At the American Society of Hematology (ASH) Annual Meeting 2025, held in Orlando, Florida, from 6 to 9 December, updated results from the global, multicentre, open-label, Phase III MajesTEC-3 clinical trial were presented. This trial evaluated the safety and efficacy of the combination of Genmab and Johnson & Johnson’s (J&J’s) Darzalex (daratumumab), a human immunoglobulin G kappa (IgGκ) monoclonal antibody that targets CD38, and Tecvayli (teclistamab), a bispecific B-cell maturation antigen (BCMA)-directed CD3 T-cell engager (TCE), in patients with relapsed or refractory (R/R) multiple myeloma (MM).
In the MajesTEC-3 trial, 587 patients with MM who had received one to three prior systemic therapies (median: two therapies), including a proteasome inhibitor (PI) and Bristol Myers Squibb’s (BMS’s) Revlimid (lenalidomide), were enrolled. Participants who had received only one prior line of therapy were required to be lenalidomide-refractory. Patients were randomised 1:1 into an experimental arm (Darzalex + Tecvayli; n=291) and a control arm, which consisted of either Darzalex with BMS’s Pomalyst (pomalidomide) and dexamethasone (DPd), or Darzalex with bortezomib, a PI, and dexamethasone (DVd) (DPd/DVd; n=296).
The primary endpoint of progression-free survival (PFS), at a median follow-up of 34.5 months, was significantly improved in the experimental arm with Darzalex + Tecvayli compared to the control arm with DPd/DVd (hazard ratio [HR], 0.17; 95% confidence interval [CI], 0.12–0.23; P<0.0001). The 36-month PFS rates were 83.4% in the control arm versus 29.7% in the experimental arm, and the PFS benefit was seen across all prespecified and clinically relevant patient subgroups. Darzalex + Tecvayli led to much deeper and more frequent responses than DPd/DVd, with higher rates of complete response (81.8% versus 32.1%, respectively; P <.0001), and minimal residual disease negativity at 10-5 sensitivity (58.4% versus 17.1%, respectively; P<0.0001). The 36-month overall survival (OS) rate was 83.3% with Darzalex + Tecvayli versus 65.0% with patients who received investigator’s choice of DPd or DVd, and OS also significantly favoured the Darzalex + Tecvayli arm (HR, 0.46; 95% CI, 0.32–0.65; P<0.0001). There were fewer deaths in the Darzalex + Tecvayli arm than in the DPd or DVd control arm (15.9% versus 33.1%, respectively), and fewer patients discontinued the treatment in the experimental arm as well (4.6% versus 20.3%, respectively). The Darzalex + Tecvayli arm and the DPd or DVd control arm showed similar rates of grade 3/4 (95.1% versus 96.6%, respectively) and grade 5 (7.1% versus 5.9%, respectively) adverse events. Serious adverse events occurred in 70.7% of patients in the Darzalex + Tecvayli arm versus 62.4% in the control arm, and treatment discontinuations due to toxicity were low in both arms (4.6% versus 5.5%, respectively). Infections were very common and were higher in the Darzalex + Tecvayli arm than in the control arm (any grade: 96.5% versus 84.1%; grade 3/4: 54.1% versus 43.4%).
Darzalex has become a cornerstone of MM treatment since its first approval in 2015, with its indications now spanning relapsed, frontline transplant-eligible and transplant-ineligible settings, as well as high-risk smouldering myeloma in Europe and the US following the AQUILA clinical trial data. The most direct competitor to Darzalex and Tecvayli in patients with R/R MM after one to three previous lines of therapy is Sanofi’s anti-CD38 antibody Sarclisa (isatuximab) in combination with carfilzomib and dexamethasone (Isa-Kd). If the final results from the MajesTEC-3 trial confirm durable PFS and OS benefit, and this steroid-free Darzalex + Tecvayli regimen is approved, it could rapidly dominate the one to three previous line R/R MM setting.
Darzalex and Tecvayli will also face competition from the company’s own Carvykti (ciltacabtagene autoleucel). However, unlike the one-time Carvykti, Darzalex + Tecvayli is an off-the-shelf subcutaneous therapy that can be started quickly in a broader range of centres and patients, including those who are older, frailer or unable to access chimeric antigen receptor (CAR) T-cell manufacturing capacity. From a sequencing perspective, Darzalex and Tecvayli are likely to be used either before or instead of BCMA CAR-T in patients who are not ideal candidates for cellular therapy, while Isa-Kd will remain an important PI-based alternative where early use of T-cell–redirecting therapy is not desirable.
According to GlobalData’s Multiple Myeloma: Eight-Market Drug Forecast and Market Analysis report, Darzalex and Tecvayli are projected to generate global sales of $5.4 billion and $1.8 billion respectively by 2031. MajesTEC-3 gives J&J a way to keep Darzalex relevant beyond its 2029 patent cliff by tying it to Tecvayli in a powerful, proprietary combination, rather than leaving it as a standalone drug that is easier for biosimilars to replace.
