Phase II, Single-Center, Oral Panobinostat in Combination With Lenalidomide and Dexamethasone in Multiple Myeloma (MM)

Inclusion Criteria

• Patients must have a history of symptomatic multiple myeloma according to the International Myeloma Working Group criteria (IMWG, 2003), as defined as the following three criteria:
• Clonal plasma cells >10% on bone marrow biopsy
• A monoclonal protein (paraprotein) in either serum or urine(except in cases of non-secretory myeloma)
• Evidence of end-organ damage felt related to the plasma cell disorder (related organ or tissue impairment, ROTI, commonly referred to by the acronym "CRAB"):
• Hypercalcemia serum Ca ≥ 11.5 mg/dL or
• Renal insufficiency attributable to myeloma. Serum creatinine > 2mg/dL
• Anemia: Normochromic, normocytic with a hemoglobin value > 2g/dL below the lower limit of normal or a hemoglobin 30% monoclonal bone marrow plasma cells.
• Patients must be suitable (according to their local product information) for treatment or re-treatment with lenalidomide & dexamethasone. Note: patients previously treated with lenalidomide & dexamethasone are eligible to participate in the trial.
• Male or female adults ≥ 18 years old
• ECOG Performance Status ≤ 2
• Life expectancy > 12 weeks
• Patients must have the following laboratory values:
• ANC ≥ 1.5 x 109/L for patients in whom 1.0 x 109/Lfor patients in whom > 50% of bone marrow nucleated cells are plasma cells.
• Hemoglobin ≥ 9 g/dl
• Platelets ≥ 75x 109/L for patients in whom 50 x 109/L for patients in whom > 50% of bone marrow nucleated cells are plasma cells.
• Calculated CrCl ≥ 50 mL/min (MDRD Formula)
• Hepatic:
• AST and ALT ≤ 2.5 x ULN,
• Serum bilirubin ≤ 1.5 x ULN
• Electrolytes:
• Serum potassium ≥ LLN,
• Total serum calcium [corrected for serum albumin] or ionized calcium ≥LLN
• Serum magnesium ≥ LLN
• Serum phosphorus ≥ LLN
• Normal thyroid function (TSH and free T4) (Clinically euthyroid patients are acceptable).
• Able to sign informed consent and to comply with the protocol

Exclusion criteria

• Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first panobinostat treatment
• Impaired cardiac function or clinically significant cardiac diseases, including any one of the following:
• History or presence of sustained ventricular tachyarrhythmia. (Patients with a history of atrial arrhythmia are eligible but should be discussed with Novartis prior to enrollment)
• Any history of ventricular fibrillation or torsade de pointes
• Bradycardia defined as HR 450 msec
• Right bundle branch block + left anterior hemiblock (bifascicular block)
• Patients with myocardial infarction or unstable angina ≤ 6 months prior to starting study drug
• Other clinically significant heart disease (e.g., CHF NY Heart Association class III or IV , uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)
• Impairment of GI function or GI disease that may significantly alter the absorption of panobinostat
• Patients with diarrhea > CTCAE grade 2
• Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes or active or uncontrolled infection) including abnormal laboratory values, that could cause unacceptable safety risks or compromise compliance with the protocol
• Patients using medications that have a relative risk of prolonging the QT interval or inducing torsade de pointes if treatment cannot be discontinued or switched to a different medication prior to starting study drug
• Patients who have received targeted agents within 2 weeks or within 5 half-lives of the agent and active metabolites (whichever is longer) and who have not recovered from side effects of those therapies.
• Patients who have received either immunotherapy within 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.
• Subject has received a cumulative dose of corticosteroids more than the equivale