Doctors treating relapsed refractory multiple myeloma have a new reason to rethink their approach. The phase 3 MonumenTAL-3 trial found that adding talquetamab to daratumumab and pomalidomide cut the risk of progression or death by 72% compared to standard regimens. Ajai Chari, MD, called these results “unprecedented.” The findings are pushing the field to look beyond BCMA-targeted therapies and consider new ways to sequence treatments.
For a long time, most myeloma treatments have focused on BCMA, using CAR T-cell therapies and bispecific antibodies. But Rahul Banerjee, MD, FACP, summed up the problem: “We’re guilty of putting all our eggs in one basket: the BCMA basket.” Infection risks and other limits with BCMA have become hard to ignore, so researchers have been searching for new targets. GPRC5D is now in the spotlight. The MonumenTAL-1 trial helped validate this target, leading to talquetamab’s accelerated FDA approval in August 2023 for patients who had already tried at least four other therapies, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody.
In August 2023, the European Commission also granted conditional marketing authorization for talquetamab monotherapy in relapsed/refractory multiple myeloma after at least three prior therapies with progression on the last regimen.
MonumenTAL-3 trial sets a new bar for efficacy
In MonumenTAL-3, patients with at least one prior therapy were randomized to get talquetamab plus daratumumab and pomalidomide (Tal-DP), talquetamab plus daratumumab (Tal-D), or daratumumab plus pomalidomide and dexamethasone (DPd). The standout result: Tal-DP dropped the risk of progression or death by 72% versus DPd (HR 0.28; 95% CI, 0.20-0.40; P <.0001). Tal-D also showed a 67% reduction (HR 0.33; 95% CI, 0.24-0.46; P <.0001). Response rates jumped to 88.2% and 88.5% in the talquetamab arms, compared to 77.6% for DPd. More patients reached complete response and MRD negativity with talquetamab-based regimens. Updated data showed 24-month progression-free survival rates of 81.3% for Tal-DP, 77.6% for Tal-D, and 51.2% for DPd. Complete response or better was seen in 71.1%, 69.0%, and 34.5% of patients, respectively.
Interim overall survival analysis brought more surprises. Hazard ratios were 0.47 for Tal-DP and 0.51 for Tal-D compared to DPd. Chari pointed out these numbers are “actually comparable to historic PFS HRs.” Banerjee agreed, saying, “the bar is being shifted with these drugs.” Both talquetamab-based combinations improved not just progression-free survival but also overall survival, as shown at the EHA 2026 Congress.
Safety data showed high rates of blood-related side effects like neutropenia (up to 84.1% in Tal-DP), but grade 3/4 infection rates were actually lower in the experimental arms than in the control (37.7% for Tal-DP, 29.2% for Tal-D, 42.4% for DPd). Other side effects included infections, taste changes, skin problems, cytokine release syndrome (CRS), and nail issues. CRS, once a big worry, is now easier to manage with preventive tocilizumab. In MonumenTAL-3, the most common blood-related toxicities were neutropenia (84.1% for Tal-DP, 40.9% for Tal-D), anemia (49.3% and 39.1%), and thrombocytopenia (49.3% and 33.9%).
Changing strategies for sequencing and combinations
The MonumenTAL-3 results are already changing how doctors think about sequencing and combination therapy. Banerjee said CAR T-cell therapy “holds a unique niche” at first relapse, with about a 33% cure rate, but works best as consolidation, not salvage. If a patient can get CAR T, bispecifics should wait to avoid T-cell exhaustion and apheresis problems. For those who can’t or won’t get CAR T, bispecifics—chosen based on side effect profiles and patient health—are the next step.
Real-world data presented at the 2026 SOHO annual congress showed a median progression-free survival of 18.2 months for patients not meeting MonumenTAL-1 eligibility criteria, compared to 9.1 months for those who did, in a retrospective cohort of 95 patients treated with talquetamab at Moffitt Cancer Center from May 2023 to November 2025.
Talquetamab’s non-BCMA targeting gives doctors another tool, especially for patients with frequent infections or lung disease. Banerjee also pointed out the benefit of scaling back dosing for patients in remission: “the dose you need to get someone into remission is very different from the dose intensity you need to keep them in remission.”
Combination strategies are moving fast. Banerjee joked, “These bispecific antibodies need friends, and we found some friends; daratumumab and pomalidomide are probably friends.” Trials are now testing talquetamab with teclistamab-cqyv and other agents. Trispecific antibodies and in vivo CAR constructs are also in development. The field is wrestling with how to bring these therapies to more patients outside major centers. Chari put it plainly: “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.”
Meanwhile, the rapid pace of bispecific antibody and CAR T-cell trials is already changing who can get these treatments, as reported earlier in other blood cancers.
Author’s analysis: myeloma therapy enters a new phase
The MonumenTAL-3 trial has set a new standard for treating relapsed refractory multiple myeloma. Talquetamab-based regimens deliver deep responses and a safety profile that challenges old ideas about infection risk. The data support using talquetamab earlier in treatment, especially for patients at risk for infections or with lung problems. The era of defaulting to triplet regimens is fading. T-cell–redirecting therapies—whether BCMA- or GPRC5D-directed—now have strong evidence for use at first relapse. The next hurdle is making sure these advances reach patients outside academic centers. With new combinations and sequencing strategies in play, and more options on the way, multiple myeloma care is entering a period of real therapeutic variety and patient-focused decisions.
