J&J’s Tecvayli combo delivers “remarkable” Phase 3 results in 2nd-line r/r MM

Edited by Robert McTiernan··3 min read

Johnson & Johnson (J&J)’s investigational combination of Tecvayli (teclistamab-cqyv) plus Darzalex Faspro (daratumumab + hyaluronidase) has shown remarkable efficacy in the Phase 3 MajesTEC-3 study in relapsed/refractory multiple myeloma (r/r MM). The data, which indicates the combo could become a new standard of care for the second-line setting, were announced at the 2025 American Society of Hematology (ASH) Annual Meeting and simultaneously published in The New England Journal of Medicine (NEJM).

Study outcomes

  • Compared with standard regimens (Darzalex Faspro plus pomalidomide-dexamethasone or bortezomib-dexamethasone), the combo reduced the risk of disease progression or death by 83% (hazard ratio 0.17; 95% CI 0.12-0.23; P < 0.0001) over nearly three years follow-up.
  • At three years, 91% of patients who were progression-free at six months remained progression-free.
  • Key secondary endpoints were also strongly improved: complete response rate ≥CR rose to 81.8% vs 32.1%; overall response rate was 89.0% vs 75.3%; minimal residual disease (MRD) negativity reached 58.4% vs 17.1%.
  • Overall survival benefit was substantial (HR 0.46; P < 0.0001), with 83.3% survival at three years vs 65.0% in controls.
  • The safety profile was comparable between arms. Rate of severe treatment-emergent adverse events was similar (approx. 95.1% vs 96.6%). Most Grade 3/4 events were cytopenias or infections. Cytokine release syndrome occurred in 60.1% (all Grade 1/2), managed with standard protocols; immune-effector cell-associated neurotoxicity was rare (1.1%). Treatment discontinuation due to adverse events was low (4.6% vs 5.5%).

Why this matters

Tecvayli is a first-in-class bispecific antibody that binds to CD3 on T-cells and BCMA on myeloma cells, while Darzalex Faspro is a subcutaneous CD38-targeted antibody. The dual-target approach appears synergistic — mobilizing immune attack via distinct yet complementary mechanisms, improving both depth and durability of response.

MajesTEC-3 is the first Phase 3 trial in r/r MM to show such dramatic improvements in both progression-free and overall survival using a bispecific-plus-antibody regimen versus standard-of-care triple therapy.

Treatment of r/r MM continues to face clinical challenges, despite significant therapeutic advances. Management of the disease is highly individualized, often involving sequential use of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibodies, and corticosteroids, frequently in combination regimens. Triplet and quadruplet therapies are now common, with regimens tailored to prior therapies, patient comorbidities, and cytogenetic risk profiles.

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CAR-T cell therapies – notably Bristol Myers Squibb’s Abcema (idecabtagene vicleucel) and J&J’s Carvykti (ciltacabtagene autoleucel) – and bispecific antibodies are emerging as standard options for heavily pretreated patients, offering deep and durable responses in some cases. Kyprolis (carfilzomib) is among the approvals for three-drug regimens.

Tecvayli itself won a first accelerated approval from the US FDA in 2022 as a fifth-line treatment for r/r MM and was cleared for biweekly dosing for r/r MM patients with sustained CR in 2024.

Despite progress, patients refractory to lenalidomide or multiple drug classes have poor outcomes, with early relapse and end-stage r/r MM associated with limited survival, while optimal sequencing of new agents is not fully established.

With these data, the combination is already under review by regulatory agencies, and many analysts believe it could reshape the standard-of-care landscape for r/r MM — enabling use earlier in treatment, improving long-term outcomes and potentially shifting treatment paradigms for a large patient population.