A Phase I/II Study of Oral Melphalan Combined With LBH589 for Patients With Relapsed or Refractory Multiple Myeloma (MM)

Inclusion Criteria

DISEASE CHARACTERISTICS:

- Diagnosis of multiple myeloma, based on the following criteria:

- Major criteria

- Plasmacytomas on tissue biopsy (1)

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

- Monoclonal immunoglobulin spike on serum electrophoresis, IgG > 3.5 g/dL or
IgA > 2.0 g/dL, and kappa or lambda light chain excretion > 1 g/day on
24-hour urine protein electrophoresis (3)

- Minor Criteria

- Bone marrow plasmacytosis (10-30% plasma cells) (a)

- Monoclonal immunoglobulin present but of lesser magnitude than given under
major criteria (b)

- Lytic bone lesions ©)

- Normal IgM < 50 mg/dL, IgA < 100 mg/dL, or IgG < 600 mg/dL (d)

- Meets any of the following sets of multiple myeloma diagnostic criteria:

- Any two of the major criteria

- Major criterion 1 plus minor criterion b, c, or d

- Major criterion 3 plus minor criterion a or c

- Minor criteria a, b, and c, OR a, b, and d

- Measurable disease, defined as a monoclonal immunoglobulin spike on serum
electrophoresis of ≥ 1 g/dL and/or urine monoclonal immunoglobulin spike of ≥ 200
mg/24 hours, or evidence of lytic bone disease

- Nonmeasurable disease (i.e., patients with nonsecretory or oligosecretory
multiple myeloma) not allowed

- Must have received ≥ 1 prior treatment regimen OR refractory to most recent
chemotherapy

- Relapsed following stabilization or response to standard first-line chemotherapy
(e.g., vincristine, doxorubicin hydrochloride, and prednisone or melphalan and
prednisone) or first-line high-dose chemotherapy

- Refractory (i.e., failure to achieve at least complete or partial response or
stable disease) to most recent chemotherapy, whether or not containing systemic
corticosteroids

- Prior treatment with ≤ 4 days of a total of 400 mg of prednisone (or an
equivalent potency of another steroid) for myeloma is not considered a regimen

- No plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy,
monoclonal protein, and skin changes (POEMS syndrome)

- No plasma cell leukemia

PATIENT CHARACTERISTICS:

- ECOG performance status ≤ 2

- Life expectancy > 3 months

- Platelet count ≥ 75 x 10^9/L (≥ 50 x 10^9/L if bone marrow is extensively
infiltrated)

- Absolute neutrophil count ≥ 1.5 x 10^9/L (≥ 1.0 x 10^9/L if bone marrow is
extensively infiltrated)

- AST and ALT ≤ 2.5 times upper limit of normal (ULN)

- Serum bilirubin ≤ 1.5 times ULN

- Creatinine clearance ≥ 30 mL/min

- Creatinine > 10 mL/min and < 30 mL/min due to significant myelomatous
involvement of the kidneys allowed with medical director approval

- Serum potassium ≥ lower limit of normal (LLN)

- Serum magnesium ≥ LLN

- Serum phosphorus ≥ LLN

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No peripheral neuropathy > grade 2

- No impaired cardiac function or clinically significant cardiac disease, including any
1 of the following:

- Congenital long QT syndrome

- History or presence of sustained ventricular tachyarrhythmia

- History of ventricular fibrillation or Torsade de Pointes

- Bradycardia, defined as heart rate (HR) < 50 beats per minute (bpm)

- Pacemaker allowed provided HR ≥ 50 bpm

- QTc > 450 msec on screening ECG

- LVEF below normal on screening ECHO or MUGA scan

- Right bundle branch block with left anterior hemiblock (bifascicular block)

- Myocardial infarction or unstable angina within the past 6 months

- Other clinically significant heart disease, including any of the following:

- NYHA class III-IV congestive heart failure

- Uncontrolled hypertension

- History of labile hypertension

- History of poor compliance with an antihypertensive regimen

- No impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of panobinostat

- No prior malignancy within the past 5 years except basal cell or squamous cell
carcinoma or carcinoma in situ of the cervix

- No other concurrent severe and/or uncontrolled medical or psychiatric conditions
(e.g., uncontrolled diabetes or active or uncontrolled infection), including abnormal
laboratory values that could cause unacceptable safety risks or compromise protocol
compliance

- No known positivity for HIV or hepatitis B or C

- No severe hypercalcemia (i.e., serum calcium ≥ 14 mg/dL)

- No significant history of non-compliance to medical regimens or unwillingness or
inability to comply with instructions given by the study staff

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Recovered from all prior therapy

- Prior localized radiotherapy allowed

- At least 3 weeks since prior chemotherapy (≥ 6 weeks for nitrosoureas)

- At least 3 weeks since prior corticosteroids (> 10 mg/day prednisone or equivalent)

- More than 4 weeks since prior major surgery

- Recent kyphoplasty allowed at investigator's discretion

- More than 8 weeks since prior immunotherapy

- More than 4 weeks since prior antibody therapy

- More than 2 weeks since prior radiotherapy to > 30% of marrow-bearing bone

- No prior panobinostat

- No concurrent medication that risk prolonging the QT interval or inducing Torsades de
Pointes