Trametinib and Akt Inhibitor GSK2141795 in Treating Patients With Relapsed or Refractory Multiple Myeloma

Inclusion Criteria

• Patients must have histologically or cytologically confirmed multiple myeloma not otherwise specified (NOS) (10028566)
• Patients must have measurable disease as defined as at least one of the following (these baseline laboratory studies for determining eligibility must be obtained within 28 days prior to enrollment):
• Serum M-protein >= 0.5 g/dl (>= 5 g/l)
• Urine M-protein >= 200 mg/24 h
• Serum free light chains (FLC) assay: involved FLC level >= 10 mg/dl (>= 100 mg/l) and an abnormal serum free light chain ratio ( 1.65)
• Biopsy proven plasmacytoma (should be measured within 28 days of first study drug administration); prior biopsy is acceptable
• If the serum protein electrophoresis is unreliable for routine M-protein measurement, quantitative immunoglobulin levels on nephelometry or turbidimetry will be followed
• A diagnosis of multiple myeloma (MM) and documentation of relapsed or relapse/refractory status following at least 2 prior lines of therapy
• Documented laboratory (lab) results confirming tumor mutational status must be obtained at screening; patients in whom mutational status cannot be determined will be deemed ineligible
• Eastern Cooperative Oncology Group (ECOG) performance status = = 60%)
• Life expectancy of greater than 6 months
• Able to swallow and retain orally-administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
• All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) version (v)4 grade = = 1.0 x 10^9/L
• Hemoglobin >= 8 g/dL
• Platelets >= 50 x 10^9/L
• Albumin >= 2.5 g/dL
• Total bilirubin = 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin = 30 mL/min OR 24-hour urine creatinine clearance >= 30 mL/min
• Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) = = institutional lower limit of normal (LLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA)
• Subjects that have been previously diagnosed with type 2 diabetes or steroid-induced diabetes must also meet the additional following criteria:
• Diagnosed with diabetes >= 6 months prior to enrollment
• Hemoglobin A1C (HbA1C) = 21 mmHg
• History or evidence of cardiovascular risk including any of the following:
• Left ventricular ejection fraction (LVEF) = 480 msec (>= 500 msec for subjects with bundle branch block)
• History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to randomization are eligible)
• Other clinically significant electrocardiogram (ECG) abnormalities including second (2nd) degree (type II) or third (3rd) degree atrioventricular (AV) block
• Subject with intra-cardiac defibrillators or pacemakers
• History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization
• History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system
• Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy
• Known cardiac metastases
• Known human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection, which will be allowed)
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• The study drug must not be administered to pregnant women or nursing