Phase II Study of Subcutaneous (SC) Bortezomib, Lenalidomide and Dexamethasone for Relapsed and/or Refractory Multiple Myeloma; Followed by SC Bortezomib Maintenance

Background:

- Multiple myeloma (MM) is an incurable plasma cell neoplasm with a median survival of
3-4 years.

- Increased survival has been achieved with the introduction of the proteasome inhibitor
bortezomib and immunomodulatory drugs (IMiDs) such as lenalidomide. Bortezomib and
lenalidomide have different but overlapping mechanism of anti-MM activity in
preclinical studies.

- Despite the benefits of novel agents, bortezomib and lenalidomide pose clinical
challenges. Bortezomib drug toxicity includes neuropathy, GI distress, myelosuppression
and herpes zoster reactivation. Together with lenalidomide, the incidence of sensory
neuropathy reaches 80%.

- Subcutaneous (SC) Bortezomib was evaluated in a prospective phase I trial for relapsed
and/or refractory MM. SC administration was found to be comparable with the established
IV route, with no differences in overall systemic availability and pharmacodynamic
activity, similar toxicity profiles, and similar response rates.

- Combining SC, rather than IV bortezomib, with lenalidomide and dexamethasone is
especially attractive given the potential for less overall neurotoxicity and improved
convenience for the patient.

- Also, using bortezomib SC as a maintenance therapy after combination therapy is a novel
strategy that has the potential to set the stage for coming oral proteasome inhibitors
as potential maintenance strategies in the future.

Objectives:

Primary Objective

- Determine response rates, of S.C. bortezomib, lenalidomide, and dexamethasone (VRd) in
relapse and/or refractory MM patients

Secondary Objectives

- Assess peripheral blood for immune cell populations in relation to SC bortezomib
maintenance

- Evaluate toxicity, including peripheral neuropathy

- Evaluate patterns of change in patient-reported quality of life and symptom distress

- Gauge the feasibility, responsiveness to change and associated effect sizes when using
patient-reported outcomes to augment clinician ratings of regimen-related treatment
toxicity, including incidence and severity of peripheral neuropathy

- Determine duration of response

- Determine progression free survival

Eligibility:

- Patients with histologically confirmed relapsed and/or refractory multiple myeloma

- Age greater than or equal to 18 years

- Without serious co-morbidity that would interfere with receipt of VRd

- If patient has neuropathy, it must be less than or equal to Grade 1 at the time of
first dose or within 14 days of enrollment

- Absolute neutrophil count (ANC) greater than equal to 1.0 K/uL, hemoglobin less than or
equal to 8 g/dL, and platelet count greater than or equal to 75 K/uL

- Adequate hepatic function, with bilirubin < 1.5 times ULN; AST and ALT < 3.0 times
ULN

- Creatinine Clearance greater than or equal to 60 ml/min. CrCl will be calculated by
Cockcroft-Gault method. CrCl (calculated) = (140 Age) times Mass (in kilograms)
times [0.85 if Female] 72 times Serum Creatinine (in mg/dL). If calculated CrCl based
on Cockcroft-Gault method is < 60 mL/min, patient will have a 24 hr urine collection
to measure CrCl. The measured CrCl must also be greater than or equal to 60 ml/min for
the patient to be eligible.

Design:

Patient will receive treatment in this single arm study for 8 total cycles (each cycle is 21
days) with the following drugs, dosages and schedule:

- Bortezomib

Cycle 1-8: 1.0 mg/m(2) SC at a concentration of 2.5 mg/ml to the thighs or abdomen on days
1, 4, 8, 11 of 21 day cycle

- Lenalidomide

Cycle 1: 15 mg oral daily on days 2-14 of 21 day cycle

Cycle 2-8: 15 mg oral daily on days 1-14 of 21 day cycle

- Dexamethasone

Cycle 1: 10 mg oral on days 2,4,5,8,9,11,12 of 21 day cycle

Cycle 2-8: 10 mg oral on days 1,2,4,5,8,9,11,12 of 21 day cycle

- Maintenance therapy

After completion of cycle 8, patients with greater than or equal to stable disease will
receive maintenance with bortezomib S.C. at a dose per end of Cycle 8. Maintenance will be
given on days 1 and 15 of a 28 day cycle, and will continue until progression or
unacceptable toxicity.

- INCLUSION CRITERIA:

2.1.1.1 Relapsed and/or refractory histologically confirmed multiple myeloma as defined
by:

1. Relapse from complete response with reappearance of the serum or urinary paraprotein,
more or equal than 5% bone marrow plasma cells, new lytic bone lesions and /or soft
tissue plasmacytomas, an increase in size of residual bone lesions and /or
development of hypercalcemia (corrected serum calcium > 11.5 mg/dl) not attributable
to another cause.

2. Progressive disease: when a complete response has not been achieved, include new or
expanding bone lesions, hypercalcemia, and a > 25% increase in serum monoclonal
paraprotein concentration, 24-hour urinary light chain excretion, or plasma cells
within the bone marrow.

3. Refractory disease: Unresponsiveness to current therapy or progressive disease within
60 days of prior treatment.

2.1.1.2 Measurable disease within the past 4 weeks defined by any one of the following:

1. Serum monoclonal protein greater than or equal to 1.0 g/dL

2. Urine monoclonal protein > 200 mg/24 hour

3. Serum immunoglobulin free light chain > 10 mg/dL AND abnormal

kappa/lambda ratio (reference 0.26-1.65)

2.1.1.3 Creatinine Clearance greater than or equal to 60 ml/min. CrCl will be calculated
by Cockcroft-Gault method. CrCl (calculated) = (140 Age) times Mass (in kilograms)
times [0.85 if Female] 72 times Serum Creatinine (in mg/dL). If calculated CrCl based on
Cockcroft-Gault method is < 60 mL/min, patient will have a 24 hr urine collection to
measure CrCl. The measured CrCl must also be greater than or equal to 60 ml/min for the
patient to be eligible.

2.1.1.4 Age > 18 years

2.1.1.5 Eastern Cooperative Oncology Group (ECOG) performance status 0-2

2.1.1.6 Female subject is either postmenopausal for at least 1 year before the screening
visit, is surgically sterilized or if they are of childbearing potential, agree to
practice 2 effective methods of contraception from the time of signing the informed
consent form through 30 days after the last dose of VELCADE, or agree to completely
abstain from heterosexual intercourse.

2.1.1.7 Absolute neutrophil count (ANC) greater than or requal to 1.0 K/uL, hemoglobin
greater than or equal to 8 g/dL (transfusions are permissible), and platelet count greater
than or equal to 75K/uL within 7 days before enrollment.

2.1.1.8 Adequate hepatic function, with bilirubin < 1.5 times ULN; AST and ALT < 3.0
times ULN

2.1.1.9 Patients must have completed prior treatments (except steroids) at least 30 days
before enrollment.

2.1.1.10 Prior allogeneic stem cell transplant without evidence of graft versus host
disease. (GVHD) will be eligible at the investigator s discretion.

2.1.1.11 Permitted concurrent systemic treatment for MM.

1. Treatment of hypercalcemia or spinal cord compression or aggressively progressing
myeloma with corticosteroids is permitted.

2. Bisphosphonates are permitted.

3. Radiotherapy is permitted. 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.

2.1.1.12 All study participants must be registered into the mandatory RevAssist
program, and be willing and able to comply with the requirements of RevAssist .

2.1.1.13 Females of childbearing potential (FCBP) (Cross) must have a negative serum
beta-human chorionic gonadotropin (beta-hCG) or urine pregnancy test within 10 14
days and again within 24 hours prior to prescribing lenalidomide for Cycle 1
(prescriptions must be filled within 7 days) 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. FCBP must also agree to
ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact
with a FCBP even if they have had a successful vasectomy.

2.1.1.14 Male subjects, even if surgically sterilized (ie, status prostatectomy) must
agree to 1 of the following: practice effective barrier contraception during the
entire study treatment period and through a minimum of 30 days after the last dose of
study drug, or completely abstain from heterosexual intercourse.

2.1.1.15 Subjects must be able to give voluntary written informed consent before
performance of any study-related procedure not part of normal medical care, with the
understanding that consent may be withdrawn by the subject at any time without
prejudice to future medical care.

2.1.1.16 Known HIV infected patients meeting the following characteristics are
eligible:

- CD4 cell count greater than or equal to 334/mm(3)

- Meeting either of the following:

- Willing to suspend antiretroviral therapy for duration of protocol therapy or

- On stable regimen of combination antiretroviral therapy that does not include
either zidovudine or stavudine for at least 12 weeks and without evidence of
toxicity

EXCLUSION CRITERIA:

2.1.2.1 Refractory to lenalidomide and/or bortezomib in the most recent line of
therapy

2.1.2.2 Prior allogeneic stem cell transplant if the patient has graft versus host
disease (GVHD).

2.1.2.3 Plasma cell leukemia

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

2.1.2.5 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.

2.1.2.6 Uncontrolled hypertension or diabetes

2.1.2.7 Active hepatitis B or C infection

2.1.2.8 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 abnormality at screening must be documented by the investigator as not medically
relevant.

2.1.2.9 Has refractory GI disease with refractory nausea/vomiting, inflammatory bowel
disease, or bowel resection that would prevent absorption

2.1.2.10 Uncontrolled intercurrent illness including but not limited to active
infection or psychiatric illness/social situations that would compromise compliance
of study requirements

2.1.2.11 Significant neuropathy greater than or equal to Grade 1 with pain or Grade 2
at the time of first dose or within 14 days of enrollment.

2.1.2.12 Contraindication to any concomitant medication, including antivirals,
anticoagulation prophylaxis, tumor lysis prophylaxis, or hydration given prior to
therapy

2.1.2.13 Active infection requiring treatment within two weeks prior to first dose

2.1.2.14 Major surgery within 1 month prior to enrollment

2.1.2.15 Hypersensitivity to bortezomib, boron, mannitol or lenalidomide

2.1.2.16 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.

2.1.2.17 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.