Dalteparin, Lenalidomide, and Low-Dose Dexamethasone in Treating Patients With Previously Untreated Multiple Myeloma

PRIMARY OBJECTIVES:

I. To select a dose of Dalteparin to be used with Lenalidomide and low-dose dexamethasone in
future trials for patients with previously untreated multiple myeloma (MM), based on
toxicity, selected biomarkers (M-spike, interleukin [IL]-6) related to response and other
markers of coagulation.

SECONDARY OBJECTIVES:

I. To evaluate overall response rate (ORR = complete response [CR] + partial response [PR]),
and time to progression (TTP) for this regimen at each of the two Dalteparin doses.

II. To evaluate the safety profile of this regimen in untreated MM patients, at each of the
two Dalteparin doses.

III. To study the effect of Dalteparin alone, and in combination with
lenalidomide/dexamethasone on serum biomarkers of multiple myeloma (MM) and thrombosis.

IV. To explore possible associations between the ORR and incidence of venous thromboembolism
(VTE) with serial syndecan-1, IL-6, tyrosine aminotransferase (TAT), D-dimer, P-selectin
levels.

OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive a
prophylactic dose of dalteparin subcutaneously (SC) on days 1-28; lenalidomide orally (PO) on
days 1-21; and low-dose dexamethasone PO on days 1, 8, 15, and 22.

ARM II: Patients receive a therapeutic dose of dalteparin SC on days 1-21 and lenalidomide PO
and low-dose dexamethasone PO as in Arm I.

In both arms, treatment repeats every 28 days for up to 6 courses in the absence of disease
progression or unacceptable toxicity. Patients with residual responding disease may receive 2
additional courses. After completion of study treatment, patients are followed up every 3
months for up to 2 years.

Inclusion Criteria:

- Patients must have a diagnosis of active MM requiring treatment, as diagnosed by a
bone marrow biopsy within 8 weeks prior to study enrollment

- Patients must not have received any previous treatment for MM (localized radiation
therapy or single agent pulse steroid therapy for acute MM crises is permitted)

- Life expectancy of greater than 12 weeks

- Eastern Cooperative Oncology Group (ECOG) performance status < 2 (Karnofsky >= 50%)

- Total bilirubin < 1.5 x upper limit of normal (ULN)

- Transaminases (aspartate aminotransferase [AST]/alanine aminotransferase [ALT]) < 2.5
x ULN

- Alkaline phosphatase < 2.5 ULN

- Platelets >= 75,000 cells/mm3

- Hemoglobin >= 8.0 g/dL

- Absolute neutrophil count (ANC) > 1,000 cells/mm3 NOTE: Patients with platelet count <
75,000 or hemoglobin < 8.0 g/dl,or ANC <1,000 cell/mm3 secondary to extensive bone
marrow disease can be enrolled at Principal Investigator's (PI) discretion with
appropriate transfusion and/or cytokine support

- Creatinine =< 2.5 mg/dL (=< 200 mmol/L) or creatinine clearance > 30 ml/min (as
calculated by the Cockcroft-Gault formula)

- Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy
test with a sensitivity of at least 50 mIU/mL within 10-14 days and again within 24
hours prior to prescribing lenalidomide for Cycle 1 and 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 she starts taking 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

- All study participants must be registered into the mandatory RevAssist program, and be
willing and able to comply with the requirements of RevAssist

- Willingness and ability to sign informed consent for the clinical trial

Exclusion Criteria:

- Patients who have had any prior chemotherapy for MM; with the exception of pulse
steroids for any myeloma-related acute events

- Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy
considered investigational

- Pregnant or lactating women

- Active serious infections uncontrolled by antibiotics at the time of treatment
initiation

- Inability to give voluntary written informed consent before performance of any
study-related procedure not part of normal medical care, with the understanding that
consent may be withdrawn by the subject at any time without prejudice to future
medical care

- Failure to comply with birth control methods as described above

- Any serious medical or psychiatric condition or reason that, in the PI's opinion,
makes the patient unsuitable to participate in this clinical trial

- Known to be human immunodeficiency virus (HIV) positive (if the status of HIV is not
known and patient is not at risk, as determined by the PI, then the patient will not
be specifically tested for HIV); HIV-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
lenalidomide and/or dalteparin. In addition, these patients are at increased risk of
lethal infections when treated with marrow-suppressive therapy

- Diagnosed or treated for another malignancy within 3 years of enrollment, with the
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
the skin, an in situ malignancy, or low-risk prostate cancer (organ-confined, early
stage disease) after curative therapy

- Patients with M protein >6 gm/dl prior to starting treatment will be excluded from the
initial "run-in" cohort on both arms of the study, but will be eligible for the
subsequent enrollment of patients who do not have a run-in phase with dalteparin