Panobinostat, Gemcitabine Hydrochloride, Busulfan, and Melphalan Before Stem Cell Transplant in Treating Patients With Refractory or Relapsed Multiple Myeloma
Panobinostat, Gemcitabine Hydrochloride, Busulfan, and Melphalan Before Stem Cell Transplant in Treating Patients With Refractory or Relapsed Multiple Myeloma
This phase II trial studies how well panobinostat, gemcitabine hydrochloride, busulfan, and
 melphalan before stem cell transplant work in treating patients with multiple myeloma that
 does not respond to treatment (refractory) or has returned (relapsed). Panobinostat may stop
 the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving
 high-dose chemotherapy, such as gemcitabine hydrochloride, busulfan, and melphalan, before a
 peripheral blood stem cell transplant helps kill any cancer cells that are in the body and
 helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to
 grow. Previously collected stem cells are then returned to the patient to replace the
 blood-forming cells that were destroyed by the chemotherapy.
PRIMARY OBJECTIVES:

 I. To determine the progression-free survival (PFS) in patients with refractory or relapsed
 myeloma receiving panobinostat/gemcitabine hydrochloride (gemcitabine)/busulfan/melphalan
 (panobinostat/Gem/Bu/Mel) with autologous stem-cell transplant, either as a first or a
 salvage stem-cell transplant.

 SECONDARY OBJECTIVES:

 I. To evaluate the complete response (CR) rate. II. To determine the overall survival (OS).
 III. To determine the CR + very good partial remission (VGPR) rate. IV. To determine the
 overall response rate (ORR). V. To determine minimal residual disease posttransplant,
 measured by multiparametric flow cytometry (MFC).

 VI. To describe the toxicity profile of panobinostat/Gem/Bu/Mel. VII. To analyze the
 predictive value of pretransplant levels in myeloma cells of X-box binding protein 1 (XBP1),
 inositol-requiring enzyme 1 (IRE1), unspliced XBP1 (XBP1u), sliced XBP1 (XPB1s), XBP1u/XPBs
 ratio and v-myc myelocytomatosis viral oncogene homolog (avian) (Myc), by analyzing their
 correlation with CR, VGPR+CR and response rate (RR).

 VIII. To study the prognostic effect of pretransplant levels in myeloma cells of XBP1, IRE1,
 XBP1u, XPB1s, XBP1u/XPBs ratio and Myc, by analyzing their correlation with PFS and OS.

 OUTLINE:

 Patients receive panobinostat orally (PO) once daily (QD) on days -9 to -2, gemcitabine
 hydrochloride intravenously (IV) over 4 hours on days -8 and -3, busulfan IV over 3 hours on
 days -8 to -5, and melphalan IV over 30 minutes on days -3 and -2. Patients then undergo
 autologous peripheral blood stem cell transplant on day 0.

 After completion of study treatment, patients are followed up at 1 month, 100 days, 6 months,
 1 year, and then every 3-6 months for at least 2 years.
Inclusion Criteria:

 -  Refractory or relapsed myeloma, defined as one or more of the following:

 -  Treated with first-line therapy including at least 2 cycles of lenalidomide,
 bortezomib or thalidomide, and one or more of the following:

 -  Less than partial response (PR) to first-line therapy

 -  Relapse after first (1st) line therapy

 -  High-risk cytogenetics, defined by deletion (del)(13q) by conventional
 cytogenetics, or by del(17p), t(4;14), t(14;16), t(14;20) or 1q+ by fluorescence
 in situ hybridization (FISH)

 -  Relapse after a prior autologous stem cell transplant (ASCT)

 -  Plasma cell leukemia

 -  Soft tissue plasmacytoma

 -  Serum creatinine =< 1.8 mg/dL and/or estimated serum creatinine clearance >= 50 ml/min

 -  Serum glutamic oxaloacetic transaminase (SGOT) and/or serum glutamate pyruvate
 transaminase (SGPT) =< 3 x upper limit of normal

 -  Serum bilirubin =< 2 x upper limit of normal, unless proven to be due to disease
 involvement

 -  Alkaline phosphatase =< 2 x upper limit of normal, unless proven to be due to disease
 involvement

 -  Adequate pulmonary function with forced expiratory volume in 1 second (FEV1), forced
 vital capacity (FVC) and diffusion capacity of the lung for carbon monoxide (DLCO) >=
 50% of expected corrected for hemoglobin and/or volume

 -  Adequate cardiac function with left ventricular ejection fraction >= 40%

 -  No uncontrolled arrhythmias or symptomatic cardiac disease

 -  Clinically euthyroid; note: patients are permitted to receive thyroid hormone
 supplements to treat underlying hypothyroidism

 -  Zubrod performance status < 2

 -  Negative beta-human chorionic gonadotropin (HCG) test in a woman of child-bearing
 potential, defined as not post-menopausal for 12 months or no previous surgical
 sterilization

 -  Availability of >= 2.5 million cluster of differentiation (CD)34+ cells/kg previously
 apheresed

 -  Ability to provide written informed consent

 Exclusion Criteria:

 -  Prior whole brain irradiation

 -  Having received radiation therapy to head and neck (excluding eyes), and internal
 organs of chest, abdomen or pelvis in the month prior to enrollment

 -  Active hepatitis B, either active carrier (hepatitis B surface antigen positive [HBsAg
 +]) or viremic (hepatitis B virus [HBV] deoxyribonucleic acid [DNA] >= 10,000
 copies/mL, or >= 2,000 IU/mL)

 -  Evidence of either cirrhosis or stage 3-4 liver fibrosis in patients with chronic
 hepatitis C or positive hepatitis C serology

 -  Active infection requiring parenteral antibiotics

 -  Known positivity for human immunodeficiency virus (HIV)

 -  Autologous stem-cell transplant in the previous six months

 -  Needing valproic acid for any medical condition during the study or within 5 days
 prior to first panobinostat treatment

 -  Impairment of gastrointestinal (GI) function or GI disease that may significantly
 alter the absorption of panobinostat

 -  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

 -  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 heart rate (HR) < 50 beats per minute (bpm); patients with
 pacemakers are eligible if HR >= 50 bpm

 -  Screening electrocardiogram (ECG) with a corrected QT (QTc) > 470 msec

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

 -  Myocardial infarction or unstable angina =< 12 months prior to starting study
 drug

 -  Other clinically significant heart disease (e.g., congestive heart failure [CHF]
 New York [NY] Heart Association class III or IV , uncontrolled hypertension,
 history of labile hypertension, or history of poor compliance with an
 antihypertensive regimen)

 -  Have undergone major surgery =< 4 weeks prior to starting study drug or who have not
 recovered from side effects of such therapy

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

 -  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

 -  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

 -  Having received immunotherapy or chemotherapy within 2 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

 -  Grade >= 3 nonhematological toxicity from prior therapy that has not resolved to =<
 grade 1