Melphalan, Prednisone, and Thalidomide or Lenalidomide in Treating Patients With Newly Diagnosed Multiple Myeloma

Inclusion Criteria: * Patients must have a confirmed diagnosis of symptomatic myeloma; for the original diagnosis of myeloma patients should have met the following criteria at one point in their disease course: * Bone marrow plasmacytosis with \>= 10% plasma cells or sheets of plasma cells or biopsy proven plasmacytoma * Patient must have had symptomatic disease at initial diagnosis that prompted the initiation of therapy as well as evidence of end-organ damage at the time of diagnosis namely; at least one of the following: anemia, hypercalcemia, bone disease (lytic bone lesions or pathologic fracture), or renal dysfunction * NOTE: Patients with asymptomatic smoldering myeloma (serum m protein \>= 3 gm/dL or bone marrow plasma cells \>= 10% or greater plus no evidence of anemia, hypercalcemia, lytic bone lesions or renal dysfunction) and monoclonal gammopathy of undetermined significance (serum m protein \< 3 gm/dL and bone marrow plasma cells \< 10% plus no evidence of anemia, hypercalcemia, lytic bone lesions or renal dysfunction) are not eligible * Patients must be \> 65 and have declined alternative treatment OR patients who are \>= 18 \< 65 are eligible if they: * Are not a candidate for autologous stem cell transplantation in the opinion of the treating physician OR * Have declined transplant or other alternative treatment * Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 * All tests below must be performed within 28 days prior to rand…