Purpose of this study?
The purpose of this study is to evaluate whether the BCMA-CD3 bispecific antibody elranatamab, alone and/or in combination with the anti-CD38 monoclonal antibody, daratumumab, can provide more benefit to people with multiple myeloma compared to a combination therapy including daratumumab, pomalidomide, and dexamethasone. People with multiple myeloma who have received previous treatment including lenalidomide and a proteasome inhibitor will be enrolled in the study. Part 1 of the study will assess the safety and activity of different doses of elranatamab in combination with daratumumab. People participating in Part 2 of the study will be randomly assigned to receive either elranatamab alone, elranatamab plus daratumumab, or daratumumab, pomalidomide, and dexamethasone. Part 2 will compare the safety and activity of (1) elranatamab alone compared to daratumumab, pomalidomide, and dexamethasone, and (2) elranatamab plus daratumumab compared to daratumumab, pomalidomide, and dexamethasone. Participants in both parts of the study will receive study treatment until their disease progresses, they experience unacceptable side effects, or they choose to no longer participate in the study.
Key Inclusion Criteria:
- Prior diagnosis of multiple myeloma as defined by IMWG criteria (Rajkumar et al, 2014).
- Measurable disease based on IMWG criteria as defined by at least 1 of the following:
- Serum M-protein ≥0.5 g/dL.
- Urinary M-protein excretion ≥200 mg/24 hours.
- Serum immunoglobulin FLC ≥10 mg/dL (≥100 mg/L) AND abnormal serum immunoglobulin kappa to lambda FLC ratio (<0.26 or >1.65).
- Prior anti-multiple myeloma therapy including treatment with lenalidomide and a proteasome inhibitor.
- ECOG performance status ≤2.
- Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade ≤1.
- Not pregnant and willing to use contraception.
Key Exclusion Criteria:
- Smoldering multiple myeloma.
- Plasma cell leukemia.
- Amyloidosis.
- POEMS Syndrome.
- Stem cell transplant within 12 weeks prior to enrolment, or active graft versus host disease.
- Active HBV, HCV, SARS-CoV2, HIV, or any active, uncontrolled bacterial, fungal, or viral infection.
- Any other active malignancy within 3 years prior to enrolment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ.
- Previous treatment with a BCMA-directed therapy.
- Anti-CD38-directed therapy within 6 months preceding the first dose of treatment in this study.
- Live attenuated vaccine within 4 weeks of the first dose of study intervention.
- Administration with an investigational product (e.g. drug or vaccine) concurrent with study intervention or within 30 days preceding the first dose of study intervention used in this study.
Primary Outcome Measures:
- Part 1 Safety Lead-In: Incidence of dose limiting toxicities [ Time Frame: First 42 days after first elranatamab dose ]
- Part 2 Randomized: Progression free survival per International Myeloma Working Group criteria [ Time Frame: From date of randomization to date of progressive disease, discontinuation from the study, death, or censoring, whichever occurs first, assessed up to 32 months ]
Secondary Outcome Measures:
- Part 1 Safety Lead-In: Progression free survival per International Myeloma Working Group criteria [ Time Frame: From date of randomization to date of progressive disease, discontinuation from study, death, or censoring, whichever occurs first, assessed up to 32 months ]
- Overall survival [ Time Frame: From date of randomization to date of discontinuation from study, death, or censoring, whichever occurs first, assessed up to 32 months ]
- Objective response rate per International Myeloma Working Group criteria [ Time Frame: From date of randomization to date of progressive disease, discontinuation from study, death, or start of new anticancer therapy, whichever occurs first, assessed up to 32 months ]
- Duration of response per International Myeloma Working Group criteria [ Time Frame: From date of confirmed objective response to date of progressive disease, discontinuation from study, death, or censoring, whichever occurs first, assessed up to 32 months ]
- Time to response per International Myeloma Working Group criteria [ Time Frame: From date of randomization to date of confirmed objective response, assessed up to 32 months ]
- Complete response rate per International Myeloma Working Group criteria [ Time Frame: From date of randomization to date of progressive disease, discontinuation from study, death, or start of new anticancer therapy, whichever occurs first, assessed up to 32 months ]
- Duration of complete response per International Myeloma Working Group criteria [ Time Frame: From date of confirmed complete response to date of progressive disease, discontinuation from study, death, or censoring, whichever occurs first, assessed up to 32 months ]
- Minimal residual disease negativity rate per International Myeloma Working Group criteria [ Time Frame: From date of randomization to date of progressive disease, discontinuation from study, death, or start of new anticancer therapy, whichever occurs first, assessed up to 32 months ]
- Sustained minimal residual disease negativity rate per International Myeloma Working Group criteria [ Time Frame: From date of randomization to date of progressive disease, discontinuation from study, death, or start of new anticancer therapy, whichever occurs first, assessed up to 32 months ]
- Progression free survival on next-line treatment per International Myeloma Working Group criteria [ Time Frame: From date of randomization to date of second objective disease progression, discontinuation from the study, death, or censoring, whichever occurs first, assessed up to 32 months ]
- Frequency of treatment-emergent adverse events [ Time Frame: From date of first dose of study intervention through minimum of 90 days after last study intervention administration. Reporting of non-serious AEs ends at start of new anti-cancer therapy. ]
- Frequency of abnormal laboratory results [ Time Frame: From date of first dose of study intervention through minimum of 90 days after last study intervention administration. Reporting of non-serious AEs ends at start of new anti-cancer therapy. ]
- Rate of Grade ≥2 cytokine release syndrome [ Time Frame: First 28 days after first elranatamab dose ]
- Elranatamab pharmacokinetics by pre- and post-dose concentrations [ Time Frame: From date of first dose through up to 14 days after date of last dose of elranatamab ]
- Elranatamab immunogenicity by anti-drug antibodies against elranatamab [ Time Frame: From date of first dose through up to 14 days after date of last dose of elranatamab ]
- Daratumumab pharmacokinetics by pre-dose concentrations [ Time Frame: From date of first dose through up to 14 days after date of last dose of daratumumab ]
- Health-related quality of life by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 [ Time Frame: From date of informed consent through up to 35 days after date of last dose of study intervention ]
- Health-related quality of life by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Myeloma 20 [ Time Frame: From date of informed consent through up to 35 days after date of last dose of study intervention ]
Study Locations in Europe: Austria, Belgium, Czech Republic, Finland, France, Germany, Greece, Italy, Netherlands, Norway, Poland, Spain, Sweden.
Estimated Study Completion Date: December 29, 2025
Further information on clinicaltrial.gov - trial number NCT05020236