Considering Talquetamab and Emerging Bispecifics in R/R Multiple Myeloma

In a recent Between the Lines program, Ajai Chari, MD, and Rahul Banerjee, MD, FACP, spoke about emerging clinical trial data for talquetamab-tgvs (Talvey) and other bispecific antibodies for patients with relapsed/refractory multiple myeloma. Their conversation covered the clinical implications of efficacy and safety data from the phase 3 MonumenTAL-3 trial (NCT05455320), real-world considerations for sequencing different cellular therapy regimens, and other ongoing areas of clinical interest in the broader multiple myeloma paradigm.

Chari is a professor of clinical medicine and director of the Multiple Myeloma Program at the University of California San Francisco. Banerjee is an associate professor in the Clinical Research Division at Fred Hutch Cancer Center and a member of the ASTCT Content Committee.

How has the earlier-line relapsed/refractory multiple myeloma paradigm evolved?

Chari and Banerjee contextualized the discussion by outlining the current standard approaches and emerging areas of interest regarding the early-line management of relapsed/refractory multiple myeloma. With the expanded employment of BCMA-directed treatments, including CAR T-cell therapies and bispecific antibodies, the field has seen an increased focus on producing deep, durable responses in the early-line and relapsed/refractory settings. Ongoing efforts include exploring sequencing strategies after the use of BCMA-directed agents as well optimizing long-term disease control and treatment tolerability.

“As a field, we’re guilty of putting all our eggs in one basket: the BCMA basket. It’s appealing, but BCMA wipes out the good, the bad, and the ugly cells, and the infection risk is high…We need better options,” Banerjee said.

Beyond BCMA, GPRC5D has also emerged as a therapeutic target in multiple myeloma, serving as the foundation for alternative immunotherapeutic strategies. Of note, the phase 1/2 MonumenTAL-1 trial (NCT03399799/NCT04634552) established GPRC5D as a viable therapeutic target in multiple myeloma while supporting the FDA accelerated approval of talquetamab for heavily pretreated patients with relapsed/refractory disease in August 2023.¹

“Whether you’ve had prior BCMA or not doesn’t seem to impact outcomes with GPRC5D targeting, at least in my experience, which is nice. We need 2 targets that are completely separate,” Banerjee added. “You’re getting the benefit of these 2 separate targets [so] that it’s just much harder for the myeloma to wiggle its way out.”

Following an accelerated approval for talquetamab in a heavily pretreated patient population, investigators aimed to provide phase 3 evidence assessing a GPRC5D-directed therapy in earlier-line relapsed/refractory disease as part of the MonumenTAL-3 study. The investigation helped contribute to ongoing discussions on target selection, sequencing, and treatment optimization while further informing the future integration of non–BCMA-targeting therapies into clinical practice.

What did MonumenTAL-3 show in relapsed/refractory multiple myeloma?

Investigators of the randomized phase 3 MonumenTAL-3 trial assessed the efficacy and safety of talquetamab-based regimens for patients with relapsed/refractory multiple myeloma across multiple centers.² The study fit alongside other efforts in the field to further address unmet needs following prior treatments, including BCMA-targeting therapy, and inform strategies for sequencing and long-term disease management.

Patients with at least 1 prior line of therapy for relapsed/refractory multiple myeloma, including required exposure to lenalidomide (Revlimid) and a proteasome inhibitor, were randomly assigned 1:1:1 to receive talquetamab plus daratumumab (Darzalex) and pomalidomide (Pomalyst; Tal-DP), talquetamab plus daratumumab (Tal-D), or daratumumab plus pomalidomide and dexamethasone (DPd). Investigators administered talquetamab via step-up dosing, with flexible dosing approaches still under evaluation to bolster long-term therapy.

Regarding the primary end point of progression-free survival (PFS), efficacy data revealed that Tal-DP reduced the risk of progression or death by 72% vs DPd (HR, 0.28; 95% CI, 0.20-0.40; P <.0001). Additionally, the Tal-D doublet showed a reduction of 67% compared with DPd for this end point (HR, 0.33; 95% CI, 0.24-0.46; P <.0001). The PFS benefit with talquetamab-based treatment was consistent across clinically relevant patient subgroups.

In the Tal-DP, Tal-D, and DPd arms, the overall response rate (ORR) was 88.2%, 88.5%, and 77.6%, respectively. Additionally, the talquetamab-based arms showed higher rates of complete response (CR) or better (71.1%, 69.0%, 34.5%), minimal residual disease (MRD)–negative CRs or better (52.3%, 46.3%, 15.9%), and 24-month PFS rates (81.3%, 77.6%, 51.2%). In an interim analysis of overall survival (OS), outcomes improved with Tal-DP (HR, 0.47) and Tal-D (HR, 0.51) compared with DPd.

“I think these HRs are unprecedented; these OS HRs are actually comparable to historic PFS HRs,” Chari said. Banerjee agreed, stating that “the bar is being shifted with these drugs.”

In the Tal-DP and Tal-D arms, respectively, the most common hematologic toxicities of any grade included neutropenia (84.1% vs 40.9%), anemia (49.3% vs 39.1%), and thrombocytopenia (49.3% vs 33.9%). Non-hematologic adverse effects (AEs) included infections (87.3% vs 84.3%), taste changes (72.8% vs 74.8%), non-rash skin toxicity (69.2% vs 64.6%), cytokine release syndrome (CRS; 67.8% vs 58.4%), and nail-related toxicity (56.2% vs 57.3%). CRS, as Chari and Banerjee highlighted, has become increasingly manageable with the use of prophylactic tocilizumab (Actemra).

Of note, the rates of grade 3/4 higher infections were lower with Tal-DP (37.7%) and Tal-D (29.2%) compared with DPd (42.4%).

“I’ve never before seen any multiple myeloma [trial] where the experimental arm had a lower rate of infection [vs] control, particularly when you consider the fact that the PFS HRs are about 0.30,” Chari said. “There’s a 70% longer time on therapy and yet a lower rate of infection, which is probably unprecedented.”

The experts also highlighted the potential to scale back dosing for patients who achieve remissions, with responders able to switch to monthly dosing by cycles 5 to 7. As Banerjee described, “the dose you need to get someone into remission is very different from the dose intensity you need to keep them in remission.”

What does MonumenTAL-3 mean for other combinations and sequencing treatment in relapsed/refractory multiple myeloma?

The MonumenTAL-3 data introduce questions surrounding other evolving combination approaches as well as sequencing different modalities across treatment settings. Emerging areas of investigation, according to Banerjee and Chari, include talquetamab in combination with BCMA-directed agents, dual-antigen targeting strategies, and earlier-line intervention.

Banerjee noted that CAR T-cell therapy “holds a unique niche” at first relapse with an approximately 33% cure fraction based on findings from the phase 1b/2 CARTITUDE-1 trial (NCT03548207).³ The modality should serve as consolidation rather than salvage therapy, as the goal involve controlling the disease first; if bridging therapy is not producing a response, clinicians should consider aborting and switching to another strategy.

If a patient is eligible for CAR T cells, the experts said they should avoid receiving bispecific antibodies first due to factors like T-cell exhaustion and other apheresis considerations. If they are ineligible or decline CAR T-cell therapy, bispecifics may then serve as more immediate alternatives, with specific selections dependent upon AE profiles and individual patient values. Someone with recurrent infections or significant respiratory comorbidities, for example, may benefit from talquetamab-based regimens, whereas BCMA-directed agents may be favorable for those who are unwilling to accept dysgeusia or weight loss.

Regarding future directions in the multiple myeloma field, Banerjee pointed to the value of novel combination strategies.

“These bispecific antibodies need friends, and we found some friends; daratumumab and pomalidomide are probably friends,” Banerjee stated. “Are there newer friends we can combine them with?”

One answer may reside in talquetamab in combination with teclistamab-cqyv (Tecvayli), which demonstrated “compelling” activity among patients with relapsed/refractory multiple myeloma and extramedullary disease (EMD) in the phase 1b/2 RedirecTT-1 trial (NCT04586426).⁴ Confirmation of the benefits with talquetamab/teclistamab in a randomized setting is underway in the phase 3 MonumenTAL-6 trial (NCT062081500), which is evaluating the combination, along with talquetamab plus pomalidomide, vs standard of care with elotuzumab (Empliciti) plus pomalidomide and dexamethasone (EPd) or pomalidomide plus bortezomib (Velcade) and dexamethasone (PVd) among those with relapsed/refractory disease.

Other long-term directions for the field include evaluating trispecific antibodies that target BCMA and GPRC5D simultaneously, CELMoDs like mezigdomide, and in vivo CAR constructs that function like a hybrid between CAR T cells and bispecifics. Additionally, expanding access to novel cellular therapies across community centers remains an ongoing initiative.

“Right now, US data suggest that 70% of patients who get bispecifics are also at centers that give [CAR T-cell therapies], and the true value of these products is not with you and me; it’s with the community where the majority of [patients with multiple] myeloma are being treated,” Chari said. “If 80% of patients in the US are being treated in the community, these drugs need to penetrate that. We need to make the accessibility of these products better.”

What are the key takeaways for the future of multiple myeloma management?

Considering the findings from the MonumenTAL-3 trial, Banerjee said that the data are “extraordinary” and that he hopes for an expanded FDA approval for talquetamab plus daratumumab, with or without pomalidomide, in earlier treatment settings. Moreover, his big takeaway from the conversation was that CAR T cells and bispecific antibodies should serve as default discussion points in a patient’s treatment plan.

“Instead of framing the discussion around [giving] triplets first and asking questions later, it should be T-cell–redirecting [therapy] first, whether it be BCMA or non-GPRC5D, ask questions later,” Banerjee said.

Chari agreed with this conclusion, noting that BCMA- and GRPC5D-directed agents in first relapse are evidence-based therapies that demonstrate PFS and OS benefits alike.

“I particularly would use a [talquetamab]-based regimen in somebody with a history of recurrent infections, or perhaps somebody with a lot of respiratory disease, like COPD or asthma history,” Chari stated. “But it’s great to have options; I think that’s the take-home message.”

References

1. U.S. FDA approved TALVEY (talquetamab-tgvs), a first-in-class bispecific therapy for the treatment of patients with heavily pretreated multiple myeloma. News release. The Janssen Pharmaceuticals. August 10, 2023. Accessed October 5, 2026. https://prn.to/3KwnjyD
2. Mina R, Beksac M, Rodríguez-Otero P, et al. Talquetamab–daratumumab in relapsed or refractory myeloma. N Engl J Med. 2026;395(7):671-683. doi:10.1056/NEJMoa2604657
3. Lin Y, Martin TG, Usmani SZ, et al. CARTITUDE-1 final results: Phase 1b/2 study of ciltacabtagene autoleucel in heavily pretreated patients with relapsed/refractory multiple myeloma. J Clin Oncol. 2023;41(suppl 16):8009. doi:10.1200/JCO.2023.41.16_suppl.8009
4. Nooka AK, Mian H, Lee C, et al. Monumental-6: a phase 3 study of talquetamab + pomalidomide or talquetamab + teclistamab vs elotuzumab + pomalidomide + dexamethasone (EPd) or pomalidomide + bortezomib + dexamethasone (PVd) in patients with relapsed/refractory multiple myeloma who received 1-4 prior lines of therapy, including lenalidomide and an anti-CD38 monoclonal antibody. Blood. 2024;144(suppl 1):47571. doi:10.1182/blood-2024-199752