Lenalidomide and Low-Dose Dexamethasone in Patients With Previously Treated Multiple Myeloma and Kidney Dysfunction

Multiple Myeloma (MM) affects approximately 20,000 Americans annually and remains an
incurable hematologic malignancy characterized by frequent early response followed by
universal treatment relapse necessitating multiple sequential therapeutic regimens. Until
recently, few effective therapies existed. Several novel agents for MM have now become
available including the immunomodulatory drugs thalidomide, lenalidomide, as well as the
proteasome inhibitor, bortezomib. Each of these agents is undergoing extensive clinical
evaluation in combination with other therapies to produce unprecedented response rates in
newly diagnosed and relapsed MM. Lenalidomide has proven to be a highly effective treatment
agent, particularly when used in combination with dexamethasone but is renally excreted and
little information is available about its use in myeloma patients with impaired kidney
function (20% have renal failure at some time after diagnosis). Defining a safe and effective
dose of lenalidomide to use is a critical step in MM treatment.

OUTLINE: This is a Phase I, dose-escalation study of lenalidomide followed by a Phase II
study. Patients are stratified according to degree of renal dysfunction (moderate [creatinine
clearance 30-60 mL/min] vs severe [creatinine clearance <30 mL/min and does not require
dialysis] vs end-stage renal disease [creatinine clearance <30 mL/min and requires
dialysis]).

Patients receive oral lenalidomide on days 1-21 and low-dose oral dexamethasone 40 mg on days
1, 8, 15, and 22. There is a 7 day rest (days 22-28) from lenalidomide. Each cycle is 28 days
and repeated in the absence of disease progression or unacceptable toxicity.

Patients enrolled in the phase II portion of the study will undergo blood sample collection
periodically for pharmacokinetic analysis of lenalidomide (Mayo Clinic sites only).

After completion of study treatment, patients are followed every 6 months for up to 3 years.

Inclusion Criteria:

- Diagnosed with previously treated multiple myeloma.

- Measurable disease assessed by one of the following ≤21 days prior to registration:

- Serum monoclonal protein ≥1 g by protein electrophoresis

- Urine monoclonal protein >200 mg on 24 hour electrophoresis

- Serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin
kappa to lambda free light chain ratio

- Monoclonal bone marrow plasmacytosis ≥30% (evaluable disease)

- If both serum and urine m-components are present, both must be followed in order
to evaluate response.

- All previous cancer therapy including chemotherapy, radiation, hormonal therapy and
surgery, must be discontinued ≥2 weeks prior to registration.

- Age ≥18 years.

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

- Acceptable organ and marrow function ≤21 days prior to registration:

- Absolute neutrophil count (ANC) ≥1000/mm³

- Platelet count ≥75,000/mm³

- Total bilirubin ≤2 mg/dL

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 x upper
limit of normal

- Renal impairment at baseline as measured by serum creatinine clearance (CrCl) ≤60
mL/min ≤21 days prior to registration.

- Females of Childbearing Potential (FCBP) must have a negative pregnancy test within
10-14 days and again within 24 hours of starting Cycle 1 and must use an effective
double-method contraception for ≥28 days prior to, during, and for ≥28 days after
completion of study therapy.

- Able to take required prophylactic anticoagulation.

- Able to understand and willingness to sign a written informed consent.

- Willing to provide blood samples for research purposes (Mayo Clinic sites only).

- If previously received lenalidomide, demonstration of clinical response of any
duration or stable disease with progression-free interval of ≥6 months from start of
that therapy.

Exclusion Criteria:

- Concurrent use of other anti-cancer agents or treatments. Growth factors and
bisphosphonates are allowed as medically indicated. Steroids may be used with an
equivalency of up to 20 mg of Prednisone per day as long as the dose has not been
adjusted upwards in past 2 weeks prior to study registration.

- Uncontrolled intercurrent illness including, but not limited to, any of the following:

- Ongoing or active infection requiring IV antibiotics

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Uncontrolled cardiac arrhythmia

- Psychiatric illness/social situation that would limit compliance with study
requirements.

- Any of the following as this regimen may be harmful to a developing fetus or nursing
child:

- Pregnant women

- Breast-feeding women

- Men or women of childbearing potential or their sexual partners who are unwilling
to employ adequate contraception.

- HIV-positive patients on combination antiretroviral therapy.

- Known hypersensitivity to thalidomide or other immunomodulatory drugs.

- History of Stevens-Johnson syndrome characterized by a desquamating rash while taking
thalidomide or similar drugs.

- Other active malignancy except for non melanoma skin cancer or in situ cervical or
breast cancer.

- Concurrent radiation therapy, except for palliation of a single painful bone lesion or
fracture.