A Phase II Trial of Romidepsin and Bortezomib for Multiple Myeloma Patients With Relapsed or Refractory Disease

Inclusion Criteria

Inclusion Criteria

Patients must fulfill all of the following criteria to be eligible for study
participation:

- Male or female patients aged ≥ 18 years old

- Has given voluntary written informed consent before any study-related procedure not
part of normal medical care, with the understanding that consent may be withdrawn by
the patient at any time without prejudice to their future medical care

- Previously diagnosed with multiple myeloma (MM) based on standard criteria as
follows:

- Major criteria:

1. Plasmacytomas on tissue biopsy.

2. Bone marrow plasmacytosis (>30% plasma cells).

3. Monoclonal immunoglobulin spike on serum electrophoresis IgG >3.5 g/dL or
IgA >2.0 g/dL; kappa or lambda light chain excretion >1 g/day on 24 hour
urine protein electrophoresis

- Minor criteria:

1. Bone marrow plasmacytosis (10 to 30% plasma cells)

2. Monoclonal immunoglobulin present but of lesser magnitude than given under
major criteria

3. Lytic bone lesions.

4. Normal IgM <50 mg/dL, IgA <100 mg/dL or IgG <600 mg/dL

Any of the following sets of criteria will confirm the diagnosis of MM:

- Any two of the major criteria

- Major criterion 1 plus minor criterion 2, 3, or 4.

- Major criterion 3 plus minor criterion 1 or 3.

- Minor criteria 1, 2, and 3 or 1, 2, and 4.

- Currently has MM with:

o Measurable disease, defined as a monoclonal immunoglobulin spike on serum
electrophoresis of >=1 gm/dL and/or urine monoclonal immunoglobulin spike of >=200
mg/24 hours, or evidence of lytic bone disease

- Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2

- Life-expectancy > 3 months

- All women of childbearing potential must use an effective barrier method of
contraception. Male patients should use a barrier method of contraception during the
treatment period and for 3 months thereafter

- Patients must meet the following laboratory criteria at Baseline (Day 1 of Cycle 1,
before study drug administration):

- Platelet count ≥ 100*10^9/L

- Absolute neutrophil count ≥ 1.5*10^9/L

- OR if the bone marrow is extensively infiltrated

- Platelet count ≥ 75*10^9/L

- Absolute neutrophil count ≥ 1.0*10^9/L

- Patients must meet the following laboratory criteria at the Screening visit conducted
within 14 days of enrollment (Day 1, Cycle 1):

- o Aspartate transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) and
alanine transaminase/serum glutamic pyruvic transaminase (ALT/SGPT) ≤ 3.0*upper
limit of normal (ULN)

- Serum bilirubin ≤ 2.0*ULN

- Calculated or measured creatinine clearance: ≥30 mL/minute. Patient with a
creatinine >10mL/min and <30 mL/min due to significant myelomatous involvement
of the kidneys may be enrolled in the study after receipt of approval from the
lead investigator and sponsor

- Serum potassium ≥ 3.8 mmol/L

- Serum magnesium >1.8 mg/dL

- Serum phosphorus ≥ lower limit of normal (LLN)

Exclusion Criteria

Patients are ineligible for entry if any of the following criteria are met:

- Chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C)
or thalidomide, lenalidomide, arsenic trioxide, bortezomib, or glucocorticosteroids
within 3 weeks prior to the first dose of romidepsin

- Prior major surgery within 3 weeks prior to the first day of treatment

- Use of any investigational agent within 4 weeks of study entry

- Prior therapy with romidepsin

- Any known cardiac abnormalities such as:

- Congenital long QT syndrome;

- QTc interval ≥ 500 milliseconds;

- Myocardial infarction within 6 months of Day 1. Subjects with a history of
myocardial infarction between 6 and 12 months prior to the first day of cycle
one who are asymptomatic and have had a negative cardiac risk assessment
(treadmill stress test, nuclear medicine stress test, or stress echocardiogram)
since the event may participate;

- Other significant electrocardiogram (ECG) abnormalities including 2nd degree
atrio-ventricular (AV) block type II, 3rd degree AV block, or bradycardia
(ventricular rate less than 50 beats/min);

- Symptomatic coronary artery disease (CAD), e.g., angina Canadian Class II-IV
In any patient in whom there is doubt, the patient should have a stress imaging
study and, if abnormal, angiography to define whether or not CAD is present;

- An ECG recorded at screening showing evidence of cardiac ischemia (ST depression
depression of ≥2 mm, measured from isoelectric line to the ST segment). If in
any doubt, the patient should have a stress imaging study and, if abnormal,
angiography to define whether or not CAD is present;

- Congestive heart failure (CHF) that meets New York Heart Association (NYHA)
Class II to IV definitions and/or ejection fraction <40% by Multi Gated
Acquisition Scan (MUGA scan) or <50% by echocardiogram and/or MRI;

- A known history of sustained ventricular tachycardia (VT), ventricular
fibrillation (VF), Torsade de Pointes, or cardiac arrest unless currently
addressed with an automatic implantable cardioverter defibrillator (AICD);

- Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or
other causes;

- Uncontrolled hypertension, i.e., blood pressure (BP) of ≥160/95; patients who
have a history of hypertension controlled by medication must be on a stable dose
(for at least one month) and meet all other inclusion criteria; or

- Any cardiac arrhythmia requiring an anti-arrhythmic medication (excluding stable
doses of beta-blockers)

- POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly,
endocrinopathy, monoclonal protein (M-protein) and skin changes)

- Plasma cell leukemia

- Primary amyloidosis

- Patients with a prior malignancy within the last 5 years (except for basal or
squamous cell carcinoma, or in situ cancer of the cervix)

- Severe hypercalcemia, i.e., serum calcium ≥14 mg/dL (3.5 mmol/L)

- Known infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C

- Other concurrent severe and/or uncontrolled medical or psychiatric conditions.

- Concomitant use of drugs that may cause a prolongation of the QTc

- Concomitant use of CYP3A4 inhibitors

- Patients who have hypersensitivity to bortezomib, boron or mannitol

- Patients who are pregnant or breast-feeding

- Patients with any significant history of non-compliance to medical regimens or
unwilling or unable to comply with the instructions given to him/her by the study
staff