MajesTEC-3 Modeling Projects 18.5-Year Life Expectancy With Teclistamab Plus Daratumumab in Early-Line RRMM
核心洞察
A relative survival mixture cure model estimated an 86.6% cure fraction for overall survival with teclistamab plus daratumumab versus 0% for standard-of-care DPd/DVd in relapsed or refractory multiple myeloma (搜索).
Model-projected remaining life expectancy reached 18.5 years with the combination, nearly four times the 4.9 years projected for DPd/DVd and approaching 21.1 years for the matched general population.
A separate post hoc analysis showed a 90% reduction in the risk of disease progression at 36 months with the combination, with no significant difference in non-relapse mortality.
Johnson & Johnson reported new model-based analyses from the Phase 3 MajesTEC-3 study indicating that teclistamab plus daratumumab may substantially extend survival for patients with relapsed or refractory multiple myeloma (搜索) (RRMM) who have received one to three prior lines of therapy. The data, drawn from a relative survival mixture cure model (MCM) and a separate post hoc competing-risk analysis, were released on Sept. 23, 2026 and will be presented in two oral sessions at the International Myeloma Society (IMS) Annual Meeting (Abstract #OA-58 and Abstract #OA-49).
Cure model projects survival approaching the general population
In the MCM analysis, a relative survival model was applied to patients treated with teclistamab plus daratumumab (n=291) and to those receiving investigator's choice of daratumumab SC with dexamethasone plus pomalidomide or bortezomib (DPd/DVd; n=296). Best-fit models estimated a cure fraction of 86.6% (95% CI, 81 to 91) for overall survival (OS) with the combination, compared with 0% (95% CI, 0 to 53) with DPd/DVd, with substantially greater uncertainty in the DPd/DVd estimates.
Model-projected remaining life expectancy was 18.5 years with teclistamab plus daratumumab, nearly four times the 4.9 years projected with DPd/DVd and approaching the 21.1 years estimated for the matched general population. Johnson & Johnson characterized the analysis as showing that approximately 87% of patients treated with the combination as early as second line may have a mortality risk and projected life expectancy comparable to an age-matched general population.
"These findings underscore how consequential treatment choice at first relapse can be in shaping a patient's long-term trajectory," said Dr. Luciano J. Costa, Professor of Multiple Myeloma (搜索) and Director of the Multiple Myeloma Research and Treatment Program at the University of Alabama at Birmingham. "The sustained disease control observed with TECVAYLI plus DARZALEX FASPRO is changing expectations for what treatment can achieve in relapsed or refractory multiple myeloma (搜索), moving beyond just delaying the next relapse toward the possibility of durable long-term disease control."
Progression reduction drives the survival signal
The post hoc analysis attributed the survival benefit to a reduction in disease progression rather than to differences in non-relapse mortality. At 36 months, the cumulative incidence of disease progression was 8.7% with teclistamab plus daratumumab versus 62.1% with DPd/DVd, a 90% reduction in the risk of progression (subdistribution hazard ratio [sHR]=0.10; 95% CI, 0.07 to 0.16; p<0.0001).
The 36-month OS rate was 83.3% with the combination versus 65.0% with DPd/DVd (hazard ratio [HR]=0.46; 95% CI, 0.32 to 0.65; p<0.0001), an 18-percentage-point gap at three years. Non-relapse mortality did not differ significantly between arms, with 36-month rates of 10.2% and 9.0%, respectively (sHR=1.16; 95% CI, 0.69 to 1.98; p=0.5668).
The survival curves separated over time. No statistically significant difference in OS was observed between treatment groups during the first 10 months (HR=1.08; 95% CI, 0.64 to 1.81). Beyond 10 months, OS favored teclistamab plus daratumumab, with a 78% reduction in the risk of death versus DPd/DVd (HR=0.22; 95% CI, 0.13 to 0.38). A prespecified restricted mean survival time analysis also supported a significant OS benefit, with a difference of 2.15 months during the period analyzed (p=0.0088).
"The continued analyses of the MajesTEC-3 trial challenge long-held expectations of what may be possible in multiple myeloma (搜索)," said Yusri Elsayed, M.D., M.H.Sc., Ph.D., Global Therapeutic Area Head, Oncology, Johnson & Johnson Innovative Medicine. "Our ambition is to build on this progress by fundamentally changing the long-term trajectory of multiple myeloma and, ultimately, creating a future in which this disease is no longer defined as incurable."
Ester in 't Groen, EMEA Therapeutic Area Head, Haematology, Johnson & Johnson, said the projected life expectancy approaching that of the general population is "an exciting and hopeful signal of what may be possible with teclistamab plus daratumumab," adding that the analyses reinforce the company's view that the combination offers a new standard of care.
Trial design and regulatory position
MajesTEC-3 (NCT05083169) is an ongoing, randomized Phase 3 study evaluating teclistamab plus daratumumab subcutaneously (n=291) versus investigator's choice of daratumumab SC and dexamethasone with either pomalidomide or bortezomib (n=296) in patients with RRMM who have received one to three prior lines of therapy. The primary endpoint is progression-free survival; secondary endpoints include complete response or better, overall response rate, minimal residual disease negativity (10⁻⁵ by next-generation sequencing), overall survival, time to worsening of symptoms (MySIm-Q), and safety. The trial is part of the MajesTEC clinical program, which is exploring teclistamab as a combination regimen.
Teclistamab is an off-the-shelf bispecific antibody administered as a subcutaneous injection that redirects T cells through two targets, BCMA (搜索) and CD3 (搜索). It received accelerated FDA approval in October 2022 as monotherapy for patients with at least four prior lines of therapy. In March 2026, the FDA approved teclistamab in combination with daratumumab and hyaluronidase-fihj for adults with RRMM who have received at least one prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent. The supplemental Biologics License Application was selected for the Commissioner's National Priority Voucher Pilot Program and granted Breakthrough Therapy Designation and Real-Time Oncology Review. The European Commission granted conditional marketing authorization for teclistamab as monotherapy in August 2022 and approved an indication extension for the combination in August 2026, providing an option as early as second line. More than 30,000 patients have been treated worldwide with teclistamab.
Daratumumab-based regimens have been used in more than 830,000 patients worldwide. Daratumumab is a CD38 (搜索)-directed antibody; CD38 is a surface protein present in high numbers on multiple myeloma (搜索) cells regardless of disease stage, and daratumumab binding inhibits tumor cell growth and causes myeloma cell death.
Safety profile in the combination setting
Teclistamab carries boxed warnings for cytokine release syndrome (CRS) and neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS), and is available only through the TECVAYLI and TALVEY Risk Evaluation and Mitigation Strategy program. In clinical trials of teclistamab as monotherapy and in combination (N=448), CRS occurred in 64% of patients at the recommended dosage, with Grade 1 in 46%, Grade 2 in 18%, and Grade 3 in 0.2%; neurologic toxicity occurred in 60%, with Grade 3 or 4 events in 6%.
In MajesTEC-3, ICANS was reported in 1.1% of patients receiving the recommended teclistamab dosage in combination with daratumumab and hyaluronidase-fihj, including Grade 4 ICANS in one patient, with all events occurring during the step-up dosing schedule. In the same combination cohort (N=283), serious infections including opportunistic infections occurred in 54% of patients, Grade 3 or 4 infections in 54%, and fatal infections in 4.6%. The most common adverse reactions (at least 20%) with the combination were hypogammaglobulinemia, upper respiratory tract infection, CRS, cough, diarrhea, musculoskeletal pain, COVID-19, pneumonia, injection site reaction, fatigue, pyrexia, headache, nausea, gastroenteritis, and weight decreased.
Disease burden and remaining questions
Multiple myeloma (搜索) is the second most common blood cancer worldwide, with more than 180,000 new cases diagnosed globally each year. In the European Union, more than 35,000 people were estimated to be diagnosed in 2024 and more than 21,900 patients died. The five-year survival rate is 59.8%. Patients experience relapses that become more frequent with each line of therapy while remissions become progressively shorter.
The MCM projections rest on modeling assumptions, and the confidence interval around the DPd/DVd cure fraction (0 to 53) was wide. MajesTEC-3 remains ongoing, and continued follow-up will assess whether observed outcomes confirm these model-based predictions. The observed 36-month OS rate of 83.3% versus 65.0% is not model-dependent, and whether that advantage holds as the trial matures toward its prespecified final analysis will be the key question for regulatory and payer assessments.