Overview

The main purpose of the study is to evaluate the safety and tolerability of the combination of elranatamab and carfilzomib and dexamethasone or elranatamab and maplirpacept.

There are 2 parts to this study. Part 1 will evaluate the safety and tolerability of elranatamab when given in combination with carfilzomib plus dexamethasone. Part 2 has 2 arms. The first will evaluate the safety and tolerability of elranatamab when given in combination with maplirpacept. The second will identify the optimal dose(s) of elranatamab plus maplirpacept.

All study medicines are given over 4-week cycles. Everyone taking part in this study will receive elranatamab as a shot under the skin. Participants in Part 1 will also receive weekly carfilzomib as an IV infusion (given directly into a vein) and dexamethasone either by mouth (as a pill) or by IV infusion. Participants in Part 2 will receive elranatamab in combination with maplirpacept as an IV infusion (given directly into a vein)

The investigators will examine the experiences of people receiving the study medicines. This will help determine if the study medicines are safe and can be used for multiple myeloma treatment. Participants will take part in this study for about 2 years after the first dose.

Eligibility

Inclusion Criteria:

• Prior diagnosis of multiple myeloma as defined by IMWG criteria.
• 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).
• Part 1: Received at least 1 but not more than 3 prior lines of therapy for multiple

  myeloma (induction therapy followed by stem cell transplant and consolidation/maintenance therapy will be considered as 1 line of therapy).

• Part 2: Received at least 3 prior lines of therapy for multiple myeloma who are refractory to at least one IMiD, one PI and one anti-CD38 antibody.
• ECOG performance status 0-1.
• Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade ≤1.
• Not pregnant or breastfeeding and willing to use contraception.
• Prior therapy with carfilzomib is allowed as long as the participant had (all apply): responded to most recent therapy with carfilzomib; Carfilzomib was not discontinued due to toxicity; Did not relapse within 60 days from discontinuation of carfilzomib; Will have at least a 6-month carfilzomib treatment-free interval from last dose received until first study treatment.

Exclusion Criteria:

• Plasma cell leukemia, Smouldering MM, Waldenströms macroglobulinemia, Amyloidosis, POEMS Syndrome, Primary refractory MM
• Impaired cardiovascular function or clinically significant cardiovascular diseases.
• Participants with any active, uncontrolled bacterial, fungal, or viral infection.
• Stem cell transplant within 12 weeks prior to enrollment, or active graft versus host disease.
• 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.
• Part 1: Previous treatment with a BCMA-directed therapy.
• Part 2: Previous treatment with any anti-BCMA directed therapy, with the exception of CAR-T. Previous treatment with a CD47-SIRP alpha-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.
• Any of the following within 3 months of enrollment: erosive esophagitis, treatment resistant peptic ulcer, infectious or inflammatory bowel disease, pulmonary embolism or uncontrolled thromboembolic event.
• Participants who are unable to tolerate carfilzomib due to suspected carfilzomib-related congestive heart failure or thrombotic microangiopathy.