Melphalan and Panobinostat (LBH589) for the Treatment of Patients With Recurrent Multiple Myeloma

• 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 (Ig) 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

• 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
• Eastern Cooperative Oncology Group (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)
• Aspartate transaminase (AST) and Alanine transaminase (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
• Prior localized radiotherapy

Exclusion criteria:

• Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS syndrome)
• Plasma cell leukemia
• Pregnant or nursing females; fertile patients must use effective contraception
• Peripheral neuropathy > grade 2
• Impaired cardiac function or clinically significant cardiac disease (including 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]; corrected QT interval > 450 msec on screening ECG; left ventricular ejection fraction below normal on screening ECHO or multigated acquisition (MUGA) scan; right bundle branch block with left anterior hemiblock (bifascicular block); myocardial infarction or unstable angina within the past 6 months; New York Heart Association class III-IV congestive heart failure; uncontrolled hypertension; history of labile hypertension; history of poor compliance with an antihypertensive regimen)
• Impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of panobinostat
• Prior malignancy within the past 5 years except basal cell or squamous cell carcinoma or carcinoma in situ of the cervix
• 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
• Known positivity for HIV or hepatitis B or C
• Severe hypercalcemia (i.e., serum calcium ≥ 14 mg/dL)
• Significant history of non-compliance to medical regimens or unwillingness or inability to comply with instructions given by the study staff
• Concurrent medication that risk prolonging the QT interval or inducing Torsades de Pointes
• Prior panobinostat
• Received chemotherapy, bortezomib, thalidomide, lenalidomide or arsenic trioxide within 3 wks of enrollment (with the exception of nitrosoureas within 6 wks of enrollment)
• Received corticosteroids (>10 mg/day prednisone or equivalent) within three weeks before enrollment.
• Received immunotherapy within \< 8 weeks; antibody within \< 4 weeks; or radiation therapy to > 30% of marrow-bearing bone within \< 2 weeks prior to starting study treatment; or who have not yet recovered from side effects of such therapies.