Teclistamab-Daratumumab Intensification Achieves 73% MRD-Negative CR Rate in High-Risk Multiple Myeloma

Frontline intensification with teclistamab-cqyv (Tecvayli; Johnson & Johnson) and daratumumab (Darzalex; Johnson & Johnson) produced a minimal residual disease (MRD)-negative complete response (CR) in 73% of patients with newly diagnosed high-risk multiple myeloma, according to findings presented at the 23rd International Myeloma Society Annual Meeting.¹

The phase 2 study used MRD results to determine whether patients continued teclistamab-daratumumab maintenance or received early rescue with talquetamab-tgvs (Talvey; Johnson & Johnson). The approach moves bispecific antibodies into frontline treatment for patients with adverse disease features, although the regimen remains investigational in this setting.

Targeting High-Risk Disease Earlier

The study enrolled 30 patients with protocol-defined high-risk multiple myeloma. Eligibility factors included high-risk cytogenetic abnormalities such as del(17p), t(4;14), t(14;16), and 1q amplification; Revised International Staging System stage 3 disease; or extramedullary or paramedullary involvement.¹

Patients initially received 4 cycles of daratumumab, bortezomib, lenalidomide, and dexamethasone (D-VRd). This was followed by 6 cycles of intensification with teclistamab and daratumumab. Patients who achieved MRD negativity proceeded to 2 years of teclistamab-daratumumab maintenance. Those with persistent MRD received early rescue treatment with talquetamab and daratumumab.¹

Teclistamab redirects CD3-positive T cells toward B-cell maturation antigen expressed on myeloma cells. Talquetamab also engages CD3 but targets G protein–coupled receptor class C group 5 member D, providing a second antigen target for disease that remains detectable after BCMA-directed therapy.

Both agents were initially developed for heavily pretreated relapsed or refractory multiple myeloma. Teclistamab is now FDA approved with daratumumab for previously treated disease, whereas talquetamab is approved after at least 4 prior lines of therapy. Their use as part of initial treatment remains investigational.^2,3

Bispecific Intensification Deepens Responses

After D-VRd induction, the overall response rate (ORR) was 76.7%, with 20% of patients achieving CR or better. The MRD-negative CR rate in the intention-to-treat population was 13.3%.¹

Responses deepened substantially following teclistamab-daratumumab intensification. ORR increased to 93.3%, and 80% of patients achieved CR or better. Twenty-two of 30 patients reached the primary end point of MRD-negative CR, producing a rate of 73% in the intention-to-treat population. Complete metabolic response by PET-CT was reported in 75% of evaluable patients.¹

At the data cutoff, 22 patients remained on teclistamab-daratumumab maintenance. Only 1 patient had switched to talquetamab-daratumumab rescue because of persistent MRD positivity. The limited use of rescue therapy means the current analysis primarily establishes the activity of teclistamab-daratumumab intensification, rather than the efficacy of sequential targeting with talquetamab.

The study extends the response-adapted strategy evaluated in the MASTER trial, which used MRD status to guide treatment duration after daratumumab, carfilzomib, lenalidomide, and dexamethasone and autologous stem cell transplantation. MASTER demonstrated that MRD can guide treatment cessation, but patients with multiple high-risk cytogenetic abnormalities continued to experience inferior outcomes despite achieving deep responses. The current study focuses directly on this difficult-to-treat population and uses persistent MRD to trigger a change in antigen target.⁴

Infection Burden Requires Close Attention

Treatment-emergent adverse events occurred in 96.4% of evaluable patients. During teclistamab-daratumumab intensification, infections occurred in 78.6%, including grade 3 infections in 14.3%. No grade 4 or 5 infections were reported.¹

Cytokine release syndrome occurred in 7 patients, or 25%, and all cases were grade 1. One patient required tocilizumab. A single case of grade 2 immune effector cell–associated neurotoxicity syndrome resolved with corticosteroids. Teclistamab was discontinued in 2 patients because of rash and peripheral neuropathy. One treatment-related death occurred during the study.¹

The infection rate is especially relevant because BCMA-directed bispecific therapy can impair normal plasma cells and immunoglobulin production. Consensus recommendations emphasize vaccination, antimicrobial prophylaxis, immunoglobulin replacement when indicated, and continued infection surveillance during bispecific-antibody therapy.⁵

For pharmacists, frontline bispecific therapy would expand responsibilities beyond step-up dosing and acute monitoring. Long-term care would require medication coordination, assessment of infection risk, immunoglobulin monitoring, and documentation of MRD-directed treatment changes.

The 73% MRD-negative CR rate provides an encouraging efficacy signal in high-risk disease. Longer follow-up is needed to determine whether these responses remain durable and whether switching targets for persistent MRD improves progression-free or overall survival.

REFERENCES

1. Rodríguez-Otero P, Ocio EM, Oriol A, et al. MRD-guided frontline T-cell redirection therapy for newly diagnosed high-risk multiple myeloma using teclistamab-daratumumab intensification and talquetamab-daratumumab early rescue intervention. Presented at: 23rd International Myeloma Society Annual Meeting; September 23-26, 2026; Glasgow, Scotland.

2. FDA approves teclistamab in combination with daratumumab and hyaluronidase-fihj for relapsed or refractory multiple myeloma. FDA. March 5, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-teclistamab-combination-daratumumab-hyaluronidase-fihj-relapsed-or-refractory-multiple

3. FDA grants accelerated approval to talquetamab-tgvs for relapsed or refractory multiple myeloma. FDA. August 10, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-talquetamab-tgvs-relapsed-or-refractory-multiple-myeloma

4. Costa LJ, Chhabra S, Medvedova E, et al. Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone With Minimal Residual Disease Response-Adapted Therapy in Newly Diagnosed Multiple Myeloma. J Clin Oncol. 2022;40(25):2901-2912. doi:10.1200/JCO.21.01935

5. Ludwig H, Terpos E, van de Donk N, et al. Prevention and management of adverse events during treatment with bispecific antibodies and CAR T cells in multiple myeloma: a consensus report of the European Myeloma Network. Lancet Oncol. 2023;24(6):e255-e269. doi:10.1016/S1470-2045(23)00159-6