MajesTEC-3: Teclistamab Plus Daratumumab Improves Progression-Free and Overall Survival in Relapsed/Refractory Multiple Myeloma

Relapsed/refractory multiple myeloma (RRMM) remains a clinically challenging disease state, particularly in earlier relapse settings where depth and durability of response are critical. The phase III MajesTEC-3 trial evaluated dual immune targeting with the B-cell maturation antigen (BCMA)-directed bispecific antibody teclistamab combined with daratumumab versus standard-of-care regimens. The combination significantly improved both progression-free survival (PFS) and overall survival (OS).

Clinical Takeaway

MajesTEC-3 is the first study of a BCMA-directed bispecific antibody combination to demonstrate both PFS and OS benefit as early as second-line therapy. The Independent Data Monitoring Committee (IDMC) recommended unblinding the study.

Drug Profile & Mechanism

• Agent:  
  • teclistamab (Tecvayli)
  • daratumumab and hyaluronidase-fihj (Darzalex Faspro)
• Class & Mechanism of Action:
  • teclistamab: Bispecific antibody targeting BCMA and CD3 that redirects T cells to eliminate malignant plasma cells
  • daratumumab and hyaluronidase-fihj: Anti-CD38 monoclonal antibody that induces complement-mediated cytotoxicity, antibody-dependent cellular cytotoxicity, and immune modulation
• Combination Rationale:
  • Dual immune targeting (BCMA + CD38) enhances depth of response through complementary plasma cell depletion and immune activation
• Route of Administration & Dosing Schedule:
  • teclistamab: Subcutaneous with step-up dosing, followed by weekly or every-other-week maintenance
  • daratumumab and hyaluronidase-fihj: Subcutaneous per labeled schedule

Target Population

• Adults with RRMM who have previously received 1–3 lines of therapy, including a proteasome inhibitor or immunomodulatory agent.

MajesTEC-3 Study Design (NCT05083169)

• Study Type: Randomized, international, open-label, phase III clinical trial
• Population: 587 patients
• Randomization: 1:1
  • Investigational Arm:
    • teclistamab + daratumumab
  • Control Arm (Investigator’s Choice):
    • daratumumab + pomalidomide + dexamethasone (DPd)
    • daratumumab + bortezomib + dexamethasone (DVd)
• Follow-Up Duration: Event-driven
  • Median follow-up: Not yet reported at interim analysis
• Primary completion: 2025 (interim efficacy threshold met)
• Estimated Study Completion: December 8, 2028

Endpoints

• Primary Endpoint:
  • PFS
• Secondary Endpoints:
  • OS
  • Overall response rate (ORR)
  • Minimal residual disease (MRD) negativity
  • Duration of response (DOR)
  • Safety

Efficacy Outcomes

• Primary Endpoint Results:
  • Statistically significant improvement in PFS and OS

This marks the first confirmation of OS benefit for a BCMA-directed bispecific combination in earlier-line RRMM.

Safety

• Overall Safety Profile: Consistent with known safety profiles of teclistamab and daratumumab:
  • teclistamab (cytokine release syndrome (CRS), infections, cytopenias)
  • daratumumab (injection-related reactions, cytopenias)
• Grade ≥3 Events:
  • Neutropenia
  • Anemia
  • Infections
• Treatment discontinuation: Low and manageable with supportive care
• Notable toxicity patterns:
  • CRS primarily low grade and manageable

No new safety signals were identified; adverse events were manageable with standard supportive care and dose modifications.

Regulatory Milestones

• Approval Status: Combination not yet approved by the FDA as of February 2026
• Current Standard of Care:
  • Common second-line regimens include:
    • daratumumab + pomalidomide + dexamethasone (DPd)
    • daratumumab + bortezomib + dexamethasone (DVd)
• Regulatory Pathway: Positive phase III data demonstrating OS benefit support potential regulatory submission.

Key Clinical Implications

✔ Establishes dual immune-targeting strategy earlier in the disease course

✔ Demonstrates overall survival benefit in second-line RRMM

✔ May shift second-line treatment sequencing for BCMA-directed therapy

✔ Supports expanding bispecific antibody use beyond heavily pretreated populations

✔ Reinforces immune-based combinations as foundational strategy in myeloma

Bottom Line

The phase III MajesTEC-3 trial demonstrates that teclistamab plus daratumumab significantly improves both PFS and OS compared with established second-line regimens in RRMM. If confirmed at full data presentation, this combination may meaningfully alter second-line treatment paradigms.

Sources:

• Johnson & Johnson. (2025, October 16). Tecvayli® plus Darzalex Faspro® combination regimen significantly improves progression-free survival and overall survival versus standard of care [Press release]. Johnson & Johnson. https://www.jnj.com/media-center/press-releases/tecvayli-plus-darzalex-faspro-combination-regimen-significantly-improves-progression-free-survival-and-overall-survival-versus-standard-of-care
• National Library of Medicine. (2026, January 16). Study of teclistamab in combination with daratumumab and hyaluronidase-fihj versus investigator’s choice in relapsed or refractory multiple myeloma (MajesTEC-3) (NCT05083169). ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT05083169