Introduction
Multiple myeloma (MM) is characterized by progressive immune dysfunction and multiple relapses. Treating relapsed/refractory MM (RRMM) is increasingly challenging 1 , 2 as the evolving frontline landscape complicates second-line treatment selection. Challenges are compounded by limited effective salvage treatment options 3 and high attrition. 4 Emerging anti–B-cell maturation antigen (BCMA) treatments, including chimeric antigen receptor T-cell (CAR-T) therapy and antibody drug conjugates, offer promise, with ciltacabtagene autoleucel showing high minimal residual disease (MRD)-negative rates and durable progression-free survival. 5 However, off-the-shelf and highly effective regimens are needed to fully address patient needs.
Teclistamab, a bispecific antibody targeting CD3×BCMA, 6 demonstrated deep and durable responses in heavily pretreated RRMM in the phase 1/2 MajesTEC-1 study. 7 , 8 Daratumumab, an anti-CD38–targeting monoclonal antibody (mAb), is a cornerstone of standard-of-care MM regimens with demonstrated survival benefit across all lines. 9 – 14 In addition to direct on-tumor effects, daratumumab sensitizes the immune microenvironment by depleting immunosuppressive T-cells and enhancing CD8+ T-cell cytotoxicity, creating synergistic effects with teclistamab-mediated eradication of myeloma cells. 15 This off-the-shelf, immunotherapy combination of teclistamab and daratumumab (Tec-Dara) is a potential therapeutic strategy to improve outcomes in second- or subsequent-line RRMM.
MajesTEC-3 is a phase 3 study evaluating the combination of Tec-Dara versus investigator’s choice of standard-of-care daratumumab-based regimen in patients with RRMM and with 1–3 prior lines. Here we report results from the primary analysis of efficacy and safety, performed at the planned first interim analysis.
Methods
Study design and oversight
This multicenter, open-label, study randomized patients between October 22, 2021, and September 29, 2023, at 150 sites across 20 countries. Local independent ethics committees and institutional review boards at each study site approved the study protocol and amendments. The study was conducted in accordance with the Declaration of Helsinki, the International Council for Harmonisation guidelines for Good Clinical Practice, and country-specific regulations. An independent data monitoring committee reviewed all safety data regularly, with efficacy included during primary analysis review. All patients provided written informed consent.
Johnson & Johnson sponsored the study and funded the medical writing assistance. Representatives of the company designed the study in consultation with key investigators and compiled, maintained, and analyzed the data. All authors had access to and can vouch for the integrity of the data and adherence to the approved protocol. All drafts were critically reviewed, revised, and approved by all authors.
Patients
Eligible patients had received 1–3 prior lines of antimyeloma therapy, including a proteasome inhibitor and lenalidomide, with documented disease progression on or after their last regimen. Patients with only 1 prior line of therapy were required to have lenalidomide-refractory myeloma (per International Working Group [IMWG] criteria). 16 – 18 Key exclusion criteria included prior BCMA-directed therapy or refractoriness to anti-CD38 mAbs. Patients with pomalidomide-refractory and bortezomib-refractory myeloma were not allowed to receive daratumumab with pomalidomide and dexamethasone (DPd) and daratumumab with bortezomib and dexamethasone (DVd), respectively. Full eligibility criteria are provided in the protocol, available at NEJM.org .
Study treatments
Patients were randomly assigned 1:1 to receive Tec-Dara or investigator’s choice of standard-of-care regimens of DPd/DVd. 19 Patients were stratified by investigator’s choice of DPd/DVd, International Staging System (ISS) disease stage (I vs. II vs. III), prior anti-CD38 mAb exposure, and number of prior lines (1 vs. 2 or 3).
The Tec-Dara group received 28-day cycles of teclistamab at 1.5 mg/kg weekly in cycle 1 following 2 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 to 6; and 3 mg/kg every 4 weeks from cycle 7 onward, which provides comparable pharmacokinetic exposure as 1.5 mg/kg every 2 weeks. Subcutaneous daratumumab was dosed per the approved dosing schedule ( Table S1 ). 20 The teclistamab dosing schedule aligns with the approved daratumumab schedule to increase dosing convenience. Dose reductions from 3 mg/kg to 1.5 mg/kg or decrease in teclistamab dosing frequency were permitted with sponsor approval. Patients who discontinued ≥1 component of study treatment could continue to receive other components, as assigned. Dexamethasone, acetaminophen, and diphenhydramine premedication was required for the first 2 weeks; subsequent dexamethasone was not required. The DPd/DVd group received treatment per established schedules ( Supplementary Appendix ; Table S2 ). 21 Treatment continued until confirmed progressive disease, death, intolerance, or withdrawal of consent.
Infection prophylaxis, including immunoglobulin supplementation, antibiotics, and prophylaxis for Pneumocystis jirovecii pneumonia and herpes zoster reactivation, was administered per institutional guidelines. Immunoglobulin replacement therapy and infection prophylaxis guidance were reinforced per protocol amendment (February 2023), which affirmed the importance of medical monitoring of immunoglobulin G levels and adherence to protocol-specified immunoglobulin supplementation guidance. Tocilizumab was permitted for grade 1 and recommended for grade ≥2 cytokine release syndrome.
Endpoints and assessments
The primary endpoint was progression-free survival as assessed by an independent review committee (IRC), defined as the time from the date of randomization to the date of first documented disease progression or death. Key secondary endpoints included complete response or better (≥CR), overall response (partial response or better), MRD negativity (10 −5 threshold), overall survival, and time to worsening of symptoms in the MySIm-Q total symptom score. Additional secondary endpoints included safety, pharmacokinetics, and immunogenicity. Additional MRD analyses and endpoint definitions are provided in the Supplementary Appendix .
Response and disease progression were assessed by a blinded IRC per IMWG criteria. 16 – 18 Disease evaluations were performed centrally; imaging and bone marrow analysis for response were performed locally. MRD was assessed in bone marrow aspirates by next-generation sequencing (NGS; clonoSEQ; Adaptive Biotechnologies) in accordance with IMWG guidelines. 18 MRD was assessed in patients with suspected ≥CR, and at 6, 12, 18, and 24 months post-cycle 1 day 1 (±1 month) for patients with confirmed ≥CR. Serum was collected to assess teclistamab and daratumumab pharmacokinetics and immunogenicity. Assessment timing is summarized in the Supplementary Appendix .
Adverse events were monitored continuously and graded per the NCI CTCAE (Version 5.0) 22 ; details are provided in the Supplementary Appendix . Cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT guidelines. 23
Statistical analysis
A sample size of 560 patients and the occurrence of 335 progression-free survival events were estimated to provide 90% power to detect a 30% lower risk of disease progression or death with Tec-Dara versus DPd/DVd at an overall 2-sided alpha level of 0.05. A group sequential design with one interim analysis was planned for progression-free survival when approximately 251 progression-free survival events occurred. The significance level required to establish progression-free survival superiority at the interim analysis was determined based on the number of events that were observed, with the use of O’Brien-Fleming boundaries, and implemented by the Lan-DeMets alpha spending method. The use of group sequential design and a hierarchical testing procedure for the key secondary endpoints ensured control for multiple testing (see Supplementary Appendix ).
For primary and efficacy endpoints, excluding MRD negativity, the intent-to-treat population was analyzed, which included all randomized patients. MRD negativity was evaluated in the NGS primary analysis set, defined as all randomized patients except for those recruited in China, in which next-generation flow was used. Adverse events were evaluated in the safety population, which included all randomized patients who received any study treatment.
Time-to-event endpoints were compared between groups using a 2-sided stratified log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using a stratified Cox regression model, with treatment as the sole explanatory variable. When proportional hazards assumption did not hold, the interpretation of the HR would represent an average effect over time, and a pre-specified analysis of restricted mean survival time (RMST) was performed. The Kaplan-Meier method was used to estimate distributions. Additional methodology regarding the handling of intercurrent events and censoring rules for progression-free and overall survival analyses are provided in the Supplementary Appendix . Binary outcomes were compared between groups using stratified Cochran-Mantel-Haenszel estimates of odds ratio with 2-sided 95% CIs and P values. Given that odds ratios may inflate the apparent magnitude of the effect, stratified estimates of risk ratios were also provided. For all stratified analyses, stratification was based on ISS staging (I vs II or III) and number of prior lines (1 vs. 2 or 3), as randomized. Of note, the width of all CIs presented have not been adjusted for multiplicity and may not be used in place of hypothesis testing. Post-hoc analyses were also performed and results should be interpreted with caution.
Results
Patients
A total of 587 patients were enrolled and randomized (Tec-Dara, n=291; DPd/DVd, n=296; Figure S1 ); 573 (Tec-Dara, n=283; DPd/DVd, n=290) received study treatment. In the control group, most patients received DPd (n=263 [90.7%]; DVd, n=27 [9.3%]). Baseline demographics and disease characteristics were similar between groups and are summarized, with prior lines of therapy, in Table 1 and Table S3 . Real-world representativeness is summarized in Table S4 .
As of the clinical cutoff date (August 1, 2025), 29.0% of Tec-Dara and 71.7% of DPd/DVd patients had discontinued study treatment, primarily due to progressive disease (Tec-Dara, 7.4%; DPd/DVd, 57.9%); 283 patients remain on study treatment (Tec-Dara, 71.0%; DPd/DVd, 28.3%). The median duration of treatment was twice as long for Tec-Dara versus DPd/DVd (32.4 vs. 16.1 months, respectively). The median relative dose intensity of teclistamab was 97.1%, and between 90.0–97.8% for daratumumab across groups ( Table S5 ). Teclistamab dose reduction was reported in 28.5% of patients who received ≥1 dose of teclistamab; most occurred in cycle 7+ ( Table S6 ). The median follow-up was 34.5 months (range, 0.03–45.3).
Efficacy
Tec-Dara resulted in a significantly lower risk of disease progression or death than DPd/DVd (P<0.0001); the P value crossed the prespecified stopping boundary for superiority for the first interim analysis (P=0.0139). Estimated 36-month progression-free survival rate was 83.4% (95% CI, 78.2–87.4) with Tec-Dara versus 29.7% (95% CI, 23.6–36.0) with DPd/DVd (HR, 0.17; 95% CI, 0.12–0.23; Figure 1A ). In subgroup analyses, progression-free survival favored Tec-Dara across all prespecified and clinically relevant subgroups ( Figure 1B ).
The proportion of patients achieving ≥CR was significantly higher with Tec-Dara versus DPd/DVd (81.8% vs. 32.1%), with a risk ratio (post-hoc) of 2.55 (95% CI, 2.14–3.03; Table 2 ). A significant difference was also seen with overall response rate (89.0% vs. 75.3%), with a risk ratio of 1.18 (95% CI, 1.09–1.27; Table 2 ). Odds ratios are reported in Table S7 . With both Tec-Dara and DPd/DVd, among responders, the median time to first response was 1.2 months, and to ≥CR, 6.9 months. The estimated percentage of patients remaining in response at 36 months was 88.5% (95% CI, 83.7–92.0) versus 36.4% (95% CI, 28.9–43.9) with Tec-Dara and DPd/DVd, respectively ( Figure S2 ).
In the MRD NGS primary analysis set, MRD-negativity rate (10 −5 ) was higher with Tec-Dara versus DPd/DVd (58.4% vs. 17.1%) with a risk ratio of 3.43 (95% CI, 2.58–4.55; Table 2 ). Odds ratios are reported in Table S7 . Additional MRD analyses are provided in Table S8 and Figure S3 .
Tec-Dara demonstrated a significantly lower risk of death than DPd/DVd (stratified log-rank test P<0.0001). Estimated 36-month overall survival rate was 83.3% (95% CI, 78.3–87.2) with Tec-Dara and 65.0% (95% CI, 58.8–70.5) with DPd/DVd ( Figure 2 ; Table S9 ). The overall survival curves crossed around 10 months of follow-up, primarily due to early infectious deaths in the Tec-Dara group. Analysis of RMST demonstrated overall survival benefit for Tec-Dara versus DPd/DVd (RMST difference [Tec-Dara minus DPd/DVd], 2.15 months [95% CI, 0.54–3.77]; Table S9 ). The proportion of patients alive at 6- and 30-months post-treatment were 92.2% and 84.3%, respectively, with Tec-Dara, suggesting a plateau starting around 6 months, and 94.5% and 69.6% with DPd/DVd.
Estimated 36-month event-free rate for symptom worsening per MySIm-Q total symptom score was 75.6% (95% CI, 68.1–81.6) with Tec-Dara and 63.3% (95% CI, 54.7–70.6) with DPd/DVd (HR, 0.50; 95% CI, 0.34–0.72; P=0.0002; Table S10 ).
Safety
The most common treatment-emergent adverse events of any grade are reported in Table 3 . The most common grade 3/4 treatment-emergent adverse event was neutropenia (Tec-Dara, 75.6%; DPd/DVd, 78.6%; Table 3 ). Serious adverse events occurred in 70.7% of Tec-Dara patients and 62.4% of DPd/DVd patients, the most common being pneumonia (Tec-Dara, 16.6%; DPd/DVd, 13.1%; Table S11 ). Treatment-emergent adverse events leading to treatment discontinuation occurred in 4.6% of Tec-Dara and 5.5% of DPd/DVd patients.
Forty-five (15.9%) Tec-Dara patients and 96 (33.1%) DPd/DVd patients died, mainly due to adverse events and disease progression, respectively ( Table S12 ). Deaths due to treatment-emergent adverse events were comparable between groups (Tec-Dara, 20 [7.1%]; DPd/DVd, 17 [5.9%]); 12 (4.2%) deaths with Tec-Dara and 5 (1.7%) with DPd/DVd were due to a treatment-emergent adverse event related to study treatment as assessed by investigator ( Table S13 ).
Cytokine release syndrome occurred in 60.1% of Tec-Dara patients, all of which were grade 1 (44.2%) or grade 2 (15.9%; Table S14 ). Cytokine release syndrome events were transient (median duration, 2 [range, 1–22] days), all resolved, and none led to treatment discontinuation. Most events occurred during the step-up dosing schedule; no grade 2 events occurred post-cycle 1 ( Table S15 ). Supportive measures are summarized in Table S14 . ICANS occurred in 3 patients (1.1%) with Tec-Dara (grade 1, n=2; grade 4, n=1); all events resolved, and the grade 4 event led to teclistamab discontinuation ( Table S16 ).
Rates of grade 3/4 neutropenia, anemia, and thrombocytopenia were similar between groups ( Table 3 ). The frequency of new-onset grade ≥3 cytopenias was highest in the first 6 months of therapy and decreased thereafter ( Table S17 ).
Infections were common in both groups (any grade: Tec-Dara, 96.5%; DPd/DVd, 84.1%; Table S18 ). Grade 3/4 infections were reported in 54.1% of Tec-Dara and 43.4% of DPd/DVd patients. New-onset grade ≥3 infections decreased after 6 months of treatment ( Table S19 ), coinciding with transition to monthly dosing. Incidence of COVID-19 infection (any grade: 43.8% vs. 33.4%; grade 3/4: 6.0% vs. 2.1%; serious: 6.7% vs. 2.1%) and COVID-19 pneumonia (any grade: 12.0% vs. 4.1%; grade 3/4: 11.3% vs. 2.4%; serious: 11.3% vs. 2.8%), by preferred term, were higher with Tec-Dara than DPd/DVd. Fatal infections occurred in 13 patients (4.6%) with Tec-Dara (3 due to COVID-19) and 4 patients (1.4%) with DPd/DVd. Twelve of 13 infection-related deaths on Tec-Dara occurred ≤6 months following treatment initiation, before the implementation of reinforced protocol-specified immunoglobulin replacement ( Figure S4 ); 9 of 12 patients did not receive any immunoglobulin coverage. Hypogammaglobulinemia occurred in 239 patients (84.5%) with Tec-Dara and 175 (60.3%) with DPd/DVd; 247 (87.3%) Tec-Dara patients and 130 (44.8%) DPd/DVd patients received ≥1 dose of immunoglobulin treatment.
Second primary cancer was observed in 35 patients (12.4%) with Tec-Dara and 25 patients (8.6%) with DPd/DVd; most cases were cutaneous or noninvasive (Tec-Dara, 8.1%; DPd/DVd, 4.5%; Table S20 ). Excluding cutaneous/noninvasive cases, incidence rates were balanced between groups.
Pharmacokinetics and immunogenicity
Teclistamab predose concentrations increased with 1.5 mg/kg weekly, remained steady with 3 mg/kg every 2 weeks, then declined with 3 mg/kg monthly, consistent with the predicted pharmacokinetics profile for the administered dosing regimen ( Figure S5 ). Predose concentrations of daratumumab in Tec-Dara patients were comparable to those observed in DPd/DVd patients ( Figure S6 ). Anti-teclistamab or anti-daratumumab antibodies developed in <1% of patients.
Discussion
After almost 3 years of median follow-up, Tec-Dara significantly improved progression-free survival in patients with RRMM exposed to 1–3 prior lines, with an 83% reduction in the hazard of disease progression or death versus standard-of-care DPd/DVd. Progression-free survival benefits favored Tec-Dara across all prespecified subgroups. Furthermore, Tec-Dara significantly improved ≥CR and overall response rates (including response durability), MRD-negativity rate (10 −5 ), overall survival, and time to worsening of symptoms, versus DPd/DVd. Treating RRMM is increasingly challenging, with progressive immune dysfunction, multiple relapses, and often poor survival outcomes. 24 Emerging treatment options in this setting include novel BCMA-targeting therapies, which have reshaped the therapeutic landscape. Ciltacabtagene autoleucel, a BCMA autologous CAR-T therapy, has significantly improved progression-free and overall survival versus DPd/PVd, with an improving adverse event profile from late to earlier lines of treatment. 5 , 25 Belantamab mafodotin, a BCMA-directed antibody-drug conjugate, has also demonstrated improved progression-free and overall survival in early-line RRMM. 26 , 27 Although grade ≥3 infections have been reported in up to half of patients receiving belantamab mafodotin, along with high incidences of ocular toxicity, regular ophthalmic monitoring, dose modifications, and supportive care can inform management decisions. 26 , 28 Other bispecific antibodies with activity in advanced myeloma and targeting BCMA, elranatamab 29 and linvoseltamab, 30 as well as GPRC5D, talquetamab, 31 are being evaluated in earlier line RRMM. Tec-Dara is a synergistic immunotherapy combination that utilizes subcutaneous administration, step-up dosing, and the well-established daratumumab dosing schedule. With the significant progression-free and overall survival benefit, and low rates of grade 2 cytokine release syndrome, Tec-Dara may address the need for a highly effective regimen and community accessibility. Guidelines on prophylactic tocilizumab and well-established infection protocols will further inform community adoption; however, treatment choice will be guided by individual risk–benefit considerations, access, and patient choice. With ciltacabtagene autoleucel and Tec-Dara offering immunotherapy–based options with plateauing survival curves, we may be entering a new era of resetting survival expectations in a malignancy historically described as incurable.
As shown, Tec-Dara conferred a significant progression-free survival benefit versus DPd/DVd. 5 , 13 , 26 , 28 , 32 Progression-free survival benefit with Tec-Dara was observed despite DPd/DVd (median progression-free survival 18.1 months) outperforming expectations per APOLLO (DPd, 12.4 months), CASTOR (DVd, 16.7 months), and CARTITUDE-4 (DPd/PVd, 11.8 months) studies. 5 , 12 , 33 Although only a few patients on MajesTEC-3 had received prior anti-CD38 therapy, progression-free survival benefit appeared to be obtained with Tec-Dara in this subgroup. The proportion of patients over age 75 years or with an Eastern Cooperative Oncology Group performance status score of 2 were also small but consistent with results reported in studies of similar populations; 5 , 26 , 28 , 33 a progression-free survival benefit was still observed with Tec-Dara in these subgroups. Ongoing studies and real-world evidence will build on the body of evidence in these groups. Finally, in the Tec-Dara group, more than 90% of patients alive at 6 months remained alive at 30 months, suggesting a plateau in the survival curve.
The Tec-Dara safety profile was well characterized. No new adverse events were noted compared to the safety profile of each individual agent. Cytokine release syndrome incidence was lower than that observed with teclistamab monotherapy in MajesTEC-1 (60.1% vs. 72.1%, respectively), 8 with most events being grade 1 and occurring during the step-up dosing schedule. Of note, prophylactic tocilizumab, not permitted in this study, is now recommended in guidelines and reduces the incidence and severity of cytokine release syndrome. 34 , 35 Nearly all patients experienced a grade 3 or higher adverse event (7.1% deaths due to treatment-emergent adverse events), most of which were cytopenias and infections. These events can be controlled with established immunoglobulin replacement and infection prevention and treatment protocols. MajesTEC-3 enrollment began during the COVID-19 pandemic, before the establishment of optimal infection prevention strategies for patients receiving BCMA-directed therapy. Following reinforced immunoglobulin recommendations and adherence to infection management recommendations, 1 fatal infection was noted with Tec-Dara and new-onset grade ≥3 infections decreased from 6 months onward, coinciding with monthly dosing. Results further emphasize the importance of early infection prevention in patients receiving bispecific antibodies, including use of immunoglobulin replacement per IMWG guidelines to reduce high-grade infections. 36 – 40 Notably, Tec-Dara was administered per approved daratumumab dosing schedule, with monthly teclistamab dosing from cycle 7 onwards, potentially easing treatment burden and providing a regimen familiar to healthcare providers. Results support the potential administration of this off-the-shelf combination in a community-based setting, as demonstrated in the real-world with teclistamab monotherapy. 41
In conclusion, MajesTEC-3 demonstrates a statistically significant benefit of Tec-Dara on progression-free survival and overall survival. It is associated with a risk of adverse events; however, the risks can be ameliorated with the use of established protocols. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org .
Supplementary Material
Acknowledgments
We would like to thank the patients who participated in the study and their families and caregivers. We would also like to thank the physicians, nurses, and staff members at each site; the members of the Study Safety Committee; Caren Minadeo and Arpan Patel, who assisted with data management and programming, respectively; additional team members who were involved in the data collection and analysis; and Holly Clarke, PhD, CMPP, and Bethany Reinecke, PhD, CMPP, of Lumanity Communications Inc., for medical writing (preparation of the first draft) and editorial assistance, funded by Johnson & Johnson.
Funding
This study and medical writing assistance were funded by Johnson & Johnson.
A complete list of investigators in the MajesTEC-3 study is provided in the Supplementary Appendix , available at NEJM.org .
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