Pivotal MagnetisMM-3 Trial Aims to Add Elranatamab in Multiple Myeloma Treatment

Alexander M. Lesokhin, MD

Patients with relapsed/refractory multiple myeloma, particularly those who have failed a prior BCMA–targeted therapy, represent a population with an unmet need for effective treatment options. Investigators are hoping to help fill this void with the initiation of the phase 2 MagnetisMM-3 study (NCT04649359).¹

The MagnetisMM-3 study will evaluate the efficacy of single-agent elranatamab (PF-06863135) in adult patients with relapsed/refractory multiple myeloma. Elranatamab is a bispecific, humanized, monoclonal antibody comprising BCMA- and CD3-targeting arms paired on an IgG2a backbone by hinge-mutation technology. The agent has been granted fast track designation by the FDA.¹

“Elranatamab is in a class of agents called specific engagers,” said Alexander M. Lesokhin, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center, in New York, New York, in an interview with OncologyLive®. “There are a group of these molecules of various formats, but the concept is that they bind at 2 specific moieties: 1 on the tumor cell and 1 on an immune cell. Elranatamab binds [to] BCMA on myeloma cells and [to] CD3 on T cells, and thereby brings together T cells and activates them in the vicinity of the myeloma cell, resulting in cell kill.”

The agent’s manufacturer, Pfizer, temporarily halted enrollment to the MagnetisMM-3 trial on May 4, 2021, after 3 cases of peripheral neuropathy were observed in the ongoing phase 1 MagnetisMM-1 trial (NCT03269136). New enrollment to the trial was paused as the company provided additional information to the FDA. Patients who were deriving clinical benefit from elranatamab were allowed to continue with treatment.²

“Two of those [cases] were patients treated in combination with pomalidomide,” Lesokhin noted. “All patients had prior peripheral neuropathy and all of them improved once the therapy was stopped. The hold has now been lifted and all the [updated] data has been presented to the FDA. There are some mitigation strategies. The main one is to exclude patients with significant prior peripheral neuropathy from participation at this time.”

Initial Safety and Efficacy Data of Elranatamab

Investigators of MagnetisMM-1 are examining elranatamab both as a single agent and in combination with dexamethasone, lenalidomide (Revlimid), or pomalidomide (Pomalyst) in adult patients with relapsed/ refractory multiple myeloma. The primary objectives of the study are to assess safety and tolerability, determine the maximumtolerated dose, and select the recommended phase 2 dose (RP2D) of elranatamab. Secondary objectives include evaluating the antimyeloma activity, pharmacokinetics, and immunogenicity of elranatamab.

In November 2019, investigators reported data from the administration of intravenous, once-weekly, noncontinuous, elranatamab monotherapy in 17 adult patients with relapsed/refractory multiple myeloma, in 6 dose-escalation groups. Most patients were men (71%), with a median age of 61 years (range, 47-82) and the median disease duration since onset was 7 years (range, 1.1-13.3). Patients had a median of 11 prior antimyeloma therapies and 5 patients had previously received BCMAtargeted therapy.³

At the April 9, 2019, data cutoff, 16 patients were evaluable for response. Among the evaluable patients, 1 achieved a minimal response, 6 had stable disease, and 9 experienced disease progression. The clinical benefit rate was determined to be 41% (95% CI, 18.4%-67.1%).³

Concerning safety, 59% of patients experienced treatment-related adverse effects (TRAEs) of any grade. Grade 1/2 TRAEs were most common and included cytokine release syndrome (CRS; 24%), thrombocytopenia (24%), and anemia (18%). Grade 3 TRAEs were observed in 18% of patients and no patients experienced grade 4/5 TRAEs or discontinued treatment because of a TRAE.³

Updated data from MagnetisMM-1, presented at the European Hematology Association 2021 Virtual Congress, reported results of the subcutaneous administration of elranatamab as a single agent. As of the February 4, 2021, data cutoff, 30 patients had received elranatamab subcutaneously at doses of 80 μg/kg (n = 6), 130 μg/kg (n = 4), 215 μg/kg (n = 4), 360 μg/kg (n = 4), 600 μg/kg (n = 6), or 1000 μg/kg (n = 6) weekly.⁴

The population was heavily pretreated, with a median of 8 (range, 3-15) prior antimyeloma treatments; all patients were treated with an immunomodulatory agent and a proteasome inhibitor in the past. Patients were mostly female (56.7%) and the median age was 63 years (range, 46-80). A large majority of patients were triple-class refractory (86.7%).⁴

Responses to treatment were observed beginning at the 215 μg/kg dose, with an overall response rate (ORR) of 70% in 20 patients who received at least 215 μg/kg of elranatamab. Patients who received elranatamab 1000 μg/kg had an ORR of 83.3%, with 1 patient experiencing a complete response. For the 14 patients who responded, the median time to response was 22 days (range, 21-50) and the median duration of response has not yet been reached.⁴

The most common TEAEs of any grade were lymphopenia (83.3%), CRS (73.3%), and anemia (60%). Grade 3/4 TEAEs included lymphopenia (83.3%), neutropenia (53.3%), and anemia (50%). No dose-limiting toxicities were observed across all subcutaneous dose levels.⁴

Based on data from this analysis, investigators stated that elranatamab had a manageable safety profile and the RP2D was 1000 μg/kg. Investigators concluded that results from the updated analysis supported further development of elranatamab both as a monotherapy and in combination with other agents for the treatment of patients with relapsed/refractory multiple myeloma.⁴

Details of the MagnestisMM-3 Trial

MagnetisMM-3 is an open-label, multicenter, nonrandomized study and investigators plan to enroll approximately 150 adult patients with relapsed/refractory multiple myeloma in the United States and Australia (Figure⁵). Patients must be refractory to at least 1 proteasome inhibitor, 1 immunomodulatory agent, and 1 anti-CD38 monoclonal antibody. Participants must also have a maximum ECOG performance status of 2.⁵

Figure. Elranatamab for Patients With Relapsed/Refractory Multiple Myeloma Phase 2, Open Label

Patients who are not eligible for the study include those with smoldering multiple myeloma, active plasma cell leukemia, or amyloidosis. Study participants must also be without any other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ. Stem cell transplant within 12 weeks prior to enrollment is not permitted.⁵

The trial will be divided into 2 cohorts: Cohort A (n = 60) will include patients who have not received prior BCMA-directed therapy and cohort B (n = 90) will include those who have received a prior BCMA-directed therapy. Elranatamab monotherapy will be administered via subcutaneous injection at a dose of 76 mg weekly after a priming dose of 44 mg.¹

“There’s a variety of step-up dose administrations that are being explored with this agent,” Lesokhin said. “It remains to be seen precisely which 1 will be used, but I suspect that there will be a step-up that will ultimately be utilized with the administration of this agent. I should say that this is a strategy that is being used across the board with similar agents in with this type of mechanism of action. This is not unique to elranatamab.”

The primary end point of the trial is to evaluate the efficacy of elranatamab as a single agent by ORR, which will be assessed approximately every 4 weeks for about 2 years by blinded independent central review. Secondary end points include duration of response, cumulative complete response rate, progression-free survival, and overall survival. The expected completion date of the trial is June 2022.⁵

“In the triple-refractory space, this and therapies of this type are very likely to become highly utilized,” Lesokhin concluded. “I say that because they are off the shelf, immediately available treatments. In this space, we [currently] have belantamab mafodotin-blmf [Blenrep] and CAR T-cell therapy. Different treatments will be appropriate for different patients. The location of patients, meaning relative proximity to a treatment center that can deliver CAR T-cell therapy, will determine the utilization of 1 therapy or another in the future. For treatments like CAR T-cell therapy and elranatamab, bispecific engagers, it’s likely that these will move into earlier-line therapies as time goes on to evaluate their impact on longevity and improvement of overall quality of life for patients.”

References

1. Pfizer initiates pivotal phase 2 MagnetisMM-3 trial of BCMA-CD3 bispecific antibody elranatamab (PF-06863135) in multiple myeloma. News release. Pfizer. February 17, 2021. Accessed August 13, 2021. https://www.pfizer.com/news/ press-release/press-release-detail/pfizer-initiates-pivotal-phase-2-magnetismm-3-trial-bcma
2. Pfizer reports strong first-quarter 2021 results. Pfizer. May 4, 2021. Accessed August 13, 2021. https://s21.q4cdn. com/317678438/files/doc_financials/2021/q1/Q1-2021PFE-Earnings-Release.pdf
3. Raje NS, Jakubowiak A, Gasparetto C, et al. Safety, clinical activity, pharmacokinetics, and pharmacodynamics from a phase I study of PF-06863135, a B-cell maturation antigen (BCMA)-CD3 bispecific antibody, in patients with relapsed/ refractory multiple myeloma (RRMM). Blood. 2019;134(suppl 1):1869. doi:10.1182/blood-2019-121805
4. Raje N, Bahlis N, Dholaria B, et al. MagnetisMM-1: phase 1 study of elranatamab (pf-06863135), a B-cell maturation antigen (BCMA) targeted CD3-engaging bispecific antibody, for patients with relapsed or refractory multiple myeloma (MM). Paper presented at: European Hematology Association 2021 Virtual Congress; June 9-17, 2021; virtual. Abstract S192. Accessed August 13, 2021. https://s3.eu-central-1. amazonaws.com/m-anage.com.storage.eha/temp/eha21_ abstract_bodies/201396.html.pdf
5. MagnetisMM-3: study of elranatamab (PF-06863135) monotherapy in participants with multiple myeloma who are refractory to at least one PI, one IMiD and one anti-CD38 mAb. Updated August 12, 2021. Accessed August 13, 2021. https://clinicaltrials.gov/ct2/show/NCT04649359