Trial of Romidepsin and Bortezomib for Multiple Myeloma

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consent before any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care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