A Phase II Study of Bevacizumab and Bortezomib in Patients With Relapsed/Refractory Multiple Myeloma

Rationale: With the identification of thalidomide as an active agent in Multiple Myeloma, the
role of angiogenesis in its pathogenesis has become a subject of much investigation. Micro
vessel density (neovascularization) is inversely related to prognosis in Multiple Myeloma.
Response to thalidomide was felt to correlate with a decline in microvessel density (Singhal
et al NEJM). While the mechanism of neovascularization is yet to be fully elucidated, a
number of models have shown VEGF to play a central role.

Thalidomide has been shown to synergize with a number of agents used to treat MM, including
bortezomib. (Wang et al ASH 2005) This would justify the use of other therapeutics with known
antiangiogenic activity in conjunction with established antimyeloma therapies.

Bortezomib, which has the precedence of known synergy with Thalidomide and has an extremely
well established optimal dose, schedule, response rate, event free survival, and overall
survival would make it an excellent candidate for combination therapy with other established
antiangiogenic compounds.

There have been several reports of the role of VEGF in multiple myeloma. It has been shown
that multiple myeloma cells secreteVEGF, which further promotes production of IL-6 in BMSCs,
as well as migration and proliferation of the tumor cells. Thus VEGF is both an autocrine
growth factor and trigger of IL-6-mediated paracrine multiple myeloma cell growth. Recent
reports have highlighted the major role of VEGF in multiple myeloma pathogenesis,
demonstrating the VEGF also increases microvessel density in the bone marrow. VEGF also
inhibits dendritic cells. Taken together, these preclinical reports make strong suggestion
for the promise of VEGF targeted agents in multiple myeloma (Le Gouill et al 2004).

Inclusion Criteria:

- Must have been previously diagnosed with multiple myeloma based on Durie-Salmon
criteria and/or the diagnostic criteria developed by the International Myeloma Working
Group (IMWG).The patient must currently require therapy for relapsed (progressive
disease, defined as a 25% increase in M-protein, development of new or worsening of
existing lesions or soft tissue plasmacytoma, or hypercalcemia, or relapse from CR. Or
patient must have disease that is refractory to most recent therapy. Defined as less
than a 50% reduction in serum paraprotein or 90% reduction in urine paraprotein.

- Must have measurable disease, defined as follows: For secretory multiple myeloma,
measurable levels of monoclonal protein: greater than or equal to 0.5g/dL on
electrophoresis or greater than or equal to 200mg of monoclonal light chain on a 24
hour protein electrophoresis.

- Must have had at least one prior line of therapy but no more than three prior lines of
therapy.

- Must understand and voluntarily sign an informed consent form.

- Must be greater than/equal to 18 years of age at time of signing consent.

- Must be able to adhere to study visit schedule and other protocol requirements.

- Must have an ECOG performance status of 0,1or 2

- Women of Child-bearing potential (WCBP) defined as a sexually mature woman who has not
undergone a hysterectomy or who has not been naturally post-menopausal for at least 24
consecutive months must have a negative serum or urine pregnancy test within 7 days of
starting study drug. In addition, sexually active WCBP must agree to use adequate
contraceptive methods (oral, injectable, or implantable hormonal contraceptive method;
tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or
vasectomized partner) while on study medication.

- All WCBP and all sexually active male patients must agree to use adequate methods of
birth control throughout the study.

Exclusion Criteria:

- Inability to comply with study and/or follow-up procedures

- Life expectancy of less than 12 weeks

- Inadequately controlled hypertension (defined as systolic blood pressure >150 and/or
diastolic blood pressure > 100 mmHg on antihypertensive medications)

- Any prior history of hypertensive crisis or hypertensive encephalopathy

- New York Heart Association (NYHA) Grade II or greater congestive heart failure or left
ventricular ejection fraction (LVEF) < 40% (Note: baseline evaluation of LVEF should
be performed for any patient who has received >450mg/m2 of any anthracycline during
prior chemotherapy.

- History of myocardial infarction or unstable angina within 6 months prior to study
enrollment

- History of stroke or transient ischemic attack within 6 months prior to study
enrollment

- Known CNS disease

- Significant vascular disease (e.g., aortic aneurysm, aortic dissection)

- Symptomatic peripheral vascular disease

- Known hypersensitivity to any component of bevacizumab and/or bortezomib

- Previously treated with Bortezomib and/or Bevacizumab.

- Received nitrosoureas within 3 weeks or any other chemotherapy, including thalidomide
or clarithromycin, or radiation therapy before enrollment.

- Received corticosteroids (greater than 10mg/day prednisone or equivalent) within three
weeks prior to enrollment.

- Received immunotherapy or antibody therapy within 8 weeks prior to enrollment.

- Received plasmapheresis within 4 weeks before enrollment.

- Had major surgery within 4 weeks before enrollment. (kyphoplasty is not considered
major surgery)

- History of allergic reactions attributable to compounds containing boron or mannitol.

- Grade 3 or greater peripheral neuropathy as defined by the NCI Common Toxicity
Criteria (NCI CTC version 3.0) Grade 3: Sensory loss or paresthesia interfering with
ADLs. Grade 4: Permanent sensory loss that interferes with function.