Talquetamab Produces Durable Responses in Relapsed/Refractory Multiple Myeloma

Bispecific antibodies, including talquetamab, are swiftly changing the multiple myeloma therapeutic landscape, providing treatment options to fill previously unmet needs in this population, according to Carolina D. Schinke, MD.

The phase 1/2 MonumenTAL-1 trial (NCT03399799/NCT04634552) evaluated the efficacy and safety of talquetamab in patients who had progressed on prior therapies or had received at least 3 prior lines of therapy. Findings from phase 1 of the trial demonstrated that at a median follow-up of 11.7 months in patients who received talquetamab at 405 μg/kg weekly and 4.2 months in those who received the agent at 800 μg/kg every other week, the overall response rates (ORRs) were 70% (95% CI, 51%-85%) and 64% (95% CI, 48%-78%), respectively.¹

The phase 2 findings, which were presented at the 2023 ASCO Annual Meeting, showed that patients who received talquetamab at 0.4 mg/kg achieved an ORR of 74.1%, and those who received the agent at 0.8 mg/kg every 2 weeks achieved an ORR of 71.7%. Moreover, the ORR in patients with prior T-cell redirecting therapy was 64.7%.²

“The earlier you get experience [with talquetamab], the better for you and your patients,” Schinke said in an interview with OncLive^®. “This is an exciting time in multiple myeloma.”

In the interview, Schinke, who is an associate professor of medicine at the Myeloma Center at the University of Arkansas for Medical Sciences in Little Rock, discussed key efficacy findings from MonumenTAL-1, adverse effects (AEs) to be aware of with this agent, and what the findings from this trial reveal about the potential future for talquetamab and other bispecific antibodies in patients with multiple myeloma.

OncLive: What is the mechanism of action of talquetamab, and how did this inform the rationale for investigating this agent in patients with relapsed/refractory multiple myeloma?

Schinke: Talquetamab is a first-in-class, off-the-shelf bispecific antibody. It has 1 arm that targets T cells and 1 arm that targets a specific antigen on myeloma cells called GPRC5D. GPRC5D is highly expressed on malignant plasma cells and has limited expression on normal plasma cells, so it’s specific for myeloma cells.

What was the rationale for the MonumenTAL-1 trial?

Patients who have had several previous treatments and are relapsed or refractory have an unmet need. There’s not much we can offer them. This whole new class of bispecific antibodies and novel immunotherapies is conquering the market now, especially in relapsed and refractory disease.

Prior early-phase clinical trials with talquetamab have shown impressive response rates of 70%, which were [previously] unseen in this patient population that is typically refractory to [all treatments] we give them. With these encouraging results of early clinical trials, we moved up to a phase 2 clinical trial using talquetamab in distinct patient cohorts.

Some patients who received talquetamab in MonumenTAL-1 had prior T-cell redirecting treatment, [meaning they] had already received bispecific antibody treatment or CAR T-cell therapy, and 2 other cohorts did not. In those 2 cohorts, the dosing schedules were a bit different. [One cohort received talquetamab] weekly, and [the other] cohort [received the agent] every other week. It was neat to compare dosing schedules for this bispecific antibody because no other bispecific antibody clinical trial has incorporated different dosing schedules.

What were the efficacy findings from this trial?

We reported ORR and some follow-up [data at the 2023 ASCO Annual Meeting]. Depending on the cohort, the median follow-up reached up to [18.8] months. Progression-free survival and duration of response [DOR] were also reported.

The ORRs were impressive, 71.7% and up to 74.1% in patients who had no T-cell redirecting treatment prior to talquetamab. In the cohort that had prior bispecific antibody therapy, [most of whom] had BCMA-targeting bispecific antibody therapy or BCMA-targeting CAR T-cell therapy, we still saw an impressive response rate of 64.7%. That was encouraging.

We evaluated the median DORs for patients who initially responded, and those were also impressive, at 9.5 months in [T-cell redirecting treatment–naïve] patients who received weekly talquetamab. Interestingly, in patients who were on the different dosing schedule and received talquetamab every other week, the median DOR was not yet reached after 12.7 months of follow-up. In the cohort of patients who had prior T-cell redirecting treatment, the median DOR was 11.9 months. [These were] impressive ORRs and DORs in patients who received this novel bispecific antibody.

What does the safety profile look like for talquetamab in patients with relapsed/refractory multiple myeloma?

Some AEs were reported. Cytokine release syndrome [CRS] is a common AE with novel immunotherapies. CRS was reported in 79.0% of patients [with no prior T-cell redirecting therapy who received weekly talquetamab]. Luckily, it was mostly grade 1 and 2, so it was treated mostly only with supportive measures. Some patients required tocilizumab [Actemra], but [most did not]. CRS also mostly occurred during the early stages, during step-up dosing, as well as with the first full dose, and usually was not seen with the following doses.

The other common AE we see with novel immunotherapies is immune effector cell–associated neurotoxicity syndrome. That was rare [in this trial, occurring in up to 11.0%] of patients throughout our cohorts.

A unique AE with talquetamab that we have not seen with BCMA-targeting bispecific antibodies is skin changes, such as rash or dry skin, as well as nail changes. Those were seen in most patients, more than 50%, but were usually just cosmetic, so it did not affect quality of life [QOL], and was reported to be mostly grade 1 and 2.

Another unique AE was dysgeusia, meaning patients cannot taste their food the way they used to. Most patients only had low-grade dysgeusia, grade 1 and 2. The caveat is that there are no grade 3 and 4 [classifications] of dysgeusia. The grading system we have currently only lists dysgeusia as grade 1 and 2, so there are no higher grades. [Therefore], we’re not sure how bad dysgeusia is in some patients. It can be associated with weight loss in a few patients. However, weight loss of more than 10% was seen in few patients [in this trial].

Overall, the AEs, albeit common, did not seem to impair QOL, and for most patients, did not lead to discontinuation of therapy.

What does the future look like for talquetamab in multiple myeloma?

One [potential future direction] is combining talquetamab with other agents. Infections as an AE were reported but were much less [common] than what we’ve seen with BCMA-targeting bispecific antibodies. Grade 3/4 infections, which have been reported in more than 50% of patients receiving BCMA-targeting bispecific antibodies, were seen less commonly with talquetamab. Only [up to 19.6%] of patients [with no prior T-cell redirecting therapy] reported grade 3 and 4 infections [in MonumenTAL-1].

That offers an opportunity to combine talquetamab with other agents, particularly daratumumab [Darzalex]. The [phase 1] TriMM-2 trial [NCT04108195], which was also presented at the 2023 ASCO Annual Meeting, had encouraging results. It looks like the addition of other myeloma agents to talquetamab can improve efficacy without worsening AEs. That’s encouraging.

[Another future direction may involve] moving talquetamab into earlier lines of treatment. Currently, in [phase 2 of] the MonumenTAL-1 trial as it was designed, patients must have had least 3 lines of prior treatment, including an immunomodulatory drug, a proteasome inhibitor, and a CD38-targeting monoclonal antibody. Now, clinical trials are moving talquetamab [earlier] for patients with only 1 prior line of treatment. In the [phase 3] MonumenTAL-3 trial [NCT05455320], patients receive [talquetamab] after their first relapse, [which is] where we think it might have better efficacy because these patients are less pretreated and less refractory.

What is your main message for colleagues regarding the use of talquetamab in patients with multiple myeloma?

Talquetamab and other bispecific antibodies are revolutionizing the therapeutic landscape of multiple myeloma. It’s here to stay. I encourage oncologists to get familiar with it, start trying it and seeing its effects on patients.

The degree of responses we’ve had in patients who had no other options has been impressive. Some of [these patients were] hospice candidates, and they still got a good amount of [response] time with talquetamab. The responses are not indefinite. Patients will likely relapse afterward. However, talquetamab extends life with relatively good QOL.

In some patients [in MonumenTAL-1], other treatment options [became available]. For example, patients could move forward to CAR T-cell therapy, whereas before, they were not candidates [for that therapy] because of cytopenias or poor performance status. Talquetamab was used as a treatment itself, but also as a bridging therapy for other options that came across.

I highly encourage everybody to get experience with the drug, particularly as more bispecific antibodies flood the market. [Determining] what bispecific antibody to use will depend on personal experience and [discussions between] patients and doctors.

This was our first clinical trial with bispecific antibodies before teclistamab-cqyv (Tecvayli) was approved [by the FDA]. We’ve seen a lot of [patients with multiple] myeloma over the years and were impressed by the deep and lasting responses that talquetamab could achieve. The AEs are unique, including dysgeusia, as well as skin and nail changes. There is still more to come regarding how to manage AEs and maybe abrogate them. More research will focus on these specific and unique AEs. However, efficacy-wise, [this agent is] convincing and impressive. We’re excited to move forward with talquetamab and other bispecific antibodies, as well as with the whole novel immunotherapy branch that’s emerging.

Disclosures: Dr Schinke reports honoraria from, consulting or advisory roles with, and research funding from Janssen.

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
2. Schinke CD, Touzeau C, Minnema MC, et al. Pivotal phase 2 MonumenTAL-1 results of talquetamab (tal), a GPRC5DxCD3 bispecific antibody (BsAb), for relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2023;41(suppl 16):8036. doi:10.1200/JCO.2023.41.16_suppl.8036