Talquetamab/Daratumumab Shows Promise in Heavily Pretreated Myeloma, Warranting Further Investigation

Ajai Chari, MD

The combination of talquetamab and daratumumab (Darzalex) appears to be an effective, tolerable, immunotherapy-based approach for heavily pretreated patients with relapsed/refractory multiple myeloma, according to Ajai Chari, MD, who added that the next step for this combination is to evaluate its activity earlier on in the treatment journey.

Initial data from the talquetamab/daratumumab cohort of the phase 1b TRIMM-2 study (NCT04108195), which were presented during the 2021 ASH Annual Meeting and Exposition,showed that at a median follow-up of 4.2 months, the regimen elicited an overall response rate (ORR) of 80.0% when talquetamab was given at a dose of 400 μg/kg every 2 weeks (n = 5).1 When talquetamab was given at a once-weekly dose of 400 μg/kg (n = 7), the ORR was even higher, at 85.7%. When the agent was given at a dose of 800 μg/kg (n = 9), the ORR was 77.8%.

The median time to first response was 1.0 month (range, 0.9-2.4) and the median duration of response had not yet been reached. The safety profile of the combination was comparable to what has been reported with the agents when they are given as monotherapies.

“If these results are so promising and well tolerated, then the natural question is, what about less heavily pretreated patients? Could we achieve a higher percentage of cures [by leveraging this approach]?” Chari questioned. “That is [what we are excited about] for the future: taking these novel agents that are so potent and well tolerated, moving them up earlier, and trying to eradicate this disease.”

In an interview with OncLive^®, Chari, professor of medicine, director of clinical research in the multiple myeloma program, and hematologic oncologist at Mount Sinai Hospital, discussed the safety and efficacy of talquetamab plus daratumumab in heavily pretreated patients with multiple myeloma, initial data from TRIMM-2, and the potential to move the combination into earlier lines of therapy.

OncLive^®: What was the rationale for subcutaneous talquetamab plus daratumumab in patients with relapsed/refractory multiple myeloma?

Chari: Historically, in multiple myeloma, to get a new drug [granted an accelerated approval] for what is considered an unmet need, you needed a response rate [ranging from] 20% to 30%, and a progression-free survival [PFS] ranging from 3 to 4 months. Now, we have a game-changing class of therapies [that are] T-cell redirecting, such as CAR T-cell [therapies] and bispecific [antibodies]. These agents have shown outstanding results, blowing those previous numbers out of the water. Instead of [response rates ranging from] 20% to 30%, we are seeing [rates of] 70% to 100%. We [currently] do not know the [average] PFS [for these agents, but] it seems to be at least 9 months with monotherapy.

The question then becomes, when you have a complex disease, like multiple myeloma, both genomically and immunologically, how does combination therapy fare? This study is 1 of our first examples of combination bispecific therapy with another agent. [Specifically], we were looking at subcutaneous talquetamab with daratumumab in [patients with] relapsed/refractory multiple myeloma.

What was the study design and the methods used for this research?

Both [talquetamab and daratumumab] have been shown to be efficacious in myeloma. When you combine them preclinically, daratumumab leads to clonal T-cell expansion, [so adding] a bispecific [antibody to the mix] makes natural sense.

A standard patient population [was enrolled to the trial]. Patients had received at least 3 or more lines of prior therapy or [were] double refractory to a proteasome inhibitor and an immunomodulatory drug [IMiD]. Prior [treatment with a] CD38 monoclonal antibody was allowed, except there was a 90-day washout.

The primary objective [of part 1] was to find a recommended phase 2 dose of [the combination]; in part 2, [it was to] characterize the safety [of this approach]. We were also looking at the antitumor activity, as well as the pharmacokinetics [PK] and pharmacodynamics [PD].

What were the key results presented during the 2021 ASH Annual Meeting?

The first and most salient feature of this particular study is the patient population. This is a preliminary update from this study, with about 30 patients [included]. What is most striking is that [it was about] 6.6 years since diagnosis [and patients had received a median of] 6 lines of therapy, so [they were] heavily pretreated, perhaps 1 of the most heavily pretreated in terms of prior BCMA exposure. Half the patients had prior BCMA therapy.

The current unmet need is not only [those who are] triple-class refractory, but [those with] prior BCMA exposure. [Of the patients enrolled to the trial], 82.6% were triple-class refractory, 73.9% were penta-drug [exposed], and 66% had been exposed to daratumumab or an anti-CD38 [agent]. In that population, adverse effects [AEs] were what you would expect from each drug—nothing unusual. [The] majority were grade 1 and 2 and no overlapping toxicities [were observed], which was nice to see in a phase 1 combination study.

Interestingly, cytopenias primarily [occurred] early on in cycle 1 and 2, perhaps due to the marrow clearing out from the disease. The highest grade 3 or 4 cytopenia was neutropenia, [which was observed] in one-third of patients, but all of that primarily [occurred] early on. [Also, there were] relatively low rates of infection; only 3 patients had grade 3 or higher infection, which was nice to see. We do see the AEs from talquetamab, which include dysgeusia, skin rashes, and nail changes, but these were almost all grade 1 and 2 [in severity]. The cytokine release was also not higher than what we would expect; all those effects were grade 1 and 2, [with] no grade 3 or 4 [effects reported].

Perhaps most striking, is that with a relatively short median follow-up of only 4.2 months, the response rate across all 3 cohorts was 80%. For such a heavily treated patient population, this is outstanding, and bodes well for the future role of combination therapy with these bispecific agents.

There were 3 different cohorts that were included [in the trial]. In 1 [cohort], talquetamab was given every 2 weeks at 400 mg; in the second [cohort,] it was given weekly at 400 mg, and in the third [cohort,] it was given at 800 mg every 2 weeks. All [the cohorts] experienced encouraging responses. The response rate was not only high, but also deep and durable. We can see in the swimmer plots on this study that all the responses were ongoing at the time of data cutoff, which bodes well not only for depth, but durability of response.

What was observed regarding PK and PD?

The PK and PD data support [the use of] this combination. There could be theoretical concern because CD30 is not only expressed on myeloma cells, but also T cells. By giving daratumumab, [it is possible to] blunt T-cell activation. However, that is not what we saw preclinically, and fortunately, it is not what we saw clinically either, as evidenced by the responses.

Also, when you look at CD38- and CD8-positive T cells, the day after daratumumab goes down, but after the bispecific, you see the usual uptick, demonstrating that the daratumumab is not affecting the ability of these drugs to work. We saw the usual cytokine activation. As such, the translational data are supporting the clinical data for the role of this combination [in these patients].

What next steps are planned for this trial?

In addition to expanding these data with longer follow-up and more patients, other cohorts are being studied. For example, a 4-drug combination of talquetamab with dexamethasone, pomalidomide [Pomalyst], and daratumumab, [is under investigation]. That is important because we know that IMiDs like pomalidomide might activate T cells, so it is natural to question how these [agents] might work in the context of bispecific agents. It will be nice to have those data.

The other interesting question with combination therapy is not only [how effective it is] in patients [with advanced disease], but how [it might] fare in earlier lines. Those studies are also in the process of being launched; combinations [will be explored] in [patients who received] 1 to 3 prior lines of therapy.

What is your take-home message to your colleagues about this research?

The take-home message for this study is that this combination of talquetamab and daratumumab is tolerable with no overlapping toxicity. Preliminary efficacy data are outstanding, [with responses observed in] over [75%] of these heavily treated patients. Preclinical data and [findings] regarding PK and PD all support this combination. These data [also] support talquetamab plus daratumumab as a novel immunotherapy-based approach for the treatment of patients with relapsed/refractory myeloma.

Reference

1. Chari A, Hari P, Bahlis NJ, et al. Phase 1b results for subcutaneous talquetamab plus daratumumab in patients with relapsed/refractory multiple myeloma. Blood. 2021;138(suppl 1):161. doi:10.1182/blood-2021-148813