Advancing Bispecific Antibodies Upstream in the Treatment Paradigm of Multiple Myeloma

Bispecific Antibodies: Evolution of T-Cell Redirection in Multiple Myeloma
Bispecific monoclonal antibodies have rapidly reshaped the therapeutic landscape of multiple myeloma by harnessing endogenous T-cell cytotoxicity to target malignant plasma cells. These agents are engineered to simultaneously bind a tumor-associated antigen on myeloma cells—most commonly B-cell maturation antigen (BCMA) or G protein-coupled receptor class C group 5 member D (GPRC5D)—and CD3 on T lymphocytes, thereby redirecting immune effector cells directly into the tumor microenvironment. Engagement of both targets leads to immunologic synapse formation, cytokine release, and subsequent myeloma cell lysis, offering a highly potent, off-the-shelf immunotherapeutic strategy.^1,2

Initial clinical development of bispecific antibodies focused on patients with heavily pretreated, relapsed or refractory multiple myeloma (RRMM), a population historically characterized by limited therapeutic options and poor outcomes. In this setting, multiple BCMA- and GPRC5D-directed bispecific antibodies demonstrated remarkable efficacy, with high overall response rates despite extensive prior exposure to proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies.^1,2 These results established bispecific antibodies as a critical option for patients with triple-class–exposed or refractory disease and provided the foundation for exploring their role earlier in the treatment course.

Established Efficacy in Later-Line Disease as a Launchpad for Earlier Use
Among approved agents, BCMA-directed bispecific antibodies—including teclistamab, elranatamab, and linvoseltamab—as well as the GPRC5D-directed bispecific antibody talquetamab have each shown consistent activity in late-line disease, effectively addressing a major unmet need.^1,2 The depth and durability of responses observed in these studies challenged the traditional paradigm that bispecific antibodies should be reserved for end-stage disease and instead raised the question of whether greater benefit could be achieved by deploying these agents earlier, when immune function is more preserved and disease burden may be lower.

This conceptual shift mirrors earlier experience with PIs and IMiDs, which demonstrated incremental benefit as they moved closer to the frontline. However, bispecific antibodies represent a fundamentally different therapeutic modality, directly engaging adaptive immunity rather than modulating intracellular signaling or the tumor microenvironment. This distinction has fueled enthusiasm for evaluating their impact earlier in the disease course.

MajesTEC-3: Redefining Therapy at First Relapse
The phase 3 MajesTEC-3 trial represents a pivotal moment in the evolution of bispecific antibodies in multiple myeloma. This randomized study evaluated the combination of teclistamab and daratumumab in patients with RRMM after 1 to 3 prior lines of therapy, comparing it with standard daratumumab-based regimens combined with pomalidomide or bortezomib and dexamethasone. Nearly 600 patients were enrolled, with balanced baseline characteristics between treatment arms. The median age was approximately 64 years, roughly one-third of patients had high-risk cytogenetic abnormalities, and more than 80% were refractory to lenalidomide, reflecting a clinically challenging population.^3,4

MajesTEC-3 met its primary endpoint of progression-free survival (PFS) with an unprecedented magnitude of benefit. With a median follow-up approaching 3 years, teclistamab plus daratumumab reduced the risk of disease progression or death by more than 80%, with a hazard ratio of 0.17. An estimated 83% of patients in the investigational arm remained alive and progression-free at 3 years, compared with less than 30% in the control arm. The PFS curves separated early and demonstrated a pronounced plateau beginning around 6 months, suggesting durable disease control in a substantial proportion of patients.^3,4 The benefit of teclistamab plus daratumumab was consistent across all prespecified subgroups, including patients previously exposed to anti-CD38 monoclonal antibodies, those refractory to lenalidomide, and patients with high-risk clinical features such as ISS stage III disease, high tumor burden, or adverse cytogenetics.

Depth of response further distinguished the investigational regimen, with an overall response rate (ORR) of nearly 90% and complete response or better achieved in over 80% of treated patients. Minimal residual disease (MRD) negativity was observed in approximately 60% of the intent-to-treat population and approached 90% among evaluable patients, highlighting the profound cytoreductive capacity of early-line bispecific antibody therapy. Overall survival data reinforced the clinical relevance of these findings, with more than 80% of patients alive at 3 years and a hazard ratio for death of 0.46 compared with standard therapy.^3,4 These outcomes represent one of the most substantial survival advances observed in the early relapsed setting to date. Regarding patients’ quality of life, time to worsening of myeloma symptoms was significantly longer in the teclistamab plus daratumumab arm vs the control arm.

Hematologic toxicities such as neutropenia were common but largely comparable between treatment arms. Cytokine release syndrome (CRS) occurred in approximately 60% of patients receiving teclistamab plus daratumumab, but all events were grade 1 or 2 and resolved with standard management. Immune effector cell-associated neurotoxicity syndrome was rare and reversible. Infectious complications emerged as a key safety signal, particularly early in the trial. Grade 3 or 4 infections were more frequent in the experimental arm, driven in part by profound hypogammaglobulinemia observed in most treated patients. Importantly, infection-related mortality was largely confined to the first 6 months of therapy, before standardized guidelines for immunoglobulin replacement therapy and antimicrobial prophylaxis were implemented. Following protocol amendments mandating proactive supportive care, infection-related mortality markedly declined with only 1 death, underscoring the importance of optimized infection prevention as these agents move upstream.^3,4

Based on the results from MajesTEC-3, the FDA proactively awarded a national priority voucher to teclistamab plus daratumumab for RRMM.⁵ This doublet regimen is now also included in the latest NCCN Guidelines for Multiple Myeloma as a preferred category 1 option for patients with RRMM after 1 prior line of therapy that included lenalidomide and a PI.⁶

Expanding Bispecific Antibodies Into Newly Diagnosed Disease
Beyond early relapse, bispecific antibodies are now being actively evaluated in newly diagnosed multiple myeloma. Early data from the phase 3 MagnetisMM-6 trial part 1 demonstrated promising efficacy with elranatamab-based combinations in transplant-ineligible patients, with confirmed ORR by investigator exceeding 95% and high rates of deep responses.⁷

Similarly, in the phase 2 IFM2021-01 trial, Cohort A is exploring a combination of teclistamab and daratumumab in elderly patients with newly diagnosed, transplant-ineligible disease. This doublet regimen yielded near-universal deep responses and a MRD negativity rate of 100% among evaluable patients.⁸ These findings suggest that bispecific antibodies may be capable of inducing profound disease control even in populations traditionally managed with continuous, lower-intensity therapy.

In transplant-eligible patients with newly diagnosed disease, bispecific antibodies are being investigated as consolidation and maintenance strategies. The phase 3 MajesTEC-4 trial is evaluating teclistamab with or without lenalidomide as post-transplant maintenance therapy. The safety run-in reported a 100% MRD negativity rate at 12 months among evaluable patients.⁹ The phase 2 IMMUNOPLANT trial further demonstrated that linvoseltamab consolidation could eradicate residual disease in patients with MRD positivity following transplant.¹⁰

Looking Ahead: Redefining the Treatment Paradigm
Collectively, these studies illustrate a fundamental reordering of the multiple myeloma treatment paradigm. Numerous phase 3 trials are now underway evaluating bispecific antibody-based regimens in early relapsed and newly diagnosed populations. Earlier use may leverage a more intact immune microenvironment, improving T-cell fitness and enhancing durability of response, while also raising important questions regarding optimal treatment duration, sequencing, and long-term infection risk.

References:

1. Parrondo RD, Ailawadhi S, Cerchione C. Bispecific antibodies for the treatment of relapsed/refractory multiple myeloma: updates and future perspectives. Front Oncol. 2024;14:1394048. doi:10.3389/fonc.2024.1394048
2. Zhou X, Waldschmidt JM, Einsele H. Bispecific antibodies in multiple myeloma: maximizing potential through rational combination therapies. Blood Rev. 2025;74:101342. doi:10.1016/j.blre.2025.101342
3. Mateos MV, Bahlis N, Perrot A, et al. Phase 3 randomized study of teclistamab plus daratumumab versus investigator’s choice of daratumumab and dexamethasone with either pomalidomide or bortezomib (DPd/DVd) in patients with relapsed refractory multiple myeloma (RRMM): results of MajesTEC-3. Blood. 2025;146(suppl_2):LBA-6. doi:10.1182/blood-2025-LBA-6
4. Costa LJ, Bahlis NJ, Perrot A, et al; MajesTEC-3 Trial Investigators. Teclistamab plus daratumumab in relapsed or refractory multiple myeloma. N Engl J Med. Published online December 9, 2025. doi:10.1056/NEJMoa2514663
5. FDA proactively awards national priority voucher based on strong phase 3 study results. FDA.gov. Updated December 15, 2025. Accessed January 22, 2026. https://www.fda.gov/news-events/press-announcements/fda-proactively-awards-national-priority-voucher-based-strong-phase-3-study-results
6. Kumar SK, Callander NS, Adekola K, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Multiple Myeloma (Version 5.2026). © 2026 National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the NCCN Guidelines®, go online to NCCN.org.
7. Dimopoulos M, Pour L, Grosicki S, et al. Elranatamab in combination with daratumumab and lenalidomide (EDR) in patients with newly diagnosed multiple myeloma (NDMM) not eligible for transplant: initial results from MagnetisMM-6 part 1. Hemasphere. 2025;9(suppl_1):S206. doi:10.1002/hem3.70151
8. Manier S, Lambert J, Macro 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):367. doi:10.1182/blood-2025-367
9. Zamagni E, Silzle T, Špička I, et al. Phase 3 study of teclistamab (Tec) in combination with lenalidomide (Len) and Tec alone versus Len alone in newly diagnosed multiple myeloma (NDMM) as maintenance therapy following autologous stem cell transplantation (ASCT): safety run-in (SRI) results from the MajesTEC-4/EMN30 trial. Blood. 2024;144(suppl_1):494. doi:10.1182/blood-2024-205608
10. Kazandjian D, Diamond B, Hoffman J, et al. A phase 2 trial of abbreviated fixed-duration (default 4 cycles) linvoseltamab immuno-consolidation to deepen responses post newly diagnosed multiple myeloma combination therapy for minimal residual disease positivity (the IMMUNOPLANT Study). Blood. 2025;146(suppl_1):248. doi:10.1182/blood-2025-248