PRIMARY OBJECTIVES:~I. To establish the safety of bortezomib-dexamethasone (BOR-D) and pembrolizumab (cohort 1) and its combination with pelareorep (PELA) (cohorts 2). (Phase 1B) II. To determine the recommended phase 2 dose (RP2D) for PELA in combination with BOR-D and pembrolizumab in patients with relapsed or refractory multiple myeloma (RRMM; cohorts 2). (Phase 1B) III. To estimate the efficacy of the combination of PELA, BOR -D and pembrolizumab in patients with RRMM. (Phase 2)~SECONDARY OBJECTIVES:~I. To evaluate the efficacy PELA in combination with BOR-D and pembrolizumab (cohorts 2) in patients with RRMM. (Phase 1B) II. To characterize the safety and tolerability of the combination, including acute and chronic toxicities. (Phase 2)~EXPLORATORY OBJECTIVES:~I. To compare changes in the tumor microenvironment (TME) and immune responses in patients treated with BOR-D and pembrolizumab (cohort 1) to patients treated with PELA, BOR-D, and pembrolizumab (cohort 2). (Phase 1B) II. To evaluate changes in the TME and immune responses in patients treated with the combination of PELA, BOR-D and pembrolizumab. (Phase 2)~OUTLINE: This is a phase IB dose escalation study followed by a phase II study. Patients are assigned to 1 of 2 cohorts.~COHORT I: Patients receive bortezomib subcutaneously (SC) or intravenously (IV) and dexamethasone orally (PO), IV, or intramuscularly (IM) on days 1, 8, and 15 of each cycle. Patients also receive pembrolizumab IV over 30 minutes on day 9 of each cycle. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity.~COHORT II: Patients receive bortezomib SC or IV and dexamethasone either PO, IV, or IM on days 1, 8, and 15 of each cycle. Patients also receive pelareorep IV over 60 minutes on days 1, 2, 8, 9, 15, and 16 and pembrolizumab IV over 30 minutes on day 9 of each cycle. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity.~After completion of study, patients are followed-up every 12 weeks or every 6 months depending on status of disease.
This phase I/II trial studies the safety of the combination of bortezomib, dexamethasone, and pembrolizumab with or without pelareorep in treating patients with multiple myeloma that has come back (relapsed) or does not response to treatment (refractory). Chemotherapy drugs, such as bortezomib and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. A virus modified in the laboratory, such as pelareorep, may be able to kill cancer cells without damaging normal cells. Giving the combination of bortezomib, dexamethasone, and pembrolizumab with pelareorep may work better in treating patient with multiple myeloma.