Phase I/II Trial of the Combination of Lenalidomide (Revlimid) and Nab-paclitaxel (Abraxane) in the Treatment of Relapsed/Refractory Multiple Myeloma

Revlimid is an important imid based therapy of myeloma. However patients will still relapse
after this drug and then have limited options. Abraxane has shown efficacy in a number of
cancers, putatively through intratumor concentration by SPARC (secreted protein acidic and
rich in cysteine). (Taxanes have shown a modest activity in myeloma. Interestingly, Revlimid
can upregulate the levels of SPARC. Thus, investigators will test the toxicity and efficacy
of a combination of Revlimid and Abraxane in relapsed/refractory myeloma.

Investigators will perform a phase I/II trial of Revlimid daily for 21 days and Abraxane
weekly for 3 weeks in patients who have failed Revlimid but have adequate blood counts and
renal function and minimal neuropathy. For study purposes, 1 cycle is considered to be 4
weeks (20 days). Subjects will get Abraxane for three weeks and will be off of this treatment
for 1 week. There are 10 visits per cycle. Accrual will be on standard 3 patient cohorts.
Once the maximum tolerated dose is reached, the level below will be expanded to 25 patients
for a pilot phase II trial. All treatments will be performed until progression. Assessments
will be made at least at the 2, 4, and 6 month timepoints and monthly thereafter until
progression.

Since both drugs can cause myelosuppression, investigators will start with doses below their
standard doses as single agents. Investigators will use 100 mg/m2 of Abraxane weekly for 3
weeks and 10 mg Revlimid daily for 21 days, with a dose escalation for Revlimid to 15 mg and
to 25 mg. Dose de-escalations will also be performed for both drugs as necessary.
Investigators will explore whether SPARC (secreted protein acidic and rich in cysteine)
expression is altered by flow cytometry and immunohistochemistry.

Inclusion Criteria:

- Patients with relapsed/refractory multiple myeloma based on standard criteria

- Renal function assessed by calculated creatinine clearance as follows

- Phase I subjects must have calculated creatinine clearance >=30ml/min by
Cockcroft-Gault formula.

- Phase II subjects must have calculated creatinine clearance >=30ml/min by
Cockcroft-Gault formula.

- Progressed (>25% increase in evaluable disease) or non response on Revlimid or within
60 days of stopping Revlimid

- > 1 prior regimen

- Total bilirubin <=1.5 x Upper limit of normal (ULN)

- AST (aspartate aminotransferase) or serum glutamic-oxaloacetic transaminase (SGOT) and
alanine aminotransferase (ALT) or serum glutamic-pyruvic transaminase (SGPT) <=3 x
ULN.

- All study participants must be registered into the mandatory Revlimid REMS® program,
and be willing and able to comply with the requirements of Revlimid REMS®.

- Females of childbearing potential must have a negative serum or urine pregnancy test
with a sensitivity of at least 50 mIU/mL (milli-International unit/milliliter) within
10 - 14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1
(prescriptions must be filled within 7 days as required by Revlimid REMS) 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
lenalidomide.

- Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients
intolerant to ASA (acetylsalicylic acid) may use warfarin or low molecular weight
heparin).

- With < or = grade 2 neuropathy

- Karnofsky performance status ≥ 50

- Patients treated with local radiotherapy with or without a brief (2 weeks or less)
exposure to steroids are eligible. Patients who require concurrent radiotherapy should
have entry to the protocol deferred until the radiotherapy is completed

- Meets the following pretreatment laboratory criteria at Baseline (Day 1 of Cycle 1,
before study drug administration)

1. Platelet count ≥ 75 x 10^3/uL (upper limit) .

2. Hemoglobin ≥ 8.0 g/dL (grams/deciliter)

3. Absolute neutrophil count ≥ 1.0 x 10^3/uL

- Age 18 years or older

Exclusion Criteria:

- > grade 2 neuropathy

- > Cr (complete response) 2.5

- LFTs (liver function test) > 2x nl (normal limit)

- Patient had myocardial infarction within 6 months prior to enrollment or has New York
Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia or active conduction system abnormalities. Prior to study entry, any ECG
(electrocardiogram) abnormality at screening must be documented by the investigator as
not medically relevant.

- Known hypersensitivity to thalidomide or Revlimid (if applicable).

- The development of erythema nodosum if characterized by a desquamating rash while
taking thalidomide or similar drugs.

- Known seropositive for or active viral infection with human immunodeficiency virus
(HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are
seropositive because of hepatitis B virus vaccine are eligible.

- Female subject is pregnant or lactating. Confirmation that the subject is not pregnant
must be established by a negative serum -human chorionic gonadotropin (hCG) pregnancy
test result obtained during screening. Pregnancy testing is not required for
postmenopausal or surgically sterilized women.

- Female patients who are lactating or have a positive serum pregnancy test during the
screening period, or a positive urine pregnancy test on Day 1 before first dose of
study drug, if applicable.

- Serious medical or psychiatric illness likely to interfere with participation in this
clinical study.

- Diagnosed or treated for another malignancy within 3 years of enrollment, with the
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.

- Participation in clinical trials with other investigational agents not included in
this trial, within 14 days of the start of this trial and throughout the duration of
this trial.

- Radiation therapy within 3 weeks before randomization. Enrollment of subjects who
require concurrent radiotherapy (which must be localized in its field size) should be
deferred until the radiotherapy is completed and 3 weeks have elapsed since the last
date of therapy.

- POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly,
endocrinopathy, monoclonal protein (M-protein) and skin changes)

- Plasma cell leukemia

- Receiving steroids daily for other medical conditions, e.g., asthma, systemic lupus
erythematosis, rheumatoid arthritis

- Infection not controlled by antibiotics

- HIV infection. Patients should provide consent for HIV testing according to the
institution's standard practice

- Known active hepatitis B or C