S1211 Bortezomib, Dexamethasone, and Lenalidomide With or Without Elotuzumab in Treating Patients With Newly Diagnosed High-Risk Multiple Myeloma

PRIMARY OBJECTIVES:

I. To determine the appropriate Phase II dose of elotuzumab to use in combination with
lenalidomide, bortezomib, and dexamethasone for patients with multiple myeloma. (Phase I) II.
To assess whether incorporation of the novel agent elotuzumab into the treatment algorithm of
high-risk multiple myeloma (HRMM) will improve progression-free survival (PFS). (Phase II)
III. To estimate the frequency and severity of toxicities of this treatment strategy in this
patient population. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of elotuzumab, followed by a phase II,
randomized study.

PHASE I:

INDUCTION: Patients receive bortezomib subcutaneously (SC) or intravenously (IV) on days 1,
4, 8, and 11; lenalidomide orally (PO) once daily (QD) on days 1-14; and dexamethasone PO or
IV on days 1, 2, 4, 5, 8, 9, 11, and 12 (and on day 15 of courses 1 and 2 only). Patients
also receive elotuzumab IV on days 1, 8, and 15 of courses 1 and 2 and on days 1 and 11 of
courses 3-8. Treatment repeats every 21 days for 8 courses in the absence of disease
progression or unacceptable toxicity.

MAINTENANCE: Patients receive bortezomib SC or IV on days 1, 8, and 15; lenalidomide PO QD on
days 1-21; dexamethasone PO on days 1, 8, and 15; and elotuzumab IV on days 1 and 15.
Treatment repeats every 28 days in the absence of disease progression or unacceptable
toxicity.

PHASE II: Patients are randomized to 1 of 2 treatment arms.

ARM I:

INDUCTION: Patients receive bortezomib SC or IV on days 1, 4, 8, and 11; lenalidomide PO QD
on days 1-14; and dexamethasone PO or IV on days 1, 2, 4, 5, 8, 9, 11, and 12. Treatment
repeats every 21 days for 8 courses in the absence of disease progression or unacceptable
toxicity (patients who received a course of chemotherapy prior to registration will begin
protocol treatment with course 2 and receive a total of 7 courses of protocol therapy).

MAINTENANCE: Patients receive bortezomib SC or IV on days 1, 8, and 15; lenalidomide PO QD on
days 1-21; and dexamethasone PO on days 1, 8, and 15. Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity.

ARM II:

INDUCTION: Patients receive bortezomib, lenalidomide, and dexamethasone as in Arm I. Patients
also receive elotuzumab IV on days 1, 8, and 15 of courses 1 and 2 and on days 1 and 11 of
courses 3-8. Treatment repeats every 21 days for 8 courses in the absence of disease
progression or unacceptable toxicity.

MAINTENANCE: Patients receive bortezomib, lenalidomide, and dexamethasone as in Arm I.
Patients also receive elotuzumab IV on days 1 and 15. Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity.

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

Inclusion Criteria:

- Patients must have newly diagnosed active multiple myeloma (MM)

- For the Phase II portion only, patients must have high-risk MM based on one or more of
the following criteria at the time of initial diagnosis (prior to any chemotherapy):

- Poor-risk genomic signature according to the University of Arkansas 70-gene model
(available clinically as myeloma prognostic risk score [MyPRS] score, Signal
Genetics, Inc) AND/OR

- Translocation (14;16), and/or translocation (14;20), and/or deletion (17p) by
fluorescence in-situ hybridization (FISH) or cytogenetics AND/OR

- Primary plasma cell leukemia (defined by either >= 2,000 plasma cells/mL of
peripheral blood, or 20% on a manual differential count) AND/OR

- Serum lactate dehydrogenase (LDH) >= 2 x institutional upper limit of normal
(IULN) AND/OR

- 1q21 amplification by FISH analysis AND/OR

- High risk by the SKY92 signature

- Patients with non-secretory MM or known amyloidosis are not eligible

- Patients must have measurable disease within 28 days prior to registration (or prior
to initiation of first induction course for patients with prior therapy)

- Patients on the Phase I portion may not have received ANY prior chemotherapy; patients
on the Phase II portion may have received one prior cycle of any non-investigational
chemotherapy; prior chemotherapy must have been completed within 56 days prior to
registration and all toxicities must have resolved to =< grade 1; patients on either
portion may have received prior treatment with dexamethasone, providing total number
of days of treatment was =< 14 days and total treatment dose was =< 360 mg

- Patients may have received prior radiotherapy for symptomatic localized bone lesions
or impending spinal cord compression only; radiotherapy must be completed at least 14
days prior to registration and all toxicities must have resolved to =< grade 1

- Absolute neutrophil count (ANC) >= 1,000 cells/mm^3 without growth factor support

- Platelet count >= 70,000 cells/mm^3 for patients who have bone marrow plasmacytosis <
50%; or >= 50,000 cells/mm^3 for patients who have bone marrow plasmacytosis of >= 50%

- Total bilirubin =< 1.5 x institutional upper limit of normal (IULN)

- Serum glutamic oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST) and
serum glutamate pyruvate transaminase (SGPT)/alanine aminotransferase (ALT) =< 2.5 x
IULN

- Creatinine clearance (CrCL) >= 30 mL/min, measured by a 24-hour urine collection or
estimated by the Cockcroft and Gault formula within 14 days prior to registration

- Patients must not have active involvement of the central nervous system (CNS) with MM
(by clinical evaluation); patients with documentation of, or clinical signs or
symptoms consistent with, CNS involvement of MM must have a lumbar puncture that is
negative for CNS involvement of MM; the lumbar puncture must be completed within 14
days prior to registration; patients with no previous history of documented CNS
involvement and with no clinical signs or symptoms consistent with CNS involvement are
not required to have completed a lumbar puncture prior to registration; note that
monitoring of CNS involvement and treatment with intrathecal therapy is recommended
during protocol treatment

- Patients who are known to be human immunodeficiency virus positive (HIV+) are eligible
providing they meet all of the following additional criteria within 28 days prior to
registration:

- Cluster of differentiation (CD)4 cells >= 500/mm^3

- Viral load of < 50 copies HIV messenger ribonucleic acid (mRNA)/mm^3 if on
combination antiretroviral therapy (cART) or < 25,000 copies HIV mRNA if not on
cART

- No zidovudine or stavudine as part of cART

- Patients who are HIV+ and do not meet all of these criteria are not eligible for
this study

- Patients must have baseline skeletal survey (whole body x-ray) to document lytic
lesions, osteopenia or compression fracture

- Patients must have Zubrod performance status =< 2

- Patients with known hepatitis B or hepatitis C infection may be eligible providing
they have viral load < 800,000 IU/L within 28 days prior to registration

- Patients must not have POEMS syndrome (plasma cell dyscrasia with polyneuropathy,
organomegaly, endocrinopathy, monoclonal protein, and skin changes)

- Patients must not have clinically significant illness including uncontrolled, active
infection requiring intravenous antibiotics, New York Heart Association (NYHA) class
III or class IV heart failure, unstable angina pectoris, myocardial infarction within
the past 6 months, uncontrolled >= grade 3 cardiac arrhythmias, uncontrolled
hypertension, or uncontrolled diabetes mellitus; patients must have undergone an
electrocardiogram (EKG) within 28 days prior to registration

- Uncontrolled diabetes: a glycated hemoglobin (Hg A1C) > 7% within 14 days prior to
registration; the same criterion will be used in patients with confirmed diagnosis of
diabetes mellitus who have been on a stable dietary or therapeutic regimen for this
condition in the last three months

- Uncontrolled blood pressure and hypertension: systolic blood pressure (SBP) > 140 mm
Hg or diastolic blood pressure (DBP) > 90 mm Hg within 14 days prior to registration;
patients are permitted to be receiving multiple anti-hypertensive medications (unless
otherwise indicated in the study); all blood pressure measurements within the 14 days
prior to registration and on day 1 of cycle 1 must be SBP =< 140 and DBP =< 90; an
exception can be made by a healthcare provider for a patient with a single blood
pressure elevation who upon rechecking has a normal blood pressure

- Patients must have history and physical examination within 28 days prior to
registration

- Patients must not have any psychiatric illness that could potentially interfere with
the completion of treatment according to this protocol

- 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; (Note: that pregnancy testing is also required within 24 hours prior to
treatment on cycle 1, day 1); furthermore, 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)

- No other prior malignancy is allowed except for the following: adequately treated
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
stage I or II cancer from which the patient is currently in complete remission, or any
other cancer from which the patient has been disease free for five years

- Patients must be offered participation in banking of specimens for future research;
with the patient's consent, specimens (serum and bone marrow biopsy core) must be
submitted to the repository; patient consent must be obtained before specimens are
submitted

- Patients must be registered to the mandatory Revlimid Risk Evaluation and Mitigation
Strategy (REMS)™ program and must be willing and able to comply with the requirements
of the Revlimid REMS™ program

- Patients or their legally authorized representative must be informed of the
investigational nature of this study and must sign and give written informed consent
in accordance with institutional and federal guidelines

- As a part of the Oncology Patient Enrollment Network (OPEN) registration process the
treating institution's identity is provided in order to ensure that the current
(within 365 days) date of institutional review board approval for this study has been
entered in the system