S1211, A Randomized Phase I/II Study of Optimal Induction Therapy of Bortezomib, Dexamethasone and Lenalidomide With or Without Elotuzumab (NSC-764479) for Newly Diagnosed High Risk Multiple Myeloma (HRMM)
Trial status: Open for Enrollment
Why is this study being done?
- 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)
- 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)
- To estimate the frequency and severity of toxicities of this treatment strategy in this patient population.
OUTLINE: This is a multicenter, phase I, dose-escalation study of elotuzumab, followed by a phase II, randomized study. Patients are stratified according to primary plasma cell leukemia and/or high lactic dehydrogenase (LDH) vs everyone else.
- Induction: Patients receive bortezomib subcutaneously (SC) or IV on days 1, 4, 8, and 11; lenalidomide orally (PO) once daily on days 1-14; and dexamethasone PO or IV on days 1, 2, 4, 5, 8, 9, 11, and 12. 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 once daily 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 once daily 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 once daily on days 1-21; and dexamethasone PO on days 1, 8, and 15. Treatment repeats 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. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study therapy, patients are followed every 3 months for up to 6 years.
Who is eligible to participate?
- Patients must have newly diagnosed active multiple myeloma (MM)
- Patients with non-secretory MM or known amyloidosis are not eligible
- 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 MyPRS score, Signal Genetics, Inc.)
- Translocation (14;16), and/or translocation (14;20), and/or deletion (17p) by florescence in-situ hybridization (FISH) or cytogenetics
- Primary plasma cell leukemia (defined by either ≥ 2,000 plasma cells/mL of peripheral blood, or 20% on a manual differential count
- Serum lactate dehydrogenase (LDH) ≥ 2 times institutional upper limit of normal (IULN)
- 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 noninvestigational chemotherapy
- 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 by MM must have a lumbar puncture that is negative for CNS involvement
- 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
- Zubrod performance status ≤ 2
- Absolute neutrophil count (ANC) ≥ 1,000 cells/mm³ without growth factor support
- Platelet count ≥ 70,000 cells/mm³ for patients who have bone marrow plasmacytosis < 50% OR ≥ 50,000 cells/mm³ for patients who have bone marrow plasmacytosis of ≥ 50%
- Total bilirubin ≤ 1.5 times institutional upper limit of normal (IULN)
- Serum glutamic oxalo-acetic transaminase (SGOT)/aspartate aminotransferase (AST) and serum glutamic pyruvate transaminase (SGPT)/alanine aminotransferase (ALT) ≤ 2.5 times IULN
- Creatinine clearance (CrCL) ≥ 30 mL/min
- Patients who are known to be human immunodeficiency virus (HIV)-positive are eligible providing they meet all of the following additional criteria within 28 days prior to registration:
- CD4 cells ≥ 500/mm³
- Viral load of < 50 copies HIV mRNA/mm³ if on antiretroviral therapy (ART) or < 25,000 copies HIV mRNA if not on ART
- No zidovudine or stavudine as part of ART
- Patients must have baseline skeletal survey to document lytic lesions, osteopenia, or compression fracture
- 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 any of the following:
- 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
- ≥ Grade 3 cardiac arrhythmias per Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
- Patients must have undergone an electrocardiogram (EKG) within 28 days prior to registration
- Uncontrolled blood pressure (BP) or hypertension
- Defined as systolic BP > 140 mm Hg or diastolic BP > 90 mm Hg within 14 days prior to registration
- An exception can be made by a healthcare provider for a patient with a single BP elevation who, upon rechecking, has a normal BP
- Patients are permitted to be receiving multiple antihypertensive medications (unless otherwise indicated in the study)
- Uncontrolled diabetes mellitus (defined as a glycosylated hemoglobin A1C (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
- 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
- FCBP 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 and continuing for at least 4 months after completion of study therapy
- Men must agree to use a latex condom during sexual contact with a FCBP, even if they have had a successful vasectomy
- Not pregnant or breastfeeding
- 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
PRIOR CONCURRENT THERAPY:
- See Disease Characteristics
- Prior chemotherapy must have been completed within 56 days prior to registration and all toxicities must have resolved to ≤ Grade 1
- 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