Extended Teclistamab/Daratumumab Indication Approaches EU Approval in R/R Multiple Myeloma

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has issued a positive opinion regarding the approval of an indication extension for teclistamab-cqyv (Tecvayli) plus daratumumab for use in adult patients with relapsed or refractory multiple myeloma who have previously received at least 1 therapy.¹

The recommendation is supported by findings from the phase 3 MajesTEC-3 study (NCT05083169), which found that at a median follow-up of 34.5 months, the estimated 36-month progression-free survival (PFS) rate was 83.4% (95% CI, 78.2%-87.4%) with teclistamab/daratumumab (n = 291) vs 29.7% (95% CI, 23.6%-36.0%) with dexamethasone plus investigator’s choice of pomalidomide (Pomalyst; DPd) or bortezomib (Velcade; DVd; n = 296).² Specifically, the median PFS was not reached in the teclistamab arm vs 18.1 months in the DPd or DVd arm (HR, 0.17; 95% CI, 0.12-0.23; P < .001). The P value crossed the prespecified superiority boundary (P = .0139) at the first interim analysis.

“Unprecedented data show a meaningful extension in overall survival [OS] and minimal progression events observed after the first 6 months. More than 90% of patients receiving the combination who were progression-free at six months remained progression-free at three years, highlighting the potential for durable long-term disease control,” Ester in’t Groen, EMEA Therapeutic Area Head of Haematology at Johnson & Johnson, stated in a news release.¹ “This CHMP opinion marks an important step towards establishing the off-the-shelf immunotherapy combination of teclistamab plus daratumumab as a new standard of care earlier in the treatment pathway for multiple myeloma.”

How was the phase 3 MajesTEC-3 trial designed?

MajesTEC-3 was a multicenter, open-label trial that randomly assigned 587 patients 1:1 across 150 sites in 20 countries to teclistamab plus daratumumab or the investigator's choice of DPd or DVd.² Eligible patients had received 1 to 3 prior lines, including a proteasome inhibitor and lenalidomide (Revlimid), with documented progression on or following the last line; those with only 1 prior line were required to have lenalidomide-refractory disease. Prior BCMA-directed therapy and anti-CD38 refractoriness were exclusion criteria. Randomization was stratified by the investigator's choice of DPd or DVd, International Staging System stage, prior anti-CD38 exposure, and number of prior lines.

Teclistamab was administered subcutaneously following 2 step-up doses (0.06 and 0.3 mg/kg), then 1.5 mg/kg weekly in cycles 1 and 2, 3 mg/kg every 2 weeks in cycles 3 through 6, and 3 mg/kg every 4 weeks from cycle 7 onward, aligned with the approved subcutaneous daratumumab schedule. In the comparator arm, 90.7% of patients received DPd. Baseline characteristics (n = 587) were balanced: median age was 64 years (range, 25-88), the median number of prior lines was 2 (range, 1-3), 35.9% had high cytogenetic risk, and only 5.3% had prior anti-CD38 exposure. The primary end point was PFS by independent review committee.

What were the OS and response outcomes with teclistamab plus daratumumab?

Teclistamab plus daratumumab also conferred a lower risk of death (P < .0001 by stratified log-rank test). The estimated 36-month OS rate was 83.3% (95% CI, 78.3%-87.2%) vs 65.0% (95% CI, 58.8%-70.5%) with DPd or DVd. The OS curves crossed at approximately 10 months, attributed primarily to early infection-related deaths in the teclistamab arm; a restricted mean survival time analysis showed a benefit favoring teclistamab plus daratumumab (difference, 2.15 months; 95% CI, 0.54-3.77).

The rate of complete response or better was 81.8% vs 32.1% (risk ratio [RR], 2.55; 95% CI, 2.14-3.03), and the overall response rate was 89.0% vs 75.3% (RR, 1.18; 95% CI, 1.09-1.27). Minimal residual disease negativity at 10⁻⁵ was reached in 58.4% vs 17.1% of patients (RR, 3.43; 95% CI, 2.58-4.55). The median time to first response was 1.2 months in both arms, and an estimated 88.5% (95% CI, 83.7%-92.0%) of responders in the teclistamab arm continued to respond at 36 months vs 36.4% (95% CI, 28.9%-43.9%) in the comparator arm.

What was the safety profile of teclistamab plus daratumumab in relapsed/refractory multiple myeloma?

Serious adverse effects occurred in 70.7% of patients in the teclistamab arm vs 62.4% in the DPd or DVd arm, with pneumonia the most common (16.6% vs 13.1%). The most common grade 3/4 adverse effect (AE) was neutropenia (75.6% vs 78.6%). Adverse effects led to treatment discontinuation in 4.6% and 5.5% of patients, respectively. Death from AEs during treatment occurred in 7.1% (n = 20) of teclistamab-treated patients vs 5.9% (n = 17); treatment-related deaths occurred in 4.2% vs 1.7%.

Cytokine release syndrome (CRS) occurred in 60.1% of teclistamab-treated patients, all grade 1 (44.2%) or grade 2 (15.9%), with a median duration of 2 days (range, 1-22); all events resolved, none led to discontinuation, and no grade 2 events occurred after cycle 1. Immune effector cell–associated neurotoxicity syndrome was reported in 3 patients (1.1%), including 1 grade 4 event. Grade 3/4 infections were reported in 54.1% vs 43.4% of patients, and fatal infections occurred in 13 patients (4.6%) vs 4 (1.4%); 12 of 13 fatal infections in the teclistamab arm occurred within 6 months of initiation, prior to reinforced protocol-specified immune globulin guidance. Hypogammaglobulinemia occurred in 84.5% vs 60.3% of patients.

What came before this with teclistamab?

In March 2026, the FDA cleared teclistamab plus daratumumab and hyaluronidase-fihj (Darzalex Faspro) for use in adult patients with relapsed/refractory multiple myeloma who have received at least 1 previous line of therapy based on MajesTEC-3 data.³

In a past exclusive interview with OncLive®, Peter Forsberg, MD, of Blood Cancer Institute, unpacked data from MajesTEC-3 shared during the 2025 ASH Annual Meeting and Exposition:⁴

References

1. CHMP recommendation advances Johnson & Johnson’s TECVAYLI®▼ (teclistamab) plus daratumumab as a potential standard of care for relapsed/refractory multiple myeloma. News release. June 26, 2026. Accessed June 26, 2026. https://www.jnj.com/media-center/press-releases/chmp-recommendation-advances-johnson-johnsons-tecvayli-teclistamab-plus-daratumumab-as-a-potential-standard-of-care-for-relapsed-refractory-multiple-myeloma
2. Costa LJ, Bahlis NJ, Perrot A, et al. Teclistamab plus daratumumab in relapsed or refractory multiple myeloma. N Engl J Med. 2026;394(8):739-752. doi:10.1056/NEJMoa2514663
3. FDA grants third approval under the national priority voucher program. FDA. March 5, 2026. Accessed June 26, 2026. https://www.fda.gov/news-events/press-announcements/fda-grants-third-approval-under-national-priority-voucher-program
4. Forsberg P. Dr Forsberg on the impact of the MajesTEC-3 trial in relapsed/refractory myeloma. OncLive.com. December 16, 2025. Accessed June 26, 2026. https://www.onclive.com/view/dr-forsberg-on-the-impact-of-the-majestec-3-trial-in-relapsed-refractory-myeloma