide, and a third of the patients were lenalidomide resistant, and these characteristics were equally distributed between the 2 arms.

There was a significant benefit in the progression-free survival in favor of the combination of belantamab with bortezomib and dexamethasone over DVd. And not only there was a PFS advantage, but also a more recent analysis indicated that there was an overall survival advantage in favor of the belantamab-based combination.

Another important study is that DREAMM-9 study. In this particular trial VRd was used as a standard regimen for nontransplant-eligible patients with multiple myeloma, and then belantamab mafodotin was given at different doses and at different intervals in several cohorts of patients. So as we can appreciate here, there were patients who started with 1.9 mg/kg given every 3 to 4 weeks or 1.4 given every 8 weeks.

And there were several of these combinations that attempted to evaluate which combination is not only the more active but also better tolerated with this quadruplet combination. Cohorts with lower dose and longer schedules were opened to assess the potential to improve tolerability while maintaining efficacy because we know that a unique property of belantamab mafodotin is that when you hold the drug patients may continue to respond while the ocular toxicity is resolving.

And these are the outstanding response rates that we observed, with responses ranging from 70% to 100% across all different doses, and we can appreciate that these responses were more pronounced for patients who started at a higher dose or belantamab mafodotin. These higher doses were associated with higher, faster MRD negativity.

However, longer dosing intervals were associated with increased time to clinically meaningful changes in the visual acuity of the patients.

Thus, not only we can induce a very high response rate in nontransplant-eligible patients with multiple myeloma with a rate of MRD negativity that we have not seen before, but also by adjusting the dose and administering the drug at longer treatment-free intervals according to the ocular complications of the patient we can manage for the majority of the patients to remain on treatment as long as there is a response of the disease. And based on this exciting data there is a study that is comparing daratumumab with lenalidomide and dexamethasone versus belantamab with lenalidomide and dexamethasone, the DREAMM-10 study.

To conclude, CAR T-cell therapies are effective therapies for both early and late patients with relapsed/refractory myeloma. There are, of course, several unsolved question. For example, how sustainable are the responses? We know that the majority of patients relapse, but there are subsets of patients even later in the course of the disease that remain without progression for an extended period of time. And there is a question, is there a plateau in the PFS curve. For example, if we use these CAR T-cell therapies earlier in the course of the disease may we achieve a cure in some myeloma patients?

Furthermore, which are the best targets? Which constructs? What dose? We know the dose is related to activity but also may be related to side effects. Are different CARs similar? Is there a role for a second dose, either as a consolidation of the first dose or in the form of maintenance given several months apart? Is there cross resistance? Are we losing the target? There are data to indicate that indeed after several months we may have a loss of BCMA, but we know that if the patient remains without therapy then BCMA may reappear.

What are the options after CAR T-cell failure? Other immunotherapies? Maybe the patients respond again to treatments they have received earlier in the course of the disease. And of course, apart from toxicity and logistics, the cost of this treatment may be a concern for several health care systems.

Immunotherapy approaches with T-cell engagers offer excellent results in late relapsed/refractory myeloma, and of course these products are being evaluated in the context of perspective randomized trials early in the course of the disease. The main problem is infections, and today we know that by using pre-emptively immunoglobulins, either subcutaneously or intravenously, and by using the drugs, these drugs at longer intervals we may, to a significant degree, decrease the rate of infection. Do we really need continuous use? Or we may have a fixed duration administration of bispecific antibodies.

And finally, belantamab mafodotin in combination with either bortezomib and dexamethasone, or with pomalidomide and dexamethasone, are becoming a new standard of care in patients with early relapsed/refractory myeloma, combinations that can be administered to outpatients over a short period of time. They do not require hospitalization. They can be given every 3 or 4 months in several patients, and they’re not associated with a high rate of infections.

Thank you.