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Dr. Doris Hansen (University of South Florida Morsani College of Medicine): So today, we'll be discussing a bit about therapeutic landscape in relapsed/refractory multiple myeloma. And certainly we know that – that has significantly evolved over the last decade.

We've had really an exciting almost explosion of immunotherapies to include two CAR T-cell therapy products that have been FDA-approved since 2021. We've also seen four bispecific antibody therapies approved alone, and most recently in combination: teclistamab with daratumumab; and an antibody drug conjugate, belantamab mafodotin, that has come back into the market.

So, as I mentioned, we do have two CAR T-cell therapy options. We have idecabtagene vicleucel and ciltacabtagene autoleucel. Both were approved in later line in 2021 and 2022, and then earlier line in April of 2024. We also have belantamab mafodotin which is approved in combinatorial strategies. And then bispecific antibodies, which we'll focus a lot of our discussion on today to include three BCMA-directed bispecific antibodies, as well as the GPRC5D-directed bispecific antibody known as talquetamab.

So bispecific antibody therapies generally are very exciting in the sense that these are off-the-shelf immunotherapies that are readily available for our patients. We do, as I mentioned, have four different bispecific antibodies which target different tumor antigens, most commonly the BCMA or B-cell maturation antigen. We have GPRC5D, which is generally found on plasma cells as well as hard keratinized epithelium. And we have some new bispecific antibodies in clinical trials such as cevostamab, which targets FcRH5.

Now, these bispecifics not only bind on antigens – tumor antigens on the myeloma cells, but they also bind to immune cell targets including CD3-positive T cells. So teclistamab, elranatamab and linvoseltamab target CD3 and BCMA. Talquetamab is a different target, so it targets CD3 and GPRC5D antigen on the myeloma cell.

So the FDA has approved these as monotherapy in patients with relapsed/refractory multiple myeloma after four or more prior lines of therapy for patients who are triple class exposed, including a proteasome inhibitor, an immunomodulatory drug, as well as an anti-CD38 monoclonal antibody.

Most commonly, these are subcutaneous administration, with one of them having an IV administration, which is linvoseltamab. And they do require step-up dosing until achieving full approved administration dose.

Generally speaking, I do believe that for specifically the BCMA bispecifics, we might see a few slight differences, but overall similar safety and efficacy profile. So I do believe any of them should be okay to use depending on what is available institutionally wise. And I think other considerations, for example, might include subcutaneous versus IV combinatorial strategies that might be approved.

For example, you can give teclistamab/dara on label, but you can consider combination with others. But generally speaking, I limit that to institutional preferences or what might be available at each institution or site, as well as considerations and discussion between patient and provider. I can't recommend one over the other. I do think they're all relatively similar from a safety and efficacy perspective.

So in terms of practical differences, as I mentioned, with the three bispecific antibodies, three of them: teclistamab, elranatamab and talquetamab are administered subcutaneously, while linvoseltamab is administered intravenously. They do all require step-up dosing, generally done on slightly different days until achieving the target dose schedule, which varies depending on the bispecific antibody used.

A lot of us are actually commonly giving bispecifics in the outpatient setting, and we do utilize prophylactic tocilizumab for these patients. We try to give it outpatient, if possible, because it is easier for the patient, but some – for some that might not be feasible, particularly those who might have a very high burden of disease, or are at high risk for developing some of these immune toxicities, we generally prefer to initiate step-up dosing in the inpatient setting.

And also, for example, if somebody is on dialysis and is needing a bispecific and they also will need their dialysis or more close monitoring, we generally do treat those patients in the inpatient setting. And then, as I mentioned, those with high disease burden, I've had some with plasma cell leukemia that we've treated in the inpatient. So I think we just have to be mindful of disease kinetics, sometimes patient preference, particularly for the step-up dosing in the setting of other comorbidities as well, where if a patient is old and frail and has comorbidities, I think it is fair to consider or have a discussion between physician and patient about perhaps inpatient step-up dosing administration for easier monitoring and mitigation of some of the immune toxicities.

And then certainly reduced dosing does depend on response, although approval is based on continuous dosing. We generally, for example, for teclistamab can continue spacing out biweekly once somebody has a complete remission at six months or so. And then depending on the bispecific antibody used, we can generally space them out depending on response, generally like a PR or VGPR for elranatamab and linvoseltamab, respectively.

And then in clinical practice, certainly this will depend on how the patient is doing, cytopenias, infections. So a lot of this dosing certainly may vary depending on patient and disease-related factors.

Now, we do know that bispecific antibodies, like CAR T-cell therapies, do cause some immune-mediated toxicities. So generally we commonly do see cytokine release syndrome, but this is a very low grade and less common than what we see with CAR T-cell therapies, particularly immune cell-associated neurotoxicity syndrome or ICANS very rarely occurs with bispecifics, though cytopenias and infections tend to be common, particularly severe infections, which tend to be a bit higher than what we see with CAR T-cell therapy. And this is really more common with the BCMA-directed bispecific antibodies compared to the GPRC5D. Generally speaking, infection is one of the main consideration when we treat our patient with bispecific antibodies. A majority of patients will develop infections. And we are concerned, genuinely concerned about severe infections.

However, in the clinical trial, a lot of the severe infections occurred in the era of COVID-19 when IVIG prophylaxis was not given. So when we treat our patients with bispecific, we do routinely recommend IVIG prophylaxis for all patients monthly during therapy, regardless of IgG levels. And certainly this is in recommendations from the IMWG. Also, for all of these patients, we do recommend prophylaxis with antivirals such as acyclovir as well as PCP prophylaxis. For a lot of our patients, we use Bactrim unless unable to tolerate. We can consider alternative options such as dapsone, atovaquone as well as pentamidine. And we do monitor CMV titers or CMV PCR for these patients commonly as well.

Importantly, I do think that seeing the patients at least monthly or so during administration, if not more frequently, is going to be very important to be able to monitor for any signs or symptoms of infections and being in close – in close communication, as well as employing some of these prophylactic and mitigation strategies is going to be very important moving forward.

The one unique toxicity, the GPRC5D-directed bispecific antibody, which is talquetamab because it also is the GPRC5D target is found on the hard keratinized epithelium, these patients do experience on-target/off-tumor toxicity such as dysgeusia. They might have dysphagia. They might have skin rashes or something like a palmar plantar erythrodysesthesia. And they also may experience weight loss, which has been seen in up to 30% of patients.

Now generally, we do recommend that patients get referred for evaluation for bispecific antibodies and generally all immunotherapies at first relapse or from the very beginning ideally, because early referral will really help us to identify what might be the patient needs, how fast does the disease relapsing and what might be the best treatment option for the patient, and what might be the best sequence for a particular patient and for their disease.

Generally speaking, bispecific antibodies, because they are off the shelf, because they can be more easily given in the community compared to CAR T-cell therapies, they are – a majority of patients should be good candidates. If not, all patients should be good candidates for bispecific antibodies, depending availability of administration.

Now consideration for use of bispecific antibodies. Certainly when we think about not just bispecific antibodies, but when we think about utilization of CAR T or antibody drug conjugates or bispecifics, we really have to consider patient factors, right? What is the patient age? Do they have frailty, comorbidities? How well have they tolerated prior treatment? And really, what are the patient's treatment goals?

We also have to think in terms of therapy selection. We have to think about disease factors. What is their disease burden? Are they quickly relapsing? Do they have high-risk features or genomics such as high-risk cytogenetics, extramedullary disease? Are they refractory to certain medications that they've had? And then what are some very important contextual factors? Right? Are they able to get access to a bispecific or to a CAR T or to an ADC? Do they have caregiver support? A lot of this does require financial, logistic and geographic considerations.

And when we think about bispecifics, as I mentioned, you can rapidly initiate it. It's available right away. It is currently approved as a continuous therapy, though rarely do we continue it that way. We do have some early data with LimiTEC presented from the University of Pennsylvania group, where a limited duration bispecific might actually be just enough and sufficient. But we do have to be very mindful of infections with bispecific.

When we think, for example, with CAR T-cell therapy, yes, this does allow for a treatment-free interval, but it does require caregiver support. It does require relocation of patients to an academic center. And it does have some more – more immune toxicities and some, for example, non-ICANS neurotoxicities and IC enterocolitis. We think about antibody drug conjugates, generally we don't see these immune toxicities, but we do have ocular or ophthalmologic toxicity that must really be considered.

Now in terms of, you know, selecting between BCMA and GPRC5D targets for bispecifics, generally speaking, the BCMA targets have been approved first. So we do have more experience with utilizing a BCMA than a GPRC5D agent. And we have seen response to GPRC5D agents post BCMA use, particularly if somebody has had, for example, idecabtagene vicleucel or ciltacabtagene autoleucel. They generally tend to respond well to bispecific antibodies, particularly if you target switch to a GPRC5D-directed therapy.

Now, certainly we don't have all of the answers in terms of consideration for subsequent therapies and optimal sequencing. As I mentioned, we do have several different drug categories and we have to really take into account, like I said, what our patient characteristics, disease characteristics, but also patient treatment history, and, you know, have some essential practical recommendations.

All the data that is available now does suggest that we generally do prefer to give a CAR before a bispecific, although that has slightly been challenged with the MajesTEC-3 data with the earlier line approval of teclistamab in combination with daratumumab.

Now in terms of new development. So we have MajesTEC-3. So this was a phase III, randomized clinical trial of teclistamab plus daratumumab as compared to some investigator's choice combination, including daratumumab/pomalidomide/dexamethasone or daratumumab/bortezomib/dexamethasone, with a primary endpoint being progression-free survival.

Now, the outcomes on MajesTEC-3 were quite impressive. We saw overall response rate of 89% in the tec/dara arm, compared to 75% in the investigator's choice arm. And we saw complete remission rates or higher, which was about 77%. More importantly, what was really exciting was that 36-month PFS rate of 83% compared to approximately 30%, with a hazard ratio of 0.17. And we really are seeing the plateauing of the curve, which might be suggestive that these patients can do well and perhaps may not require another therapy, though I think that's yet to be seen with longer follow up.

In terms of overall survival, this was also very impressive with a 36-month overall survival, which was very similar at 83% and much improved compared to dara/pomalidomide/dexamethasone or daratumumab/bortezomib/dexamethasone.

Certainly, this is very exciting because it does allow us or our patients more opportunity for treatment earlier on with immunotherapy agents. And then in terms of sequencing these agents, again, this is very much evolving. But we have to think about how the trials were designed and practicality of sequencing. For example, if you have patients who have a first progression after upfront quadruplet therapy and transplant, generally speaking, a majority of these patients may be daratumumab-exposed or perhaps refractory.

So in that case, we generally consider giving cilta cel, though – or a CAR T, though we do have to take into account a small risk of neurologic toxicities or colitis. If you have patients who maybe are CD38-naive, which is more similar to the MajesTEC-3 population or CD38 sensitive patients, this is more MajesTEC-3 like, in this situation, tec/dara could be utilized as well as cilta-cel. And then we have to think if you have somebody who is frail, perhaps tec/dara might be a good option. Or if you have somebody who has rapidly relapsing disease where, you know, you cannot wait for apheresis and infusion of CAR T cells. And this is where bispecific or a bispecific combinatorial approach could be a very good option.

As I mentioned, certainly these sequencing strategies are very much evolving. But generally I do think now, with the availability of cilta-cel and tec/dara, and we'll have some exciting new data likely being presented at ASCO. We've seen press releases for MajesTEC-9 with single-agent teclistamab use in patients who have had daratumumab, so likely refractoriness and sensitivity, and then MagnetisMM-5 as well with a new press release just recently as well that shows very encouraging results with single-agent elranatamab.

But very exciting times for our patients, and I'm also very excited to see how the sequencing arena evolves over time. But I do think that when we sequence these drugs, we have to be very mindful of what is going to provide our patients the longest benefit, not just currently, right? The best outcome now, but also in the long term, how will our patients do? And I do think that to achieve the new functional cure, which we recently had a definition of and we're very excited about, we're going to have to use all of our tools in our armamentarium to get the best outcomes for our patients.

So one of the very exciting combinatorial strategies is RedirecTT-1. So RedirecTT-1 is a combination of talquetamab and teclistamab in patients with relapsed/refractory multiple myeloma who have been triple-class exposed to a PI and IMiD and a CD38 monoclonal antibody and refractory to last therapy.

This study showed impressive outcomes, particularly for patients with extramedullary disease, who generally are a population with a very high unmet need. We saw response rates that were impressive at 79% and complete response rate of over 50%. So certainly, particularly for patients who have extramedullary disease, a RedirecTT-1 combination of two bispecific antibodies has been very effective, perhaps the most effective we've seen, and very excited to have this option available for our patients.

In terms of other bispecific. So certainly we have another bispecific called etentamig, as well as cevostamab, as I mentioned, which in combinatorial strategies has shown impressive outcomes. And what I like about it is that it is a different target than what we have. So it's the FcRH5 compared to BCMA and GPRC5D. And certainly we have many ongoing clinical trials in the newly diagnosed early line and later relapse with different combinatorial strategies with the existing bispecific antibodies with either CD38, PI and IMiDs. And very exciting to see some of these studies move forward and – and see some of these results upcoming in the next conferences.