Big survival gains in relapsed/refractory multiple myeloma seen with immunotherapy combo

For patients with multiple myeloma who have received up to three lines of therapy, combination treatment with the bispecific antibody teclistamab plus the monoclonal antibody daratumumab yields significant improvements in progression-free survival (PFS) and overall survival (OS), according to the phase III MajesTEC-3 trial.

Compared with investigator’s choice of triplet therapy (daratumumab plus dexamethasone plus pomalidomide [DPd] or bortezomib [DVd]), the immunotherapy combination reduced the risk of disease progression or death by 83 percent (median PFS, not reached vs 18.1 months; hazard ratio [HR], 0.17, 95 percent confidence interval [CI], 0.12–0.23; p<0.001) during a median follow-up of 34.5 months. [N Engl J Med 2025;doi:10.1056/NEJMoa2514663]

A total of 83.4 percent (95 percent CI, 78.2–87.4) of patients in the teclistamab–daratumumab arm remained free of progression at 3 years—the highest rate seen to date in any relapsed myeloma study—as opposed to only 29.7 percent (95 percent CI, 23.6–36.0) in the DPd/DVd arm, reported senior investigator Dr María-Victoria Mateos from the University of Salamanca in Salamanca, Spain.

OS results were also superior with the immunotherapy combination. Patients in the teclistamab–daratumumab arm had a 54-percent lower risk of death compared with those in the DPd/DVd arm (HR, 0.46, 95 percent CI, 0.32–0.65; p<0.0001). The estimated 36-month OS was 83.3 percent and 65 percent, respectively.

Mateos described the efficacy of teclistamab plus daratumumab as “unprecedented.” The PFS and OS curves plateaued after 6 months, “suggesting potential for functional cure.”

Synergistic combination

Teclistamab and daratumumab, both approved for use in multiple myeloma treatment, work synergistically, according to Mateos.

“Teclistamab is a bispecific antibody targeting CD3 on T-cell surfaces and B-cell maturation antigen on myeloma cells and B cells,” she explained. “Daratumumab effectively primes and activates T-cells and the tumour microenvironment for teclistamab via immune modulatory mechanism, resulting in rapid eradication of multiple myeloma cells.”

Furthermore, teclistamab plus daratumumab is a combination free of steroids after the eighth day of the first cycle, “and this is extremely important from the patient perspective,” Mateos said.

Beyond the primary endpoint of PFS and secondary endpoint of OS, the immunotherapy combination also performed better than the triplet therapy across the other efficacy metrics. Mateos noted that the depth of response was greater with teclistamab plus daratumumab.

A significantly higher percentage of patients in the teclistamab–daratumumab arm than in the DPd/DVd arm achieved complete response or better (81.8 percent vs 32.1 percent; risk ratio [RR], 2.55, 95 percent CI, 2.14–3.03). More than half (58.4 percent) of the patients who received the immunotherapy combination tested negative for minimal residual disease as opposed to only 17.1 percent of those who received triplet therapy (RR, 3.43, 95 percent CI, 2.58–4.55). The median duration of response was not estimable in the teclistamab–daratumumab arm vs 23.5 months in the DPd/DVd arm.

Safety profile

Serious adverse events occurred in 70.7 percent of the patients in the teclistamab–daratumumab arm and in 62.4 percent of those in the DPd/DVd arm. Deaths were roughly 50-percent lower with the immunotherapy combination vs triplet therapy (15.9 percent vs 33.1 percent), and there were few treatment discontinuations due to adverse events (AEs) in both treatment arms (4.5 percent vs 5.5 percent, respectively).

Notably, 71 percent of patients remained on teclistamab plus daratumumab at the time of analysis, according to Mateos. The median duration of treatment was 32.4 months with teclistamab plus daratumumab vs 16.1 months with DPd/DVd.

Cytokine release syndrome occurred in 60.1 percent of patients in the teclistamab–daratumumab arm (grade 1 in 44.2 percent, grade 2 in 15.9 percent). The incidence of immune effector cell-associated neurotoxicity syndrome was low at only 1.1 percent.

The most common haematological AE was neutropenia of any grade, reported in 78.4 percent of patients in the teclistamab–daratumumab arm and 82.8 percent of those in the DPd/DVd arm. Grade 3-4 infections, such as COVID-19 and upper respiratory tract infections, were the most common nonhaematological AE, occurring in 54.1 percent and 43.4 percent of patients in the respective arms.

Mateos pointed out that infections were much more frequent in the teclistamab-daratumumab arm in the first 6 months of treatment, after which the incidence declined over time and became comparable with that observed in the DPd/DVd arm. Explaining why there was an initial increase in infections with the immunotherapy combo, the investigator said MajesTEC-3 was initiated prior to the approval of teclistamab, when there was no established protocol for infection management or prevention.

“The trial protocol was subsequently amended, and it was reinforced that investigators should use immunoglobulin replacement therapy and antimicrobial prophylaxis,” she added. 

MajesTEC-3 trial

The analysis included 587 patients (median age 64 years, 55.4 percent male, 65.4 percent White) with multiple myeloma who previously received a median of two lines of therapy. These patients were randomly allocated to the teclistamab-daratumumab arm (n=291) or the DPd/DVd arm (n=296).

Patients in the immunotherapy combination arm received teclistamab subcutaneously in 28-day cycles, at 1.5 mg/kg of body weight weekly in cycle 1, following two step-up doses of 0.06 and 0.3 mg/kg; 1.5 mg/kg weekly in cycle 2; 3 mg/kg every 2 weeks in cycles 3–6; and 3 mg/kg every 4 weeks from cycle 7 onward. Mateos noted that the teclistamab administration schedule aligned with the approved daratumumab schedule to increase dosing convenience. Premedication with dexamethasone, acetaminophen, and diphenhydramine was required for the first 2 weeks. Meanwhile, patients in the DPd/DVd arm received treatment according to established schedules. Treatment in the two arms continued until confirmed progressive disease, death, unacceptable side effects, or withdrawal of consent.

Overall, the MajesTEC-3 findings bring a new standard of care for the second- or subsequent-line treatment of relapsed or refractory multiple myeloma, Mateos said. “The cytokine release syndrome profile and combinability of teclistamab with daratumumab on approved daratumumab schedule support potential for community adoption.”