PRIMARY OBJECTIVES:~I. To compare the overall survival between two strategies of lenalidomide maintenance following induction with a proteasome inhibitor? immunomodulatory drug (IMiD) combination: limited duration of maintenance (24 months) versus indefinite maintenance therapy until disease progression.~II. To compare progression-free survival between bortezomib, lenalidomide, and dexamethasone (VRd) and carfilzomib, lenalidomide, and dexamethasone (CRd) induction followed by lenalidomide maintenance in patients with newly diagnosed symptomatic multiple myeloma.~SECONDARY OBJECTIVES:~I. To compare the progression-free survival between two strategies of lenalidomide maintenance following induction with a proteasome inhibitor?IMiD combination: limited duration of maintenance (24 months) or indefinite maintenance therapy until disease progression.~II. To compare induction rates of response between VRd and CRd arms. III. To evaluate time to progression, duration of response and overall survival between VRd and CRd induction therapy.~IV. To compare induction rates of toxicity between VRd and CRd arms. V. To evaluate toxicity during lenalidomide maintenance. VI. To compare minimal residual disease (MRD) negative rates between VRd and CRd arms at end of induction therapy.~TERTIARY OBJECTIVES:~I. To compare the short and long-term health-related quality of life impact between the two strategies of lenalidomide maintenance.~II. To compare the impact on health-related quality of life between VRd and CRd induction therapy.~III. To evaluate the association between early induction response and change in health-related quality of life.~IV. To describe changes in health-related quality of life during the induction, active maintenance and observation phases.~V. To evaluate correlation between treatment adherence during maintenance and health-related quality of life.~VI. To compare MRD negative rates between the two strategies of lenalidomide maintenance.~VII. To compare MRD negative rates between VRd and CRd arms during induction therapy.~VIII. To examine patterns of change in MRD levels over time and examine conversion from detectable to MRD negative status.~IX. To evaluate agreement and association between International Myeloma Working Group (IMWG) and MRD based disease-free status.~X. To describe the mutational profile of newly diagnosed multiple myeloma. XI. To identify mutations associated with resistance to VRd and CRd induction therapy.~XI. To identify expression profiles associated with MRD negative status with each induction therapy.~XII. To determine the ability of MRD status at induction end to predict short-term and long-term overall and progression-free survival.~XIII. To determine the effects of tobacco, operationalized as combustible tobacco (1a), other forms of tobacco (1b), and environmental tobacco exposure (ETS) (1c) on provider-reported cancer-treatment toxicity (adverse events [both clinical and hematologic] and dose modifications).~XIV. To determine the effects of tobacco on patient-reported physical symptoms and psychological symptoms.~XV. To examine quitting behaviors and behavioral counseling/support and cessation medication utilization.~XVI. To explore the effect of tobacco use and exposure on treatment duration, relative dose intensity, and therapeutic benefit.~OUTLINE:~INDUCTION: Patients are randomized to 1 of 2 treatment arms.~ARM A: Patients receive bortezomib subcutaneously (SC) or intravenously (IV) on days 1, 4, 8, and 11 of courses 1-8 and days 1 and 8 of courses 9-12; lenalidomide orally (PO) daily on days 1-14; and dexamethasone PO daily on days 1, 2, 4, 5, 8, 9, 11, and 12 of courses 1-8 and days 1, 2, 8, and 9 of courses 9-12. Treatment repeats every 3 weeks for 12 courses in the absence of disease progression or unacceptable toxicity.~ARM B: Patients receive carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16; lenalidomide PO daily on days 1-21; and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 4 weeks for 9 courses in the absence of disease progression or unacceptable toxicity.~MAINTENANCE: After completion of induction therapy (or completion of at least 6 courses in Arm A but stopped early due to unacceptable toxicity, or at least 4 courses in Arm B but stopped early due to unacceptable toxicity), patients are then randomized to 1 of 2 maintenance treatment arms.~ARM C: Patients receive lenalidomide PO daily on days 1-21. Treatment repeats every 4 weeks for 24 courses in the absences of disease progression or unacceptable toxicity.~ARM D: Patients receive lenalidomide PO daily on days 1-21. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.~After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually for 10 years.
This randomized phase III trial studies bortezomib, lenalidomide, and dexamethasone to see how well they work compared to carfilzomib, lenalidomide, and dexamethasone in treating patients with newly diagnosed multiple myeloma. Bortezomib and carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Lenalidomide may help the immune system kill abnormal blood cells or cancer cells. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether bortezomib, lenalidomide, and dexamethasone are more or less effective than carfilzomib, lenalidomide, and dexamethasone in treating patients with multiple myeloma