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ASH 2020 | Factors influencing response to talquetamab in myeloma

Niels van de Donk, MD, PhD, VU University Medical Center, Amsterdam, Netherlands, explains the findings of an investigation into the determinants of response to talquetamab, a novel GPRC5DxCD3 bispecific antibody, in multiple myeloma cells. Important response determinants were found, including GPRC5D expression, T-cell count, effector:target ratio, or frequency of immune-suppressing Tregs. The analysis revealed that both the microenvironment and tumor characteristics were influential to antibody response, meaning optimization of these factors could improve response rates. This interview took place during the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, 2020.

Transcript (edited for clarity)

This agent that you mentioned is now also called talquetamab. It’s a GPRC5D targeting bispecific antibody, so it brings T-cells to the myeloma cells.

At this ASH meeting, there was a preclinical presentation from our laboratory. The abstract was presented by Christie Verkleij. She showed in her presentation that talquetamab is very effective in killing myeloma cells from patients with a dose-dependent lysis of the tumor cells...

This agent that you mentioned is now also called talquetamab. It’s a GPRC5D targeting bispecific antibody, so it brings T-cells to the myeloma cells.

At this ASH meeting, there was a preclinical presentation from our laboratory. The abstract was presented by Christie Verkleij. She showed in her presentation that talquetamab is very effective in killing myeloma cells from patients with a dose-dependent lysis of the tumor cells. In this study, we were interested to identify determinants of response because when you know the determinants of response, you may be able to increase the efficacy by making rational combination strategies.

What we found was that patients whose tumor cells had higher GPRC5D expression had a better response ex-vivo in the lab to talquetamab. We also found that a higher effector-to-target ratio was predictive of response in our ex-vivo system. And we found as an important predictor of response that Tregs, regulatory T-cells, so immune suppressor cells, were able to impair talquetamab-induced myeloma cell lysis. So we found several predictors of response, which may allow us to make more rational combinations.

One of these rational combinations is the combination with daratumumab because daratumumab is able to eradicate CD38-positive Tregs, the most oppressive Treg subset. Indeed, in our lab, we find that daratumumab is able to boost the activity of talquetamab. We already published in Clinical Cancer Research a couple of months ago that daratumumab is also able to synergize with a BCMA, redirecting a BCMA-specific bispecific antibody. We tested teclistamab, also a Janssen compound.

Also because the effector-target ratio is predictive of response, it should be interesting to test whether prior induction therapy or reinduction therapy whereby the tumor load is reduced, T-cells increased, is able to further improve the clinical activity of talquetamab.

Interestingly, at this ASH meeting, there was also a clinical oral abstract on talquetamab, which was presented by Dr. Chari. He showed high efficacy of talquetamab in patients that were extensively pretreated, even those with triple class refractory disease, and talquetamab had, in this study, a manageable toxicity profile.

Most patients had some sort of CRS, cytokine release syndrome, in the first one or two infusions, but this was almost always grade one or grade two, and this cytokine release syndrome could be adequately managed by either steroids or tocilizumab. Grade three was only seen in one or two patients. Infections were also relatively low in terms of frequency, which is important in such a heavily pretreated population, and some patients experienced skin reactions.

But overall, I think talquetamab is a new bispecific antibody, which will be evaluated in earlier phases of multiple myeloma because of its high efficacy and favorable toxicity profile. So together with the BCMA, bispecifics GPRC5D targeting will be a new effective way of eradicating myeloma cells.

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