Results presented during the 2025 ASH Annual Meeting showed that with a median follow-up of 10.3 months, all 37 patients in the intention-to-treat (ITT) population achieved a very good partial response (VGPR) or better with the doublet as their best response. This included a VGPR rate of 32%, a complete response (CR) rate of 8%, and a stringent CR (sCR) rate of 59%. The VGPR or better rate after 4 cycles was 79%, and the overall response rate (ORR) after 4 cycles was 95%; partial response, VGPR, and CR rates were 16%, 76%, and 3%, respectively.
Moreover, all evaluable patients (n = 27) achieved MRD negativity at a sensitivity of 10-6 by next-generation sequencing (NGS) at 6 months. This rate was 73% for patients in the ITT population who underwent MRD evaluation by NGS.
[Additionally], the progression-free survival [PFS] and overall survival [OS] rates were 100%, and there [were no instances of] grade 3 or higher cytokine release syndrome or immune effector cell–associated neurotoxicity syndrome [observed],” Salomon Manier, MD, PhD, an associate professor in the Department of Hematology at Lille University Hospital in France, stated in his oral presentation of the data. “These results support further exploration of frontline combinations of BCMA/CD3 bispecific antibodies plus anti-CD38 monoclonal antibodies in phase 3 clinical trials.”
What was the rationale for evaluating this all-antibody regimen in the front line for patients with newly diagnosed multiple myeloma?
The current standard-of-care for elderly patients with newly diagnosed multiple myeloma include daratumumab-containing triplet and anti-CD38 antibody–based quadruplet regimens. Although these regimens prolong survival and produce MRD negativity rates at 10-5 between 32% to 61%, many patients will ultimately relapse; accordingly, further optimization is key.
“Recently, the combination of teclistamab and daratumumab has demonstrated strong efficacy in the late-relapsed setting [as well as] the early-relapsed setting,” Manier shared.
Initial results from cohort 1 (n = 26) of the safety-run-in portion of the phase 3 MajesTEC-7 trial (NCT05552222) showed that, at a median follow-up of 13.8 months (range, 2.0-15.4), teclistamab administered in combination with daratumumab and hyaluronidase-fihj (Darzalex Faspro) plus lenalidomide (Revlimid) produced a VGPR or better rate of 92.3% and a 12-month PFS rate of 96.2%.2 Moreover, the phase 3 MajesTEC-3 trial (NCT05083169) recently met its primary PFS end point after approximately 3 years of follow-up with teclistamab plus daratumumab and hyaluronidase vs investigator’s choice of therapy in patients with relapsed/refractory multiple myeloma who had received 1 to 3 prior treatment lines.3
“We hypothesized that a doublet regimen with [just] teclistamab and daratumumab…would be effective and limit toxicity in elderly patients with newly diagnosed multiple myeloma,” he said.
How was IFM2021-01 designed?
IFM2021-01 is an open-label, multicenter, single-arm, phase 2 study evaluating 2 doublets in the frontline setting for transplant-ineligible patients with newly diagnosed multiple myeloma: teclistamab plus daratumumab (Cohort A) and teclistamab plus lenalidomide (Cohort B; n = 37).1 Patients are also required to be older than 65 years of age and have an ECOG performance status (PS) between 0 and 2.
In cohort A, teclistamab is administered subcutaneously (SC) in 2 step-up doses, followed by a 1.5 mg/kg dose on days 8 and 15 of cycle 1, and maintenance dosing at 3 mg/kg every 4 weeks thereafter. SC daratumumab is administered weekly at a dose of 1800 mg for 8 weeks, every 2 weeks for 16 weeks, and every 4 weeks thereafter.
Following an amendment to the study protocol, teclistamab is now administered at a dose of 3 mg/kg every 8 weeks after cycle 13 if patients achieved a CR or better; treatment interruption was permitted if patients sustained MRD negativity for 2 years. A prespecified safety and efficacy analysis was conducted after 18 patients received at least 2 cycles.
The primary end point in cohort A is the rate of VGPR or better after 4 cycles. Secondary end points include response rates, PFS, OS, time to next treatment, MRD negativity at 10-6 by NGS at 6 months, sustained MRD 10-6 ,and treatment-emergent adverse effects (TEAEs).
What should be known about the baseline characteristics of patients in this study?
Overall, the patient population in cohort 1 was representative of the larger transplant-ineligible, newly diagnosed population.
The median age was 73 years (range, 66-87), with the majority of patients between 70 to 75 years of age (49%), and 32% of patients being 75 years or older. Most patients were female (54%), had an ECOG PS of 1 (65%), had stage II disease (51%), did not have extramedullary disease (95%), and had a creatinine clearance of 60 mL/min or greater (62%). According to the International Myeloma Working Group Frailty score, 44% of patients were fit, 33% were intermediate, and 22% were frail. Types of measurable disease included immunoglobulin G (59%), immunoglobulin A (22%), and serum-free light chain only (19%).
The majority of patients had standard cytogenetic risk (68%). Among patients with high-risk disease (32%), mutations included 1q gains (38%); 17p deletions (14%); TP53 mutations (10%); t(4;14), t(14;16), and t(14;20) mutations (3% each); and 1p32 deletions (7%).
As of the data cutoff date of November 4, 2025, 36 patients remain on treatment, with only 1 patient having discontinued treatment due to AEs. The median duration of treatment was 10.3 months (range Q1-Q3, 9.3-16.6), and patients received a median of 12 total treatment cycles (range, 10-18). The median relative dose intensity was 95% (range, 89%-100%) for teclistamab and 96.6% for daratumumab (range, 90.5%-100%).
What did additional assessments of tumor burden biomarkers show?
Additional assessment of tumor burden biomarkers using clonotypic mass spectroscopy at 6 months showed a deep decrease of chronotypes and soluble BCMA at 6 months.
“Only 3 patients had a chronotype below 5 mg, which is considered the equivalent of emergency negativity at 10-5,” Manier shared, noting that, “ of course, we need to consider that this is an early time point in regards to the elution of the monoclonal components.”
Additionally, flow cytometry indicated immune remodeling at 6 months, with an increase in terminal effector memory T-cells and a decrease in regulatory T cells and natural killer cells.
“[This increase in memory T-cells] reflects the continuous antigen exposure; the [decrease in regulatory T cells and natural killer cells] is likely due to the combination with dartumumab,” Manier added. “That can explain the synergy between the 2 drugs.”
What was the safety profile of this doublet?
In the ITT population, the incidence of grade 3 or higher AEs and serious AEs was 78% and 27%, respectively. No grade 5 AEs were observed. Hematologic AEs included lymphopenia (57%), neutropenia (43%), anemia (5%), and thrombocytopenia (3%). Non-hematologic AEs included infection (14%), hepatic cytolysis (5%), and skin rash (5%). AEs of special interest included infections (any-grade 65%; grade 1/2, 52%; grade 3 or higher, 14%); CRS (59%; grade 1, 35%; grade 2, 24%), injection site reactions (19%, all grade 1/2), and second primary malignancies (3%, all grade 1/2). The cumulative incidence of grade 3/4 infections was spread across time.
“One important thing is that we had a strong recommendation in the trial to give immunoglobulin supplementation systematically to all patients as soon as cycle 1…so 95% of the patients received an immunoglobulin supplementation,” Manier reported. “The median cycle of initiation of this supplementation was indeed cycle 1, and this was able to maintain the level of IgG around 7 g/L across the course of treatment.”
Additionally, systematic monitoring of cytomegalovirus (CMV) by PCR every 3 months showed that there was no correlation with CMV reactivation and the count of CD4 T cells.
Disclosures: Manier has served as a consultant for Abbvie, Adaptive Biotechnology, Amgen, Celgene/BMS, GSK, Janssen, Novartis, Regeneron, Roche, Sanofi, and Takeda; he has also received research funding from Celgene/BMS and Janssen.
References
- Ahn I, Parrondo R, Thompson M, et al. A phase 2 Study of teclistamab in combination with daratumumab in elderly patients with newly diagnosed multiple myeloma: The IFM2021-01 teclille trial, cohort a. Blood. 2025;146(suppl 1):85. doi:10.1182/blood-2025-85
- Tecvayli and Talvey - MajesTEC-7 (MMY3005) study. J&J Medical Connect. Updated July 31, 2025. Accessed December 7, 2025. https://www.jnjmedicalconnect.com/products/tecvayli/medical-content/tecvayli-and-talvey-majestec7-mmy3005-study#Touzeau2024
- Tecvayli plus Darzalex Faspro combination regimen significantly improves progression-free survival and overall survival versus standard of care. News Release. Johnson&Johnson. October 16, 2025. Accessed December 7, 2025. 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
