Bortezomib and Lenalidomide in Treating Patients With Relapsed or Refractory Mantle Cell Lymphoma

PRIMARY OBJECTIVES:

I. To determine the overall response (complete response [CR] and partial response [PR]) rate
and the complete response (CR) rate to bortezomib + lenalidomide therapy in patients with
relapsed or refractory mantle cell lymphoma.

SECONDARY OBJECTIVES:

I. To determine the time to progression after therapy with bortezomib + lenalidomide in
patients with relapsed or refractory mantle cell lymphoma.

II. To determine the disease-free survival and overall survival after therapy with bortezomib
+ lenalidomide in patients with relapsed or refractory mantle cell lymphoma.

OUTLINE:

Patients receive induction therapy comprising bortezomib intravenously (IV) over 3-5 seconds
on days 1, 4, 8, and 11 and lenalidomide orally (PO) once daily (QD) on days 1-14. Treatment
repeats every 21 days for up to 8 courses in the absence of disease progression or
unacceptable toxicity. Patients achieving a complete or partial response as best response
after completion of induction therapy receive maintenance therapy comprising bortezomib IV on
days 1 and 8 and lenalidomide PO QD on days 1-14. Treatment repeats every 21 days for up to 6
years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years,
every 6 months for 2 years, and then annually for 2 years.

Inclusion Criteria:

- Histologically documented mantle cell lymphoma, with the following immunophenotypic
characteristics: cluster of differentiation (CD)5+, CD23-, cyclin D1+; this may be
from an initial diagnostic biopsy, or one obtained at time of relapse

- Bone marrow biopsies as the sole means of diagnosis are not acceptable, but they
may be submitted in conjunction with nodal biopsies; fine needle aspirates are
not acceptable

- Failure to submit pathology specimens within 60 days of patient registration will
be considered a major protocol violation

- Institutional flow cytometry or immunohistochemistry must confirm CD5 antigen
expression, lack of CD23 antigen expression, and expression of cyclin D1

- Prior therapy with at least one regimen, which may have been single agent or
multi-agent, and consisted of traditional cytotoxic agents and/or biologic agents;
patient may not have received prior bortezomib or lenalidomide therapy; patient must
have progressive disease or refractory disease following that initial regimen(s);
refractory disease will be defined as stable disease (SD) or progressive disease (PD)
as best response to prior therapy, or CR or PR as initial response followed by disease
progression within 6 months

- Prior autologous, but not allogeneic, stem cell transplant is allowed

- No corticosteroids within two weeks prior to study, except for maintenance therapy for
a non-malignant disease; maintenance therapy dose may not exceed 20 mg/day prednisone
or equivalent

- No prior radioimmunotherapy within 12 months of study entry

- No >= grade 3 peripheral neuropathy within a month prior to study entry

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Measurable disease must be present either on physical examination or imaging studies;
non-measurable disease alone is not acceptable; any tumor mass > 1 cm by physical
exam, computed tomography (CT), magnetic resonance imaging (MRI), or conventional
radiograph is acceptable; lesions that are considered non-measurable include the
following:

- Bone lesions (lesions, if present, should be noted)

- Ascites

- Pleural/pericardial effusion

- Lymphangitis cutis or pulmonis

- Bone marrow (involvement by non-Hodgkin lymphoma should be noted)

- No known central nervous system (CNS) involvement by lymphoma

- Patients with human immunodeficiency virus (HIV) infection are eligible, provided they
meet the following: CD4+ cell count > 350/mm^3; treatment sensitive HIV and, if on
anti-HIV therapy, HIV viral load < 50 copies/mm^3; no history of acquired
immunodeficiency syndrome (AIDS)-defining conditions or other HIV-related illnesses;
no concurrent zidovudine or stavudine

- Non-pregnant and non-nursing; females of childbearing potential (FCBP) must have a
negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within
10-14 days prior to registration; further, they must either commit to continued
abstinence from heterosexual intercourse or begin TWO acceptable methods of birth
control: one highly effective method and one additional effective method AT THE SAME
TIME, at least 28 days before starting lenalidomide; FCBP must also agree to ongoing
pregnancy testing; men must agree to use a latex condom during sexual contact with a
FCBP, even if they have had a successful vasectomy; a FCBP is a sexually mature woman
who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been
naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at
any time in the preceding 24 consecutive months); all patients must be counseled by a
trained counselor every 28 days about pregnancy precautions and risks of fetal
exposure; documentation of counseling is required on Cancer and Leukemia Group B
(CALGB) form S-041

- Patients with a recent history (within 3 months of study entry) of deep vein
thrombosis (DVT)/pulmonary embolism (PE) are not eligible; patients with a distant
history (greater than 3 months before study entry) of DVT/PE are eligible, but must
receive either prophylactic aspirin or low molecular weight heparin, unless
contraindicated

- Left ventricular ejection fraction (LVEF) >= 45% by multigated acquisition (MUGA) scan
or echocardiogram

- No New York Heart Association class III or class IV congestive heart failure at study
entry

- No myocardial infarction within the past 6 months of study entry

- No known positivity for hepatitis A, B, or C

- Absolute neutrophil count (ANC) >= 1,000/uL (>= 500/uL if marrow involvement)

- Platelets >= 75,000/uL

- Creatinine =< 1.5 x upper limit of normal (ULN) (unless attributable to non-Hodgkin's
lymphoma) and estimated creatinine clearance >= 30 mL/min (patients on dialysis are
not eligible)

- Total bilirubin =< 2 x ULN (unless attributable to non-Hodgkin's lymphoma and
Gilbert's disease)

- Urine (U)-human chorionic gonadotropin (HCG) or serum HCG negative