A Phase I Study Of Panobinostat/Lenalidomide/Bortezomib/Dex for Relapsed And Relapsed/Refractory Multiple Myeloma

In this research study, the participant will be given a study drug-dosing diary for each
treatment cycle. Each treatment cycle lasts 21 days (3 weeks) . The diary will also include
special instructions for taking the study drug(s).

The investigator are looking for the highest dose of the study drug that can be administered
safely without severe or unmanageable side effects in participants that have multiple
myeloma, not everyone who participates in this research study will receive the same dose of
the study drug. The dose each participant will get will depend on the number of participants
who have been enrolled in the study before each participant and how well they have tolerated
their doses.

Each treatment cycle will be 21 days long. The participant will have to come to the clinic on
days 1, 4, 5, 8, 10 and 11 in Cycle 1 and on days 1, 4, 8 and 11 in Cycles 2 and beyond. Days
1 and 5 of Cycle 1 will take about 8 hours. Every other visit should take about 1-4 hours,
however there is always the possibility that it could take longer.

Study Drugs:

- Panobinostat is a capsule that the participant will take three times a week for the
first two the weeks of each cycle. Then participant will have one week off study
medication.

- Bortezomib will be administered in clinic as a subcutaneous injection twice a week
during the first two weeks of each 21 day cycle.

- Lenalidomide will be taken orally once daily on days 1-14 of each cycle.

- Dexamethasone will be taken orally on the days of and after bortezomib administration
during Cycles 1-8, and on days 1, 8 and 15 for Cycles 9 and beyond.

Planned Follow-up: The investigators would like to monitor the participant's medical
condition even after the participants are no longer participating in the study. The
investigators would like to do this by calling the participants on the telephone once every 6
months to see how the participant is doing. Keeping in touch with the participant and
checking on their condition helps the investigator look at the long-term effects of the
research study.

Inclusion Criteria:

- Patients must meet the following criteria on screening examination. All laboratory
assessments should be performed within 21 days of initiation of protocol therapy
unless otherwise specified.

- Participants must have a previous diagnosis of Multiple Myeloma, according to
International Myeloma Foundation 2003 Diagnostic Criteria

- Patients must have relapsed or relapsed and refractory disease after receiving 2 or
more lines of therapy.

- Relapse is the occurrence of any of the following: 1) >25% increase in M-protein from
the baseline levels; 2) reappearance of M-protein that had disappeared; or 3) definite
increase in the size and number of lytic bone lesions recognized on radiographs
(compression fractures per se do not constitute a relapse).

- Subjects will be considered refractory to therapy, as defined by progression during
treatment or within 60 days after the completion of salvage treatment. Subjects with
primary refractory disease are excluded.

- This includes: 1) non-responding, non-progressing; and 2) progressive; primary
refractory, progressive disease where patients meet criteria for true progressive
disease (Durie 2006).

- Participants must have measurable myeloma, defined as one or more of the following:

- serum M-protein ≥ 0.5 g/dl,

- urine M-protein ≥ 200 mg/24 h, and/or

- serum FLC assay: involved FLC level ≥ 10 mg/dl with abnormal serum FLC ratio.

- Age ≥ 18 years at the time of signing informed consent.

- ECOG performance status <2 (Karnofsky >60%)

- Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy
test with a sensitivity of at least 50 mlU/mL 10 to14 days prior to therapy and
repeated again within 24 hours of starting lenalidomide and must either commit to
complete abstinence from heterosexual contact or begin TWO acceptable methods of birth
control, one highly effective method and one additional effective (barrier) method, AT
THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also
agree to ongoing pregnancy testing. Men must practice complete abstinence or agree to
use a condom during sexual contact with a FCBP even if they have had a successful
vasectomy. All participants agree to enroll and comply with the RevAssist® program for
the prevention of pregnancy.

- A female of childbearing potential is a sexually mature female who: 1) has not
undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally
postmenopausal (amenorrhea following cancer therapy does not rule out childbearing
potential) for at least 24 consecutive months

- Ability to understand and the willingness to sign a written informed consent document.
Voluntary written informed consent must be obtained before performance of any
study-related procedure not part of normal medical care, with the understanding that
consent may be withdrawn by the participant at any time without prejudice to future
medical care.

Exclusion Criteria:

- Participants who exhibit any of the following conditions at screening will not be
eligible:

- Participants with primary refractory disease

- Participants who have a history of prior MM treatment with panobinostat, or an
alternative HDAC-inhibitor.

- Participant has ≥ Grade 2 peripheral neuropathy on clinical examination within 21 days
before initiation of protocol therapy.

- Renal insufficiency, defined as creatinine clearance < 60 mL/min (either actual or
calculated value), within 21 days of initiation of protocol therapy. The
Cockcroft-Gault formula should be used for calculating creatinine clearance values:
140-age) x Body mass (kg) x 0.85 (female) or 1.0 (male)/serum creat. (mg/dL) x 72

- Platelet count <75,000cells/mm3at time of screening evaluation. Transfusion may not be
used to meet platelet eligibility criteria within 7 days of obtaining screening
evaluation.

- Participants with an absolute neutrophil count (ANC) < 1500 cells/mm3 at time of
screening evaluation. Growth factor may not be used to meet ANC eligibility criteria
within 7 days of obtaining screening evaluation.

- Participants with hemoglobin level < 8.0 g/dL, at time of screening. Transfusion may
not be used to meet eligibility criteria within 7 days of obtaining screening
evaluation.

- Participants with hepatic impairment, defined as bilirubin > 1.5 x institutional upper
limit of normal (ULN) or AST (SGOT), ALT (SGPT), or alkaline phosphatase > 2x
institutional ULN, within 21 days of initiation of protocol therapy. Patients with
benign hyperbilirubinemia (e.g., Gilbert's syndrome) are eligible

- Other ongoing anti-myeloma therapy. Patients may be receiving concomitant therapy with
bisphosphonates and low dose corticosteroids (e.g., prednisone up to but no more than
10 mg p.o. q.d. or its equivalent) for symptom management and comorbid conditions.
Doses of corticosteroid should be stable for at least 7 days prior to study
treatment.)

- Concomitant use of drugs that may cause a prolongation of the QTcF or inducing torsade
de pointes if treatment cannot be discontinued or switched to a different medication
prior to starting study drug.

- Concomitant use of CYP3A4 inhibitors at time of screening. If use of CYP3A4 inhibitors
becomes medically necessary during study, they must be used with caution.

- Anti-myeloma therapy, including radiotherapy, within 2 weeks or within 5 half-lives of
the agent and active metabolites (whichever is longer) prior to Day 1 and who have not
recovered from side effects (to ≤ Grade 1) of those therapies.

- Known significant cardiac abnormalities, including:

- History or presence of sustained ventricular tachyarrhythmia. (Participants with a
history of atrial arrhythmia are eligible but should be discussed with the
investigator prior to enrollment).

- Any history of ventricular fibrillation or torsade de pointes

- Bradycardia defined as HR < 50 bpm. Participants with pacemakers are eligible if HR ≥
50 bpm

- QTcF interval ≥ 450 milliseconds on screening ECG;

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

- Participants 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)

- Serious, intercurrent illness including, but not limited to, clinically relevant
active infection, known active hepatitis B or C viral infection, known HIV infection,
uncontrolled diabetes mellitus, or serious co-morbid medical conditions such as
chronic restrictive pulmonary disease, and cirrhosis.

- Any condition, including laboratory abnormalities, that in the opinion of the
investigator places the subject at unacceptable risk if he/she were to participate in
the study.

- Prior malignancy (within the last 5 years) except for adequately treated basal cell or
squamous cell skin cancer, or in situ cervical cancer

- Known hypersensitivity to acyclovir or similar anti-viral drug

- POEMS syndrome or AL Amyloidoses

- Known intolerance to steroid therapy

- Participants who have had prior allogeneic stem cell transplantation with evidence of
active graft-versus-host disease requiring immunosuppressive therapy

- Participants receiving any other investigational agents.

- Participants with known brain metastases.

- Poor tolerability or known allergy to any of the study drugs or compounds of similar
chemical or biologic composition to lenalidomide, bortezomib, panobinostat and/or
dexamethasone.

- Female participants pregnant or breast-feeding.

- Impairment of GI function or GI disease that may significantly alter the absorption of
panobinostat.

- Participants with diarrhea > CTCAE grade 2

- Participants who have undergone major surgery ≤ 4 weeks prior to starting study drug
or who have not recovered from side effects of the surgery.

- Participants 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.