Banerjee Discusses Dose De-Escalation and GPRC5D Toxicity Management in RRMM

Rahul Banerjee, MD

Assistant Professor

Clinical Research Division, Fred Hutchinson Cancer Center

Division of Hematology and Oncology, University of Washington

Seattle, WA

CASE SUMMARY

• The patient is a 72-year-old man who was diagnosed 6 years ago with multiple myeloma (MM), 60% plasma cells, t(14;20).
• His medical history includes respiratory infections (2 episodes of pneumonia and multiple episodes of bronchitis over the past 10 years).
• He has received 5 prior lines of therapy, most recently chimeric antigen receptor (CAR) T-cell infusion.
• He now presents with disease progression (increased free light chains, creatinine 2.3 mg/dL).
• His ECOG performance status is 2.
• He was treated with talquetamab (Talvey) via step-up dosing on days 1, 4, and 7, reaching a treatment dose of 0.8 mg/kg every 2 weeks starting on day 10.

Could the step-up dose of talquetamab be done on days 1, 4, and 8 to allow more flexibility for dosing on weekdays?

BANERJEE: At the time [of the MonumenTAL-1 trial; NCT03399799/NCT04634552], they mandated inpatient dosing for everyone, so they tried to make it 2 days apart and then 2 days apart and so forth. In my practice, we operationalized outpatient bispecifics in the last month, and we are doing [days] 1, 4, and 8, practically speaking. Some centers swear by it. Cytokine release syndrome [CRS] can happen whenever it wants, and it typically happens at night. Whether you dose on a Sunday or Monday, it won’t make that much of a difference. Logistically speaking, we have tried to avoid weekend dosing for step-ups unless we have to, and typically, for those kinds of patients, we do it in a hospital setting. Technically, it’s not required. I’ve heard of centers—though I do not do this—that are trying to do days 1, 8, and 15. There are other investigational bispecifics that have this kind of pattern…but there’s no right answer.

Do practical considerations such as fixed dosing or subcutaneous administration affect the choice of bispecific therapy?

We don’t have fixed dosing yet. [Some] lymphoma bispecifics have fixed dosing. They have [agents given for] 6 months or 12 months. [In some cases], if they achieve a complete response, you stop; if not, you go on and then stop. [In MM], the dosing is until progression. There are ongoing studies…looking at this idea: If someone achieves a deep response, can you stop bispecific therapy? Anecdotally, it can work right in the same way that CAR T is not curative, but it holds remission for a long time for some people, which might be possible here if you suppress the myeloma deep enough.

I have offered some of my patients [the choice] to stop bispecific antibodies. They don’t want to because, in later lines, the bispecific truly has saved their life. At that point, I [have said they] could stop it. They [say] they’ll just stick to once-a-month dosing, assuming the toxicities are manageable.

[In terms of] intravenous [IV] vs subcutaneous, all of these are subcutaneous. Linvoseltamab, when it’s approved, will be IV, but some people don’t mind. I prefer subcutaneous. The only counterargument that could be made is that with the IV products, CRS…tends to happen sooner and is less likely to happen, at least anecdotally, in the middle of the night and more likely to happen within 3 hours of them going home. It’s probably just the pharmacokinetics of the drug are different, and the bioavailability is faster…but for the long haul, I prefer subcutaneously.

How do you approach patients with relapsed/refractory MM (RRMM) to the referring oncologist after the step-up dose?

Driving distances often bring people back. I try to do that because our clinic is already bursting at the seams, and I feel like my partners in the community just have much more efficient practices for care delivery than we do. I’m here to help with stressful decisions or…managing those first step-up doses. I routinely try to send patients back. I sent several patients back to [the referring hematologist]. I’d much rather have [community oncologists] handle these ongoing doses than me.

I regularly [suggest] de-escalating dexamethasone, bortezomib [Velcade], [etc]. [With talquetamab], you can do every-other-week dosing from the beginning. I have 3 patients who are on talquetamab and…come down to Seattle, and every- 2-week dosing has been hugely helpful. One of them is now moving to every-4-week dosing, so that’s a good strategy.

CASE UPDATE

• After 1 month of treatment, the patient is in stringent complete response but is experiencing the following adverse events (AEs): Complete loss of taste and dry mouth
• Dry skin and skin exfoliation on the hands and feet
• Ridging and peeling of nails

Could you discuss the AEs associated with talquetamab in RRMM?

The [AEs] that can come up with talquetamab are manifold. GPRC5D, which is a target of this, is what’s called an orphan receptor. [We don’t understand] why this protein is on plasma cells, tongue cells, skin cells, and nail cells.

CRS is expected with any T cell–redirecting agent, whether it be CAR T-cell therapy or a bispecific antibody. In general, there’s a little less high-grade CRS with this [than with] CAR T-cell therapy, but it could certainly still happen. Immune effector cell–associated neurotoxicity syndrome [ICANS] can happen [but is] much less common. With CAR T, you’re looking at a 10% to 15% incidence of ICANS, and there is none of that here [any grade, 7.7%; grade 3/4, 1.8%].¹

The rate of infections looks pretty high here [any grade, 64%]. GPRC5D bispecifics do not have the same infectious profile as BCMA [B-cell maturation antigen] bispecifics. [Although] we don’t have a randomized study of teclistamab [Tecvayli] vs talquetamab…it’s worth noting that GPRC5D is primarily found on malignant plasma cells and is not found that much on B cells. BCMA is found on B cells. So...grade 3 and 4 infections [are] only 18% with talquetamab; with a BCMA [bispecific, it’s more like 50%, in terms of infections.^1,2 I have 1 patient in whom I’m using talquetamab first because he has these [atypical] lung nodules. I don’t want to take any chances with [infection].

The bad news is [that there are] skin issues, nail issues, and tongue issues. [There are] tongue issues and taste disturbances in at least 50%³; here, they [report] 72%.¹ It’s not always something that a taste test can diagnose. The patients are describing that their taste feels off and foods don’t taste as good. Several patients…lost weight, whether they were planning to or not and whether they’re having dysgeusia or not, which is interesting. Even with dose de-escalation, I haven’t always been able to see this reverse, and the trials have not shown that either.

But for everything else, we’re starting to get better. Dysgeusia can get better. Dysphasia can get better. Rashes can happen because [the target] is found on skin cells. It’s often not as bad for me, and you’re typically able to resolve that with dose holds pretty quickly. The nails [can] get a little harder and more brittle. They sometimes get a little rough. They’re not going to fall off spontaneously, but I’ve had patients where their nail gets caught…and just slips off. I tell them to be careful or to wear gloves, nail lacquer, or artificial nails. Those go a long way in preventing that from happening.

I have never seen palmar-plantar desquamation…that is more with weekly dosing. If you’re not dosing every week, you’re not going to have the skin cells get flogged week after week after week. Nail change is very common. Body rash can happen…. I’ve seen that sometimes [in areas of skin] where there’s hair. I’ve had some patients who don’t need to shave anymore once they’ve started…. Injection site reactions can happen with any of these bispecifics. If someone’s having bad injection site reactions, continuing dexamethasone premedication is often helpful here.

The weight loss is pernicious. Patients swear they are eating and the weight still drops. It’s not [necessarily] dangerous to lose weight.

Do you see other markers of malnutrition, such as hypoalbuminemia?

I have not had them feel like they’re malnourished, per se. I don’t think I’ve had anyone whose prealbumin or albumin has dropped…. It may be because they’re seeing our nutritionist. Our nutritionists are on top of it with [giving them] protein shakes…they may be able to head it off. I think it is generally fat because their appetite goes down. Anorexia is the biggest driver of this… When I put people onto once-a-month dosing, I don’t think it’s been that bad. I’ve never had a patient…feel weak from it. In the early days, there were patients we put on total parenteral nutrition and enteral feeds. I [haven’t had to do] that for my patients in the past year.

CASE UPDATE

• The patient received the following supportive care: Acetaminophen 1000 mg for grade 1 CRS
• Heavy moisturizing cream, ammonium lactate 12% lotion, nail hardener, topical vitamin E oil, and triamcinolone 0.025% ointment for dermatologic AEs
• Dexamethasone/nystatin oral rinse, diet changes, dose reduction at cycle 6 from 800 mg to 400 mg, and change to monthly dosing for oral AEs
• He remains in a stringent complete response; taste changes are intermittent and grade 1 or lower
• Skin exfoliation is resolved in cycle 2
• Nail changes continue

When this patient got grade 1 CRS, he received 1 dose of acetaminophen. He did not require tocilizumab. Tocilizumab is not required per the package insert to treat CRS with bispecifics, so you don’t have to do it by any means. We are doing “pocket dexamethasone,” [where] everyone gets 10 mg of dexamethasone at home. If they call us and they have a fever, [they can] come in or go to the emergency department but take dexamethasone first. If they come and the fever is broken and they’re doing great, then you’re done. Not everyone needs tocilizumab.

For the dermatologic [AEs], heavy moisturizing cream and ammonium lactate seem to help with this. We recommend that to all our patients. There’s a nail hardener, which seems to help, [as does] a topical vitamin E oil. Oral dexamethasone mouthwash has not been studied here rigorously, but people have done it.

For the diet changes. There’s a diet [technique] called FASS [fat, acid, salt, and sweet]. You always carry lemons, hot sauce, sugar, and something else [with fat]. Whenever a food tastes weird, you identify what taste it is, and you take the antidote to it. If a food tastes too bland, add something spicy. That food now tastes sour, so let me add some sugar. You train your body to neutralize whatever it feels is happening, and that seems to help.

What tips are there for the prevention and management of GPRC5D-related AEs?

I cannot emphasize enough that education is a key part of [management]. If patients know that it’s coming, it’s very helpful. We have a nutritionist visit…at cycle 1, day 22. In the beginning, everyone is worried about CRS. All these toxicities don’t manifest for the first 3 weeks minimum. Typically, it’s the first couple of months. It’s often better to remind them about it at the beginning, but remind them [again] beginning week 3 or 4. No more CRS, but now is the time to keep an eye out for these things. I’ve often found that patients who are well prepared do great. An example is to have sour citrus or candies before meals.⁴ There are some other examples for dry mouth and dysphagia [Figure⁴]. Nystatin is fine to use if [glossitis and thrush] happen. Having nutritionists involved can’t fix everything [related to weight loss], but even as a placebo effect, having the patient feel that they have some agency in the matter is very helpful.

For dry skin, I don’t know that we recommend short, lukewarm showers to our patients; some people love showers, some people hate them, but heavy lotion definitely helps. Ammonium lactate helps [for hand/foot peeling]. Patients should keep their nails clean; some people like artificial nails. If they have a skin reaction, dexamethasone can help. Otherwise, loratadine is fine.

Can patients maintain a response with reduced dose intensity?

Ajai Chari, MD, from University of California, San Francisco, presented this past December at the American Society of Hematology Annual Meeting and Exposition…. It has a small number of patients [n = 19].⁵ That’s the only caveat, but there were pretty dramatic results…. For patients who had achieved the response, you dose de-escalated them either to 0.4 mg/kg every 2 weeks to cut the dose in half or went from every-other-week dosing to every-4-weeks dosing.

After you maintain the switch, everyone was able to maintain an overall response rate of 79%. The median progression-free survival is 13 months here, and the duration of response is going to easily be close to 2 years for these patients [Table⁵]. There’s some selection bias because the ones who are responding are…going to keep responding. But from the time of de-escalation, they maintain that response quite vigorously. You have fewer myeloma cells left, so giving a lower dose or lower frequency makes sense in terms of myeloma control and…AEs. You’re not flogging their T cells all the time. But in terms of T-cell efficacy, that’s the wild card. I can’t say this for sure, but is it possible that the T cells are less exhausted and, therefore, more functional if you’re not constantly redirecting them every single week or every 2 weeks?

_REFERENCES

_{1. Chari A, Krishnan A, Rasche L, et al. Clinical management of patients with relapsed/ refractory multiple myeloma treated with talquetamab. Clin Lymphoma Myeloma Leuk. 2024;24(10):665-693.e14. doi:10.1016/j.clml.2024.05.003}

_{2. Moreau P, Garfall AL, van de Donk NWCJ, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2022;387(6):495-505. doi:10.1056/NEJMoa2203478}

_{3. 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}

_{4. Catamero D, Purcell K, Ray C, et al. Practical management of patients with relapsed/ refractory multiple myeloma receiving talquetamab, a GPRC5D×CD3 bispecific antibody: experience in monumenTAL-1. Clin Lymphoma Myeloma Leuk. 2023;23(suppl 2):S314-S315. doi:10.1016/S2152-2650(23)02116-X}

_{5. Chari A, Oriol A, Krishnan A, et al. Efficacy and safety of less frequent/lower intensity dosing of talquetamab in patients with relapsed/refractory multiple myeloma: results from the phase 1/2 MonumenTAL-1 study. Blood. 2023;142(suppl 1):1010. doi:10.1182/blood-2023-181228}