Pomalidomide, Dexamethasone, and Filgrastim in Treating Patients With Relapsed or Refractory Multiple Myeloma

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of pomalidomide and dexamethasone when given
with growth factor support in patients with relapsed and refractory multiple myeloma. (Phase
I) II. To evaluate the safety of pomalidomide and dexamethasone at the MTD. (Phase II)

SECONDARY OBJECTIVES:

I. To obtain preliminary estimates of the anti-myeloma activity of higher doses of
pomalidomide given with low dose dexamethasone and growth factor support in patients with
relapsed and refractory multiple myeloma.

II. Activity will be defined by the overall response rate (ORR); (partial response [PR] or
better) and clinical benefit response (CBR) rate (minor response [MR] or better), as well as
by the response durability (duration of response [DOR], progression-free survival [PFS], and
time to progression [TTP]).

III. To further evaluate the safety of pomalidomide and dexamethasone at the maximum
tolerated dose (MTD).

TERTIARY OBJECTIVES:

I. To examine the influence of cereblon expression and activation of the wingless-type
(Wnt)/beta-catenin pathway on the activity of high dose pomalidomide with low dose
dexamethasone.

OUTLINE: This is a phase I, dose-escalation study of pomalidomide followed by a phase II
study.

INDUCTION: Patients receive pomalidomide orally (PO) daily on days 1-21, dexamethasone PO on
days 1, 8, 15, and 22, and filgrastim subcutaneously (SC) on days 22-28. Treatment repeats
every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients receive lower-dose pomalidomide PO daily on days 1-21 and dexamethasone
PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year and
then every 6 months thereafter.

Inclusion Criteria:

- Relapsed and/or refractory multiple myeloma with measurable disease, as defined by one
or both of the following (assessed within 14 days prior to initiation of therapy): a)
serum myeloma protein (M-protein) >= 0.5 g/d; b) urine Bence-Jones protein >= 200
mg/24 hours

- Patients with light chain only myeloma are eligible; the involved free light chain
level >= 100 mg/L with abnormal serum free light chain ratio

- Patients must have prior treatment with >= 2 cycles of lenalidomide and >= 2 cycles of
bortezomib (either in separate regimens or as part of the same regimen) (primary
refractory of subjects refractory to the most recent regimen are eligible)

- The patient has received =< 5 lines of prior therapy

- Eastern Cooperative Oncology Group performance status 0 - 2

- Serum alanine aminotransferase (ALT) < 3.5 times the upper limit of normal within 7
days of time of consent

- Serum direct bilirubin < 2 mg/dL (34 Omol/L) within 7 days of time of consent

- Absolute neutrophil count (ANC) >= 1.0 x 10^9/L within 7 days of time of consent,
without granulocyte- colony stimulating factor (G-CSF)

- Hemoglobin > 9 g/dL (80 g/L) within 7 days of time of consent (subjects may be
receiving red blood cell transfusions in accordance with institutional guidelines)

- Platelet count > 100 x 10^9/L

- Creatinine clearance > 50 mL/minute within 7 days of time of consent, either measured
or calculated using a standard formula (e.g., Cockcroft and Gault)

- Written informed consent in accordance with federal, local, and institutional
guidelines

- All study participants must be registered into the mandatory POMALYST (pomalidomide)
Risk Evaluation and Mitigation Strategy (REMS) program, and be willing and able to
comply with the requirements of the POMALYST REMS program

- Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy
test with a sensitivity of at least 25 mIU/mL within 10 - 14 days and again within 24
hours prior to starting cycle 1 of pomalidomide and must either commit to continued
abstinence from heterosexual intercourse or begin TWO acceptable methods of birth
control, one highly effective method and one additional effective method AT THE SAME
TIME, at least 28 days before she starts taking pomalidomide; FCBP must also agree to
ongoing pregnancy testing and follow pregnancy testing requirements as outlined in the
POMALYST REMS program; men must agree to use a latex condom during sexual contact with
a FCBP even if they have had a successful vasectomy; all patients must be counseled at
a minimum of every 28 days about pregnancy precautions and risks of fetal exposure

Exclusion Criteria:

- Hypersensitivity to previous lenalidomide or thalidomide

- History of serious allergic reactions to pegfilgrastim or filgrastim

- Chemotherapy (approved or investigational) within 3 weeks prior to signing consent

- Antibody therapy within 6 weeks prior to signing consent

- Radiotherapy to >= 3 sites at the same time within 1 week prior to signing consent

- Immunotherapy within 28 days prior to signing consent

- Pregnant or breast feeding females

- Major surgery within 21 days prior to signing consent

- Acute active infection requiring treatment (systemic antibiotics, antivirals, or
antifungals) within 14 days prior to signing consent

- Known human immunodeficiency virus infection

- Known active hepatitis B or C infection

- Unstable angina or myocardial infarction within 4 months prior to registration, New
York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina,
history of severe coronary artery disease, severe uncontrolled ventricular
arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia
or grade 3 conduction system abnormalities unless subject has a pacemaker

- Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to signing
consent

- Non-hematologic malignancy within the past 3 years with the exception of a) adequately
treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b)
carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason grade 6 or
less with stable prostate-specific antigen levels; or d) cancer considered cured by
surgical resection or unlikely to impact survival during the duration of the study,
such as localized transitional cell carcinoma of the bladder or benign tumors of the
adrenal or pancreas

- Significant neuropathy (grades 3 - 4, or grade 2 with pain) within 14 days prior to
signing consent

- Subjects with known or likely systemic amyloidosis

- Ongoing graft-vs-host disease

- Any other clinically significant medical disease or condition that, in the
investigator's opinion, may interfere with protocol adherence or a subject's ability
to give informed consent