This partially randomized phase I/II trial studies the side effects and best dose of elotuzumab and to see how well it works when given together with lenalidomide, bortezomib, and dexamethasone in treating patients with newly diagnosed multiple myeloma that is likely to recur (come back), or spread (high-risk). Lenalidomide and bortezomib may stop the growth of multiple myeloma by blocking blood flow to the tumor. Also, bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as lenalidomide and dexamethasone, also work in different ways to kill cancer cells, by stopping them from dividing, or by stopping them from spreading. Giving elotuzumab together with lenalidomide, bortezomib, and dexamethasone may be a better way to block cancer growth.

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