Talquetamab Monotherapy Shows Early Promise in Relapsed/Refractory Multiple Myeloma

Two different doses of the bispecific antibody talquetamab have demonstrated encouraging response rates with acceptable safety when examined in patients with relapsed/refractory multiple myeloma, according to Monique Minnema, MD. However, more research is needed to optimize dosing of the agent and efforts are underway to evaluate novel combinations.

Updated data from the phase 1/2 MonumenTAL-1 trial (NCT03399799), which were presented during the 2022 ASCO Annual Meeting, showed that 405-μg/kg weekly and 800-μg/kg biweekly doses of subcutaneous talquetamab resulted in overall response rates (ORR) of 70.0% (n = 21/30) and 63.6% (n = 28/44), respectively, in this patient population.1 In these cohorts, the very good partial response (VGPR) or better rates achieved with the agent were 56.7% and 56.8%, respectively.

“Weare still trying to find the best way todose [the agent]. At the same time, we are [conducting] studies [that will] combine talquetamab with other established drugs,” Minemma, lead study author on the trial and a professor at the University Medical Center Utrecht, noted. “We are also looking forward to [doing] more translational research to [better understand] why patients become refractory to this drug, or why not all patients respond to this bispecific antibody. Perhaps with that research, we can find more logical combinations [to explore] in the future.”

In an interview with OncLive^®, Minnema, who is also a member of the HOVON working parties for Multiple Myeloma, Lymphoma, and IEC, and the vice president of the Lunenburg Lymphoma Consortium for phase I/II studies, expanded on the rationale of the MonumenTAL-1 trial examining talquetamab in multiple myeloma, the safety and efficacy reported thus far with the bispecific antibody, and next steps for further exploration.

OncLive^®: What is unique about the targeting mechanisms of talquetamab? What was the rationale for targeting GPRC5D in multiple myeloma?

Minnema: The rationale for starting this study was the specific antigen that was found on [malignant] plasma cells, such as [those in] multiple myeloma, called GPRC5D. The antigen is expressed in almost all plasma cells; it is always there, and it is not [frequently] present in other types of cells in the human body, which is why it is a perfect antigen to target with different types of immunotherapy.

For this study, we chose to have a bispecific antibody that targets both GPRC5D on the plasma cells, as well as CD3, which is on the T cells. Therefore, we have a very direct effect of T cells attacking the plasma cells, and [those are] most of the working mechanisms of this drug.

Could you discuss the design of the phase 1/2 MonumenTAL-1 trial? What were the key objectives of this research?

This was a phase 1 study, and in the beginning, we were just looking for the recommended phase 2 dose [RP2D], and we found 2. First, we started with the drug as an intravenous dosing, but then switched to subcutaneous dosing. We [used] step-up dosing before we [administered] the first full dose of the agent, [due to] signs of cytokine release syndrome [CRS], which [is seen with] most bispecific antibodies.

We identified 2 RP2Ds: 405 μg/kg weekly and 800 μg/kg biweekly. Those 2 cohorts were further explored, and the results were presented during the 2022 ASCO Annual Meeting.

What were the key findings shared during the meeting?

Safety and efficacy data were shared from the 2 cohorts of patients [who received the agent]. The [weekly] cohort had 30 patients in it, and the biweekly cohort had 44 patients in it.

[We found that] talquetamab is a very tolerable drug, and that it is also very effective. If we look at the response rate in the 405-μg/kg weekly cohort, we saw an ORR of 70.0% [with the agent]. In the second cohort, the ORR [with talquetamab] was 63.6%. Most of those responses were a VGPR or better, so these were very nice responses [reported in] heavily pretreated patients.

Of the patients who did respond [to treatment], the median duration of response was [10.2 months in the 405-μg/kg cohort] and 13.0 months [in the 800-μg/kg cohort]. That is very promising for most patients with relapsed/refractory multiple myeloma.

Could you expand on the safety data that were reported?

[One of the most common] adverse effects [AEs] that we have seen [with talquetamab] was CRS, and [those cases] were mostly confined to the step-up doses and the first full dose. In all cases but one, [these cases] were grade 1 or 2 [and patients] responded well to medication such as tocilizumab [Actemra], which we typically use for this type of AE.

Other AEs [reported with the agent] included skin-related events, which is typical [with] this [kind of] drug; [this included] dry skin and nail changes. A specific AE [observed with the agent was] dysgeusia, which is altered taste, and that is why patients sometimes lose weight [while on treatment]. Dysgeusia and skin-related AEs were mostly managed with dose delays or reductions, and patients responded well. In some patients, after several weeks or months, the AE passed. Although [dysgeusia] is a very particular AE, it is very manageable in most patients.

Other AEs [observed] included neutropenia, although [these cases] were also confined to the first cycle, and some infections. Infections of [any] grade were confined to [46.7% of patients in the 405-μg/kg cohort and 38.6% of patients in the 800-μg/kg cohort].

What are next steps for this research?

We are still not finished with [the phase 1/2] protocol. We are still trying to find the best way to dose this drug in the relapsed/refractory population. You can imagine that receiving a drug for almost a year and coming to the clinic every week can be a burden for patients.

We have a very effective drug in a monotherapy setting, a type of drug that may be used in many hospitals. [Talquetamab] is quite a safe drug, and most AEs are manageable, so I am looking forward to the future, [where we will learn more about the agent].

Reference

1. Minnema MC, Krishnan AY, Berdeja JG, et al. Efficacy and safety of talquetamab, a G protein-coupled receptor family C group 5 member D x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM): updated results from MonumenTAL-1. J Clin Oncol. 2022;40(suppl 16):8015. doi:10.1200/JCO.2022.40.16_suppl.8015