Highlight
This phase 1/1b study of the BCMA-targeting bispecific T-cell engager pavurutamab (AMG 701) evaluated its safety and clinical activity in heavily pretreated relapsed/refractory multiple myeloma (RRMM) patients. Pavurutamab demonstrated a manageable safety profile with cytokine release syndrome (CRS) as the most common adverse event, mostly low grade and manageable. At the recommended phase 2 dose (RP2D) of 18,000 μg, the overall response rate (ORR) reached 65.8%, with a median duration of response (DOR) of 36.6 months and progression-free survival (PFS) of 16.8 months. These results support further development of BCMA-directed T-cell engager therapy for triple-class RRMM patients.
Study Background
Multiple myeloma (MM) is a plasma cell malignancy characterized by clonal proliferation of malignant plasma cells within the bone marrow, causing significant morbidity and mortality. Therapeutic advances have improved survival substantially, but patients eventually develop relapsed and refractory disease, especially after exposure to the three major drug classes: proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies. For patients with triple-class relapsed/refractory MM, treatment options remain limited, often associated with poor outcomes and short progression-free intervals.
B-cell maturation antigen (BCMA) is a transmembrane receptor expressed primarily on late-stage B cells and plasma cells, making it an attractive target for immunotherapy in MM. BCMA-targeted therapies, including antibody-drug conjugates, CAR T cells, and bispecific T-cell engagers (BiTEs), can redirect cytotoxic T cells to eradicate MM cells with BCMA expression. Pavurutamab (AMG 701) is a novel BCMA-directed bispecific T-cell engager designed to bind both BCMA on MM cells and CD3 on T cells, promoting targeted cytotoxicity.
Study Design
This was a phase 1/1b, open-label, dose-escalation and dose-expansion study evaluating the safety, tolerability, pharmacokinetics, and efficacy of intravenous (IV) pavurutamab monotherapy in adult patients with triple-class relapsed/refractory MM. Eligible patients were heavily pretreated, refractory to at least proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies.
The dosing ranged from 5 μg to 18,000 μg administered weekly with a step-up dosing regimen during the first treatment week to mitigate cytokine release syndrome. The primary endpoints of phase 1 included establishing the recommended phase 2 dose (RP2D) based on dose-limiting toxicities (DLTs). Secondary endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), safety, and pharmacokinetics.
Key Findings
A total of 172 patients received at least one dose of pavurutamab. Among these, 73 patients were treated at the RP2D of 18,000 μg, with two step-up dosing regimens applied in phase 1b.
Safety and Tolerability
DLTs were observed in 12 patients, comprising mainly cytokine release syndrome (CRS) and elevated liver transaminases; however, none occurred at the RP2D. CRS occurred in 74.4% of patients, mostly grade 1 or 2, manageable with standard supportive measures. Other common treatment-emergent adverse events included anemia (61.0%), neutropenia (47.1%), and hypophosphatemia (45.3%). Grade 3 or higher infections were reported in 34.9% of patients, indicating significant immunosuppression that warrants vigilant monitoring.
Efficacy
The overall response rate (ORR) across all dose levels was 46.5%. Notably, at the RP2D, the ORR increased to 65.8%, with 60.3% of patients achieving very good partial response (VGPR) or better. Median duration of response at median follow-up of 17.2 months was 36.6 months (95% CI, 22.3 to not estimable), indicating deep and durable responses in this heavily pretreated cohort.
Median progression-free survival (PFS) improved correspondingly: for all patients, PFS was 5.5 months (95% CI, 2.8–10.1), while at the RP2D, median PFS was notably longer at 16.8 months (95% CI, 5.0 to not estimable). These findings suggest dose optimization impacts clinical benefit.
Pharmacokinetics and Biomarkers
Pavurutamab exposure increased in a dose-proportional manner. Elevated soluble BCMA levels correlated with lower drug exposure, potentially due to antigen sink effects, which may inform patient selection or dosing strategies in future studies.
Expert Commentary
This study is among the first to report clinical results with pavurutamab, a BCMA-targeting bispecific T-cell engager, in triple-class relapsed/refractory MM patients. The manageable safety profile, with predominantly low-grade CRS and absence of DLTs at the RP2D, supports a favorable therapeutic window. The observed ORR and durable responses in such a heavily pretreated population are clinically meaningful and compare favorably to other BCMA-directed therapies.
However, high rates of infections highlight immunosuppression risks, likely linked to T-cell engagement and profound plasma cell depletion, necessitating careful infection prophylaxis and monitoring. The heterogeneity of step-up dosing regimens and the open-label, non-randomized design limit direct comparisons. Longer follow-up and randomized trials will be required to confirm durability and survival benefit and to optimize dosing protocols.
Mechanistically, the correlation of soluble BCMA with lower drug exposure suggests that circulating antigen levels may modulate therapeutic availability, representing an important biomarker for response stratification. Such insights may guide precision dosing or combination strategies.
Conclusion
Pavurutamab represents a promising BCMA-directed immunotherapeutic option for patients with triple-class relapsed/refractory multiple myeloma, demonstrating encouraging efficacy and an acceptable safety profile in this phase 1/1b study. The dose-dependent improvement in response rates and progression-free survival at the RP2D supports its continued development. Further studies, including larger phase 2/3 trials, are needed to establish its role in the MM treatment landscape, explore combinatorial approaches, and define patient subsets most likely to benefit.
Funding and Clinical Trial Registration
This study was sponsored by Amgen Inc. and was registered on ClinicalTrials.gov under the identifier NCT03287908.
References
- Lee HC, Plattel WJ, Harrison SJ, et al. A phase 1/1b study of the BCMA-targeting bispecific T-cell engager pavurutamab for relapsed/refractory multiple myeloma. Blood. 2026 Jul 9;148(2):199-212. PMID: 41950113.
- Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384(8):705–716.
- Munshi NC, et al. BCMA-targeted therapies in multiple myeloma: recent advances and future outlook. Nat Rev Clin Oncol. 2022;19(7):405–423.
