Velcade + Cyclophosphamide in Newly Diagnosed Multiple Myeloma

A total of 35 patients will be accrued to this single arm, open label, phase II trial over a
period of about 18 months, studying induction chemotherapy with VELCADE, cyclophosphamide
and dexamethasone administered on an attenuated dosing schedule to accommodate
non-candidates for high-dose chemotherapy with autologous stem cell transplantation - an
often frail patient population. Maintenance therapy will follow with alternating
lenalidomide and VELCADE. All patients should receive antiviral (zoster) prophylaxis, and
peptic ulcer prophylaxis is recommended. Aspirin and/or anticoagulation are left to study
physician discretion. All patients will be treated with the same experimental regimen.
Several novel features are being explored: the substitution of cyclophosphamide for
melphalan; once weekly AND subcutaneous bortezomib instead of standard twice weekly,
intravenous dosing; and alternating bortezomib and lenalidomide in maintenance. The
overarching aim is to preserve efficacy while minimizing toxicity and inconvenience to this
often frail patient population.

Inclusion Criteria:

- 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not part of normal medical care, with the understanding that consent may be withdrawn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.

- Age ≥18 years at the time of signing the informed consent form.

- Able to adhere to the study visit schedule and other protocol requirements.

- Multiple Myeloma (MM) diagnosed according to the following standard criteria (all
three criteria must be met):

- Monoclonal plasma cells in bone marrow ≥10% and/or presence of biopsy-proven
plasmacytoma

- Laboratory tests meet the levels specified in the protocol

- Measurable disease requiring systemic therapy.

- No prior systemic therapy or radiation therapy active against myeloma lasting more
than four weeks duration. Any prior therapy must be completed a minimum of 21 days
before starting study drugs. Enrollment of subjects who require 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.

- Karnofsky performance status (KPS) of ≥ 60% at study entry.

- In order to obtain lenalidomide, patients must be registered into the mandatory
RevlimidREMS® program during the maintenance phase of therapy, and be willing and
able to comply with the requirements of RevlimidREMS®

- Female subjects must be postmenopausal for at least 1 year before the screening visit
or surgically sterilized. If females are of childbearing potential, they must adhere
to required pregnancy testing; male and female subjects must use specified effective
birth control methods.

- Patients should receive concomitant therapy with bisphosphonates, regardless of the
presence of bony lesions, although study physicians may use their discretion based on
presence of renal insufficiency or other mitigating factors.

Exclusion Criteria:

- Abnormal laboratory tests within the ranges specified in the protocol

- Serum creatinine will not be used to exclude patients. Patients on renal-replacement
therapy (e.g., hemodialysis or peritoneal dialysis) will be eligible to participate.

- Light-chain (AL) amyloidosis. Patients with secondary amyloidosis due to MM are
eligible.

- ≥ Grade 2 peripheral neuropathy

- 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
Electrocardiography (ECG) abnormality at screening must be documented by the
investigator as not medically relevant.

- Hypersensitivity to VELCADE, boron, mannitol, or any other component of protocol
therapy.

- Female subject is pregnant or lactating. Confirmation that the subject is not
pregnant must be established by a negative serum beta-human chorionic gonadotropin
(b- hCG) pregnancy test result obtained during screening as specified in section
7.11.

- 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 2 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.

- Concurrent use of other anti-cancer agents or treatments

- Known HIV positivity

- Known active hepatitis A, B or C