Wild-type Reovirus in Combination With Carfilzomib and Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma

PRIMARY OBJECTIVES:

I. Determine safety and tolerability, and define the maximum tolerated dose of reolysin
(wild-type reovirus), 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 wild-type reovirus.

Patients receive dexamethasone intravenously (IV), carfilzomib IV over 30 minutes, and
wild-type reovirus IV over 60 minutes on days 1, 2, 8, 9, 15, and 16. Courses 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

- Presence of serum and/or urinary measurable monoclonal protein or light chains

- 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

- 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)

- 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; 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