Talquetamab Dose Modification Maintains Efficacy in Multiple Myeloma

As oncologists become more familiar with bispecific T-cell engagers, more efforts are being made to explore the most effective ways to customize them for the needs of their patients. In the MonumenTAL-1 trial (NCT04634552) that investigated talquetamab (Talvey) in patients with multiple myeloma, different dose levels and schedules were evaluated, and additional analyses of dose modification were reported. During a virtual Case-Based Roundtable event for oncologists in North Carolina and Virginia, Christopher J. Ferreri, MD, clinical assistant professor in the Department of Hematologic Oncology and Blood Disorders at Atrium Health Levine Cancer, examined the reported efficacy in patients with dose modification and how effective this was in managing different adverse events (AEs).

Register today to join a Case-Based Roundtable near you.

This article is part 2 of a 2-part series from a Case-Based Roundtable event.

Targeted Oncology: Could prophylactic use of tocilizumab (Actemra) become approved for use with bispecific antibodies in multiple myeloma?

Christopher J. Ferreri, MD: I don’t know if they will conduct the type of study that would lead to FDA approval. But a recent change is that the use of prophylactic tocilizumab is now on the NCCN guidelines, so we have found more success with getting that covered. I would say the majority of our outpatient step-up dosing we do with a little extra dexamethasone prophylaxis the day after each dose. We do have a nice infrastructure to monitor. I think we would use prophylactic tocilizumab more if we didn’t have the assistance of our hospital-at-home crew, and…we’ve been having more success recently with getting coverage for prophylactic tocilizumab. It may be worth exploring, because the majority of times in the last few months when we have wanted to give it, we have gotten it covered, based on it being listed in the guidelines.

One thing is to talk about it with your pharmacist, usually a week or two in advance when you’re going to start a patient. Our pharmacist is putting in a second plan, essentially a tocilizumab plan, that sometimes is for prophylactic tocilizumab, but other times is just to be able to give it outpatient, without having to admit the patient if things unfold that way. We usually will know before they get dosed whether that tocilizumab plan has been authorized, as long as they’re putting it in with advance notice.

Was the COVID-19 pandemic a factor in reporting infections in trials of bispecific therapies?

It’s absolutely a fair point [that is discussed] when we talk about BCMA (B-cell maturation antigen) bispecifics, [because] the phase 1/2 MajesTEC-1 study [NCT03145181; NCT04557098] was conducted at the height of the pandemic. Largely speaking, I think [the infection profile] is borne out in the studies and real-world experience. The BCMA-directed bispecifics tend to carry a bit of a higher infection risk than the GPRC5D-targeted talquetamab. That being said, severe infections still do occur, and opportunistic ones can occur. We are also providing Pneumocystis jirovecii prophylaxis for our patients on bispecifics. For chimeric antigen receptor T-cell therapy, we often will go by giving it at least 6 months and seeing where the CD4 counts are.

What role does dose modification have on the efficacy of talquetamab?

I think [dose modification] is the most effective approach for managing these adverse events [AEs]. Patients were looked at both retrospectively and prospectively about dose modifying. Patients were slotted to get it either every week or every other week, but they explored modifications at less frequent dosing, every 4 weeks instead of every 2 weeks, or coming down from that highest dose to a lower dose for subsequent dosing.

These are relatively small numbers, but [they analyzed outcomes in] patients whose dose was either lowered or spaced out further compared with those patients who did not have a dose modification.¹ In fairness, patients were probably not having their dose changed if they weren’t in a response. That being said, most of these patients were responders, so what we’re seeing seems like a better durability curve in terms of progression-free survival [PFS] for the patients who did have a dose modification. At a minimum, they should encourage you that once you’ve captured a response, backing off on the dosing frequency does not seem to have a detrimental effect on your ability to maintain that response.

The median duration of response for these patients who modified their dose was quite impressive, at 19.8 months, not yet reached, and 24.2 months, respectively, across the subgroups [of weekly dosing, every-2-weeks dosing, and prior T-cell redirection therapy].

Similarly, looking at the dose modification, patients in that cohort were more likely to respond, [with an overall response rate of] 79% [vs 71.7% in the every-2-weeks cohort].^1,2 Again, they probably weren’t dose modified if they weren’t in a good response, but the median PFS was 13 months.¹

How did dose modification affect patients with AEs?

Here is where that impact on toxicity comes in. For patients with skin rash toxicity, almost two-thirds of the patients had the toxicity resolved vs less than half without it. For non-rash [skin toxicity], so dry skin pruritus, 50% resolved vs only 15%. For oral toxicity, [which was] primarily taste loss and dry mouth, we saw about one-third of the patients have a resolution in their taste issues [vs 26.9% in those with no dose reduction]. So, this isn’t a foolproof method, but it does seem that as you go to a modified dose, particularly decreased dose frequency, the toxicities get a little bit more manageable or may even resolve. Again, we see that there wasn’t a negative impact on the durability of the response.

What is your approach to dose modification in your practice?

Typically, I’ll start with a reduction from every 2 weeks to every 4 weeks. I response adapt it. But if we’ve normalized the light chains, if we’re in a complete response within 4 to 6 cycles, I’m already looking to space it out to monthly dosing, [partially] for toxicity and [also] because I think that as we look across bispecific data as a whole, there seems to be a pattern that less frequent dosing may promotes better durability, maybe because of less T-cell stimulation and exhaustion.

I think we can find a way to push through it and modify things. But it’s very important to counsel patients upfront about what will very likely happen, which is that with almost 100% certainty, taste is going to be significantly altered or lost, and they’re going to have some dry mouth and dry skin, but that it’s a very efficacious medicine that can improve outcomes when there are not a lot of other great options left.

DISCLOSURES: Ferreri previously reported a consulting or advisory role for Sanofi and Janssen, and stock/other ownership in Affimed Therapeutics.

REFERENCES:

1. 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

2. Touzeau C, Schinke C, Minnema M, et al. Pivotal phase 2 MonumenTAL-1 results of talquetamab (tal), a GPRC5DxCD3 bispecific antibody (bsab), for relapsed/refractory multiple myeloma (RRMM). Presented at: European Hematology Association 2023 Congress; June 8-15, 2024; Frankfurt, Germany. Abstract S191.