Lenalidomide Maintenance Therapy for Multiple Myeloma

Background:

Multiple myeloma (MM) remains largely an incurable disease with an estimated median survival
of 6-7 years in standard risk myeloma and 2-3 years in high risk disease despite treatment
with autologous stem cell transplantation (ASCT).

Maintenance therapy to achieve sustained suppression of residual disease following
chemotherapy or ASCT has long been viewed as a desirable approach for extending survival in
MM.

Giving the immunomodulatory drug lenalidomide after induction or re-induction treatment may
stimulate the immune system in various ways to stop or slow the return of cancer.

It is not yet known how immune stimulatory effects of extended dosing with lenalidomide in
the maintenance setting correlate with clinical benefits.

Objectives:

Assess T cell (CD4, CD8), NKT and NK cell numbers in peripheral blood during the

course of lenalidomide maintenance therapy in treated MM patients.

Eligibility:

Patients with multiple myeloma who have achieved stable disease or better response, assessed
at greater than or equal to 4 weeks after completing induction or re-induction treatment

Age greater than or equal to 18 years

ECOG PS of 0-2

Adequate hematological parameters defined by: absolute neutrophil count greater than or
equal to 1.0 K/microL, hemoglobin greater than or equal to 8 g/dL, and platelet count
greater than or equal to 75 K/microL

Adequate hepatic function, with bilirubin < 1.5 times the ULN, and AST and ALT < 3 times ULN

Adequate renal function with creatinine clearance (CrCl) of greater than or equal to 40
mL/min. CrCl will be calculated using the Cockcroft-Gault method. If the calculated CrCl
based on Cockcroft-Gault method is < 40 mL/min, patient will have a 24 hr urine collection
to measure CrCl. The measured CrCl must also be greater than or equal to 40 ml/min

Design:

Single arm, single stage, phase II trial of lenalidomide maintenance for treated MM patients
who have stable or responsive disease.

After screening, eligibility determination, and enrollment; subjects will receive
lenalidomide 10 mg by mouth daily on days 1-21 of repeated 28-day cycles. When necessary,
lenalidomide will be held and restarted in accordance with accepted clinical dose
modification guidelines.

Subjects may continue lenalidomide until disease progression or unacceptable toxicity or
completion of two years of lenalidomide therapy and the 30 day safety follow-up visit.

Blood will be obtained to assess changes in T cell (CD4, CD8), NKT and NK cell numbers by
flow-cytometric analysis at pre-specified time points during lenalidomide maintenance.

Blood samples and/or bone marrow samples where possible, will be used for additional
research studies, which may include functional analyses of immune-cell subsets, analyses for
cytokines, chemokines, antibodies, tumor cell antigen targets, and/or other markers.

- INCLUSION CRITERIA:

- Patients with multiple myeloma treated with induction therapy or re-induction
therapy, who at the time of study enrollment have documented evidence of stable
disease response or better according to International Myeloma Workshop Consensus
Panel. The response assessment must occur at least 4 weeks after completion of their
last treatment.

- Age greater than or equal to 18 years. Because no dosing or adverse event data are
currently available on the use of lenalidomide in patients

- ECOG performance status less than or equal to 2.

- Patient must have adequate hematologic, renal, hepatic, and cardiac function as
defined by:

- Absolute neutrophil count greater than or equal to 1.0 K/microL independent of
growth factor support

- Platelets greater than or equal to 75K/microL

- Hemoglobin greater than or equal to 8 g/dL (transfusions are permissible)

- Calculated creatinine (CrCl) clearance of greater than or equal to 40 mL/min.
using the Cockcroft-Gault method. If the calculated CrCl based on
Cockcroft-Gault method is

- Total bilirubin less than or equal to 1.5 mg/dL, AST (SGOT) and ALT (SGPT) less
than or equal to 3 times ULN

- Females of childbearing potential (FCBP) must agree to use two effective forms of
contraception simultaneously or to practice complete abstinence from heterosexual
intercourse during the following time periods related to this study: 1) for at least
28 days before starting study drug; 2) while participating in the study; and 3) for
at least 28 days after discontinuation from the study. The two methods of effective
contraception must include one highly effective method (i.e. intrauterine device
(IUD), hormonal [birth control pills, injections, or implants], tubal ligation,
partner's vasectomy) and one additional effective (barrier) method (i.e. latex
condom, diaphragm, cervical cap). FCBP must be referred to a qualified provider of
contraceptive methods if needed.

- A FCBP is defined as 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).

- A FCBP must have two negative serum or urine pregnancy tests prior to starting study
drug. The first pregnancy test must be performed within 10-14 days prior to the start
of study drug and the second pregnancy test must be performed within 24 hours prior
to prescribing the study drug. The prescriptions of study drug must be filled within
7 days.

- Male patients must agree to use a latex condom during sexual contact with FCBP while
participating in the study and for at least 28 days following discontinuation from
the study even if he has undergone a successful vasectomy.

- Patient must be able to take aspirin (81 or 325 mg) daily as prophylactic
anticoagulation. Patients intolerant to ASA may use warfarin or low molecular weight
heparin.

- Patient must understand and voluntarily sign an informed consent form, with the
understanding that the patient may withdraw consent at any time without prejudice to
future medical care.

EXCLUSION CRITERIA:

- Patients with progressive or refractory MM, as defined by International Myeloma
Workshop Consensus Panel criteria.

- Refractory to lenalidomide in the most recent line of therapy, as defined by the
International Myeloma Consensus Panel criteria - as failure to achieve minimal
response or development of progressive disease while on lenalidomide or within 30
days of lenalidomide therapy

- Patients who are receiving any other investigational agents with the intent to treat
myeloma. Permitted concurrent therapies include:

- Bisphosphonates

- Radiotherapy to single stable disease site

- Plasma cell leukemia

- Pregnant or lactating females. Because there is a potential risk for adverse events
to nursing infants secondary to treatment of the mother with lenalidomide, lactating
females must agree not to breast feed while taking lenalidomide.

- Uncontrolled hypertension or diabetes

- Active hepatitis B or C infection

- Diagnosed or treated for another malignancy within 3 years prior to study enrollment,
with the exception of complete resection of non-melanoma skin cancer, or an in situ
malignancy

- Previous diagnosis of another malignancy with any evidence of residual disease.

- Patients seropositive for the human immunodeficiency virus (HIV), and/or those who
are taking anti-retroviral treatment for HIV/AIDS

- Prior organ transplant requiring immunosuppressive therapy

- Prior allogeneic stem cell transplant

- Patients requiring continuous, systemic immunosuppressive therapy

- Patients with myocardial infarction within 6 months prior to enrollment, New York
Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe
uncontrolled cardiac arrhythmias, or electrocardiographic evidence of acute ischemia

- Patients with conditions that would prevent absorption of the study drug

- Uncontrolled intercurrent illness including but not limited to uncontrolled infection
or psychiatric illness/social situations that would compromise compliance with study
requirements

- Significant neuropathy greater than or equal to Grade 3 at baseline

- Contraindication to concomitant anticoagulation prophylaxis

- Major surgery within 1 month prior to enrollment

- Patients who were previously exposed and who developed severe adverse events,
hypersensitivity or desquamating rash to either thalidomide or lenalidomide