The purpose of this clinical trial is to (1) learn whether the BCMA-CD3 bispecific antibody elranatamab can provide more benefit to people with multiple myeloma compared to a combination therapy including daratumumab, pomalidomide, and dexamethasone, and (2) learn about the safety and activity of elranatamab in combination with the anti-CD38 monoclonal antibody daratumumab. People with multiple myeloma who have received previous treatment including lenalidomide 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 evaluate the safety and activity of (1) elranatamab alone compared to daratumumab, pomalidomide, and dexamethasone, and (2) elranatamab plus daratumumab.

Part 3 will assess the effect of increased measures to protect against infection in people treated with either elranatamab alone or together with daratumumab.

All people participating in 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.

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.

• 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.

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.
• 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.

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical\_trials/trial\_data\_and\_results/data\_requests.