This phase II trial compares the combination of selinexor, daratumumab, Velcade (bortezomib), and dexamethasone (Dara-SVD) to the usual treatment of daratumumab, lenalidomide, bortezomib, and dexamethasone (Dara-RVD) in treating patients with high-risk newly diagnosed multiple myeloma. Selinexor is in a class of medications called selective inhibitors of nuclear export (SINE). It works by blocking a protein called CRM1, which may keep cancer cells from growing and may kill them. Daratumumab is in a class of medications called monoclonal antibodies. It binds to a protein called CD38, which is found on some types of immune cells and cancer cells, including myeloma cells. Daratumumab may block CD38 and help the immune system kill cancer cells. Bortezomib blocks several molecular pathways in a cell and may cause cancer cells to die. It is a type of proteasome inhibitor and a type of dipeptidyl boronic acid. Dexamethasone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Lenalidomide is in a class of medications called immunomodulatory agents. It works by helping the bone marrow to produce normal blood cells and by killing abnormal cells in the bone marrow. The drugs daratumumab, lenalidomide, bortezomib, dexamethasone and selinexor are already approved by the FDA for use in myeloma. But selinexor is not used until myeloma comes back (relapses) after initial treatment. Giving selinexor in the initial treatment may be a superior type of treatment for patients with high-risk newly diagnosed multiple myeloma.

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.