This phase II trial is studying how well giving bevacizumab together with lenalidomide and dexamethasone works in treating patients with relapsed or refractory stage II or stage III multiple myeloma. Monoclonal antibodies, such as bevacizumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Bevacizumab and lenalidomide may stop the growth of multiple myeloma by blocking blood flow to the cancer. Dexamethasone may stimulate the immune system in different ways and stop cancer cells from growing. Giving bevacizumab together with lenalidomide and dexamethasone may kill more cancer cells.

PRIMARY OBJECTIVES:

I. Determine the overall response rate (complete response and partial response) in patients with relapsed or refractory stage II or III multiple myeloma treated with bevacizumab, lenalidomide, and dexamethasone.

SECONDARY OBJECTIVES:

I. Determine time to progression in these patients. II. Determine the toxicity and tolerability of this regimen. III. Determine the effect of bevacizumab and lenalidomide on markers of myeloma activity in myeloma cells and stromal cells, including interleukin-6, macrophage inflammatory protein-1α, vascular endothelial growth factor, and STAT3.

IV. Assess local cytokine milieu using tissue microarrays of bone marrow biopsy specimens.

OUTLINE: This is a multicenter, open-label study.

Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15, oral lenalidomide on days 1-21, and oral dexamethasone on days 1, 8, 15, and 22. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Blood samples are collected at baseline and before courses 2 and 4. Blood samples are examined for vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) polymorphisms by pyrosequencing and VEGF, VEGFR1, VEGFR2, interleukin-6, and macrophage inflammatory protein 1 by immunoenzyme techniques. Relationships between plasma cell myeloma and stroma and the effect of study treatment on these relationships are examined in tissue sections of bone marrow before and after treatment utilizing microvessel density measurements, VEGF staining, and STAT3 staining (by immunohistochemistry and fluorescent in situ hybridization [FISH]).

After completion of study treatment, patients are followed periodically for at least 5 years.

Inclusion Criteria:

• Histologically or cytologically confirmed symptomatic multiple myeloma:

  • Stage II or III disease
  • Relapsed or refractory disease after >= 2 courses of prior chemotherapy

• Measurable levels of monoclonal protein (M protein) > 1.0 g/dL by serum protein electrophoresis OR > 200 mg of monoclonal light chain by 24-hour urine protein electrophoresis

• Measurable bone disease, defined as >= 1 unidimensionally measurable lesion (longest diameter to be recorded) >= 20 mm with conventional techniques OR >= 10 mm with spiral CT scan (for patients with lytic bone disease)

• No known brain metastases

• ECOG performance status (PS) 0-2 OR Karnofsky PS 70-100%

  • Patients with PS of 3 are eligible if it is due to pain that is likely to improve with treatment

• Life expectancy > 6 months

• No known HIV positivity

• No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months

• No active infections requiring oral or intravenous antibiotics within the past week

• No proteinuria (i.e., albuminuria) > 1,000 mg/24 hours unless related to the diagnosis of multiple myeloma

  • Patients with light chain (i.e., "Bence-Jones") proteinuria are still eligible if the non-light chain component of protein is < 1,000 mg/24 hours

• No serious nonhealing wound or ulcer

• No blood pressure > 150/90 mm Hg (even with medication)

• No significant traumatic injury within the past 28 days

• No clinically significant peripheral vascular disease

• No evidence of bleeding diathesis or coagulopathy

• No unstable angina or myocardial infarction within the past 6 months

• No stroke within the past 6 months

• No New York Heart Association class III or IV heart failure

• No secondary malignancy within the past 2 years except squamous cell or basal cell carcinoma of the skin or carcinoma in situ of the cervix

• Hemoglobin > 9 g/dL (may be supported by transfusion or growth factors)

• WBC >= 2,000/mm^3

• Absolute neutrophil count >= 1,000/mm^3

• Platelet count >= 75,000/mm^3

• Bilirubin =< 2.5 mg/dL

• At least 4 weeks since prior chemotherapy or radiotherapy and recovered

• More than 7 days since prior minor surgical procedures, fine-needle aspirations, or core biopsies:

More than 24 hours since prior bone marrow biopsy or central veinous access placement

• More than 28 days since prior major surgical procedure or open biopsy

• At least 4 weeks since prior and no concurrent participation in another experimental drug study

• Prior autologous peripheral blood stem cell transplantation allowed

• No prior lenalidomide

• Concurrent full-dose anticoagulants allowed provided all of the following criteria are met:

  • No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
  • No thrombocytopenia requiring transfusion
  • Platelet count > 75,000/mm3
  • INR 2-3 and stable

• No concurrent major surgery

• No concurrent sargramostim (GM-CSF)

• No other concurrent investigational agents

• No other concurrent anticancer agents or therapies

• AST and ALT =< 5 times upper limit of normal

• Creatinine < 2.5 mg/dL

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use 2 methods of effective contraception 4 weeks before, during, and 4 weeks after completion of study treatment

• No history of allergic reactions attributed to compounds of similar chemical or biological composition to lenalidomide and/or bevacizumab or other agents used in the study