Abstract
Background Elranatamab (PF-06863135) is a humanized bispecific molecule that targets multiple myeloma (MM) cells via B-cell maturation antigen (BCMA) and T cells via CD3 to induce T cell-mediated cytotoxicity. In MagnetisMM-1 (NCT03269136), an ongoing, phase 1 study in patients with relapsed or refractory MM (RRMM), subcutaneous (SC) elranatamab yielded an overall response rate (ORR) of 64% and had a manageable safety profile (Jakubowiak et al, J Clin Oncol, 2022). In the phase 2 MagnetisMM-3 (NCT04649359) study in patients with heavily pretreated RRMM, SC elranatamab was well tolerated and yielded an ORR of 61% at the recommended phase 2 dose (Lesokhin et al, J Clin Oncol, 2022).
Study Design and Methods MagnetisMM-4 (NCT05090566) is a phase 1B/2, open label, non-randomized, multicenter, umbrella study of elranatamab in combination with other anti-cancer treatments for patients with MM. The estimated enrollment is 105 patients. The study is split into 2 sub-studies (Figure 1). In each sub study, a 2 step-up priming dose of elranatamab will be employed to mitigate the risk of cytokine release syndrome and a Bayesian logistic regression model will be utilized for dose escalation.
Sub-study A (SSA) is comprised of 2 phases in which patients will receive elranatamab + the gamma-secretase inhibitor (GSI) nirogacestat. Studies have shown that GSIs block BCMA cleavage and can potentially enhance BCMA-directed therapy (Eastman et al, Blood, 2019; Pont et al, Blood, 2019; Cowan et al, Blood, 2019). Phase 1 of SSA is designed to evaluate the safety, tolerability and select a recommended dose and regimen for the combination of elranatamab and nirogacestat. The primary endpoint for SSA Phase 1 is dose limiting toxicity (DLT) up to 35 days. Phase 2 of SSA will further evaluate the efficacy and safety of the combination of elranatamab and nirogacestat. The primary endpoint for SSA phase 2 is objective response rate (ORR) assessed every 4 weeks for ~2 years. A key secondary endpoint in both phases of SSA is the incidence of treatment-emergent adverse events (TEAEs).
In sub-study B (SSB), patients will receive elranatamab + lenalidomide + dexamethasone. The dose escalation part of SSB is designed to assess the safety and tolerability of elranatamab in combination with lenalidomide and dexamethasone. The primary outcome of the dose escalation part is DLT up to 42 days. The dose expansion part of SSB is designed to evaluate the overall safety profile of elranatamab in combination with lenalidomide and dexamethasone. The primary endpoints of the dose expansion part of SSB are incidence of TEAEs and laboratory abnormalities across the duration of the study. A key secondary endpoint in SSB is ORR. Additional secondary endpoints in both SSA and SSB are time to response, duration of response, complete response (CR) rate, duration of CR, progression-free survival, overall survival, minimal residual disease negativity rate, immunogenicity to elranatamab, and elranatamab pharmacokinetics.
Inclusion criteria in SSA and SSB include age ≥18 years, RRMM with ≥3 prior lines of therapy, refractory to at least one immunomodulatory drug, one proteasome inhibitor, and one anti-CD38 antibody, measurable disease by serum M-protein ≥0.5g/dL, urinary M-protein excretion ≥200mg/24h, or serum immunoglobulin free light chain (FLC) ≥10mg/dL and abnormal serum immunoglobulin kappa to lambda FLC ratio, and Eastern Cooperative Oncology Group performance status ≤1 (Table 1). Exclusion criteria include active plasma cell leukemia, amyloidosis, stem cell transplant within 12 weeks prior to enrolment or active graft-versus-host disease, POEMS syndrome, any active uncontrolled infection, impaired cardiovascular function or clinically significant cardiovascular disease within 6 months prior to enrolment, and previous administration with an investigational drug within 30 days or 5 half-lives preceding the first dose of study treatment. In SSA, patients who received prior treatment with a BCMA-bispecific antibody are excluded, and in SSB, patients who received prior treatment with BCMA-directed therapy are excluded. The study is enrolling the Phase 1 portions and is being opened at multiple sites in the United States and Canada.
Disclosures
Landgren:Janssen: Honoraria, Other: Independent Data Monitoring Committee (IDMC) member for clinical trials, Research Funding; Tow Foundation: Research Funding; Amgen: Honoraria, Research Funding; Leukemia & Lymphoma Society: Research Funding; MMRF: Honoraria; Aptitude Health: Honoraria; Rising Tide Foundation: Research Funding; Riney Foundation: Research Funding; Merck & Co., Inc.: Other: Independent Data Monitoring Committee (IDMC) member for clinical trials; Pfizer Inc: Consultancy; Theradex: Other: Independent Data Monitoring Committee (IDMC) member for clinical trials; NCI/NIH: Research Funding. Kazandjian:Plexus Communications: Honoraria; SINTOMA: Honoraria; MMRF: Honoraria; Curio Science: Honoraria; Aptitude Health: Honoraria; Arcellx: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; CURE: Honoraria. O'Connell:Pfizer Inc: Current Employment, Current holder of stock options in a privately-held company. Finn:Pfizer: Current Employment, Current equity holder in publicly-traded company. Raje:Amgen: Consultancy, Honoraria; Medscape: Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Research to Practice: Honoraria; Two Seventy Bio: Research Funding; Massachusetts General Hospita: Current Employment; Celgene: Honoraria; Janssen: Consultancy, Honoraria.
