Phase II Study of Efficacy and Safety of Lenalidomide, Subcutaneous Bortezomib and Dexamethasone Therapy for Newly Diagnosed Multiple Myeloma

This research study is a Phase II clinical trial, which tests the safety and effectiveness of
an investigational combination of drugs to learn whether the combination of drugs works in
treating a specific cancer. "Investigational" means that the combination of drugs is being
studied. It also means that the FDA (the U.S. Food and Drug Administration) has not yet
approved the combination of drugs for your type of cancer.

Each of the individual drugs, lenalidomide , subcutaneous bortezomib, and dexamethasone, are
approved by the U.S. Food and Drug Administration (FDA). The combination has not been
approved yet for multiple myeloma or any other type of cancer. Subcutaneous bortezomib is
currently approved by the U.S. FDA for the treatment of patients with relapsed/refractory
multiple myeloma. Lenalidomide is currently approved for use with dexamethasone for patients
with multiple myeloma who have received at least one prior therapy and for the treatment of
certain types of myelodysplastic syndrome (another form of cancer affecting the blood). Both
Bortezomib and Lenalidomide kill tumor cells and help the body cells to fight cancer.
Dexamethasone is commonly used, either alone, or in combination with other drugs, to treat
multiple myeloma. Dexamethasone heps to reduce irritation and cell injury (inflammation).

In this research study, the investigators are looking to explore the drug combination of
lenalidomide, subcutaneous bortezomib and dexamethasone to see what side effects it may have
and how well it works for treatment of newly diagnosed multiple myeloma. This 3 drug regimen
showed promising results in previous studies, however administration of intravenous
bortezomib caused high levels of nerve injury (a condition involving the nerves of the upper
and lower extremities associated with numbness, tingling and burning). In this study, the
investigators are testing the hypothesis that subcutaneous administration of bortezomib will
result in less nerve toxicity. Therefore, the combination of lenalidomide, dexamethasone and
subcutaneous bortezomib may be better tolerated and may allow for a longer duration of
therapy.

Inclusion Criteria:

- Diagnosis of symptomatic MM, according to International Myeloma Foundation 2003
Diagnostic Criteria:

- Clonal plasma cells >10% on bone marrow biopsy

- A monoclonal protein (paraprotein) in either serum or urine(except in cases of
non-secretory myeloma)*

- Myeloma-related organ dysfunction (1 or more) of the following (evidence of
end-organ damage felt related to the plasma cell disorder related organ or tissue
impairment (ROTI), commonly referred to by the acronym "CRAB"):

- Serum Ca ≥ 10.5 mg/dL or

- Renal insufficiency attributable to myeloma. Serum creatinine > 2mg/dL

- Anemia: Normochromic, normocytic with a hemoglobin value > 2g/dL below the
lower limit of normal or a hemoglobin <10 g/dL

- Bone lesions (lytic lesions, severe osteopenia or pathologic fractures) or
osteoporosis. *If no monoclonal protein is detected (non-secretory disease),
then >/= 30% monoclonal bone marrow plasma cells and/or a biopsy-proven
plasmacytoma required.

- Has received no prior treatment with any systemic therapy for the treatment of
multiple myeloma

- Prior treatment of hypercalcemia or spinal cord compression with corticosteroids
does not disqualify the patient (the dose should not exceed the equivalent of 160
mg of dexamethasone in a 2 week period).

- Bisphosphonates are permitted.

- Local radiation as long as two weeks have lapsed since last date of radiotherapy,
which is recommended to be a limited field.

- Age ≥18 years at the time of signing Informed Consent

- ECOG performance status ≤ 2 (Karnofsky ≥ 50%)

- Voluntary written informed consent

- Subject must be able to adhere to the study visit schedule and other protocol
requirements.

- Females of reproductive potential must adhere to the scheduled pregnancy testing
as required in the Revlimid REMS® program. Females of childbearing potential
(FCBP) must have a negative serum or urine pregnancy test with a sensitivity of
at least 50 µL/mL 10 to14 days prior to therapy and repeated again within 24
hours prior to prescribing lenalidomide for Cycle 1 and must either commit to
complete abstinence from heterosexual contact or begin TWO acceptable methods of
birth control, one highly effective method and one additional effective (barrier)
method, AT THE SAME TIME, at least 28 days before she starts taking lenalidomide.
FCBP must also agree to ongoing pregnancy testing. Men must practice complete
abstinence or agree to use a condom during sexual contact with a FCBP even if
they have had a successful vasectomy. All study participants must be registered
into the mandatory Revlimid REMS® program, and be willing and able to comply with
the requirements of the REMS® program- Ability to understand and the willingness
to sign a written informed consent document

Exclusion Criteria:

- Participants who exhibit any of the following conditions at screening will not be
eligible for admission into the study.

- Renal insufficiency (serum creatinine levels > 2.5 mg/dL, calculated Crcl with
Cockcroft-Gault formula, see Appendix B, < 45 ml/min)

- Subjects with evidence of mucosal or internal bleeding and/or platelet refractory
(i.e., unable to maintain a platelet count ≥ 50,000 cells/mm3)

- Subjects with an absolute neutrophil count (ANC) < 1000 cells/mm3. Growth factors may
not be used to meet ANC eligibility criteria

- Subjects with a hemoglobin < 8.0 g/dL

- AST (SGOT) and ALT (SGPT) > 2 x institutional ULN, bilirubin levels ≥1.5 institutional
ULN

- Concomitant therapy medications that include corticosteroids (except as indicated in
inclusion criteria).

- Myocardial infarction within 6 months prior to enrollment or has New York Heart
Association (NYHA) Class III or IV heart failure (Appendix C), uncontrolled angina,
severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia or active conduction system abnormalities.

- Clinically relevant active infection requiring treatment (antibiotics, antivirals,
antifungals).

- Any serious co-morbid condition, including laboratory abnormalities, that in the
opinion of the Investigator places the subject at unacceptable risk if he/she were to
participate in the study.

- Female subject is pregnant or breast-feeding.

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

- Uncontrolled diabetes mellitus.

- Contraindication to any required concomitant drugs or supportive therapies including
hypersensitivity to all anticoagulation and antiplatelet options or hypersensitivity
to acyclovir or similar anti-viral drug.

- History of allergic reaction/hypersensitivity attributed to compounds containing
boron, mannitol, polysorbate 80 or sodium citrate dehydrate.

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

- Known seropositive for or active HIV infection or hepatitis B or C viral infection.

- Patients who are seropositive because of hepatitis B virus vaccine are eligible.

- Known intolerance to steroid therapy.

- Patient has hypersensitivity to bortezomib, boron, or mannitol.

- 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.

- Radiation therapy within 2 weeks of enrollment. Enrollment of subjects who require
concurrent radiotherapy (which must be localized in its field size) should be deferred
until the radiotherapy is completed and 2 weeks have elapsed since the last date of
therapy.

- Participant must be able to swallow pills.