Nooka Discusses Talquetamab Toxicities and Promise of Outpatient Bispecifics in Relapsed/ Refractory Multiple Myeloma

Ajay Nooka, MD, MPH

Associate Director of Clinical Research

Scientific Director, Winship Data and Technology Applications Shared Resource

Winship Cancer Institute of Emory University

Professor, Department of Hematology and Medical Oncology

Director, Myeloma Program, Department of Hematology and Medical Oncology

Emory University School of Medicine

Atlanta, GA

Peers & Perspectives in Oncology: What adverse events (AEs) were observed in the MonumenTAL-1 trial (NCT03399799/ NCT04634552) findings of talquetamab?

Nooka: GPRC5D is expressed on hair shafts, the nails, and the papillae of the tongue. You’re able to see some of the [AEs] clearly reflecting where the target was. The taste-related adverse events are seen [in] almost three-fourths of the patients. We see skin-related events and nail-related events in half of the patients [Table 1¹].

When and with what severity does cytokine release syndrome (CRS) occur with talquetamab?

CRS and ICANS [immune effector cell– associated neurotoxicity syndrome] happen very early in the course. In any bispecific antibody…with the first dose escalation and the second one, before the patients reach the target dose, you already have finished the [risk period of] CRS. Even though the number reaches 60% to 70%, most of these are grade 1 AEs; you see grade 2 events in 20% of patients. The median time from the first dose is 2 days and lasts for 2 days. By the time the patient is out of the hospital, you don’t need to worry about CRS and ICANS.

We expected ICANS to be much higher with [talquetamab], but ICANS was less than 5%. If you look at different trials, the definition of ICANS varies. Sometimes, as with elranatamab [Elrexfio], even a headache [was considered] ICANS, so the numbers are much higher. I would encourage you to look only at the higher-grade ICANS.

What was your experience using prophylactic tocilizumab in patients receiving bispecific T-cell engagers?

[At Emory University Hospital in Atlanta, Georgia], we started with the bispecific agents first. That experience helped us to give the drugs as an outpatient treatment, and we moved everything to the outpatient [setting]. We started using tocilizumab as prophylaxis among all the patients [receiving teclistamab (Tecvayli)] so that it reduces the risk of the CRS, and when we saw the results, instead of 70% grade 1 toxicities, we’re seeing 20% to 30% [grade 1] toxicities.²

Whenever you’re giving a drug, you are worried about [whether] it will have any effect on the safety, any effect on the efficacy, and whether it is cost-effective. It is checking all the boxes. It doesn’t make any sense not to give it once [we see] the rates of CRS are significantly reduced. Our first 50-patient experience worked when we had seen that [time to onset of CRS] is so predictable. It made us change our practice to the outpatient setting, which we’ve been doing since October [2023]. It helps us improve on our outpatient process.… For the first patients before October of last year, we published a paper talking about the rates of CRS.

You can see how by giving prophylactic tocilizumab, you can transition from an inpatient to an outpatient setting [Figure²].

The outpatient program is meant both for the lymphoma and myeloma bispecifics. We have done both simultaneously. What we have done was bring the patient, give tocilizumab, give the first dose, and give them a number to call. They can go home, but they need to stay closer to us, and they can come anytime. If they have a fever, they can call us 24/7. We waited for our 24/7 oncology intermediate care center to be open before we initiated this process.

Do you need to use steroids to manage CRS in addition to tocilizumab?

We are not using [steroids], but other centers are using [them]. There will be a lot of data that will be coming in. The problem with using steroids is, if you use steroids, you can still see CRS afterward. When you’re using tocilizumab, you don’t see CRS afterward.

What is your approach to giving tocilizumab?

It’s only 1 dose. It was a learning curve for us. When we first started doing prophylactic doses, in the first 15 patients, we looked at when the CRS was happening. It was happening at [a median of ] 48 hours. We said, “Why don’t we start doing it 4 hours before [48 hours]?” Then we transitioned to outpatient [treatment]. There was 1 patient who had CRS at 12 hours or so. We did not want to take that risk, so we changed that prophylactic dose of tocilizumab prior to dose 1.

What did MonumenTAL-1 findings show about reducing dose intensity of talquetamab?

One thing that we knew is the schedule is intensive at every week or every other week at double the dose. When patients achieve a good response, can we back off and start giving them lower dosing or extend the dosing interval? When they looked at the original cohort of all the patients, [approximately] 50 patients had dose reductions. Learning from the existing trial, [they analyzed] how these patients did. At the same time, if patients achieved a predefined response [of] partial response, could they go on to receive 0.4 mg every other week or 0.8 mg every 4 weeks? What they were able to show is the [patients who received] lesser dosing frequency did better than the overall population [Table 2³].

Of course, this is a skewed study. If somebody achieved a PR or achieved a desired response [before] going down on the dose, [this] means you’re selecting for these patients, but clearly, it tells us that there’s a possibility for you to dose reduce and yet gain those long-term benefits down the line. The MonumenTAL-1 prospective cohort maintained response after the switch, [with] PFS [progression-free survival] lasting beyond the 12-month mark. It’s a very small cohort, [but] they saw a median PFS of close to 14 months.

If you look at these prospective cohorts, the numbers are small, but what you’re seeing is with less frequent dosing, you maintain the response and you go down on the AEs. You don’t need to bombard the patients with the same enhanced dosing. At some point, you can go down on the dosing schedule.

What we have done as a group is follow the daratumumab schedule for every antibody: weekly for 8 weeks, then on to every other week, then after the first 6 months to every month. We don’t have the data that are published yet with this regimen, but we all agree that the current dosing schedule is probably much more than what is needed. By extending the dosing intervals, you’re not only helping to resolve the AEs but you’re also able to maintain those responses over a longer period.

What is the rate of grade 3 or higher infections with talquetamab, and do we still need to give prophylaxis for infections?

[It is] 10%.¹ For all the BCMA bispecific antibodies, we typically use intravenous immunoglobulin [IVIG]. We have to have them vaccinated and have all the antimicrobials as needed. For [talquetamab], I’m not as concerned. Those patients who have a tendency to get repeated infections are the only patients to whom I tend to give IVIG.

Are the unique toxicities of talquetamab challenging for patients?

[In terms of ] the weight loss, the loss of taste, and the dysgeusia, as long as the patients are aware and this is expected, the patient education seems to work a lot. In our initial cohorts, when they started using them, patients were not prepared because we didn’t know what to expect. [We are treating] patients who were supposed to go to hospice…[who] are not going to hospice; they’re coming into the clinics. What is more interesting is if you give them the treatment and you have a break, [such as] if they have to undergo surgery, you [still] see those responses. We’ll learn more as we treat more patients, but…these responses are happening very quickly, within the first 4 to 6 weeks.

The loss of taste is real. There are some patients who lose specific tastes. There are ongoing trials that are trying to ascertain which tastes are lost and what can you do to [improve this].

REFERENCES:

1. Chari A, Minnema MC, Berdeja JG, et al. Talquetamab, a T-cell-redirecting GPRC5D bispecific antibody for multiple myeloma. N Engl J Med. 2022;387(24):2232-2244. doi:10.1056/NEJMoa2204591

Scott SA, Marin EM, Maples KT, et al. Prophylactic tocilizumab to prevent cytokine 2. release syndrome (CRS) with teclistamab: a single-center experience. Blood Cancer J. 2023;13(1):191. doi:10.1038/s41408-023-00963-y

3. Rasche L, Schinke C, Tozeau C, et al. Long-term efficacy and safety results from the phase 1/2 MonumenTAL-1 study of talquetamab, a GPRC5D×CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma. Presented at: 29th European Hematology Association Congress; June 13-16, 2024; Madrid, Spain. Accessed August 12, 2024.