Managing Toxicity Following Bispecific Therapy in R/R Multiple Myeloma

Sagar Lonial, MD, FACP

Emory University School of Medicine

Cesar Rodriguez, MD

Mount Sinai Hospital in New York City

Luciano Costa, MD

University of Alabama at Birmingham

Donna Catamero, NP

Mount Sinai Hospital in New York City

At an Around the Practice^® program hosted by CancerNetwork^®, a panel of expertsspoke about updates in clinical data for relapsed/refractory multiple myeloma, and how these findings may impact the treatment landscape. Specifically, they spoke about data supporting the use of newly approved bispecific therapies in this patient population and managing adverse effects (AEs) including dysgeusia as well as nail and skin changes in the context of a specific patient case. The panel was led by Sagar Lonial, MD, FACP, professor and chair in the Department of Hematology and Medical Oncology at Emory University School of Medicine.

Lonial was joined by Cesar Rodriguez, MD, the clinical director of Multiple Myeloma at Mount Sinai Hospital in New York City; Luciano Costa, MD, a physician at the University of Alabama at Birmingham; and Donna Catamero, NP, associate director of Myeloma Research at Mount Sinai Hospital.

Currently Approved Treatment Options

Lonial: There are 3 approved bispecific therapies in the context of relapsed/refractory multiple myeloma. We have teclistamab-cqyv [Tecvayli], talquetamab-tgvs [Talvey], and elranatamab-bcmm [Elrexfio]. What are some of the updates on data with teclistamab?

Rodriguez: For teclistamab, we have data on people who had 3 or more prior lines of therapy from the phase 1/2 MajesTEC-1 trial [NCT03145181; NCT04557098].¹ The overall response rates [ORRs] are very impressive compared with what we’re used to seeing for single-agent therapies. We were used to the 30% ORRs with agents including selinexor [Xpovio] and daratumumab [Darzalex]. Now that we have these T-cell redirecting therapies, we’re seeing ORRs of 65% and 64%, which is amazing. The depth of the response is great, as is the percentage of minimal residual disease [MRD] negativity.

With the MajesTEC-1 trial, patients with an average of 6 prior lines of therapy experienced an ORR of 63%, which is excellent. There were some AEs commonly seen with T-cell redirecting therapy, like cytokine release syndrome [CRS], neurotoxicity, and increased risk of infections. The main highlight for the MajesTEC-1 trial and teclistamab is that the ORR of 63% led to the FDA approval of this agent.²

Lonial: What do the data look like for talquetamab?

Costa: Talquetamab, as I sometimes explain to patients, is the twin of teclistamab. They are very similar molecules, except talquetamab has a different affinity for GPRC5D. There is a little bit of flexibility with the treatment schedule. Talquetamab got approved with 2 different schedules: one with weekly dosing, and the other with dosing every other week.³ I’m still trying to find a good rationale for ever using the weekly dose schedule. The data are almost identical for each schedule, both in terms of efficacy and in terms of toxicity. We have those off-tumor effects with dysgeusia, nail changes, and skin changes, which are not life-threatening but very uncomfortable to patients.

On the plus side, data show that the infection signal may be somewhat different, which may cause less infection. It often sets up a trade-off: on one path your nails look good, but you may have more infection; on the other, food does not taste quite right, but you may be a little bit safer [from infection] in that regard. It’s a little challenging to assess the duration of response for any of those.

The population and the treatment timing may get confounded with the infection signal. As a result, some people needed to go off study treatment, and some died in trials during the pandemic. We’re going to learn a little bit more about that when we look at the upcoming larger randomized trials for talquetamab.

Lonial: What do data from the phase 2 MagnetisMM-3 trial [NCT04649359] highlight about elranatamab?

Rodriguez: Elranatamab got approved around the same time as talquetamab in August 2023.⁴ Just like teclistamab, elranatamab is B-cell maturation antigen [BCMA]-directed. It is given subcutaneously, although there are some differences in how it’s being administered due to the step-up dosing and how it’s administered afterward. Teclistamab has 2 step-up doses and then the first full dose, which can be given between 48 and 72 hours, and it’s recommended to be given in the hospital for management of CRS and neurotoxicity. The hospital stay would be 7 to 9 days before discharge and continuing treatment on a weekly basis.

Elranatamab is slightly different in the sense that it has 2 step-up doses and then one final dose. The first 2 step-up doses are to be given in an inpatient [setting], but the final dose can be given in the outpatient [setting]. The timing is a little bit skewed. You could do 48 to 72 hours between the first and second step-up dose, but between the second step-up and the final dose, you do need to respect the 4-day pause based on the package insert. For outpatient, you continue weekly, but you could transition to giving it every other week after 6 months if a patient achieves a good response. That allows us to space out treatment, which is great.

In terms of the responses, elranatamab yielded an ORR of 62%.⁵ The degrees of CRS, neurotoxicity, and other toxicity are pretty much similar between elranatamab and teclistamab. The patient characteristics in each trial were slightly different. With the MajesTEC-1 trial, the inclusion criteria were an M spike of 1 or greater, an ECOG performance of 0 or 1, and a renal function with a creatinine clearance of 40 mL/min/1.73 m² or higher. The MagnetisMM-3 trial was a little bit different. The M spike requirement was as low as 0.5, the performance status needed to be 0 to 2, and the required renal function was as low as 30 mL/min/1.73 m².

We won’t be able to compare these 2 studies precisely because of the differences in the inclusion criteria.

Managing Skin and Nail Changes Associated with Talquetamab Therapy

Lonial: What can we tell patients what to expect with taste changes as well as some of the other AEs with talquetamab, particularly the skin and the nail changes?

Rodriguez: For talquetamab, approximately 70% of the patients have skin toxicities and about 60% have dysgeusia of some sort. Unfortunately, the way that we have currently classified dysgeusia is not very representative of what the patient is experiencing because the grading doesn’t factor in taste loss or the quality of life. One of the things that we’re noticing is that approximately 90% of our patients are having a change in their taste.

Sometimes, treatment impacts their taste completely or impacts their taste for savory or for sweet [food]. How long it takes for them to recover this taste is variable. It is a big problem for those who lose their taste completely because we are seeing patients lose weight. They don’t want to eat. We don’t know exactly why patients are losing taste. We know that GPRC5D is expressed in high-keratinized cells as well as the nail beds, the hair follicles, the epididymis, and myeloma cells. There isn’t any expression in the taste buds or the saliva glands.

There are some plasma infiltrates in the saliva glands; this could be a potential factor affecting taste. We had a case where we did a PET scan on this patient, and there was uptake in the saliva glands that was not there before they started talquetamab. Based on that observation, our research team is doing some experimental trials on potential ways of preventing this.

When a patient describes that they are losing taste, feeling that their mouth is dry, or that it is harder for them to swallow after chewing, it’s very consistent with the decrease in the production of saliva. However, we do know that there is some GPRC5D expression in the tongue next to the taste buds, so if there’s some inflammation, it could potentially be affecting it.

Catamero: [Dysgeusia] is a challenging AE to manage. We’re trying [ice cubes] for patients, which can be challenging during the step-up dosing as an inpatient because we do see that uptake in the glands. We’re trying saliva substitutes, icing, dexamethasone, nystatin syrup, and zinc oxide. We’re also tracking patients, but I think the best way to mitigate these AEs—patients are responding beautifully to these drugs—is to extend the period. Maybe we don’t need to give dose holds or dose reductions so frequently, especially if patients are having these nice, durable responses. As we saw in our clinical experience when patients had prolonged dose holds, their taste came back, and their response was maintained.

Lonial: What’s your threshold for changing the dose frequency or implementing a dose hold?

Costa: I am a little skeptical that dose holds would be effective with talquetamab, but a lot of those symptoms tend to get better over time, particularly the dysgeusia. I sometimes wonder: if symptoms get better after a dose reduction, were they going to get better anyway?

However, I’m okay with the dose reduction. We do treatment as aggressively as we can when patients are on a trial, where talquetamab is being explored with a monthly dosing schedule. I’m not necessarily guided by the toxicity.

Lonial: How do you approach managing dysgeusia?

Rodriguez: We don’t have any data to say talquetamab may help reduce the dysgeusia in these patients or that it’s causing the alteration in the taste. However, we have 2 strategies at Mount Sinai. We can favor every-other-week dosing or weekly dosing with talquetamab, as the FDA approval gives us both options.

We don’t know if the AEs are caused by the intensity or the frequency of the dose, so we’re favoring the every-other-week schedule. If a patient achieves a good response, we space it out to monthly dosing. If the patient is having symptoms beforehand, and these symptoms are really impacting their quality of life and causing a drop in their weight, we either reduce the dose or space it out as well.

Lonial: What can you expect in terms of skin and nail changes in the average patient who’s receiving talquetamab?

Catamero: We see these skin changes within the first few weeks of treatment. We can manage them well with heavy moisturizers and ammonium lactate lotion.

Patients are going to have ridging and weak, brittle nails for the duration of therapy. We recommend nail hardener, but it’s mostly aesthetic. These are not painful toxicities. We’ve done a good job of making them very self-limiting; they resolve, and we can move on. These aren’t anything that we’re discontinuing patients for. We manage it in continued treatment without incidence.

Rodriguez: The nail tends to be the biggest problem. We do see patients who have some skin changes in the palms and the feet, but they are not as bad or as frequent as the nail changes. Very few patients describe changes in sensitivity in the bed of the nails. The use of these creams or sometimes even steroid application does help with the symptoms. It hasn’t been a cause to discontinue therapy.

Once we space out the dosing, we do start to see the nail regrow.

BCMA-Directed AEs and Infections

Lonial: What are some strategies you use to handle BCMA-directed AEs?

Costa: The cytopenias are something that we as hematologists are not particularly scared of. They tend to be transient and amenable to support with growth factor, resulting in mostly very quick neutropenia. Unfortunately, the Achilles heel of those therapies is the infection. We have an aggressive strategy in which we give an oral antibiotic during the first month. We start intravenous immunoglobulin (IVIG) on all patients at the beginning of the second month and continue for the duration of therapy; this sometimes takes longer if patients remain hypergammaglobulinemic.

We also do universal pneumocystis jirovecii pneumonia (PJP) prophylaxis. We also have a universal varicella-zoster virus prophylaxis in our myeloma practice. This is an expensive and cumbersome package, particularly the IVIG therapy, but it has served us well. In the days before we encountered these problems with the BCMA bispecifics, we saw death—particularly in the setting of COVID-19—cytomegalovirus (CMV), and PJP. The last year or so has been much better with respect to these AEs.

Lonial: Does anyone else do anything differently?

Rodriguez: No, my strategy is very similar. We have a better understanding of this pattern of infections. The MajesTEC-1 trial reported a 40% risk of infections, and we are seeing now with the real-world data that the longer you stay on BCMA-directed therapy, the rate can go as high as 70%.

In addition to the antiviral prophylaxis, the PJP prophylaxis, and the IVIG starting on cycle 2 due to the hypogammaglobulinemia, we are also trying to determine when it is safe to stop therapy. We haven’t made that decision yet, but it’s a discussion that we’re having to see if it helps reduce the risk of infection.

Costa: I will go back to the point of drawing comparisons between bispecifics. We take some things as dogmatic for a lot of those agents: one treatment may have 2 step-up doses, and one might have 3 step-up doses. These practices have more to do with how and when they were developed. All those things are amenable to being modified by practice and by future data, so nothing is written in stone.

Rodriguez: One thing that we have noticed now with the clinical trials and our experience with commercial BCMA bispecifics is viral reactivation. We’re paying a bit closer attention to CMV reactivation. We’re also seeing warts appear in hands. We’re trying to make sure that patients continue with their human papillomavirus vaccines. We also have dermatologists evaluate these warts because as long as patients are continuing on a BCMA bispecific therapy, they will have the risk of more of these lesions showing up in their hands or wherever they have the virus.

References

1. Moreau P, Garfall AL, van de Donk N, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2022;387:495-505. doi:10.1056/NEJMoa2203478
2. FDA approved teclistamab-cqvy for relapsed or refractory multiple myeloma. News Release. FDA. October 25, 2022. Accessed November 14, 2022. https://bit.ly/3Fgsi4s
3. U.S. FDA approved TALVEY (talquetamab-tgvs), a first-in-class bispecific therapy for the treatment of patients with heavily pretreated multiple myeloma. News release. The Janssen Pharmaceuticals. August 10, 2023. Accessed November 14, 2023. https://prn.to/3KwnjyD
4. Pfizer’s Elrexfio receives U.S. FDA accelerated approval for relapsed or refractory multiple myeloma. News release. Pfizer. August 14, 2023. Accessed November 14, 2023. https://bit.ly/3DTCRIY
5. Mohty M, Tomasson MH, Arnulf B, et al. Elranatamab, a B-cell maturation antigen (BCMA)-CD3 bispecific antibody, for patients (pts) with relapsed/refractory multiple myeloma (RRMM): Extended follow up and biweekly administration from the MagnetisMM-3 study. J Clin Oncol. 2023;41(suppl 16):8039. doi:10.1200/JCO.2023.41.16_suppl.8039