Phase II Study of Simvastatin for Relapsed/Refractory Myeloma

OBJECTIVES

Primary To estimate the overall response rate (ORR) (complete response (CR) + very good
partial response (VGPR) + partial response (PR)) of patients with multiple myeloma who have
relapsed or are refractory after bortezomib treatment and will now receive a combination
therapy of simvastatin, zoledronic acid, bortezomib, bendamustine and methylprednisolone.

To evaluate safety and tolerability of studied therapy.

Secondary

1. To estimate the progression-free Survival (PFS), time to progression (TTP), overall
survival (OS) and duration of response (DOR).

2. To describe toxicities (frequency and severity) during the treatment. 3 To estimate
clinical benefit response (CBR) (ORR + minor response (MR)) and stable disease (SD).

4 Explore factors associated with ORR, PFS, OS, toxicity.

Inclusion Criteria:

- Patients must have a diagnosis of Multiple Myeloma (using the International Myeloma
Working Group Guidelines)

- Patients must have failed at least one prior treatment regimen containing bortezomib.

They may be refractory to primary therapy or relapsed and have measurable or assessable
disease. (Refractory disease is defined as anything less than PR or progression within 60
days of completing therapy.)

- Patients with Multiple Myeloma must have measurable active, progressive or
symptomatic disease. Measurable disease may be paraprotein or free light chains in
serum or urine, or the presence of bone marrow plasma cells.

- Age- must be at least 18 years of age.

- Prior therapies may include bendamustine, bortezomib, methylprednisolone, radiation,
and autologous hematopoietic cell transplant.

- Patients who have received therapy must be at least 4 weeks beyond prior chemotherapy
(excluding corticosteroids).

- If female patient with reproductive capacity: on effective means of birth control
during the entire duration of the treatment.

- Patients must have recovered from acute toxicities resulting from therapy
administered prior to entering this study to grade 1 or less. Alopecia may not be
resolved.

- Ability to understand and willingness to sign a written informed consent document.

- Life expectancy of greater than 8 weeks.

- ECOG performance status 0, 1, or 2 (Karnofsky > 60%; see Appendix A).

- Patients must have adequate bone marrow function as defined below:

absolute neutrophil count > 500/ul platelets > 30,000/ul

-Patients must have adequate liver function as defined below: total bilirubin < 2 times
the upper limit of normal AST(SGOT), ALT(SGPT) < 3 x upper limit of normal

- Patients must have adequate renal function as defined by a creatinine clearance > 40
mL/min (measured or estimated by the Cockcroft-Gault formula).

- Patients must have no signs of significant rhabdomyolysis determined by CPK levels
with a CK < 5 times the upper limit of normal.

Exclusion Criteria:

- Patients who have not received any chemotherapy treatment for multiple myeloma prior
to being enrolled in the study.

- Patients who were receiving simvastatin (dose > 40 mg/day), or the equivalent dose of
another statin) during last prior chemotherapy for multiple myeloma.

- Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering
the study or those who have not recovered from adverse events due to agents
administered more than 4 weeks earlier.

- Patients receiving any other investigational agent(s).

- Active second malignancy in the last 5 years except for non-melanoma skin cancer or
carcinoma-in-situ.

- History of hypersensitivity reactions attributed to simvastatin, bortezomib,
bendamustine or zoledronic acid.

- Pregnant women are ineligible, as treatment involves unforeseeable risks to the
embryo or fetus.

- Patients receiving medications that may increase risk of rhabdomyolysis such as
itraconazole, ketoconazole, erythromycin, cyclosporine, amiodarone, verapamil,
niacin, HIV protease inhibitors.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, myopathy, untreated hypothyroidism,
hereditary myopathy in the family history, unstable angina pectoris, liver disease
not due to multiple myeloma, cardiac arrhythmia that is symptomatic or not rate
controlled, active connective tissue disease, active autoimmune disease, or
psychiatric illness/social situations that would limit compliance with study
requirements.