A Single Agent Study to Evaluate the Overall Response Rate, Safety and Tolerability of Orally Administered Vemurafenib

This is an open-label study to evaluate the objective response rates of orally administered
Vermurafenib for patients with double refractory multiple myeloma. Double refractory
multiple myeloma is myeloma that has become refractory to two chemotherapeutic agents such
as bortexomib and lenalidomide. The study will be conducted in two stages with an interim
data analysis performed after enrollment of the initial 21 subjects to determine whether the
study will enroll an additional 20 subjects.

Inclusion Criteria:

- Been identified as having multiple myeloma with activating NRAS, KRAS or BRAF
genetic mutations on CD138+ cells, identified by F1 testing

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

- Clonal bone marrow plasma cells >10%

- Presence of serum and/or urinary M-protein

- Evidence of end-organ damage that can be attributed to the underlying plasma cell
proliferative disorder, specifically, one or more of the following:

- Hypercalcemia: serum calcium >11.5 mg/100 mL

- Renal insufficiency: serum creatinine >2 mg/dL

- 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

- Bone lesions: lytic lesions, severe osteopenia, or pathologic fractures

- Have measurable disease defined by the following:

- Serum M-protein ≥1g/dL or urine M-protein ≥200 mg/24 hours by protein
electrophoresis

- 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

- Patient must be at least 3 weeks beyond the last multiple myeloma therapy and any
previous therapy related toxicities must be CTCAE (Version 3.0) ≤ Grade 2 (except
alopecia)

- Have an Zubrod Performance Status of 0 to 2 (Appendix D)

- Have life expectancy of at least 3 months in the opinion of the enrolling
investigator

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

- For women and men 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 weeks after completing the study, this must include two
forms of birth control, including surgical sterilization, a reliable barrier method
with spermicide, birth control pills, or contraceptive hormone implants.

- Women of childbearing potential must have a negative serum pregnancy test within 24
hours before the initiation of VMFB therapy.

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

- Unsupported platelet count >35,000/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

- 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 non-secretory myeloma

- Have evaluable disease only according to CRAB diagnostic criteria and International
Staging System (ISS)

- No previous history of NRAS/KRAS/BRAF inhibitor

- Have an active infection or ,in the opinion of the enrolling investigator, have a
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 enrollment

- In the opinion of the enrolling investigator, be eligible to receive any other
standard therapy available that is known to extend life expectancy

- Be pregnant, nursing, unwilling or unable to utilize two forms of birth control,
including surgical sterilization, a reliable barrier method with spermicide, birth
control pills, or contraceptive hormone implants.

- 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 as
determined by the enrolling investigator

- 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 enrollment and/or daily or
weekly chemotherapy without the potential for delayed toxicity within 14 days prior
to enrollment.

- Current use of a prohibited medication (Appendix F).

- 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 cardiovascular risk including any of the following:

- Ejection fraction by ECHO or MUGA must be > 40% and must be performed within 60
days prior to enrollment, unless the patient has received chemotherapy within
that period of time in which case the LVEF must be repeated

- New York Heart Association (NYHA) Class III or Class IV heart failure

- History or evidence of current clinically significant uncontrolled arrhythmias.
NOTE: Exception: Subjects with controlled atrial fibrillation for >30 days
prior to study enrollment

- History of acute coronary syndromes (including myocardial infarction and
unstable angina), coronary angioplasty, or stenting within 6 months prior to
study enrollment

- 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;

- Patients with intra-cardiac defibrillators;

- Known cardiac metastases