Melphalan, Prednisone, and Thalidomide or Lenalidomide in Treating Patients With Newly Diagnosed Multiple Myeloma

PRIMARY OBJECTIVES:

I. To compare progression-free survival between patients receiving melphalan, prednisone, and
thalidomide versus melphalan, prednisone, and lenalidomide in newly diagnosed multiple
myeloma patients who are not candidates for high-dose therapy.

SECONDARY OBJECTIVES:

I. To compare overall survival between the arms. II. To compare response rates and depth of
response. III. To compare the incidence of toxicities. IV. To validate the translocation
classification (TC) of myeloma as a prognostic tool using gene expression profiling at
diagnosis.

TERTIARY OBJECTIVES:

I. To compare quality-of-life (QOL) change between arms based on the Functional Assessment of
Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT-Ntx) Trial Outcome Index (TOI)
from registration (prior to initiation of treatment) to the end of cycle 24 (maintenance
therapy).

II. To examine the impact of differential treatment response (PFS), if observed, on QOL based
on the FACT-Ntx TOI up to cycle 38 (maintenance therapy).

III. To obtain prospective data on myeloma specific QOL attributes.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I:

INDUCTION THERAPY: Patients receive melphalan orally (PO) and prednisone PO once daily (QD)
on days 1-4, and thalidomide PO QD on days 1-28. Treatment repeats every 28 days for up to 12
courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive thalidomide PO QD and continue in the absence of
disease progression.

ARM II:

INDUCTION THERAPY: Patients receive melphalan PO and prednisone PO QD on days 1-4, and
lenalidomide PO on days 1-21. Treatment repeats every 28 days for up to 12 courses in the
absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive lenalidomide PO QD on days 1-21. Courses repeat every
28 days in the absence of disease progression.

After completion of study treatment, patients are followed up periodically for 10 years.

Inclusion Criteria:

- Patients must have a confirmed diagnosis of symptomatic myeloma; for the original
diagnosis of myeloma patients should have met the following criteria at one point in
their disease course:

- Bone marrow plasmacytosis with >= 10% plasma cells or sheets of plasma cells or
biopsy proven plasmacytoma

- Patient must have had symptomatic disease at initial diagnosis that prompted the
initiation of therapy as well as evidence of end-organ damage at the time of
diagnosis namely; at least one of the following: anemia, hypercalcemia, bone
disease (lytic bone lesions or pathologic fracture), or renal dysfunction

- NOTE: Patients with asymptomatic smoldering myeloma (serum m protein >= 3
gm/dL or bone marrow plasma cells >= 10% or greater plus no evidence of
anemia, hypercalcemia, lytic bone lesions or renal dysfunction) and
monoclonal gammopathy of undetermined significance (serum m protein < 3
gm/dL and bone marrow plasma cells < 10% plus no evidence of anemia,
hypercalcemia, lytic bone lesions or renal dysfunction) are not eligible

- Patients must be > 65 and have declined alternative treatment OR patients who are >=
18 < 65 are eligible if they:

- Are not a candidate for autologous stem cell transplantation in the opinion of
the treating physician OR

- Have declined transplant or other alternative treatment

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- All tests below must be performed within 28 days prior to randomization:

- Serum free light chain assay

- Kappa free light chain

- Lambda free light chain

- NOTE: The serum free light chain test is required to be done if the patient
does not have measurable disease in the serum or urine; measurable disease
in the serum is defined as having a serum M-spike >= 1 g/dL; measurable
disease in the urine is defined as having a urine M-spike >= 200 mg/24 hr

- NOTE: urine protein electrophoresis (UPEP) (on a 24 hour collection) is
required, no substitute method is acceptable; urine must be followed monthly
if the baseline urine M-spike is >= 200 mg/24 hr; please note that if both
serum and urine m-components are present, both must be followed in order to
evaluate response

- Hemoglobin > 7 g/dL

- Platelet count > 75,000 cells/mm^3

- Absolute neutrophil count > 1000 cells/mm^3

- Creatinine < 2.5 mg/dL and creatinine clearance (measured or calculated) > 60 mL/min

- Total bilirubin =< 1.5 mg/dL

- Serum glutamate pyruvate transaminase (SGPT) [alanine aminotransferase (ALT)] and
serum glutamic oxaloacetic transaminase (SGOT) [aspartate aminotransferase (AST)] =<
2.5 times the upper limit of normal

- Patients must be previously untreated for myeloma, although prior treatment for
myeloma with prednisone or dexamethasone for less than 4 weeks total dosing alone or
in combination with thalidomide or lenalidomide for less than 2 weeks total dosing is
allowable

- Patients may be receiving bisphosphonates or growth factors (erythropoietin) for
multiple myeloma; although erythropoietin is allowed, it is strongly discouraged due
to increased risk of thrombosis when employed alongside thalidomide and/or
lenalidomide therapy

- Patients must be willing and able to take prophylaxis with either aspirin at 325
mg/day or alternative prophylaxis with either low molecular weight heparin or Coumadin

- 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 and again within 24
hours prior to starting cycle 1 of lenalidomide; 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

- Patients must not have uncontrolled inter-current illness that would limit compliance
with the study including:

- Uncontrolled hypertension

- Symptomatic congestive heart failure

- Unstable angina

- Uncontrolled cardiac arrhythmia

- Uncontrolled psychiatric illness or social situation

- Prior history of Stevens Johnson syndrome

- Patients must not have grade 2 or higher peripheral neuropathy

- Patients must not have an active, uncontrolled infection

- Female patients MUST NOT be pregnant or breastfeeding; the use of these drugs in this
patient population is ABSOLUTELY CONTRAINDICATED; for women of childbearing potential,
a negative serum pregnancy test is required within 10-14 days prior to randomization;
for female patients of childbearing potential a negative serum pregnancy test must be
repeated within 24 hours prior to initiation of treatment, weekly for the first 4
weeks of treatment and then every 4 weeks if the patient's periods are regular or
every 2 weeks if they are not; women of childbearing potential must be willing to
refrain from sexual intercourse or must be willing to employ a dual method of
contraception, one of which is highly effective [intrauterine device (IUD), birth
control pills, tubal ligation or partner's vasectomy] and another additional method
(condom, diaphragm or cervical cap) starting 4 weeks prior to and while taking
lenalidomide and thalidomide and for four weeks after discontinuing this therapy; the
male partner of a female using a single form of birth control should use a condom
regardless of his vasectomy status

- Sexually active males must be willing to use a condom (even if they have undergone a
prior vasectomy) while having intercourse with any woman, while taking lenalidomide
and thalidomide and for 4 weeks after stopping treatment

- Patients must not have had a second active malignancy requiring treatment within the
last 2 years, with the exceptions of basal or squamous cell carcinoma of the skin, in
situ carcinoma of the cervix