STOCKHOLM — Patients with relapsed or refractory multiple myeloma (RRMM) benefit from teclistamab plus daratumumab (Tec-Dara), irrespective of cytogenetic and functional risk status, according to research presented at the European Hematology Association (EHA) 2026 Congress.

“With any therapy in RRMM, there are winners and losers,” said Rahul Banerjee, MD, assistant professor of hematology and oncology at the Fred Hutchinson Cancer Center and the University of Washington in Seattle, who presented a post hoc analysis of MajesTEC-3 results in high-risk subgroups. He noted the importance of focusing on patients who don’t maintain the same margin of benefit as other patients. This group of hard-to-treat patients includes those with high cytogenetic and functional risk, who need more effective therapies.

Solid Premises, New In-Depth Analyses

The MajesTEC-3 trial established Tec-Dara as a standard of care for patients with MM and one to three prior lines of therapy. In that study, the treatment was associated with improved progression-free survival (PFS, the primary endpoint), complete response (CR), minimal residual disease negativity (MRD neg), and overall survival (OS), compared with daratumumab plus dexamethasone plus pomalidomide or bortezomib (DPd/DVd). Tec-Dara is now approved in the US for the treatment of patients with RRMM with one or more prior lines of treatment, including proteasome inhibitors and immunomodulatory drugs.

The subgroup analysis included a prespecified and an extended definition of high cytogenetic risk. In the prespecified definition of high cytogenetic risk, t(4;14), t(14;16), or del(17p) were considered, while the revised (extended) definition also included gain(1q21) or amp(1q21). Standard and high risk were defined as 0 or ≥ 1 high-risk cytogenetic abnormalities (HRCAs), respectively, per prespecified definition and 0 or ≥ 1 HRCAs per revised definition. The presence of ≥ 2 HRCAs per revised definition was considered ultrahigh risk.

Patients included in the functional high-risk (FHR) group had one prior line of therapy with progressive disease £ 18 months after autologous stem-cell transplant or the start of initial therapy. The investigators examined PFS and MRD neg in patients with available next-generation sequencing data. A high proportion of the 587 patients (Tec-Dara, n = 291; DPd/DVd, n = 296) were classified as having high cytogenetic risk based on the extended criteria (58.1% and 60.8% in Tec-Dara and DPd/DVd groups, respectively), and 24.1% of the patients with only one prior line of therapy in the Tec-Dara group were classified as having FHR compared with 17.5% in the DPd/DVd group.

Risk Doesn’t Matter

Tec-Dara was associated with consistent improvements in PFS compared with DPd/DVd, regardless of disease biology. The estimated 36-month PFS rates by prespecified cytogenetic risk were, respectively, 37.1% and 11.5% in patients at standard and high risk treated with standard therapies. Corresponding rates in the Tec-Dara group were 87.4% and 77.7%, mirroring the overall study effect and suggesting that the combination performs similarly in high-risk and standard-risk disease.

Moreover, Tec-Dara was associated with substantial increases in rates of MRD-neg CR or better in all subgroups, with MRD-neg CR or better (10^-6) rates up to 10-fold higher than those of DPd/DVd. Rates for the prespecified risk definition (10^-6) were 58.9% vs 14.7% (P < .0001 for both) for standard risk and 54.7% vs 5.4% (P < .0001 for both) for high risk. Using the revised risk definition, rates were 67.4% vs 6.3% (P < .0001 for both) for the standard risk and 53.4% vs 11.3% (P < .0001 for both) for the high risk, 48.3% vs 14.3% (P < .0001 for both) for 1 HRCA and 61.4% vs 6.5% (P < .0001 for both) for ≥ 2 HRCAs.

Regarding functional risk, in patients with only one prior line of therapy, Tec-Dara was associated with better PFS compared with DPd/DVd in patients with FHR (estimated 36-month PFS rate, 77.3% vs 0%) and without FHR (89.9% vs 35.9%). MRD-neg CR rates also favored Tec-Dara in patients with and without FHR (MRD-neg CR 10^-6, 38.1% vs 0% and 58.8% vs 19.3%, respectively).

The trajectory of PFS with Tec-Dara in high-risk disease through 36 months suggests that the combination mitigates the adverse prognostic impact historically seen with this type of disease, said Banerjee. “Tec-Dara should be considered a new standard of care from second line across all risk groups and practice settings,” he concluded.

In an interview with Medscape News Europe, Session Chair Maria Gavriatopoulou, MD, PhD, associate professor of therapeutics and oncology at the National and Kapodistrian University of Athens, Athens, Greece, highlighted the importance of the study. “We know that patients with high cytogenetic risk are the ones with worse prognosis. If a specific treatment can overcome this adverse prognosis, this means that our patients are going to have extended PFS and possibly an extended OS, meaning patients will live longer, which is our main goal,” she said. She also stressed that these results should not lead clinicians to skip genetic and functional risk assessment. “When you decide which treatment is most appropriate for each patient, you need to personalize your choice for each line of treatment. Findings from these tests are necessary to inform the therapeutic decision,” she said.

The study was sponsored by Johnson & Johnson. Banerjee reported consulting for AbbVie, Adaptive Biotech, Arcellx, BMS, Caribou Biosciences, Genentech, Gilead, GSK, Janssen, Karyopharm, Legend Biotech, Pfizer, Sanofi, and SparkCures as well as receiving research support from AbbVie, BMS, Gilead, Janssen, Karyopharm, Novartis, Pack Health, Prothena, and Sanofi. Gavriatopoulou reported having no relevant financial relationships. 

Cristina Ferrario is a molecular biologist and former researcher in molecular oncology at three institutes in Milan. She has a master’s degree in communication and health from the University of Milan and a master’s degree in cancer genetics from the University of Pavia. She has worked as a science journalist for more than 20 years.