Clinical Summary: 

• Design/Population: The phase 3 MonumenTAL-3 trial randomized patients with relapsed or refractory multiple myeloma who had received at least one prior line of therapy, including lenalidomide and a proteasome inhibitor, to talquetamab plus daratumumab, talquetamab plus daratumumab and pomalidomide, or daratumumab, pomalidomide, and dexamethasone.
• Key Outcomes: Both talquetamab-containing regimens significantly improved progression-free survival, complete response rates, and MRD negativity compared with standard therapy. The combinations also demonstrated encouraging early overall survival trends and manageable safety profiles, with lower rates of severe infections observed with the talquetamab-daratumumab doublet than have been reported with BCMA-directed bispecific antibody combinations.
• Clinical Relevance: These findings support talquetamab-based combinations as effective GPRC5D-directed treatment strategies for patients with early relapsed multiple myeloma and provide an alternative to BCMA-targeted therapies for selected patients.

Peter Voorhees, MD, Atrium Health Levine Cancer Institute, Charlotte, North Carolina, discusses results from the phase 3 MonumenTAL-3 trial evaluating talquetamab-based combinations in patients with relapsed or relapsed or refractory multiple myeloma. The study compared talquetamab plus daratumumab, with or without pomalidomide, against daratumumab, pomalidomide, and dexamethasone.

The study demonstrated substantial improvements in progression-free survival and depth of response with both talquetamab-containing regimens while maintaining acceptable safety profiles. Dr Voorhees also discusses how the distinct toxicity profile of GPRC5D-directed therapy and lower rates of severe infections compared with BCMA-targeted bispecific antibodies may help individualize treatment selection for patients with relapsed multiple myeloma.

These results were presented at the European Hematological Association (EHA) Congress in Stockholm, Sweden. 

Transcript: 

Hello, my name is Peter Voorhees from Atrium Health Levine Cancer Institute in Charlotte, North Carolina. I'm happy to walk you through the high-level results from the phase 3 MonumenTAL-3 study that was recently reported at the European Hematology Association meeting in early June and has since been published in the New England Journal of Medicine.

MonumenTAL-3 was a randomized phase 3 study conducted in patients with relapsed or refractory multiple myeloma who had received at least one prior line of therapy. Patients had to have received both lenalidomide and a proteasome inhibitor with previous treatment. They were randomized to one of three different arms. There were two experimental arms, both of which included the GPRC5D bispecific antibody talquetamab. One arm was talquetamab in combination with the CD38 antibody daratumumab. The other experimental arm was talquetamab in combination with both daratumumab and the immunomodulatory drug pomalidomide. The control arm was daratumumab, pomalidomide, and dexamethasone. 

The primary end point of the study was progression-free survival, with other key secondary end points including overall response rate, depth of response including MRD status, overall survival, and safety.

With regard to the primary end point, the combination of talquetamab and daratumumab reduced the risk of disease progression or death by 67%, whereas the combination of talquetamab, daratumumab, and pomalidomide reduced the risk of disease progression or death by 72% compared with the daratumumab, pomalidomide, and dexamethasone control arm. Both of these results were highly statistically significant.

When you look at 2-year progression-free survival, it was 81% in the talquetamab, daratumumab, and pomalidomide arm, 78% in the talquetamab and daratumumab arm, and 51% in the control arm. When we looked at progression-free survival across clinically relevant subgroups, we found that both talquetamab-containing arms improved progression-free survival irrespective of patient age, prior exposure to daratumumab, the presence of ISS stage III disease at study entry, and the presence of high-risk cytogenetics. Notably, for patients who had received only one prior line of therapy, the progression-free survival hazard ratio in favor of the talquetamab triplet was 0.19, and it was 0.23 for those receiving the talquetamab and daratumumab doublet.

When we looked at complete response rates, we saw complete responses in approximately 70% of patients in the two talquetamab-containing arms of the study, whereas complete responses were seen in only about half that rate, 35%, in the control arm. Not surprisingly, the rates of MRD negativity at the 10^-6 level of sensitivity ranged from 42% to 48% in the talquetamab arms and were only 10% in the control arm.

The initial overall survival analysis also looked quite favorable. The talquetamab, daratumumab, and pomalidomide triplet reduced the risk of death from any cause by 53%, whereas the talquetamab and daratumumab doublet reduced that risk by 49%. We would argue that these are clinically significant findings, but the P values have not yet crossed the prespecified boundary for superiority, so we'll need longer follow-up to declare statistical significance.

With regard to safety, there was a higher rate of grade 3 and 4 treatment-emergent adverse events in the two triplet arms of the study, and fewer in the talquetamab and daratumumab doublet. Importantly, treatment-emergent adverse events leading to treatment discontinuation were similar across the arms and ranged from 6.7% to 10.5%. Treatment-emergent adverse events leading to death were also very similar across all three arms of the study and were less than 5% in all instances. 

There were more high-grade infections in the two triplet arms, both the control arm and the talquetamab, daratumumab, and pomalidomide arm. The rate of grade 3 and 4 infections was lower with the talquetamab and daratumumab doublet at 29%.Contrast that with the rates of grade 3 and 4 infections seen with the BCMA bispecific antibody teclistamab plus daratumumab, where those rates were upwards of 54%.

The hypogammaglobulinemia that we see with talquetamab is not as severe as what we typically see with BCMA bispecific antibodies. Interestingly, GPRC5D is expressed on select epithelial structures of the skin and tongue. It is also expressed in the inferior olivary nucleus of the cerebellum, which gives rise to this distinct on-target, off-tumor side-effect profile. Taste changes, such as dysgeusia, were quite common in this study. Skin-related side effects were also common but were largely grade 1 and 2 in severity. Nail changes were also common and similarly were largely grade 1 and 2 in severity.

We did see weight loss in this study, but again, this was largely grade 1 and 2 in severity, with very few instances of grade 3 weight loss. We also saw ataxia and balance disorders occurring in 12.4% to 14.5% of patients in the talquetamab arms of the study, with grade 3 events occurring in 2.2% to 2.9% of patients.  When you look at all of these unique side effects, they led to treatment discontinuation in less than 5% of patients across the board. When we looked more carefully at the weight loss, interestingly, most of the weight loss occurred within the first six months of treatment and was more notable in patients who were either overweight or obese by BMI criteria. Patients who entered the study at a healthy weight or who were underweight were less likely to lose weight. The trajectory of this weight loss corresponds very well with the taste changes we see with this agent because those also improve over the course of the first six months of therapy.

I think these data strongly support the use of talquetamab-based combination therapies in early relapsed myeloma and represent yet another T-cell–redirecting strategy for patients relapsing for the first time or beyond. As I think about where to position these combinations in the treatment continuum, the way I look at it is that the combination of talquetamab and daratumumab, for example, would be a nice option for a patient whose disease course has been characterized by recurrent high-grade infections that would make a BCMA-targeted therapy less desirable.

I also think that if you have a patient with severe pulmonary disease who would not tolerate a respiratory tract infection well, a talquetamab-based strategy would make a lot of sense. If a patient lives in a part of the world where there is no access to IVIG, or if insurance declines coverage for IVIG, then a talquetamab combination also makes sense. Another good setting for these combinations would be a patient relapsing after a BCMA-targeted CAR T-cell therapy such as ciltacabtagene autoleucel.

Source: 

Voorhees P, Mina R, Rodriguez-Otero P, et al. Phase 3, randomized study of talquetamab (TAL) plus daratumumab (DARA) ± pomalidomide (POM) vs DARA plus PM and dexamethasone (DPD) in relapsed/refractory multiple myeloma (RRMM): MONUMENTAL-3. Presented at EHA Congress. June 11 - June 14, 2026. Stockholm, Sweden. Abstract EHA-2503.