Wild-Type Reovirus, Bortezomib, and Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) with the maximum REOLYSIN (wild-type
reovirus) dose limited to 4.5 x 10^10 tissue culture infection dose (TCID)50 and the safety
profile of REOLYSIN in combination with bortezomib and dexamethasone in patients with
relapsed or refractory multiple myeloma (MM). (Phase 1b) II. To further explore the safety
and tolerability of the combination and to determine the overall response rate (ORR)
(complete response [CR] + partial response [PR]) to REOLYSIN in combination with bortezomib
and dexamethasone in patients with relapsed or refractory MM. (Phase 1b Dose Expansion)

SECONDARY OBJECTIVES:

I. To determine ORR in the Phase 1b part to the combination at escalating doses.

II. To determine the progression-free survival (PFS) of patients with relapsed or refractory
MM treated with REOLYSIN in combination with bortezomib and dexamethasone.

III. To evaluate the effect of REOLYSIN in combination with bortezomib and dexamethasone
treatments on overall survival (OS).

IV. To conduct pharmacodynamic studies as described.

OUTLINE: This is a phase Ib, dose-escalation study of wild-type reovirus followed by a phase
Ib expansion trial.

Patients receive dexamethasone orally (PO), intravenously (IV), or intramuscularly (IM) and
bortezomib subcutaneously (SC) (preferably) or IV over 3-5 seconds on days 1, 8, and 15.
Patients also receive 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 at 1 month and then every 3
months thereafter.

Inclusion Criteria:

- Have relapsed or refractory MM after at least one line of therapy

- Have a confirmed diagnosis of MM with measurable disease, as defined by the presence
of monoclonal immunoglobulin protein in serum electrophoreses of at least 0.5 g/dL for
immunoglobulin G (IgG) or 0.25 g/dL for IgA, or measurable light chain in serum (100
mg/L) or urinary excretion of at least 200 mg monoclonal light chain per 24 hours

- Have NO continuing acute toxic effects (except alopecia) of any prior chemotherapy,
radiotherapy or surgical procedures; all such effects must have resolved to Common
Terminology Criteria for Adverse Events (CTCAE, Version 4.03) grade =< 1; surgery
(except minor procedures such as biopsies, IV line placement, etc.) must have occurred
at least 28 days prior to study enrollment

- Have received NO anti-cancer therapy within 28 days prior to receiving study drug

- Have received NO radiotherapy within 14 days prior to receiving study drug

- Have an Eastern Cooperative Oncology Group (ECOG) Performance score =< 2

- Have a life expectancy of at least 3 months

- Absolute neutrophil count (ANC) >= 1 x 10^9 (International System [SI] units 10^9/L)
(with or without filgrastim [G-CSF])

- Platelets >= 50 x10^9 (SI units 10^9/L)

- Serum creatinine =< 2 x upper limit of normal (ULN)

- Bilirubin =< 1.5 x ULN

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN (=< 5 x ULN
if patients have liver involvement with MM)

- Proteinuria < grade 2

- Have a negative pregnancy test if a female with childbearing potential

- Have signed an informed consent indicating that the patient is aware of the neoplastic
nature of their disease and have been informed of the procedures of the protocol, the
experimental nature of the therapy, possible alternative therapies, potential
benefits, side effects, risks, and discomforts

- Be willing and able to comply with scheduled visits, the treatment plan, and
laboratory tests

Exclusion Criteria:

- Have a history of or current evidence of intracranial disease; patients with brain
metastases must be excluded from this clinical trial

- Be on immunosuppressive therapy or have human immunodeficiency virus (HIV) infection
or active hepatitis B or C

- Be a pregnant or breast-feeding woman; female patients of childbearing potential must
agree to use effective contraception, must be surgically sterile, or must be
postmenopausal; male patients must agree to use effective contraception or be
surgically sterile; barrier methods are a recommended form of contraception

- Have clinically significant cardiac disease (New York Heart Association, class III or
IV) including pre-existing arrhythmia, uncontrolled angina pectoris, myocardial
infarction 1 year prior to study entry, or a known history of grade 2 or higher
compromised left ventricular ejection fraction

- Have dementia or altered mental status that would prohibit informed consent

- Have any other severe, acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or study
drug administration or may interfere with the interpretation of study results and, in
the judgment of the principal investigator, would make the patient inappropriate for
this study

- Have a history of allergic (anaphylactic) sensitivity to bortezomib, boron or mannitol

- Have grade 2 or greater neuropathy at the time of screening