In a phase II MagnetisMM-3 study conducted in heavily pretreated patients with relapsed or refractory multiple myeloma, elranatamab demonstrated a high rate of deep and durable responses, including in patients who achieved at least complete response (CR), with a manageable safety profile. Administration of a two step-up priming dose regimen successfully mitigated the rate and severity of cytokine release syndrome (CRS) with a predictable profile supporting the potential for outpatient administration.
Although additional follow-up is needed, maintenance or deepening of response was observed with elranatamab following the switch to a biweekly schedule. Biweekly administration may provide greater patient convenience with potentially less toxicity. Elranatamab is also a readily accessible, off-the-shelf therapy, which provides an option for patients unable to access CAR T-cell therapy. The findings are published by Dr. Alexander M. Lesokhin of the Division of Hematology and Oncology, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College in New York City, NY, US, and colleagues on 15 August 2023 in the Nature Medicine.
The authors wrote in the background that introduction of immunomodulatory drugs, proteasome inhibitors and anti-CD38 monoclonal antibodies has transformed the treatment landscape in multiple myeloma. The addition of these agents has substantially improved survival; however, outcomes for patients with disease progression after these agents remain poor with a median progression-free survival (PFS) of 4.6 months and median overall survival (OS) of 12.4 months with a standard of care therapy. In recent years, the development of T-cell-redirecting therapies has shown promise in this patient population.
The authors explained that B-cell maturation antigen (BCMA), a member of the tumour necrosis factor receptor superfamily, is highly expressed on malignant plasma cells, making it an ideal target for the treatment of multiple myeloma. Several BCMA-directed therapies, including belantamab mafodotin, idecabtagene vicleucel, ciltacabtagene autoleucel and teclistamab, have shown efficacy in clinical studies and are approved for the treatment of relapsed or refractory multiple myeloma.
Elranatamab is a humanised bispecific antibody that targets both BCMA on myeloma cells and CD3 on T cells. Elranatamab activates and directs T cells to induce a cytotoxic T-cell response against myeloma cells. Preliminary data from the ongoing phase I MagnetisMM-1 study demonstrated encouraging safety and efficacy of elranatamab in patients with relapsed or refractory multiple myeloma.
The registrational phase II MagnetisMM-3 study evaluated the efficacy and safety of elranatamab monotherapy in patients with relapsed or refractory multiple myeloma. Results in patients without prior BCMA-targeted treatment (cohort A) after approximately 15 months of follow-up, including clinical experience in patients who switched to biweekly dosing after persistent response, are reported in the article published in the Nature Medicine. Cohort B, which enroled patients previously treated with BCMA-directed therapies, will be reported separately.
In the ongoing phase II MagnetisMM-3 study, patients with relapsed or refractory multiple myeloma received subcutaneous elranatamab at a dose of 76 mg once weekly after two step-up priming doses of 12 mg and 32 mg during the first week of treatment. After six cycles, persistent responders switched to biweekly dosing. The authors reported the results from 123 patients in cohort A, which enroled patients without prior BCMA-directed therapy. The primary endpoint of confirmed objective response rate (ORR) by blinded independent central review was met with an ORR of 61.0% (75 of 123 patients); 35.0% achieved at least CR.
Fifty responders switched to biweekly dosing, and 40 (80.0%) improved or maintained their response for at least 6 months. With a median follow-up of 14.7 months, median duration of response (DoR), PFS and OS (secondary endpoints) have not been reached. Fifteen-month rates were 71.5%, 50.9% and 56.7%, respectively. A consistent benefit was observed across clinically relevant subgroups,
Common adverse events (any grade; grade 3–4) included infections (69.9%, 39.8%), CRS (57.7%, 0%), anaemia (48.8%, 37.4%), and neutropenia (48.8%, 48.8%). With biweekly dosing, grade 3–4 adverse events decreased from 58.6% to 46.6%.
The authors concluded that elranatamab induced deep and durable responses with a manageable safety profile. Switching to biweekly dosing may improve long-term safety without compromising efficacy. They commented that the interpretation of the results is limited by single arm design and lack of direct comparison with other treatment options, as well as by the small sample size in some subgroups. Longer-term follow-up is required to confirm benefits in DoR, PFS and OS.
Current results support further investigation of elranatamab as monotherapy and its further investigation in combination with standard or new therapies for patients with multiple myeloma. An ongoing open-label, randomised phase III study is evaluating elranatamab monotherapy versus elranatamab plus daratumumab versus standard of care daratumumab plus pomalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma who have received lenalidomide and a proteasome inhibitor.
This study was funded by Pfizer.
Reference
Lesokhin AM, Tomasson MH, Arnulf B, et al. Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results. Nature Medicine; Published online 15 August 2023. DOI: https://doi.org/10.1038/s41591-023-02528-9
