This phase I trial studies the side effects and best dose of wild-type reovirus when combined with carfilzomib and dexamethasone in treating patients with multiple myeloma that has come back following treatment (relapsed) or does not respond to treatment (refractory). Chemotherapy drugs, such as dexamethasone and carfilzomib, 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. A virus called wild-type reovirus may be able to kill cancer cells without damaging normal cells and seems to work best when given with chemotherapy. Giving wild-type reovirus with chemotherapy may be a more effective treatment than chemotherapy alone.

PRIMARY OBJECTIVES:

I. Determine safety and tolerability, and define the maximum tolerated dose of pelareorep (Reolysin), carfilzomib and dexamethasone in patients with relapsed multiple myeloma.

II. Obtain evidence of reovirus entry into myeloma cells via localization of reoviral ribonucleic acid (RNA) in multiple myeloma (MM) cells (in situ hybridization [ISH]), and active viral proliferation/replication via localization of reoviral capsid protein (immunohistochemistry [IHC]) in MM cells in cycle 1 day 9 bone marrow biopsies in all patients enrolled in dose escalation cohorts.

SECONDARY OBJECTIVES:

I. Obtain preliminary data on response as determined by International Myeloma Working Group criteria after protocol therapy.

II. Obtain overall and progression free survival data for all treated patients. III. Assess cytokine arrays of peripheral blood obtained on days 1, 2, 9, 15 and once during days 22-28 of cycle 1, and day 1 of cycle 2 and each successive cycle to obtain exploratory data regarding inflammatory cytokine concentrations and their correlation with response.

IV. Investigate pretreatment cycle 1 days 1 and 9 bone marrow aspirate interferon (IFN)-beta in MM cells as a potential marker of Reolysin resistance.

V. Measure the induction of endoplasmic reticulum (ER) stress and autophagy markers to explore their respective roles in MM cell death following combination Reolysin and carfilzomib in patients treated in all dose escalation cohorts.

VI. Evaluate pretreatment cycle 1 days 1 and 9 peripheral blood to explore the antiviral humoral response by measuring the production of neutralizing reoviral antibody (NARA) using a functional killing assay.

VII. Obtain cycle 1 day 1 pretreatment and 1 and 4 hours after treatment, and pretreatment cycle 1 days 2 and 9 peripheral blood, and pretreatment cycle 1 days 1 and 9 bone marrow aspirate samples to investigate the role of carfilzomib in modulating the antiviral immune mediated response.

OUTLINE: This is a dose escalation study of Reolysin.

Patients receive dexamethasone intravenously (IV), carfilzomib IV over 30 minutes, and Reolysin IV over 60 minutes on days 1, 2, 8, 9, 15, and 16. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks and then every 6 months thereafter.

Inclusion Criteria:

• Patient must have relapsed or refractory myeloma that fits or did fit International Myeloma Working Group (IMWG) diagnostic criteria for symptomatic myeloma (although new or worsening end organ damage is not required to be eligible) as defined below:

  • Presence of clonal bone marrow plasma cells

  • Evidence of any end organ damage criteria listed below (at any time) attributed to the patient's myeloma:

    • Hypercalcemia: serum calcium > 11.5 mg/dL or
    • Renal insufficiency: serum creatinine > 2 mg/dL
    • Anemia > 2 g/dL below the lower limit of normal or a hemoglobin value < 10 g/dL
    • Bone lesions: lytic lesions, severe osteopenia or pathologic fractures

• In the safety expansion 10 patient group but not during dose escalation, patients must have measurable disease defined as any of the following:

  • Serum monoclonal protein >= 500 mg/dL by protein electrophoresis
  • > 200 mg of monoclonal protein in the urine on screening 24-hour electrophoresis
  • Serum immunoglobulin free light chain >= 100 mg/L AND abnormal serum immunoglobulin kappa to lambda free light chain ratio

• Patients must have been previously treated with an immunomodulatory drug (IMiD) and proteasome inhibitor, must be refractory to carfilzomib defined as progression on or within 2 months of a carfilzomib-containing therapy, and must be progressing

• Prior autologous and/or allogeneic transplant is permitted although transplant must have occurred greater than 90 days prior to registration

• Both men and women of all races and ethnic groups are eligible for this study

• Prior radiation is permitted; however, at least 2 weeks must have elapsed since the completion of prior radiation therapy and patients must have recovered from all radiation-associated toxicities to no greater than grade 1 at the time of registration

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) is required for eligibility; those patients with lower performance status based solely on bone pain secondary to multiple myeloma are eligible

• Absolute neutrophil count (ANC) >= 1000/uL

• Platelet count >= 75,000 and transfusion independent

• Total bilirubin < 1.5 mg/dL

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x the institutional upper limit of normal

• Ability to understand and the willingness to sign a written informed consent document

• Patients must be able to avoid direct contact with pregnant or nursing women, infants and immunocompromised individuals during the days of Reolysin treatment and for two days after

• Patients must not have known human immunodeficiency virus (HIV) infection or active hepatitis B or C infections

• Systolic cardiac function will be assessed at screening if clinically indicated by history and physical; only patients with left ventricular ejection fraction (LVEF) >= 50% will be eligible for enrollment

• Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL prior to starting therapy and prior to beginning another cycle (if applicable)

• The effects of Reolysin on the developing human fetus are unknown; for this reason women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) starting 28 days prior to starting the study until at least 90 days following discontinuation of the trial therapy; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

• A female of childbearing potential (FCBP) is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

• Patients must agree not to donate blood, sperm/ova during the course of taking protocol therapy and for at least 4 weeks after stopping treatment

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 2 weeks prior to entering the study; patients may be receiving concomitant therapy with bisphosphonates and low dose corticosteroids (e.g., prednisone up to but no more than 10 mg by mouth daily or its equivalent) for symptom management and comorbid conditions; doses of corticosteroid should be stable for at least 7 days prior to study treatment
• Patients who are receiving any other therapeutic investigational agents
• Patients previously treated on clinical trial with Reolysin
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, myocardial infarction in the preceding 6 months, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study because protocol therapy has the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to protocol treatment of the mother, breastfeeding should be discontinued
• Patients with a "currently active" second malignancy that, in the opinion of the principal investigator, will interfere with patient participation, increase patient risk, shorten survival to < 1 year, or confound data interpretation
• Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M-protein), and skin changes (POEMS) syndrome
• Concurrent use of complementary or alternative medicines that in the opinion of the principal investigator would confound the interpretation of toxicities and/or antitumor activity of the study drug