Bortezomib and Bendamustine to Treat Relapsed/Refractory Myeloma

Patients with relapsed and refractory myeloma who have a measurable paraprotein in the serum
or urine or measurable protein by Freelite or measurable disease by plasmacytoma will be
given a combination of bendamustine and bortezomib each cycle. Response rate (PR or better
after 2 cycles) and duration of response will be assessed. Therapy will be continued until
disease progression. The bendamustine would be used in a day 1, day 4 dosing schedule after
each dose of bortezomib to take advantage of the chemosensitizing properties of bortezomib.
This minimizes the days of treatment to just the first week and allows rebound of blood
counts. This will be a phase II trial with dose reduction as necessary.

Bendamustine is a drug which appears to be non-cross-resistant with other alkylating agents
in vitro and in vivo. Thus, we hypothesize that the combination of bortezomib and
bendamustine will have activity in relapsed/refractory myeloma.

Inclusion Criteria:

1. Voluntary written informed consent

2. Age 18 years or older

3. Female subject is either post-menopausal or surgically sterilized or willing to use an
acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine
device, diaphragm with spermicide, condom with spermicide, or abstinence) for the
duration of the study.

4. Male subject agrees to use an acceptable method for contraception for the duration of
the study.

5. Diagnosis of multiple myeloma based on standard criteria as follows:

Major Criteria

- Plasmacytomas on tissue biopsy

- Bone marrow plasmacytosis (>30% plasma cells)

- Monoclonal immunoglobulin spike on serum electrophoresis (IgG >3.5 g/dL or IgA
>2.0 g/dL) or kappa or lambda light chain excretion >1 g/day on 24 hour urine
protein electrophoresis

Minor Criteria

- Bone marrow plasmacytosis (10 to 30% plasma cells)

- Monoclonal immunoglobulin present but of lesser magnitude than given under major
criteria

- Lytic bone lesions

- Normal IgM <50 mg/dL, IgA <100 mg/dL, or IgG <600 mg/dL

- Any of the following sets of criteria will confirm the diagnosis of Multiple
Myeloma:

- Any two of the major criteria or

- 1 major plus 2 minor criteria.

6. Measurable disease, defined as a monoclonal immunoglobulin spike (M-Spike) on serum
electrophoresis of ≥1 g/dL and/or urine monoclonal immunoglobulin spike of ≥200 mg/24
hours. Non-secretors must have measurable protein by Freelite or measurable disease by
plasmacytoma to be eligible.

7. Patients must have refractory myeloma as defined by a greater than 25% increase in
their M-protein. They should have progressed on bortezomib.

8. Karnofsky performance status ≥50

9. Patients treated with local radiotherapy with or without a brief exposure to steroids
are eligible. Patients who require radiotherapy should have entry to the protocol
deferred until the radiotherapy is completed by at least 4 weeks prior to initiation
of study drug.

10. Meets the following pretreatment laboratory criteria at baseline (Day 1 of Cycle 1,
before study drug administration)

- Absolute neutrophil count ≥1 x 10^3/uL

- Platelet count ≥75 x 10^3/uL

- Hemoglobin ≥8.0 g/dL

- Calculated or measured CrCL ≥ 40 mL/min

- AST or ALT and total bilirubin < 3 x ULN

11. Echocardiogram with a >50% Ejection Fraction

Exclusion Criteria:

Patients meeting any of the following exclusion criteria are not to be registered on study:

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

2. Plasma cell leukemia

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

4. Infection not controlled by antibiotics

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

6. Known active hepatitis B or C

7. New York Hospital Association (NYHA) Class III or IV heart failure, Echo or MUGA
ejection fraction < 40% (if known), or EKG evidence of acute ischemic disease

8. Other serious medical or psychiatric illness that could potentially interfere with the
completion of treatment according to this protocol

9. Second malignancy requiring treatment in the last 3 years

10. Patient has a calculated or measured creatinine clearance of <40 mL/min within 14 days
before enrollment

11. Patient has >Grade 2 peripheral neuropathy within 14 days before enrollment

12. Patient has hypersensitivity to bortezomib, boron or mannitol and bendamustine

13. Positive pregnancy test in women of childbearing potential or subject is pregnant or
breast-feeding. Confirmation that the subject is not pregnant must be established by a
negative serum betaa human chorionic gonadotropin test result obtained during
screening. Pregnancy testing is not required for post-menopausal or surgically
sterilized women.

14. Patient has received other investigational drugs with 14 days before enrollment

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

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.