Talquetamab Helps Usher in Era of Bispecific Antibodies in Relapsed/Refractory Myeloma

The recent FDA approval of talquetamab-tgvs (Talvey) for patients with heavily pretreated relapsed/refractory multiple myeloma not only provides an effective alternative to BCMA-directed therapies in a difficult-to-treat population, but it is indicative of the growing importance of bispecific antibodies and other T-cell redirecting therapies in the multiple myeloma space, according to Ajai Chari, MD.

Talquetamab was granted accelerated approval by the FDA on August 10, 2023, for patients with relapsed/refractory multiple myeloma who have received at least 4 prior therapies, including an immunomodulatory agent, an anti-CD38 antibody, and a proteasome inhibitor. The regulatory decision was based on data from the phase 2 MonumenTAL-1 trial (NCT04634552), in which the agent produced clinically meaningful and durable responses patients who had also not been exposed to prior T-cell redirecting therapy (n = 187).

Talquetamab elicited an overall response rate (ORR) of 73.6% (95% CI, 63.0%-82.4%) in patients administered a biweekly dose of 0.8 mg/kg (n = 87). The ORR in patients treated with 0.4 mg/kg per week (n = 100) was 73.0% (95% CI, 63.2%-81.4%). Median duration of response (DOR) was not reached in the 0.8 mg/kg cohort, and it was 9.5 months in the 0.4 mg/kg cohort. Notably, a cohort of heavily pretreated patients who had been previously exposed to T-cell redirection therapy (n = 32) achieved an ORR of 72.0% (95% CI, 53%-86%) with the 0.4 mg/kg weekly dose.

“What's really exciting about talquetamab is that its AE profile is unique and combinable with other drugs,” Chari said in an interview with OncLive®. “The choices [in relapsed/refractory multiple myeloma] are going to be increasing.”

In the interview, Chari, who is director of clinical research in the Multiple Myeloma Program at the UCSF Helen Diller Family Comprehensive Cancer Center, discussed how the FDA approval of talquetamab addresses several unmet needs in relapsed/refractory multiple myeloma, expanded on the agent’s efficacy data and safety profile observed in MonumenTAL-1, and emphasized how the agent may prove even more effective when combined with other therapeutics in this setting.

OncLive: What is the significance of the recent FDA approval of talquetamab in relapsed/refractory multiple myeloma?

Chari: We're in this era of T-cell redirection therapy. These CAR T-cell [therapies] and bispecific antibodies are a game changer for patients in terms of the number of patients who respond and how long they respond. That in and of itself is great. However, talquetamab is also the first product [approved] that is targeting GPRC5D. Until now, all the approved [T-cell] products in this category were targeting a protein called BCMA.

I would also say [talquetamab] is an off-the-shelf [agent]. Finally, its adverse effect [AE] profile is unique and makes it combinable [with other agents], which is exciting. Those [factors] are what make this agent's approval so important.

What unmet needs have historically existed for patients with relapsed/refractory multiple myeloma, and how could the approval of talquetamab help address them?

Historically, the most common unmet needs [have been for] heavily pretreated patients, [such as] patients who were multi-drug refractory. In particular, we think about [patients who are] triple-class refractory [to] proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies, and also [those who are] penta-drug refractory [to] lenalidomide [Revlimid], pomalidomide [Pomalyst], bortezomib [Velcade], carfilzomib [Kyprolis], and either daratumumab [Darzalex] or isatuximab-irfc [Sarclisa]. When patients have exhausted those therapies, their choices are limited.

Historically for heavily treated patients like that, the ORR [needed for] an accelerated approval was between 20% to 30%. [With talquetamab], we saw a ORRs [higher than] 70%, and the [12-month] PFS [rate was 54.4 percent] with twice-monthly dosing at 0.8 mg/kg. [These are] exciting results in a heavily treated population.

I would add that [48.5% of patients treated at 0.8 mg/kg and 43.2% of patients treated at 0.4 mg/kg] with extramedullary disease responded. We need to do more [for patients with extramedullary disease], but these are exciting results overall.

How did talquetamab perform in patients who had received a prior bispecific antibody or CAR T-cell therapy?

Here the response rate was [72%], and [treatment for this patient population] is also an unmet need. Of all these CAR T-cell therapies and bispecific antibodies that have been approved, none of them have actually [been] studied in this population.

We're [also] seeing really good results, for example, with talquetamab in combination with daratumumab [or] the sister drug teclistamab [Tecvayli]. We know monotherapies are the first thing to get approved, but we look forward to quickly seeing more mature data and being able to use [talquetamab] in a combination setting.

Could you expand on the safety profile of talquetamad observed in MonumenTAL-1? What makes its toxicity profile unique compared with other bispecific antibodies?

Cytokine release syndrome [CRS] is quite common [with talquetamab, with an incidence of] 70% to 80%. As a category of bispecifics, I think there's no difference [between this and other bispecific agents]. [CRS was] generally low grade.

The other AEs are unique to GPRC5D. It is overexpressed on heavily keratinized tissues, so we do see some rashes with this drug, which are quite manageable. They tend to occur early and are manageable with topical creams such as emollients and topical steroids. Rarely, if it's a high-distribution, high-grade rash, an oral steroid course may be indicated. We do see nail changes, [including brittle] nails, fragility, and changes in the texture. Those are fortunately not painful, but they [can be] cosmetically disturbing. The third thing is taste and oral toxicity. We're not fully sure why this occurs. For this, we do recommend hydrating solutions like artificial saliva, candies, etc.

The good news about all these AEs is that the time to response with this agent is quite rapid. Should a patient have these AEs, we tell them that we can hold the drug, and if [AEs are] significant, we can even reduce the dose and schedule. I have patients [who have been] on these treatments for over 4 years. At my previous institution [Mount Sinai in New York, New York], where we treated nearly 100 patients, only 1 patient came off treatment for any AE.

Finally, we talked about the AEs the drug does have, but it also important to highlight the AEs this drug does not have.The rates of high-grade infections are quite modest, [with 16% of infections] grade 3 and higher. [In comparison], some of the similar data sets with bispecifics targeting BCMA, [these rates] can be as high as 45%. Also, some of those other products have had infectious deaths. Here, there were zero deaths due to AEs. That's remarkable and speaks to the ability of giving this drug. I've seen in my own practice that we didn't lose patients to COVID-19 with this drug, even though in New York, we were in the epicenter and lots of patients were getting this. We also showed in the laboratory that people can have COVID antibody production [while on talquetamab].

It's a different [safety] profile. No question, we do need to work on that oral toxicity, dysgeusia, to further to understand the pathophysiology so we can get more directed therapies. In the meantime, it's an exciting drug to add to our arsenal.

What does this approval mean for the future role of bispecific antibodies in the multiple myeloma treatment landscape?

Bispecific antibodies are here to stay. Myeloma is probably leading the way with teclistamab and talquetamab, but they are also [being developed] in lymphoma. Community oncologists need to get trained [for the use of these agents], and not just for themselves, [but] their whole team of nurses, nurse practitioners, and pharmacists. Every institution needs to start getting on board with bispecifics, because they're going to come to your doorstep. I would say it's the monoclonal antibody of a couple of decades ago. Now we're in the bispecific era.

These are going to be game changing for patients. When some of these patients at our center went from research drugs to commercial drugs, the teams that are now starting to see these drugs are astounded by the responses. It's super gratifying, and it's worth learning how to manage CRS and the AEs, because the benefits far outweigh the risks.

Reference

U.S. FDA approves Talvey (talquetamab-tgvs), a first-in-class bispecific therapy for the treatment of patients with heavily pretreated multiple myeloma. News release. Janssen. August 10, 2023. Accessed August 16, 2023. https://www.janssen.com/us-fda-approves-talveytm-talquetamab-tgvs-first-class-bispecific-therapy-treatment-patients-heavily