A cross-trial analysis using individual patient data suggests that the combination of teclistamab and daratumumab delivers substantially better progression-free survival, overall survival, and depth of response than standard daratumumab-based proteasome inhibitor regimens in patients with relapsed or refractory multiple myeloma. After adjustment, the combination was associated with a 78 percent lower risk of progression or death versus DKd and an 89 percent lower risk versus DVd, alongside a 60 percent and 76 percent reduction in the risk of death, respectively.
In that trial, with a median follow-up of 34.5 months, the combination significantly improved progression-free survival with a hazard ratio of 0.17 and overall survival with a hazard ratio of 0.46 compared with the control regimens. However, most control patients in MajesTEC-3 received DPd, with only 27 of 290 patients, or 9.3 percent, receiving DVd, and 85.5 percent of control patients were refractory to an immunomodulatory drug. Because no head-to-head trial exists against DKd, and the DVd comparison within MajesTEC-3 involved a small subgroup, the researchers turned to individual patient data from the pivotal CANDOR and CASTOR trials to build larger comparator cohorts.
The final analysis included 291 patients treated with teclistamab plus daratumumab, 108 treated with DKd from CANDOR, and 52 treated with DVd from CASTOR.
After weighting, key baseline characteristics were well balanced across cohorts, with covariates considered balanced when the absolute standardized mean difference was below 0.25. Before adjustment, the teclistamab combination cohort had a lower proportion of patients with stage III disease and a higher proportion with high-risk cytogenetics, while the DVd cohort had a lower proportion of double refractory patients.
The survival results were striking. In adjusted analyses, teclistamab plus daratumumab was associated with significantly longer progression-free survival versus DKd, with a hazard ratio of 0.22 and a 95 percent confidence interval of 0.15 to 0.33, and versus DVd, with a hazard ratio of 0.11 and a 95 percent confidence interval of 0.07 to 0.17, both with P values below 0.001. Adjusted median progression-free survival was 28.1 months with DKd and 9.8 months with DVd, while median progression-free survival was not reached in the teclistamab combination group in unadjusted observations. The adjusted 30-month progression-free survival rate was 45.6 percent with DKd and 17.2 percent with DVd, compared with an unadjusted rate of 84.1 percent for the combination. Overall survival followed the same pattern, with adjusted hazard ratios of 0.40 versus DKd and 0.24 versus DVd. Adjusted median overall survival was not reached with DKd and was 25.1 months with DVd, and the adjusted 30-month overall survival rate was 67.6 percent with DKd and 45.6 percent with DVd.
Response outcomes showed even larger differences, particularly for deeper responses. The observed overall response rate was 89.0 percent with teclistamab plus daratumumab compared with 77.8 percent with DKd and 71.2 percent with DVd. Observed rates of very good partial response or better were 86.6 percent for the combination versus 62.0 percent with DKd and 42.3 percent with DVd, and observed complete response or better rates were 81.8 percent versus 24.1 percent and 13.5 percent, respectively. After adjustment, patients on the combination were 1.33 times more likely to achieve very good partial response or better versus DKd and 2.20 times more likely versus DVd, and 2.84 and 5.17 times more likely to achieve complete response or better, respectively. The overall response rate risk ratios were more modest, at 1.11 versus DKd and 1.10 versus DVd, indicating that the greatest separation between treatments lay in the depth rather than the mere occurrence of response.
Sensitivity analyses supported the robustness of these findings. Removing the MajesTEC-3 censoring rule for patients with two or more consecutively missed disease evaluations left the progression-free survival benefit intact, with adjusted hazard ratios of 0.24 versus DKd and 0.12 versus DVd. When progression-free survival was defined per International Myeloma Working Group criteria in CASTOR rather than investigator-based assessment, the adjusted hazard ratio versus DVd remained 0.11. Alternative weighting estimands, including average treatment effect, average treatment effect for the controls, and overlap weighting, as well as doubly robust and multivariable regression methods, all produced results consistent with the primary analysis across survival and binary response endpoints.
The authors and analysts caution that several limitations temper the interpretation of these cross-trial comparisons. Because MajesTEC-3 measured progression-free survival by independent review committee while CANDOR and CASTOR used investigator-based assessment, the comparison carries an assessment-method difference, though the two methods showed high concordance within MajesTEC-3. Cytogenetic risk could not be adjusted for in the DKd analysis due to high missingness, and the proportion of patients with extramedullary disease was limited in both cohorts, potentially affecting generalizability. Prior anti-CD38 exposure was too low across trials to permit meaningful conclusions about its impact, reflecting the era in which CANDOR and CASTOR were initiated, when daratumumab was not yet a major treatment backbone. Differences in median follow-up, which ranged from 34.5 months in MajesTEC-3 to 50.6 months in CANDOR and 72.6 months in CASTOR, and in the availability of subsequent therapies, including bispecific antibodies and CAR-T cell therapy for MajesTEC-3 patients, may also influence long-term overall survival comparisons.
Residual confounding remains an inherent risk in any adjusted comparison of nonrandomized cohorts, and the researchers note that while propensity weighting aligns measured prognostic factors, unmeasured differences between trial populations cannot be ruled out. Nonetheless, the consistency of results across multiple statistical approaches, the use of patient-level rather than aggregated data, and the alignment of eligibility criteria across trials strengthen the evidence. The findings suggest that teclistamab plus daratumumab, a fully immunotherapy-based and steroid-sparing combination, may offer a new standard of care for patients with relapsed or refractory multiple myeloma as early as second-line treatment, providing clinicians with comparative evidence against established daratumumab-proteasome inhibitor regimens where direct randomized data do not exist.
Subject of Research: Adjusted cross-trial comparison of teclistamab plus daratumumab versus daratumumab-based proteasome inhibitor regimens in relapsed or refractory multiple myeloma
Article Title: Teclistamab Plus Daratumumab Versus Standard Daratumumab-Based Proteasome Inhibitor Combinations for Relapsed/Refractory Multiple Myeloma: An Inverse Probability of Treatment Weighting Analysis
Article References: Anderson, L. D., Jr., Nair, S., Keng, M. J., Sun, W., Ammann, E., Ramos, D. F., Ong, F., O’Hara, M., Slavcev, M., Gupta-Werner, N., Doyle, M., & Plattel, W. (2026). Teclistamab Plus Daratumumab Versus Standard Daratumumab-Based Proteasome Inhibitor Combinations for Relapsed/Refractory Multiple Myeloma: An Inverse Probability of Treatment Weighting Analysis. Advances in Therapy. https://doi.org/10.1007/s12325-026-03832-9
Image Credits: AI Generated
DOI: 10.1007/s12325-026-03832-9
Keywords: multiple myeloma, teclistamab, daratumumab, bispecific antibody, proteasome inhibitor, inverse probability of treatment weighting, progression-free survival, overall survival, CANDOR trial, CASTOR trial, MajesTEC-3, relapsed refractory myeloma
News Source: Ophelia Keating. (November 5, 2026). Teclistamab-Daratumumab Combo Outperforms Standard Proteasome Inhibitor Regimens in Adjusted Myeloma Analysis. Scienmag.
