Bevacizumab With or Without Thalidomide in Treating Patients With Relapsed or Refractory Multiple Myeloma
Bevacizumab With or Without Thalidomide in Treating Patients With Relapsed or Refractory Multiple Myeloma
RATIONALE: 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 deliver cancer-killing substances to them. Thalidomide may stop the growth
 of cancer cells by stopping blood flow to the tumor. It is not yet known whether bevacizumab
 works better with or without thalidomide for multiple myeloma.

 PURPOSE: This randomized phase II trial is to see if bevacizumab works better with or without
 thalidomide in treating patients who have relapsed or refractory multiple myeloma.
OBJECTIVES:

 -  Compare the response rate and time to progression in patients with relapsed or
 refractory multiple myeloma treated with bevacizumab with or without thalidomide.

 -  Compare the toxicity of these regimens in these patients.

 -  Compare the effects of these regimens on histological and molecular biomarkers of
 angiogenesis, tumor invasion, and cell death in these patients.

 -  Correlate plasma and urine vascular endothelial growth factor and basic fibroblast
 growth factor levels and other potential markers of angiogenesis and myeloma cell
 proliferation with outcome in patients treated with these regimens.

 -  Determine the pharmacokinetics of thalidomide in these patients.

 -  Compare the effects of these regimens on the psychological/physical well being of these
 patients.

 OUTLINE: This is a randomized, multicenter study. Patients are stratified according to prior
 treatment with thalidomide (yes vs no).

 Patients who have received no prior treatment with thalidomide are randomized to 1 of 2
 treatment arms.

 -  Arm I: Patients receive bevacizumab IV over 30-90 minutes on days 1, 15, 29, and 43.
 Patients also receive oral thalidomide once daily.

 -  Arm II: Patients receive bevacizumab as in arm I. Patients who have received prior
 treatment with thalidomide receive bevacizumab as in arm I.

 Courses repeat every 56 days in the absence of disease progression or unacceptable toxicity.

 Patients are followed monthly for 3 months and then every 3-4 months for 3 years.

 PROJECTED ACCRUAL: A total of 55-103 patients (16-32 who have received prior thalidomide,
 16-32 in arm I, and 23-39 in arm II) will be accrued for this study within 2.5 years.
DISEASE CHARACTERISTICS:

 -  Histologically confirmed progressing multiple myeloma

 -  Stages I, II, or III

 -  More than 25% increase in urine or plasma paraprotein levels

 -  More than 5% malignant plasma cell involvement in bone marrow

 -  Smoldering myeloma is eligible provided there is evidence of progressive disease
 requiring therapy

 -  At least 25% increase in M protein levels or Bence Jones excretion

 -  Hemoglobin no greater than 10.5 g/dL

 -  Frequent infections

 -  Hypercalcemia

 -  Rise in serum creatinine above normal on 2 separate occasions

 -  Nonsecretory multiple myeloma that is bidimensionally measurable by MRI or CT scan is
 eligible provided the disease site is new or has shown an increase in M protein levels
 or Bence Jones excretion is greater than 30% from baseline

 -  No prior or concurrent CNS involvement with primary or metastatic tumor

 -  No nonquantifiable monoclonal proteins or IgM peaks unless there is evidence of
 bidimensionally measurable disease by MRI or CT scan

 -  No history of hemorrhagic tumor or hemorrhagic metastasis

 PATIENT CHARACTERISTICS:

 Age:

 -  18 and over

 Performance status:

 -  Karnofsky 70-100%

 Life expectancy:

 -  At least 3 months

 Hematopoietic:

 -  See Disease Characteristics

 -  Absolute neutrophil count ≥1,000/mm^3

 -  Platelet count ≥ 50,000/mm^3

 -  No hemorrhagic illness within the past 3 weeks

 Hepatic:

 -  Bilirubin ≤ 1.5 mg/dL

 -  SGOT/SGPT≤ 2.5 times upper limit of normal (ULN)

 -  INR ≤ 1.5

 -  aPTT < 1.5 times ULN

 Renal:

 -  See Disease Characteristics

 -  Creatinine ≤ 2 mg/dL

 -  Creatinine clearance ≥ 40 mL/min

 -  Calcium ≤ 12 mg/dL

 -  No nephrotic syndrome

 Cardiovascular:

 -  No active coronary artery disease

 -  No New York Heart Association class II-IV congestive heart failure

 -  No grade II or greater peripheral vascular disease (i.e, ischemic rest pain,
 non-healing ulcer, or tissue loss)

 -  No uncontrolled hypertension

 -  No history of deep venous thrombosis

 -  No vascular illness within the past 3 weeks

 -  No arterial thromboembolic event within the past 6 months, including any of the
 following:

 -  Transient ischemic attack

 -  Cerebrovascular accident

 -  Unstable angina

 -  Myocardial infarction

 Pulmonary:

 -  No history of pulmonary embolus

 Other:

 -  No other prior malignancy unless the patient has been in complete remission for at
 least 2 years

 -  No peripheral neuropathy or CNS abnormalities ≥ grade 2

 -  Patients with prior exposure to thalidomide and assigned to arm I may have grade
 2 peripheral or CNS abnormalities

 -  No seizure disorder

 -  No serious non-healing wound, ulcer, or bone fracture

 -  No trauma within the past 3 weeks

 -  No significant inflammatory illness within the past 3 weeks

 -  No known hypersensitivity to Chinese hamster ovary cell products

 -  No known hypersensitivity to other recombinant human or humanized antibodies and/or
 positive human antimurine antibodies/human antichimeric antibodies

 -  No other significant medical, psychological, or social problem that would preclude
 study participation

 -  Not pregnant or nursing

 -  Negative pregnancy test

 -  Fertile patients must use effective contraception for at least 2 weeks before and
 during study participation

 PRIOR CONCURRENT THERAPY:

 Biologic therapy:

 -  See Chemotherapy

 -  Prior nonmyeloablative transplantation allowed provided the following are true:

 -  Patient is not receiving concurrent immunosuppressive therapy

 -  Patient has no signs of graft-versus-host disease

 -  Concurrent epoetin alfa allowed if started at least 4 weeks prior to study entry

 Chemotherapy:

 -  No more than 5 prior chemotherapy regimens

 -  Thalidomide, steroids, and interferon are not considered part of prior regimens

 -  Mobilization with chemotherapy followed by either single or tandem autologous
 transplantation is counted as 1 prior regimen

 -  Mobilization with chemotherapy followed by autologous and subsequent
 nonmyeloablative HLA-matched sibling allogeneic transplantation is counted as 1
 prior regimen

 -  At least 3 weeks since prior chemotherapy

 -  No concurrent chemotherapy

 Endocrine therapy:

 -  See Chemotherapy

 -  At least 2 weeks since prior steroids

 -  No concurrent steroids

 Radiotherapy:

 -  At least 3 weeks since prior radiotherapy

 -  No concurrent radiotherapy

 Surgery:

 -  At least 3 weeks since prior surgery, including biopsy of a visceral organ

 Other:

 -  At least 10 days since prior anticoagulants, including aspirin

 -  At least 2 days since prior nonsteroidal anti-inflammatory agents

 -  Concurrent bisphosphonates allowed