Phase 3, Randomized Study of Talquetamab (tal) Plus Daratumumab (dara) ± Pomalidomide (pom) Vs Dara Plus Pom and Dexamethasone (dpd) in Relapsed/refractory Multiple Myeloma (rrmm): Monumental-3
Year: 2026
Type: article
Study design: Clinical Trial
Abstract: Background Tal (anti-GPRC5D bispecific antibody) has shown deep, durable responses in late-line RRMM with a favorable infection profile. Its B-cell–sparing mechanism supports combination with Dara and Pom, potentially enhancing efficacy in earlier lines. We report efficacy and safety from a pre-planned interim analysis of MonumenTAL-3 (NCT05455320) comparing Tal-DP and Tal-D vs DPd in RRMM after ≥1 prior LOT. Methods Phase 3 study randomizing pts with RRMM after ≥1 prior LOT including lenalidomide (Len) and a proteasome inhibitor 1:1:1 to Tal-DP, Tal-D, or DPd. Primary endpoint was IRC-assessed PFS for Tal-DP vs DPd and Tal-D vs DPd. Secondary endpoints included response, ≥CR, MRD-negative ≥CR (10−5; NGS), OS, and safety. Results Overall, 864 pts were randomized (Tal-DP, N=287; Tal-D, N=287; DPd, N=290). Baseline characteristics were balanced across arms. Median age was 64.0 yrs (range 30–88), median prior LOT was 2 (range 1–8); 11.8% were anti-CD38 (nearly all Dara) exposed; 85.1% and 93.4% were refractory to Len or last LOT, respectively; 30.9% had high risk cytogenetics. At 24.6 mo median follow-up, Tal-DP and Tal-D significantly improved PFS vs DPd (HRs 0.28 [0.20–0.40], P<0.0001 and 0.33 [0.24–0.46], P<0.0001. 24-mo PFS rates favored Tal-DP (81.3% [75.8–85.7]) and Tal-D (77.6% [71.7–82.5]) vs DPd (51.2% [44.8–57.1]) PFS benefit was consistent across clinically relevant subgroups. ORRs (88.2%, 88.5%, 77.6%) ≥CR rates (71.1%, 69.0%, 34.5%) and MRD-negative ≥CR rates (52.3%, 46.3%, 15.9%) were significantly higher for Tal-DP and Tal-D vs DPd, respectively. OS HRs (95% CI) vs DPd were 0.47 (0.30–0.73; P=0.0006) for Tal-DP and 0.51 (0.33–0.78; P=0.0015) for Tal-D. At data cutoff, 70.3% (Tal-DP), 69.7% (Tal-D) and 47.3% (DPd) of pts remained on study tx. AEs were manageable and consistent with expectations for each agent; overall AE rates (gr 3-4, gr 5) Tal-DP (96.7%, 1.8%), Tal-D (78.8%, 4.0%), DPd (95.8%, 4.6%). AEs leading to discontinuation (d/c) of all study tx occurred in 10.5% (Tal-DP), 8.0% (Tal-D), and 6.7% (DPd). Rates of cytopenias (any gr, gr 3-4) were: Tal-DP (91.7%, 87.7%), Tal-D (68.2%, 51.8%) and DPd (91.9%, 89.0%). Infection rates (any gr, gr 3-4, gr 5) were: Tal-DP (87.3%, 37.0%, 0.7%) Tal-D (84.3%, 27.7%, 1.5%), and DPd (83.0%, 41.0%, 1.8%). With Tal-DP and Tal-D, respectively, CRS (any gr: 67.8%; 58.4%) and ICANS (any gr: 2.9%; 1.8%) were mostly gr 1-2. Any gr GPRC5D-related AEs with Tal-DP, Tal-D and DPd, respectively, included taste changes (72.8%; 74.8%; 3.9%) and decreased weight (45.7%; 38.3%; 7.4%); most events were gr 1-2 and did not lead to Tal d/c. Ataxia/balance disorders (gr 1-2, gr 3) with Tal-DP (11.6%, 2.9%), Tal-D (10.2%, 2.2%) and DPd (0.4%, 0%) were primarily low gr (none gr ≥4); events led to Tal d/c in 4.7% (Tal-DP) and 2.2% (Tal-D). Conclusions Tal-DP and Tal-D demonstrated a significant and profound PFS benefit vs DPd, clinically meaningful OS improvements and gr ≥3 infection rates similar to or lower than DPd. Tal was combinable, with low rates of tx d/c. Efficacy appeared numerically better with Tal-DP vs Tal-D but with a higher gr 3-4 cytopenia rate, as expected with Pom. Tal-D with or without Pom represents a new standard of care for RRMM as early as 2L across all practice settings.
Authors: Peter VOORHEES, Roberto MINA, Paula RODRÍGUEZ OTERO, Wenming CHEN, María Victoria MATEOS, Jian LI, Philippe MOREAU, Yael COHEN, Chang KI MIN, Roman HAJEK, Christine YE, Hila MAGEN, Sam RUBINSTEIN, Weijun FU, Vania HUNGRIA, Guldane CENGIZ SEVAL, Joao Samuel SAMUEL FARIAS, Jakub RADOCHA, Senem MARAL, Mehmet TURGUT, Youngil KOH, Daniel O'LEARY, Jayr SCHMIDT FILHO, Raymond THERTULIEN, Gang AN, Shang YI HUANG, Sebastian GROSICKI, Agata TYCZYNSKA, Rahul BANERJEE, Matthew PIANKO, Joaquín MARTÍNEZ-LÓPEZ, Pawel STECKIEWICZ, Dai Maruyamadai MARUYAMA, Kentaro FUKUSHIMA, Albert ORIOL, Jordi LOPEZ PARDO, Hartmut GOLDSCHMIDT, Charlotte PAWLYN, Aurore PERROT, Elena ZAMAGNI, Meletios Athanasios DIMOPOULOS, Leo RASCHE, Jaszianne TOLBERT, Jaszianne TOLBERT, William TERRY, Christelle COURTOUX, Xiao LIU, Sandra Y VASEY, Kaitlyn CONNORS, Maria Cristina FESTA, Christoph HEUCK, Angélique LANGLOIS, Lisa O'ROURKE, Jiangxiu ZHOU, Xiang QIN, Jiashen LU, Jue GONG, Diego VIEYRA, Meral BEKSAC
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
Funder: Johnson and Johnson
OpenAlex ID: W7223093227