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

Exclusion Criteria

• •History of another malignancy; exception: patients who have been disease-free for 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent second malignancies, are eligible; consult the Cancer Therapy Evaluation Program (CTEP) medical monitor if unsure whether second malignancies meet the requirements specified above
• •History of interstitial lung disease or pneumonitis
• •Diabetes mellitus currently requiring insulin; subjects with a history of steroid-induced hyperglycemia may be enrolled provided that HbA1C at screening visit is =\< 8%
• •Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 28 days prior to randomization and/or daily or weekly chemotherapy or other approved anti-myeloma therapy without the potential for delayed toxicity within 14 days prior to registration
• •Use of other investigational drugs within 28 days preceding the first dose of trametinib and during the study
• •Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression
• •Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib or excipients or to dimethyl sulfoxide (DMSO) or GSK214795
• •Current use of a prohibited medication; the following medications or non-drug therapies are prohibited:
• •* Other anti-cancer therapy while on study treatment; (note: megestrol \[Megace\] if used as an appetite stimulant is allowed)
• •* Concurrent treatment with bisphosphonates is permitted; however, treatment must be initiated prior to the first dose of study therapy; prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for the treatment of osteoporosis
• •* The concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra \[ma huang\], gingko biloba, dehydroepiandrosterone \[DHEA\], yohimbe, saw palmetto, or ginseng)
• •In vitro data indicate that GSK2141795 is a cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) substrate; drugs that potently inhibit CYP3A4 could lead to increased GSK2141795 exposure in subjects, and should either be prohibited or used with caution; drugs which are strong inducers of cytochrome P450, family 3, subfamily A (CYP3A) and may result in lower exposures of GSK2141795 should also be prohibited; GSK2141795 also appears to be a moderate in vitro inhibitor of cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) (50% inhibitory concentration \[IC50\] 3 mcM) and CYP3A4 (IC50 11 mcM); drugs that are substrates of CYP3A4 or CYP2C8 with a narrow therapeutic index may be prohibited; drugs that are sensitive substrates of CYP3A4 or CYP2C8 should be used with caution
• •History or current evidence/risk of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED):
• •* History of RVO or RPED, or predisposing factors to RVO or RPED (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes)
• •* Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or RPED such as evidence of new optic disc cupping, evidence of new visual field defects, and intraocular pressure \> 21 mmHg
• •History or evidence of cardiovascular risk including any of the following:
• •* Left ventricular ejection fraction (LVEF) \< LLN
• •* A QT interval corrected for heart rate using the Bazett's formula Fridericia corrected QT interval (QTcB) \>= 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 mothers; women of childbearing potential should be advised to avoid pregnancy and use effective methods of contraception; men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception; if a female patient or a female partner of a patient becomes pregnant while the patient receives trametinib, the potential hazard to the fetus should be explained to the patient and partner (as applicable); these potential risks may also apply to GSK2141795