In relapsed/refractory multiple myeloma, prior therapy can affect subsequent treatment efficacy, highlighting the importance of thoughtful sequencing and consideration of alternative targets. Listen to Jesus G. Berdeja, MD, and Ajai Chari, MD, as they discuss sequencing of antibody–drug conjugates, bispecific antibodies, CAR T-cell therapy, and other novel treatment modalities for patients with relapsed/refractory multiple myeloma.
Listen to Jesus G. Berdeja, MD, and Ajai Chari, MD, as they discuss sequencing of antibody–drug conjugates (ADCs), bispecific antibodies, CAR T-cell therapy, and other novel treatment modalities for patients with relapsed/refractory multiple myeloma.
Presenters:
Jesus G. Berdeja, MD
Director of Myeloma Research
Greco-Hainsworth Centers for Research
Partner
Tennessee Oncology
Nashville, Tennessee
Ajai Chari, MD
Professor of Clinical Medicine
Director of Multiple Myeloma Program
UCSF Helen Diller Family Comprehensive Cancer Center
University of California, San Francisco (UCSF) Medical Center
San Francisco, California
Content based on an online CME program supported by an educational grant from GSK.
Link to full program:
https://bit.ly/3TZSmuf
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This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
Dr. Berdeja: We have these incredible therapies that have moved into the early relapse space in myeloma. These are mostly T‑cell redirecting therapies, including CAR Ts, including ADCs and are becoming such a wonderful option for our patients, but we are now starting to struggle with the idea of sequencing them. Is there a rational way to give these drugs to maximize the options for patients? That is one of those things that we all struggle with. Perhaps I thought we start with maybe just discussing what are our options now in a patient who is relapsing after one or two prior lines of therapy?
Dr. Chari: My high‑level comment on this is, historically, we told everybody, "Do not expect overall survival improvement. We are going to do three drugs versus two drugs. You are going to like it, and it is going to have a PFS improvement, and you are going to suck it up and accept that as gold standard." Now it is amazing how different the field is. We have two positive phase III studies, KarMMa‑3 and CARTITUDE‑4, where the CAR T was compared to triplet comparator arms. Then we have two ADC studies, DREAMM‑7 and DREAMM‑8, where the belantamab‑based triplets were compared to SoC triplets. Then, finally, bispecifics. We have had, first was MajesTEC‑3 with daratumumab and teclistamab compared to triplet SoC. We also have MajesTEC‑9 recently, which is teclistamab monotherapy against standard‑of‑care triplets. Then finally, MonumenTAL‑3 just resulted at EHA, which is talquetamab‑based doublet or triplet, so talquetamab + daratumumab, talquetamab + daratumumab + pomalidomide versus triplet SoC.
First message here is that these regimens are comparing not against doublets but against triplets. We are not trying to set the odds in favor of the experimental arm. Despite that, the value add is even better than what we were seeing with doublets. You are getting control arms doing quite well. This is, I think, an important theme, but sometimes the control arms, for example, MonumenTAL‑3's PFS with daratumumab + pomalidomide + dexamethasone was 24 months, which we had never seen before.
The control arms are doing quite well, and despite that, the experimental arms are knocking them out of the world here and there. Hazard ratios are 0.2 to 0.5. Finally, I will just say that those are actually translating into overall survival in multiple studies. To me, the first message from all of these data sets are that in relapsed myeloma, it is time to take advantage of these incredible immunotherapy options. We can talk about factors on how to pick, but if you have the access ‑ one thing we did not discuss, access. Some parts of the world, unfortunately, do not have access to all these therapies. In the US, I would say these are evidence‑based improvements on what we were doing. What is your take?
Dr. Berdeja: Yes, I completely agree. I think the data you just discussed is crazy positive for these therapies compared to our old standards of care. If a patient is still getting a standard of care, then there has to be a good reason why they are not getting one of these novel therapies, whether it is a bispecific, an ADC, or CAR T. There are those patients, unfortunately, and we can discuss it in the disparities where there are some patients that may not be able to access these. The hope is that every patient should have access to, if not all of these, to at least some of these options for them.
Before we move on to moving away from the target, the majority of the therapies we just talked about are going against BCMA as the antigen. I am curious. In your practice, you have CAR T, you have bispecific combinations or single agents, you have ADC combinations, all directed against BCMA. In very similar indications, how do we choose?
Dr. Chari: One thing to keep in mind is that, particularly for patients, we were saying that if everybody is using lenalidomide induction and transplant and maintenance, everybody is lenalidomide refractory. What we do not appreciate is the impact of being double refractory to CD38. I would strongly encourage everybody listening to reach for one of these new products for that population. Why? Because that is the new unmet need. When you look at the three studies that had significant representation of CD38 and lenalidomide double refractory, first was KarMMa‑3, where the control arms PFS was four months, then came MajesTEC‑9, where again about 80% were double refractory. Even with Kd, which was an appropriate regimen when you have double refractory, because again, when these studies were designed, if you are CD38 and lenalidomide refractory, basically Kd was a really good option. That PFS was eight months.
Finally, we had SUCCESSOR‑3, which is mezigdomide‑Kd versus Kd, also with about 80% double refractory in eight months.
The message here is that if in early relapse a patient is double refractory, eight months is not great; we need to do better. The good news is that you can pick one of these. To me, I think the first question we always ask ourselves at academic medical centers, because we have all of these at our disposal, is: Is this patient CAR T eligible? Because cilta‑cel, to date, has had the best single agent response rate in PFS. We know from the long‑term follow‑up that a third of patients in CARTITUDE‑1 with a median of five to six lines of therapy were relapse‑free for five years. Perhaps the foreshadowing of a functional cure.
To me, what are the first questions I ask about CAR T candidacy? Is this patient fit? Meaning, can they tolerate grade 2 CRS? Maybe we can highlight who might not: frail, elderly, with heart failure, renal failure, somebody you are going to have trouble with, say, keeping up with hypotension and hypoxia.
The second big criteria for CAR T is, is this patient's disease progression relatively slow? If it is explosive, doubling in front of your face every day you see them, that is not somebody who is going to get to CAR T. To me, if somebody does not have those, I first discuss with them CAR T and then counsel them on all the risk and benefit. It is really not one‑and‑done; it is some‑and‑done. There is collection, lymphodepletion, administration, and monitoring. The final part I will say is, it is amazing response, amazing PFS, amazing quality of life for the treatment‑free interval, but is those rare but non‑zero toxicities like the delayed neurotoxic colitis, secondary malignancy, which might be very low, but if you are the patient that gets it, statistics do not apply to you.
The patient's tolerance for those rare serious AES is why this is called shared decision‑making.
What is your thought process on the first product?
Dr. Berdeja: Before I do that, though, you mentioned something that I just want to point out really quickly. I think sometimes for patients, especially if they live far away from an academic center, there is that tendency to say, "We have all these great therapies, but we can use them later." Oftentimes, they will go to another ‑ even though it is a potentially inferior therapy from phase III trials, it looks like there are inferior therapies because these are going to be available.
However, the truth is the responses that are seen with these therapies, just like with everything in myeloma, are astronomically different and better than what we saw in the true relapsed/refractory space. It is not just about using this, but actually using them early in my opinion.
Dr. Chari: I wanted to add to that because the fact that CARTITUDE‑4, DREAMM‑7, MajesTEC‑3, MajesTEC‑9, and MonumenTAL‑3 all are showing overall survival benefit trends, which means that this concept, what you just described, saving it for later is not supported by the data. In fact, in several of these studies, the control arm patients did have access to T cell redirection. Despite that, you still are seeing overall survival. What this highlights is attrition. This concept of saving your good stuff for later is not borne out by the data because, unfortunately, not everybody gets to the later, and there is a tremendous selection bias. In each line of therapy, we unfortunately lose patients. I completely agree that that is an important message for patients.
If you are deciding between CAR Ts, bispecifics, or ADCs, how are you picking?
Dr. Berdeja: That is the million‑dollar question. I do not think there is one right answer. You alluded to the patient, A, it is about the patient themselves. It is about the disease biology, how aggressive it is progressing, whether you have actual therapies that can be used as bridging because not just about the disease progressing quickly, but is this a patient that you can get back under control? Because that could still keep them CAR T‑eligible. We know that autologous CAR T cells are logistically complicated. They are probably the hardest ones to get to all patients. Because of that, unfortunately, we do know that the majority of patients that would benefit or would be eligible for CAR T are not going to get a CAR T.
I agree with you that if the patient is eligible for all therapies, I usually discuss CAR T with them. Unless the patient absolutely says, "No, I do not want a CAR T," that is usually my go‑to first. For the majority of patients who are not going to be CAR T‑eligible, it goes back between the bispecifics and the ADC. I do believe that the bispecific data is stronger. I do believe that we are getting deaths of remission that we had not seen before that we also do not see with the ADC combination. I think, between the two, all things being equal, I would [inaudible 00:51:10] towards the bispecific antibodies.
The ADCs are great therapies for those patients who need to have something done completely away from an academic center or who really have issues accessing health care and want to be able to potentially decrease their trips to the clinics. The great thing about the ADCs is that even though initially you need to be a little more aggressive and most likely to start with every three‑to‑four‑week dosing, depending on the study, eventually, if the patient has a response, you can really cut back and potentially even go down to like every three months. The durability of those responses is actually quite impressive. That is the one that probably is the least intrusive, potentially for a patient.
Dr. Chari: Big feature here, or the big consideration. If you are not doing CAR T for whatever reason, then big consideration is infection risk for this patient. Why? Because I would say that the biggest risk with the BCMA bispecific is infection, including fatal infections, opportunistic infections. Never before have we seen some of the infections. The good news is it can be greatly mitigated with IVIG. We also do PJP prophylaxis. However, if you already have a patient with a history of recurrent respiratory illnesses, they do not have a lot of buffer or reserve to tolerate another serious respiratory infection. That might be the patient where you may either lean towards a BCMA‑ADC or a GPRC5D‑based bispecific.
As you alluded to, the benefits of an ADC are no step‑ups, not a mandate for IVIG. There is a risk of infection, but it is not quite the same as a bispecific, and so IVIG access or infusions is a problem. Lastly, technically, DREAMM‑7 is what we have approved in the US, which is BelaPd. BelaPd is a pomalidomide‑based backbone which is technically not approved in the US, but as you alluded to, if the patient can get the BelaPd every three months, you have really cut back on the patient's infusion visits.
That may be very advantageous to a patient that is very debilitated, hard to leave the home, lives very far from an infusion center that does not want to keep coming for the IVIG. Unlike a BCMA bispecific, where I would just emphasize not only you should think about a BCMA bispecific as a minimum doublet, meaning if you are giving a bispecific, you need to give IVIG, and even if you stop the BCMA bispecific, you need to keep the IVIG going for potentially six months.
The GPRC5D bispecific briefly does not have the same infection risk. In fact, it has an improvement in humoral immunity, does not mandate immunoglobulin replacement as monotherapy. In the MonumenTAL‑3 data, we saw something unprecedented where even though the PFS was almost 70% longer, the infection rates unadjusted for time on therapy is actually lower, which you have never seen before, and it just speaks to the immune protection, the infection mitigation. Unfortunately, you do get loss of taste, weight loss, skin and nail changes. Again, shared decision‑making, you can give patients the option. Most patients probably would pick a BCMA first, but in the rare patient who you have a lot of infection concern, that may be another strategy. I think it is good to have these choices.
I am curious to hear your thoughts on that, and also how you would respond to the doctor that might say, "Right now, this patient does not want to go to CAR T, so I am just going to start one of these other drugs." What would you say to that?
Dr. Berdeja: That is an excellent point. Of course, you already talked about the GPRC5D bispecific. I was going to segue into that, but I think you said perfectly well backwards, so that is good. I think the question becomes sequencing. Even if we are going against a different antigen, but definitely we are going against the same antigen, we still do not know the best way to sequence these drugs. A lot of the sequencing data that we have is in patients who are very refractory to therapy, who basically have received one of these therapies as their last prior treatment, then moving on to another treatment. For example, having had a CAR T and then, at first relapse, going to a bispecific or vice versa. In that scenario, we know that giving a CAR T right after a bispecific is a really bad idea for various reasons.
Just to back up a little bit. When you get the CAR T to BCMA, it is rare that a patient actually loses BCMA. The majority of patients who relapse after CAR T tend to relapse ‑ except for the rare patient that has no response whatsoever ‑ tend to relapse in a year to three years later. That is what the data tells us. These patients have been off therapy and often still retain BCMA. Theoretically, they should be able to respond to a subsequent therapy.
If you go to a patient who is getting a BCMA bispecific and they are relapsing on that bispecific, those patients have had continuous T cell engagement. There is a potential that those T cells are just not as functional as they would have been without the bispecific. We are starting to understand that there is an increased risk not only of mutations at the binding site of BCMA, but also BCMA loss. For those reasons, at least in my mind, it makes sense that a CAR T cell would not work as well after a bispecific.
We actually do not know the data with the ADCs. It does not look like they lead to loss. There is, I think, downregulation of BCMA, but not necessarily loss. It does not appear that there are mutations that are induced. I think the data with those are less so.
Having said that, we do know that if the patients relapsing on an ADC, they also significantly affect the efficacy of the CAR T or the bispecific afterwards. There is something about going straight from one BCMA‑directed therapy to another. The question, eventually, that I will ask, Dr. Chari, will be, what happens when we start using the limited duration of bispecific frontline, and the patient relapses eight years later? Is that the same patient that I just described? Most likely it is not, but we actually do not know for sure.
When about maximizing the options based on that data, as flawed as it is, I would argue that if your patient is a CAR T candidate and the patient actually wants a CAR T, but in the meantime, we are going to hold his therapy or his myeloma under control with a bispecific antibody against BCMA, I would say that is a very bad idea. That would not be what I would recommend based on the potential that you are really going to harm that patient's ability to get a CAR T that works for them. I would say, no, that is not a good idea. Unless the patient says "I am never having a CAR T," and then yes, the bispecific antibody should work really well for the patient.
Curious as to what do you think about the patient that gets a limited duration of an ADC therapy as frontline, which we have touched upon in the prior podcast, but now is relapsing, let us say five‑plus years later?
Dr. Chari: I do want to address that, but first, I wanted to step back a second and just remind the listeners that we have ‑ the holding period is the period that we talk about before apheresing, and bridging is after apheresing. There is a big distinction. I would say one of the things we probably both agree on is, if you are thinking of patients CAR T‑eligible, even if you are not sure, refer early because by the time we see the patient get insurance approval in apheresis, a lot can happen. That early referral, which is the holding period, is important.
During that period, you do not want to give any of the immunotherapy products because we have not yet collected the T cells. Once the T cells are collected, then there is more and more data for talquetamab as a bridging strategy because sometimes you need to lock the myeloma down.
Another cool therapy choice for bridging will probably be [inaudible 00:59:46]‑based regimen, which talked about SUCCESSOR CD38‑Kd. Might be something we could... Sorry. Because these patients could be CD38 refractory, Mezigdomide‑Kd. SUCCESSOR might be a great way of bridging somebody who you have collected T cells or holding.
Now, when we talk about the sequencing ‑
Dr. Berdeja: Actually, before you go on to that, I misunderstood your question. I thought you were asking not about holding or bridging therapy, but as moving CAR T after giving a bispecific. However, I completely agree with the comments you just made about holding versus bridging, to be very careful. I agree. I think the data with the talquetamab bridging for BCMA CAR T looks fantastic.
Dr. Chari: Yes, that was my question, but I realized we had not covered this, so it was important to separate that out. What we now know, in my view, when I look at the data about sequencing, whether it is a CAR T or whether it is a bispecific prior touching of that antigen for BCMA, adversely affects the PFS. That is really important. Cilta‑cel prior ADC and bispecific lower the PFS. Teclistamab, elranatamab, and also recently, etentamig, all BCMA bispecifics have all shown a compromise in PFS.
I would summarize the data saying that while you may get a response rate, the PFS goes down by anywhere from 40 to 80%, even if you are switching the modality. That applies even for an ADC because you could argue that it is this T cell exhaustion that everybody likes to talk about. The ADCs are not known to impair T cell function, nor are they known to lower BCMA expression. What is going on? I do not think we know. I would say if you are getting a BCMA‑CAR T, one message is when these patients relapse, switch to GPRC5D because GPRC5D bispecific talquetamab has been shown in prospective studies that you do not compromise the PFS with prior CAR T.
Now, the caveat for all of these studies, which is where Jesus was leading to, is these are small studies, 20 to 30 patients. There is an imbalance in the risk. There is a difference between somebody who has had 10 lines of therapy with a prior bispecific, ADC, CAR versus somebody who has had five lines of therapy. They are not really fair. We are comparing apples and oranges. The other thing is likely these products were being given until progression. If they had a prior bispecific or ADC, they were given an RP2D till progression. That is what is compromising.
The question is, let us say we were to do fixed duration. Will this be different? I think it is a major unanswered question, but I would argue that as of today, the burden of proof is to show that it is not going to be impaired because the two data sets we have ‑ again, all the studies I am talking about are prospective studies, because a lot of the retrospective real world data sets are majorly confounded by the fact that these claims that may be more interval between therapies abrogates the risk, the confounding there is the biology. You cannot wait longer for somebody whose disease is exploding.
However, teclistamab and cevostamab ‑ cevostamab was first done with fixed duration. It was FcRH5 for one year. The PFS was modest, so not everybody got to that one year, but of those patients, when they relapsed down the road, only one out of six responded to therapy. Teclistamab, limited data recently presented at ASH, about 50 patients treated for six to nine months and stopped because they had a good response. When these patients have relapsed, none of the 12 patients relapsing within a year have responded, and only one out of five that relapsed later. The aggregate of this suggests that even if you are doing fixed duration, we need to show that it does not compromise the next treatment.
I am curious what you think, Jesus.
Dr. Berdeja: I have to say, I am glad you brought that up because that has always been my fear, is that we keep saying we do not know, and yes, it is a very biased population and very heavily pre‑treated. That has been very sobering to me to see that just with the very small amount of exposure to a bispecific, you develop mutations because these therapies work so well. We have all seen the patient that has 80% plasma cells, then after just one cycle, two max, it is gone, they are gone. The idea that after six months, if you stop, whatever survived ‑ maybe they survived because they already had mutations. That has always been my concern, is that that myeloma that develops later on is going to be compromised, like you said. I am hoping that is not the case, but that is why it is good that we do, in my opinion, because we do have more options, like a GPRC5D‑based bispecific. You fed cevostamab against FcRH5. Hopefully, as we have more of these options that go to a different antigen, we may be able to sequence them a little bit better. If you have the option, in my opinion, you do switch the antigen as well as the modality if possible.
Dr. Chari: What I have to mention, though, is that the probably MajesTEC‑3 data with teclistamab + daratumumab, that PFS curve looks quite darn flat. I bring that up because the converse to the sequencing question is by definition, we are stacking the odds against retreatment because we are only talking about patients who have relapsed. The patients who have not relapsed have not been rechallenged. I think, as you mentioned, if it is years later, it could be a totally different era. I think that is a major unanswered question.
I will say one other important topic we did not pull out explicitly, which needs to be highlighted because it is now an NCCN Compendia listing, is the combination of teclistamab and talquetamab for rapidly progressing EMD patients. Really, 18‑month PFS is incredible. In somebody where you do not think you can sequence, just do them together, is one message.
Also, I want to throw that to you, Jesus, as maybe our closing thoughts on future exciting topics. What do you think about dual targeting and newer approaches of giving these products?
Dr. Berdeja: You touched on the CELMoDs. The CELMoDs are exciting because I think they will play well with these types of therapies. They can potentiate T cells for CAR T manufacturing, the bispecific for redirection. Those will be good adjunct or combination strategies that will help our current therapies.
In terms of things that are coming down the pike, you mentioned targeting multiple antigens at once. We know we have trispecifics coming down the line against BCMA and GPRC5D. There is a trispecific against BCMA and CD38 that is looking very interesting as well. We actually have CAR Ts doing the same thing. We did not mention CAR Ts against GPRC5D, but also, we have CAR Ts against GPRC5D and BCMA, so dual‑targeting CAR Ts, and of course, a CAR T against BCMA and CD19, which is also being tested. All those are fantastic.
One of the things that is really what I am most intrigued by is, for the longest time, we have talked about the downsides and the difficulty of autologous CAR Ts not being off the shelf and having all these logistic issues, but being the one‑and‑done or as you say some‑and‑done, compared to the bispecific, which are currently are given continuously or at least for a prolonged protracted period of time.
Now we finally have some good data with allogeneic CAR Ts that we have been trying to get forever, but somehow they just do not seem to have the efficacy as autologous CAR T. We are now starting to see some that maybe are. The in vivo CAR Ts are looking quite impressive. The idea that you can create the autologous CAR T inside the person themselves becomes off‑the‑shelf and is a one‑time treatment that is also looking very promising. I am very excited about those potentials.
Dr. Chari: We actually have now in vivo bispecifics and trispecifics being you inject a patient with a nanoparticle and have them produce their own agent. We do not yet have clinical data.
The take‑home message for relapsed/refractory myeloma is this: first generations of ADCs, bispecifics, and CARs are really impressive and belong in early relapse, and they are translating into overall survival benefits, but please do work with your academic partners for early to make sure that we are not inadvertently excluding CAR T for a patient without due diligence. Any other closing thoughts from you, Jesus?
Dr. Berdeja: No. We are going to keep arguing the whole sequencing thing till the cows come home, but it is very possible that we may not need to sequence because all these new therapies will then be our next best option.
Dr. Chari: Very important to highlight that we now have a proposed definition of cure in myeloma. IMWG this year did discuss that perhaps five years of consecutive MRD negativity ‑ this was ideally for registrational or clinical trial ‑ five years of treatment‑free interval with MRD negativity is the goal that we are striving for. I think the future is looking very bright. Thank you all for listening. We hope you found this podcast enjoyable.