MLN9708 (Ixazomib) in Combination With Panobinostat and Dexamethasone in Multiple Myeloma

Inclusion Criteria

• Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed
• Patients must carry a diagnosis of symptomatic multiple myeloma according to international myeloma working group criteria and have relapsed or refractory disease according to international uniform response criteria and must have previously received therapy with a proteasome inhibitor and an IMiD™
• Must have measurable disease defined as any of the following: Serum m-spike ≥ 1g/dL, 24 h urine m-spike of at least 200mg/d, involved serum free light chains ≥ 100mg/L with abnormal serum free light chain ratio, bone marrow plasma cells of at least 30%
• ECOG PS ≤ 2
• No gastro-intestinal condition, that in the opinion of the treating physician or the principal investigator significantly limits oral absorption
• No serious uncontrolled coexisting medical condition
• Patients must meet the following laboratory criteria:
• ANC ≥ 1.0 x 10^9/L without use of pegfilgrastim in the preceding 21 days and without non-pegylated G-CSF or GM-CSF within 7 days prior to study entry
• Hemoglobin ≥ 8 g/dl (may be after transfusion of packed red blood cells or use of erythropoiesis stimulating agents)
• Platelets ≥ 70x 10^9/L without platelet transfusion 7 days prior to study entry
• AST and ALT ≤ 2.5 x ULN
• Serum bilirubin ≤ 1.5 x ULN
• Serum potassium ≥ LLN and serum magnesium ≥ LLN (electrolyte levels may be achieved with repletion or other supportive medications like potassium sparing diuretics)
• Creatinine clearance ≥ 30 mL/min according to Cockroft-Gault formula
• Clinically euthyroid. Note: Patients are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism.
• Baseline MUGA or ECHO must demonstrate LVEF ≥ 45%
• Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days prior to start of study treatment
• Male patients, even if surgically sterilized (i.e., status post vasectomy), have to either:
• Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study treatment, OR
• Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
• Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.
• Female patients have to fulfill one of the following:
• Be postmenopausal for at least 1 year before the Screening visit, OR
• Be surgically sterile, OR
• If of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 90 days after the last dose of study treatment
• Oral contraceptives are generally metabolized by CYP3A4. Since the induction potential of panobinostat to induce CYP3A4 is unknown, patients who are using oral contraceptives as a method of contraception, and are sexually active, should use another effective contraceptive method, AND Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
• Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
• At least 7 days must have passed since the last treatment with lenalidomide, pomalidomide, thalidomide, proteasome inhibitors, or low dose cyclophosphamide (up to 50mg daily), at least 21 days must have passed since the last treatment with daratumumab, elotuzumab, investigational therapy and most conventional chemotherapy including cyclophosphamide above 50mg per dose, bendamustine, doxorubicin, cisplatin, and eto