UARK 2014-08 A Phase II Open-Label, Multiple-Dose, Single Agent Study to Evaluate the Overall Response Rate of Orally Administered Trametinib

The effect of on tumor response will be determined using the International Myeloma Working
Group uniform response criteria by analyzing changes in serum and urine values of monoclonal
protein immunoglobulin kappa and lambda free light chain and ratio, microglobulin, lactate
dehydrogenase, hemoglobin and C-reactive proten.

Inclusion Criteria:

- Been identified as having multiple myeloma with activating NRAS, KRAS or BRAF genetic
mutations on CD138+ cells, identified by molecular genetic testing

- Have been diagnosed with multiple myeloma by having met all three of the following
IMWG criteria:

a Clonal bone marrow plasma cells >10% b Presence of serum and/or urinary M-protein (If no
monoclonal protein is detected (non-secretory disease), then >/= 30% monoclonal bone
marrow plasma cells and/or a biopsy-proven plasmacytoma required.) c Evidence of end-organ
damage that can be attributed to the underlying plasma cell proliferative disorder,
specifically, one or more of the following: (i) Hypercalcemia: serum calcium >11.5 mg/100
mL (ii) Renal insufficiency: serum creatinine >2 mg/dL (iii) Anemia: normochromic,
normocytic with a hemoglobin value >2 g/100 mL below the lower limit of normal or a
hemoglobin value <10 g/100 mL (iv)Bone lesions: lytic lesions, severe osteopenia, or
pathologic fracture.

- Have measurable disease defined by the following:

(i) Serum M-protein ≥1g/dL or urine M-protein ≥200 mg/24 hours by protein
electrophoresis (ii) If neither serum nor urine M-protein meet the criteria above,
then kappa or lambda serum FLC must be ≥10 mg/dL accompanied by an abnormal kappa to
lambda ratio (<0.26 or >1.65) (Serum FLC should only be used for patients without
measurable serum or urine M-protein spike.)

- Have relapsed or refractory disease after two or more prior multiple myeloma
treatment regimens, each of which may have consisted of either single or multiple
therapies

- Be at least 3 weeks beyond the last multiple myeloma therapy and have recovered from
acute toxicities of prior therapies measured by CTCAE Ver 3.0.

- Have an Eastern Cooperative Oncology Group performance status of 0 to 2

- Have life expectancy of at least 3 months

- Be ≥18 years of age and willing to provide written informed consent

- For women of childbearing potential, must have used effective contraceptive methods
for previous 4 weeks and agree to continue using such methods during the study and
for at least 4 months after completing the study, this must include the use of a
male/female latex barrier method of contraception (for male participants (See
APPENDIX K). TMTB is a pregnancy category D drug. A female of childbearing potential
is defined as a female who has not been in natural menopause for the previous,
consecutive 24 months, or undergone hysterectomy or bilateral oophortectomy. Women of
childbearing potential must have a negative serum pregnancy test within 24 hours
before the initiation of TMTB therapy.

- Have an absolute neutrophil count >1,000/mm3

- Have a platelet count >50,000/mm3

- Have total direct bilirubin <2.0 mg/dL

- Have aspartate aminotransferase and alanine aminotransferase ≤3 times the upper limit
of normal

- Have serum creatinine ≤2.5 times the upper limit of normal

- Have hemoglobin ≥8.5 g/dL

- All prior treatment- related toxicities must be CTCAE (Version 3.0) ≤ Grade 1 (except
alopecia)

- Subject is 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

Exclusion Criteria:

- Have an active infection or serious comorbid medical condition

- Be receiving other concurrent anticancer agents or therapies

- Be receiving other concurrent investigational therapies or have received
investigational therapies within 3 weeks of screening, not inclusive of molecular
genetic testing

- Be eligible to receive any other standard therapy available that is known to extend
life expectancy

- For women be pregnant, nursing, unwilling or unable to utilize two forms of birth
control, including the use of a latex condom.

- Have a history of another malignancy, except as noted below Exception: Subjects who
have been disease-free for 3 years, or subjects with a history of completely resected
non-melanoma skin cancer and/or subjects with indolent second malignancies are
eligible.

- Any serious and/or unstable pre-existing medical disorder (aside from malignancy
exception above), psychiatric disorder, or other conditions that could interfere with
subject's safety, obtaining informed consent or compliance to the study procedures.

- History of interstitial lung disease or pneumonitis.

- Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO).

- Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity,
biologic therapy, or immunotherapy within 21 days prior to randomization and/or daily
or weekly chemotherapy without the potential for delayed toxicity within 14 days
prior to randomization.

- History of retinal vein occlusion (RVO)

- Symptomatic or untreated spinal cord compression.

- Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C
Virus (HCV) infection (subjects with laboratory evidence of cleared HBV and HCV
infection will be permitted).

- History or evidence of cardiovascular risk including any of the following (See
APPENDIX M for more details):

a LVEF formula (QTcB;).

c History or evidence of current clinically significant uncontrolled arrhythmias.

Exception: Subjects with controlled atrial fibrillation for >30 days prior to study
enrollment d History of acute coronary syndromes (including myocardial infarction and
unstable angina), coronary angioplasty, or stenting within 6 months prior to study
enrollment

* History or evidence of current ≥ Class II congestive heart failure as defined by New
York Heart Association (NYHA).

a Treatment refractory hypertension defined as a blood pressure of systolic> 140 mmHg
and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy; b
Patients with intra-cardiac defibrillators; c Known cardiac metastases