Activity Transcript

Philippe Moreau, MD: Hi, my name is Philippe Moreau. I'm working at the University Hospital of Nantes in France, and I'm very happy to discuss with you today about the management of patients with relapsed and refractory multiple myeloma in the era of BCMA targeting agents. And today I'm joined by 3 very good experts in the field. Dr Hermann Einsele from Germany is the head of the hospital in Würzburg in Germany. I'm also joined by Dr Nooka from the Emory University School of Medicine in the US. And joined as well by Dr Popat from the UK, he's working at the University College Hospital in London. So welcome, guys. And I think that with this very good faculty, we are going to have a good discussion today.

So, in this program, we'll discuss some important points about the management of patients with triple-class refractory multiple myeloma, and how we are using already some BCMA-targeted therapies. We will also propose some cases to illustrate how we can deal with this very difficult to treat patient population.

So, this picture is showing the outcome of patients that are refractory to 3 classes of agents: proteasome inhibitors, IMiDs (immunomodulatory imide drugs), and CD38 antibodies. And we are calling those patients triple-class refractory. We are also discussing penta-refractory patients. Penta means that they are: refractory to 2 IMiDs, pomalidomide and lenalidomide, refractory to 2 proteasome inhibitors, carfilzomib and bortezomib, and refractory to a CD38 antibody.

And you see that in the real life, and this is a picture from the very important paper published in Leukemia, showing the overall survival of patients that are refractory to these 3 classes of agents. And you see that the median overall survival is very short and for penta-refractory patients, the overall survival is less than 6 months, and this is really defining the unmet medical need, and definitely more patients, more and more patients are becoming refractory to these 3 classes of agents very quickly after 2 to 3 lines of treatments, since we are using combinations of IMiDs and PIs and CD 38 antibodies.

So definitely, we need new agents. We need new therapies for those patients.

So where are we now with BCMA-targeted therapy? And I told you previously, we have these 3 different classes of agents available, antibody drug conjugate with belantamab mafodotin that is approved by FDA and EMA since August 2020. We have CAR T-cell therapies, and we have different CAR T's that are in development. Ide-cel is approved by FDA and also by EMA a few weeks ago. And we are currently waiting for the reimbursement of this agent, but we have very strong data on ide-cel.

We have another CAR T that is targeting BCMA in development, cilta-cel, with very good results as well. And at ASH in a couple of weeks, we are going to hear the long-term data. In fact, long term, that's the update analysis with a 2 year follow up of cilta-cel. And we also have all the CAR Ts in development targeting BCMA, and you see that we have at least 4 bispecific antibodies that are not yet approved, that are currently targeting BCMA from different companies and at ASH as well, we are going to hear the updated results on these very promising agents.

So first, let's discuss about belantamab mafodotin, this antibody drug conjugate, and Dr Popat from the UK is going to show us some important data on this interesting agent.

Rakesh Popat, MD: Thank you very much Phillipe, it's my pleasure to talk to everyone today. So, as you said, belantamab mafodotin is now licensed and approved for use, both within the US and European geographical regions. This is based on the phase 2 clinical trial known as DREAMM-2. DREAMM-2 characteristics you can see on the slide in front of you, but essentially this is an open-label study looking at belantamab mafodotin monotherapy for patients with multi-relapsed multiple myeloma. And typically, these patients have been exposed to the 3 different main classes of drugs.

You can see on this slide that actually the patients were heavily pretreated with a median of 7 prior lines. And actually, in the 2.5 milligrams per kilogram cohort, which is the licensed dose, patients were fully triple-class refractory. And you mentioned that this is a difficult to treat population. These are the results that have now been published. The overall response rate for monotherapy, just pointing out again, there's no dexamethasone in this regimen, there're no steroids as part of the premedication. The overall response rate is 31%.

And what's interesting about that response rate is that the majority of patients actually have quite deep responses. You get a VGPR (very good partial response) in a number of patients. Immediate progression fee survival is 2.9 months. But for those patients who do respond, they have a median duration of response of 11 months.

Now, talking about the adverse events that we would see, the commonest adverse event known to this is keratopathy. And keratopathy is more of a sign that is picked up by eye-care professionals when they look at the eye and these are typically deposits, or cyst like deposits which form on the corneal membrane, in the peripheries of moving to the center. But there are some other toxicities, thrombocytopenia, cyclical and improved spontaneously, and you can see that there's a low rate of infusion related reactions.

So just to talk a little bit more about the ocular toxicity, so there's additional data coming out of DREAMM-2, you can see that the majority of patients do have some sort of ocular event being described, whether it's keratopathy or not, but in those patients who do have keratopathy, all patients were able to resume therapy, after interruption.

So, the important feature here is that the keratopathy is reversible. However, having said that, there is a mandatory testing program in place, which requires a patient to have an ocular examination prior to commencing therapy and prior to each subsequent cycle. And in Europe, it's for the 4 four cycles. In the US, it's for every single cycle. Now it's important that if significant keratopathy or reduction in visual acuity is noted, then you interrupt treatment and allow this to improve before there is a dose reduction made, and then treatment again. So that's why it's really important to have a close working relationship with an eye care professional.

There are a number of studies investigating belantamab mafodotin. There's a number of phase 3 trials running, and DREAMM-8 is 1 of many studies that are currently running to make sure that this exonerated approval turns into a full approval from the regulatory authorities. DREAMM-6 is a phase one study, which is looking at multiple different cohorts of belantamab mafodotin with different doses and different schedules in combination with RD or VD, trying to work out what the best schedule is to try and minimize that keratopathy. And then DREAMM-5 is a really interesting study looking at various different novel agents, including gamma-secretase and inhibitors. And with that, I'd like to finish my part, Philippe. Over back to you.

Dr Moreau: Thank you, Rakesh, for this nice overview on belantamab mafodotin. And now we are going to discuss about the important results achieved in the KarMMa study with ide-cel, that is the first EMA and FDA approved BCMA CAR T-cell therapy. And I'd like to hear the opinion of Hermann Einselle with using CAR T routinely, I would say, in Germany. So please, Hermann?

Hermann Einsele, MD: So, these are data from the KarMMa trial, and in the Karma trial ide-cel was used to treat patients with at least 3 prior lines of therapy. And was approved for the treatment of patients with 4 or more lines of therapy in the US. And for at least 3 prior lines of therapy in Europe.

Here you see the data on patients receiving 3 prior lines of therapy or 4 or more lines of therapy. And you can see that the overall response rate was 73%. And the complete remission rate ranged between 30 and 53%. The main toxicity was hematological adverse events. And you could see that 89% of patients develop grade 3/4 neutropenia, 61% grade 3/4 anemia, and 52% grade 3/4 thrombocytopenia. In contrast to other CAR T-cell products that have been used for patients with Non-Hodgkins Lymphoma or ALL, the CRS was rather low. Very few patients actually developed a grade 3/4 CRS or neurotoxicity, and it mainly occurred 1 day following CAR T- cell infusion, and the median duration was 5 days.

And here you see the progression-free survival, which was consistent in patients with 3 or 4 and more prior lines. So, the median progression-free survival was 8.6 or 8.9%. But in patients that actually achieved a complete remission with progression-free survival was beyond 20 months. And here you see the overall survival, which again, for patients with 3 or more than 4 lines of therapy was between 22 and 25%.

And here, there's a specific look to high-risk patients. So, for example, patients with high-risk cytogenetics, or patients with extramedullary disease, or patients with triple-refractory, multiple myeloma, and you can clearly see that in these patients, the median progression-free survival was still beyond 20 months. So, the drug is also effective in patients with high-risk features and, furthermore, patients beyond age 65 and actually in a subgroup also patients beyond age 70 could be safely treated with ide-cel. And you can see that the progression-free survival was not really different between the different age groups. And the next one now is cilta-cel, this is going to be addressed.

Dr Moreau: Yes, Hermann, thank you for summarizing the very good data that we have with ide- cel, and that's true that the paper was published in the New England Journal of Medicine with Dr Munchi and Hamman, who showed us some very new data presented at the last International Myeloma Workshop on difficult to treat subgroups of patients with very good results as well.

And that's amazing to see that in triple-class, penta-refractory patients, we are achieving a PFS of 12 months and number of survival that is above one year and a half. So definitely a huge impact for the future, for sure. But we also have another CAR T-cell in development, cilta-cel, and we've heard about the earlier results of the CARTITUDE-1 study. And I think that Dr Nooka is going to show us the results of this CARTITUDE study, looking at cilta-cel, another CAR T with a target of BCMA.

Ajay Nooka, MD, MPH, FACP: Thanks, Philippe. So CARTITUDE-1 is an early phase 1 trial and later on expanded to a phase 2 trial that was evaluating cilta-cel, which is a BCMA-targeted CAR T treatment that was originally made by the Chinese company. LEGEND, the construct, was moved on to have this evaluated in the United States with CARTITUDE-1. The PDUFA (Prescription Drug User Fee Act) date initially was meant to be in December 2021. Later on, it was changed to February 2022.

These results clearly show that, among the 100 patients that were enrolled in the trial, the overall response rates were significantly higher. Almost every single patient got a response with on the CARTITUDE-1 trial. Moreover, if you look towards the left side, the stringent complete responses are seen in 4 of the 5 patients. So, excellent responses, great depth in responses. If you look at the MRD negative data, you are seeing 90% of the patients achieved MRD (minimal residual disease) negativity up to the threshold of 10^-5. It is excellent data. The long term follow up will be presented at ASH (American Society of Hematology) of 2021. They're all looking forward for this. So, looking at the PFS (progression-free survival), the 18-month PFS is 66%. The median PFS is close to 22 months. Among this heavily refracted patient population. And as you can see, the results are extremely promising and the longer follow up is what they're all waiting for.

Similar to what we had seen with the KarMMa trial with ide-cel, the adverse events are primarily hematological. You look at the neutropenia rates, any grade neutropenia is seen in almost every patient, 95% could be attributed to the lymph for depression therapy, similar to what you see with the ide-cel treatment that was approved earlier.

Anemia seen in 80% of the patients. Grade 3/4 seen in 70% of these patients. Thrombocytopenia seen in close to 4 out of 5 patients. So, any grade CRS (cytokine release syndrome) was seen in 92% of the patients. But if you look at the grade 3/4 higher CRS rates, these were significantly lesser. Similar to what we'd seen with the prior CAR T as well. There's a significant difference in the time median time to onset of the CRS between these 2 compounds. And the median time to onset was 7 days with CARTITUDE, with cilta-cel and median duration is 4 days. What is very encouraging is you don't see a lot of non-hematological side effects, especially when you see with CARTITUDE that the grade 3/4 toxicities of electrolyte imbalances. If the other ones that were shown as the most severe adverse events with these CAR T compounds, I'm extremely encouraged by that.

So, comparing the incidence of the CRS between these two compounds in KarMMa, 84% in general, compared to 95% with the cilta-cel. More than grade 2 events requiring in 36% of the KarMMa-2 trial vs 44% in the CARTITUDE trial. Again, similar to what I alluded to before, the median onset is one day median onset to CRS, is 1 day in the KarMMa trial versus median onset is seven days in the CARTITUDE trial.

So, when you look at the CRS management, this CRS management, initially, when you look across these compounds, the toxicities and the timings are varying anywhere ranging from fever, hypertension, more importantly, the grading has been well established and absolutely using the grading to guide the management certainly helps to mitigate these toxicities.

A risk enacted strategy following the CRS markers very closely, frequent monitoring, anybody needing more than anybody having more than grade 2 toxicity being given tocilizumab or the IL-6 antagonist. And clearly, the guidelines have been very well written at this point of time, so that it was easily managed, the risk mitigation is absolutely well watched at this time.

Dr Moreau: Thank you so much, Dr Nooka. That's very important to look not only at the results in terms of efficacy, but also in terms of safety. And you described very well, the toxicity that is absorbed with the use of CAR T-cell therapy. And now let's move to some cases to better illustrate the results, and how we can treat our patients with these new agents. So, translating clinical trials to the real life, and please, Dr Popat, if you can discuss with us a case of 1 patient treated with an antibody drug conjugate.

Dr Popat: Thank you, Philippe. Yes. So let me take you through a case of one of my patients who we treated with belantamab mafodotin. So, this is a gentleman who is 67 years of age. He was diagnosed with kappa light chain myeloma, ISS (International Staging System)2, and standard risks, such genetics. He has a number of comorbidities, predominantly cardiac, you can see on the screen, myocardial infarction, previous bypass operations. And he's been exposed to a number of different treatments, and I'll show that in the next slide, but essentially, he was thought of as being frail, and had an ECOG performance status of 2. If we look at his previous treatments, you can see he's gone through 2 autologous stem cell transplants, he's gone through elotuzumab, lenalidomide and dexamethasone followed by carfilzomib, daratumumab, dexamethasone, and pomalidomide, cyclophosphamide, and dexamethasone. So, this patient is at least triple-class refractory, if not refractory to more agents than that.

So, we elected to treat him with belantamab mafodotin monotherapy. And you can see on the slide the scheme of what's happened. He commenced treatment with 2.5 milligrams per kilogram, and as tends to happen with some of these very frail refractory patients, he had infectious complications very early on in the treatment course, predominantly upper respiratory tract infections, which led to some treatment delays. But we managed to get him through that. When we got him through that, he had his second cycle of treatment. He developed thrombocytopenia. We are aware that thrombocytopenia is part of this, but he spontaneous resolved and was able to move on with treatment for cycle 3. Now at cycle 3, you can see that he's now achieved a minor response, but he now has developed some ocular symptoms. And typically, he's got a grade 2 reduction in his visual acuity. And as soon as you get a reduction in visual acuity, that's your key to interrupt treatment. So, he stopped treatment and he commenced high frequency, preservative free eye drops at that stage. So, we then were able to continue with treatment because his symptoms improved. But unfortunately, he got a further infection, was admitted to hospital with a community acquired pneumonia.

Once he came out hospital, he was found to have grade 3 keratopathy with a reduction of visual acuity. And that led to us holding treatment for a further 3 cycles. But you can see now that we've achieved a partial response, and despite having to hold treatment for 3 cycles, then he was able to maintain that response. We were then able to re-initiate treatment cause his symptoms had improved. But of course, once you've held treatment due to impaired visual acuity, you need to reduce the dose of belantamab down to 1.9 milligrams per kilogram.

He's still maintaining his partial response and we were able to get 2 more doses of treatment in before he developed further toxicity in terms of reduction in his visual acuity. So, he held treatment for a further 3 cycles. There was then reversibility, improvement of his visual acuity, and they were able to give him a further 2 cycles.

Despite this stop and start, he did maintain his partial response. By the end of cycle 14, he suffered from another respiratory tract infection. He was in the hospital for a long period of time. And by which point, we unfortunately lost his response. He had disease progression and we stopped treatment at that stage. So, that's a kind of a summary of what happened with my patients with belantamab mafodotin, and I think it's probably quite typical of many of your experience, but I'd like to hear what you think, Philippe.

Dr Moreau: Yes thank you Rakesh. That's very interesting to see how you could manage this patient, and you imagine clearly that we have this 30% response rate with belantamab in triple-class or penta-refractory patients. And you also indicate that the duration of response is roughly one year, so a new agent, a new class of agent, and definitely something that could be interesting in this unmet medical need. And what are the potential challenges to your opinion, Hermann, with this agent?

Dr Einsele: Yeah, so the corneal toxicity is clearly an issue, and in a few patients, you actually have to stop treatment. The good news is that if you stop treatment, some of our patients are still maintaining their remission. And due to the fact that the corneal toxicity is reversible, after a certain time and often the patients are remaining in a good remission, you can actually restart the treatment with belamaf. So, another advantage is really the short infusion time, only every 3 weeks. So, it's very good to really keep the patient and the outpatient department. And apart from this corneal toxicity, the drug is really very well tolerated.

Dr Moreau: Thank you. And Dr Nooka in the US, belamaf was approved in August 2020. In your routine practice, when patients are failing IMiD, PI (proteosome inhibitor), and CD38, are you frequently using this IV (intravenous) drug every 3 weeks?

Dr Nooka: We do use, Philippe. So, this is, alluding to what Hermann said before, this is 1 of the treatments where we have the liberty of giving it every 3 weeks. There are not many drugs where we can use that kind of a schedule. Which is very enticing to the patients. And at the same time, understanding the toxicities is helping us to manage these toxicities much, much better.

So, we've been using it for the last year and a half, or year and 3 months and the tolerance and the responses that we see, the duration of responses, especially among the responders, are extremely exciting for us to continue this drug moving forward.

Dr Moreau: So, interesting to have this agent IV every 3 weeks. The issue of the ocular toxicity unfortunately would say only 30% of response, but nevertheless, that's quite important in patients failing the usual conventional agents. So maybe we can move now to another case of another patient treated with CAR T-cell therapy, and maybe Hermann, you can present this patient case for us.

Dr Einsele: Yeah. Thanks. Thanks so much. So, this is actually the first patient that we treated in Würzburg with CAR T-cells. So, this patient was age 71, and this patient was diagnosed with a multiple myeloma type IGG in May 2016. At that time, he had an ISS stage 3, had a bone marrow infiltration of 60%, was found by cytogenetics to have a 70P deletion. And actually, what we also did in this patient was a genomic analysis. And this patient had a biallelic deletion of P53. At the presentation, the patient had a hypercalcemia and multiple osteolysis. So, a really high-risk patient.

Yeah. So how did we treat the patient? Patient received VCD (bortezomib, cyclophosphamide, dexamethasone) 4 cycles, and really looking at this very high-risk patient, it was not surprising that he only achieved a partial remission. Now, due to the fact that he was an ultra-high-risk patient, and that the response to the induction therapy was suboptimal, he received a tandem stem cell transplantation, and only 8 months later, the patient had a serologic progress.

So, the patient wanted to have an oral therapy. So, we offered him Ixa-Rd (ixazomib, lenalidomide plus dexamethasone), and, not unexpectedly, the patient only received 3 cycles and then had, again, a progressive disease then was switched to PVD. Again, developed a progressive disease carfilzomib, dexamethasone, daratumumab, 2 cycles. Again, progressive disease, then because of a poor marrow function, we gave him another stem cell transplantation and only had 3 months of response. Then we switched him to pomalidomide, dexamethasone and daratumumab, and he did not respond. And then he received a quite intensive salvage treatment. Again, no response. And at that time, the patient was really out of any treatment options, and we offered the patient to actually join the KarMMa-2 trial.

The patient, fortunately, despite this heavy pretreatment, still had a good renal function. This is important because the lymphodepletion therapy includes fludarabine and cyclophosphamide. And fludarabine is only allowed to be administered if the creatinine clearance is beyond 45 milliliters per minute. He was 71 years old, but he was very fit. And I showed you the data from the KarMMa trial. So there really is no age limitation. So, patients up to the age of 77 or 78 were actually included in the KarMMa trial, the patient was still fit. So, the patient was fit to tolerate grade 3 CRS, had an adequate cardiac and an adequate respiratory function. So, we felt this patient was suitable for CAR T-cell therapy.

Now, how does the referral of patients to the CAR T-cell treatment centers actually work? So, often we get approached by office-based hematologists or non-academic hospitals with patients that were heavily pretreated or did not respond to the current treatment schedules. And then they inquire about CAR T-cell therapy. But our experience is that a lot of patients are directly going to the CAR T-cell treatment center and inquiring about treatment options.

So how do we manage CAR T-cell therapy? And CAR T-cell therapy is a treatment that really requires multidisciplinary approaches. So, we have a CAR T coordinator, we have a nursing team, we have allied health, professional, psychological counselors, a long term follow up team. Of course, the manufacturer for the CAR T-cell product, the pharmacists get involved, the stem cell lab because of the management of a live cell product, the apheresis unit we need for some of the toxicities I showed you, that there are some neurological toxicities that some patients, because of intensive CRS syndrome, or ICANS (immune effector cell-associated neurotoxicity syndrome), actually have to be admitted to an intensive care unit. So, we need these specialists and it's important to get them really into the team so that they know what they have to do, and whether the patients are really requiring their special expertise. And of course, the HemOnc specialist who mainly sees the patients.

So how did we proceed with this patient? So, the patient, we also did an MRI at the time when he actually was going onto the CAR T-cell therapy, and this MRI showed multiple focal lesions. So, the patient also had an extramedullary disease. So, he received lymphoid depletion with fludarabine and cyclophosphamide. He received the dose of CAR T-cell, which is now approved for clinical use. 450 million CAR T-cells were infused. And the patient only had a very mild CRS. So, the patient really was questioning why he had to stay for 2 weeks in the hospital. So very mild toxicity. So that was after 1 month already, we saw a complete clearance of the extramedullary disease, and the patient actually became MRD negative already after 1 month following the CAR T-cell therapy. So, I'll give back to Philippe.

Dr Moreau: Well, Hermann, incredible results. In fact, when you are discussing about this patient, very aggressive one, not responding to any conventional treatment, even stem cell transplantation with this P53 deletion in fact, and to become MRD negative in this setting is really outstanding, I would say.

But for you, the potential challenge, would you like to use this for all your patients that are becoming triple-class or penta-refractory, or do you think that we need more data before using in routine, or proposing to specialize centers, this strategy?

Dr Einsele: First of all, I think your point is very well taken. I think the CAR T-cell therapy is restricted to specialized centers, and that means that the patients actually have to be referred to these specialized centers to really get offered this kind of therapy. I think with the data that we have in our experience with ide-cel is that we see very limited toxicity. And you've seen this patient, 71 years old, heavily pretreated. And the toxicity was really quite limited despite of this heavy pretreatment and an age of 71 years. So, I think it's a very interesting treatment. It's do-able even in patients beyond age 70, but clearly there are restrictions like cardiac function, pulmonary function, renal function. And I would also be hesitant to put a patient on a CAR T-cell program that has a really rapidly progressing disease with high LDH. I think that's probably not the ideal patient. If you have a patient like this, probably you need to bridge to CAR T-cell therapy, and that's already the next issue that is shown here.

Dr Moreau: Yes. Yes. Thank you, Hermann. And that's very important to highlight that the patient populations enroll into KarMMa and CARTITUDE were selected patients with renal function that was remaining quite good, above 45 milliliter per minute. That's also something that may restrict the use of CAR T.

Dr Moreau: So how do we choose which BCMA-targeted therapy? A very difficult question, we could spend more than 1 hour discussing about this topic, especially when, bispecific antibodies, targeting BCMA will also come very soon. So, Rakesh, can you tell us what are you going to do in fact, are you going to propose systematically, if possible, CAR T instead of belantamab for your patients?

Dr Popat: Yeah, incredibly difficult. I mean, certainly for those patients who are fit enough to potentially have high risk disease, then I would recommend CAR T-cell therapy for those patients. So, you get the highest response rates of the highest MRD negativity rates. Belantamab, that is more of an off the shelf treatment, and the frailer patients can tolerate that a little bit better.

Dr Moreau: And Ajay, your view on this question?

Dr Nooka: Sure. Similar to what we had in terms of the transplant eligible versus transplant ineligible patients, I think we need to define those criteria, who would be eligible for CAR T? Because it needs good organ functions. And it also needs the time for the manufacturing and the patient should be able to sustain through this process. We can easily tease out the patients who are really good for CAR Ts, or really good for the other BCMA directed therapies. And the question becomes more complex when we have other bites that will be available to us soon.

Dr Moreau: Thank you. And Hermann, your last comment on belantamab vs CAR T for you?

Dr Einsele: So clearly, if we go for long-term disease control, it should be the CAR Ts product. On the other hand, it takes time until we receive them. They need a certain organ function. So, it's a selected patient population who we can really target with CAR T-cells. Now belamaf is very well tolerated as part of this keratopathy, the side effects are really very acceptable. So, we have treated, I've just seen a patient today who is beyond 80 years, and we offered her belamaf and she tolerated the drug extremely well. So, it's a drug that you can really use also in the outpatient setting for elderly, frail patients, which is definitely not the patient population we would go for CAR T-cell therapy.

Dr Moreau: Thank you so much, Hermann. And with that, we are going to the end of this program. And I would like to thank you for your very kind attention and for participating in this event today.

This transcript has been edited for style and clarity.