Panobinostat (LBH589): Multiple Myeloma - Autologous Hematopoietic Cell Transplantation (HCT)

• Panobinostat (Drug), also known as LBH589: Maintenance therapy dosing as outlined in Cohorts A and B.

Primary outcomes

• Relative Dose Intensity (RDI) Per Cohort [Up to 2 years]: Investigators will calculate RDI for each cohort. Relative dose intensity (RDI) represents the ratio of the amount of a drug actually delivered \[actual dose intensity (DI)\] to the amount planned (planned DI). The purpose of calculating RDI is to evaluate whether the planned DI of a chemotherapy treatment was actually achieved which may suggest the feasibility of planned treatment regimen. There are multitude of reports demonstrating a correlation between RDI and survival in cancer treatment. RDI = (total dose received by the patient = mg)/(planned full dose of drug = mg).

Secondary outcomes

• Complete Response Rate [Up to 5 years]: Complete Response (CR) rate to panobinostat maintenance therapy after autologous HCT. CR: Negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and < 5% plasma cells in bone marrow.
• Progression Free Survival (PFS) [at 2 years]: Progressive Disease (PD) according to Uniform Response Reporting Criteria for Multiple Myeloma by the International Myeloma Working Group (IMWG). Increase of 25% from lowest response value in any of the following: * Serum M- component (absolute increase must be ≥ 0.5 g/dL) * Urine M-component (absolute increase must be ≥ 200 mg/24 h) * Only in patients without measurable serum and urine M protein levels and without measurable disease by free light chain (FLC) levels, bone marrow plasma cell percentage (absolute percentage must be ≥ 10% ) * Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas * Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL) that can be attributed solely to the plasma cell proliferative disorder
• Overall Survival (OS) [at 2 years]: OS: The length of time from either the date of diagnosis or the start of treatment for a disease, such as cancer, that patients diagnosed with the disease are still alive.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Adult patients, age ≥ 18 years old
* Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed
* Histologically confirmed diagnosis of multiple myeloma
* Meeting the Criteria for Symptomatic Multiple Myeloma (CRAB criteria) before the initiation of systemic chemotherapy
* Received high-dose melphalan (≥ 140 mg/m\^2) followed by autologous HCT based on the institutional guidelines and within +45 and +180 after autologous HCT at the time of panobinostat maintenance initiation
* Must have achieved at least partial response (PR) prior to autologous HCT and must not have progressive disease (PD) prior to the initiation of maintenance therapy
* Must meet the following laboratory criteria (prior to the initiation of panobinostat maintenance): Absolute neutrophil count (ANC) ≥ 1 x 10\^9/L; Hemoglobin ≥ 8 g/dl; Platelets ≥ 50 x 10\^9/L (without transfusion support); Creatinine clearance ≥ 40 ml/min or serum creatinine ≤ 2.5 x upper limit of normal (ULN); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN; Serum bilirubin ≤ 1.5 x ULN; Albumin > 3.0 g/dl; Clinically euthyroid. Note: Participants are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism.
* Baseline (pre-HCT) multigated acquisition (MUGA) or echocardiogram (ECHO) must demonstrate left ventricular ejection fraction (LVEF) ≥ the limit of normal (LLN) of the institutional normal
* Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2 or Karnofsky performance status ≥ 70%
* Prior histone deacetylase (HDAC), deacetylase (DAC), HSP90 inhibitors or valproic acid for the treatment of cancer is allowed

Exclusion Criteria:

* Potential participants who have purely non-secretory multiple myeloma (i.e., the absence of a measurable protein in serum by electrophoresis and immunofixation and the absence of Bence-Jones protein in the urine defined by use of electrophoresis and immunofixation)
* Prior allogeneic HCT
* Prior solid organ transplant requiring immunosuppressive therapy
* Potential participants 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
* Diarrhea > Common Terminology Criteria for Adverse Events (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
* 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
* 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.
* Have received either immunotherapy within < 8 weeks; chemotherapy 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
* Have undergone major surgery ≤ 4 weeks prior to starting study drug or have not recovered from side effects of such therapy
* Women who are pregnant or breast feeding or women of childbearing potential (WOCBP) not using an effective method of birth control. WOCBP must have a negative serum pregnancy test within 24 hours of receiving the first dose of study medication.
* Male patients whose sexual partners are WOCBP not using effective birth control
* A prior malignancy with in the last 5 years (except for basal or squamous cell carcinoma, or in situ cancer of the cervix)
* Known positivity for human immunodeficiency virus (HIV) or hepatitis C; baseline testing for HIV and hepatitis C is not required
* 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

Participant flow

Outcome results

• Relative Dose Intensity (RDI) Per Cohort (Primary), Median, percentage of dose: Cohort A: Maintenance Therapy 97.9 (77.1 to 100); Cohort B: Maintenance Therapy 89.6 (63.1 to 100)
• Complete Response Rate (Secondary), Number, percentage: Cohort A: Maintenance Therapy 73.33 (44.9 to 92.2); Cohort B: Maintenance Therapy 66.6 (38.4 to 88.2)
• Progression Free Survival (PFS) (Secondary), Median, percentage of participants: Cohort A: Maintenance Therapy 71.8 (41.1 to 88.4); Cohort B: Maintenance Therapy 53.3 (26.3 to 74.4)
• Overall Survival (OS) (Secondary), Median, percentage of participants: Cohort A: Maintenance Therapy 100 (NA to NA); Cohort B: Maintenance Therapy 100 (NA to NA)

Adverse events

Time frame: Adverse events collected from date of consent until off study date, 4 years, 2 months.

Serious adverse events by term

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2017-04-13)

• Taiga Nishihori, M.D., Principal investigator, H. Lee Moffitt Cancer Center and Research Institute