Inclusion Criteria:

• POEMS syndrome requiring therapy, previously treated or untreated
• Plasma vascular endothelial growth factor (VEGF) > 2 x upper limit of normal (ULN)
• Presence of a plasma cell clone (any of the following):
  • Monoclonal protein in the serum or urine
  • Measurable light chains by free light chain assay
  • Measurable plasmacytoma
  • Monoclonal plasma cells in bone marrow
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, 2, or 3
• Absolute neutrophil count (ANC) ≥ 1000/uL
• Platelet count (PLT) ≥ 75,000/uL
• Total bilirubin ≤ 2.0 mg/dL unless due to known Gilbert's disease
  • NOTE: If total bilirubin is > 2 mg/dL, a direct bilirubin should be performed and must be < 1.5 mg/dL for Gilbert's to be diagnosed
• Alanine aminotransferase (ALT/serum glutamic pyruvic transaminase [SGPT]) and aspartate aminotransferase (AST, serum glutamic oxaloacetic transaminase [SGOT]) ≤ 3 x upper limit of normal (ULN)
• Creatinine clearance ≥ 30 mL/min/1.73 m^2 (as determined by Cockcroft-Gault equation)
• Negative serum pregnancy test done ≤ 7 days prior to registration, for women of childbearing potential only
  • NOTE: Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS program
• Birth control
  • Female patients of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication
    • NOTE: Patients of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
  • Male patients must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy
    • NOTE: Abstinence is acceptable (for either males or females) if this is the established and preferred method of contraception for the subject
• Willing to adhere to the guidelines of the Revlimid REMS (formerly known as RevAssist) program
  • NOTE: The counseling must be documented
• Provide written informed consent
• Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
  • Note: During the active monitoring phase of a study (i.e., active treatment and observation), participants must be willing to return to the consenting institution for follow-up
• No contraindication to be on a minimum of 81 mg aspirin a day (or other anticoagulant therapy as prescribed) for thromboembolism prophylaxis
• Willing to provide mandatory blood and bone marrow samples for research purposes
• Ability to complete questionnaire(s) by themselves or with assistance

Exclusion Criteria:

• Recent prior chemotherapy:
  • Newly diagnosed patients (regardless of group); any prior chemotherapy for POEMS with the following exceptions:
    • Prior immunomodulators like azathioprine, cyclosporin, and/or corticosteroids are not exclusionary therapies if used for prior diagnosis of chronic inflammatory demyelinating polyneuropathy
    • Prior chemotherapy directed at a "myeloproliferative neoplasm" like hydroxyurea is not exclusionary
  • Previously treated patients (group 2)
    • Alkylators (e.g. melphalan, cyclophosphamide) ≤ 28 days prior to registration
    • Anthracyclines ≤ 28 days prior to registration
    • High dose corticosteroids, immune modulatory drugs (thalidomide or lenalidomide), or proteosome inhibitors (e.g. ixazomib or bortezomib) ≤ 28 days prior to registration
• Requirement for concomitant high dose corticosteroids
  • EXCEPTION: Patients may be on chronic steroids (maximum dose 20 mg/day prednisone equivalent) if they are being given for adrenal insufficiency, rheumatoid arthritis, etc
• Receiving any other investigational agent, which would be considered as a treatment for the primary neoplasm
• Participation in other clinical trials, including those with other investigational agents not included in this trial, ≤ 30 days prior to registration and throughout the duration of this trial
• Prior refractoriness to proteasome inhibitor or immunomodulatory drugs (IMiD)
• Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:
  • Pregnant women
  • Nursing women
  • Men or women of childbearing potential who are unwilling to employ adequate contraception
• Other active malignancy ≤ 3 years prior to registration
  • EXCEPTIONS: Non-melanotic skin cancer, ductal carcinoma in-situ, or carcinoma-in-situ of the cervix
  • NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens, e.g. uncontrolled infection (infection requiring systemic antibiotic therapy or other serious infection ≤ 14 days prior to registration); or uncompensated heart or lung disease
• Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy
• Systemic treatment with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John's wort ≤ 14 days prior to registration
• History of myocardial infarction ≤ 6 months prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
• Radiotherapy ≤ 14 days prior to registration
• Major surgery ≤ 14 days prior to registration
• Failure to fully recover (i.e. ≤ grade 1 adverse event [AE]) from the reversible effects of prior chemotherapy
• Known allergy to any of the study medications, their analogs, or excipients in the various formulations of any agent
• Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of the study drugs including difficulty swallowing
• Ongoing or active systemic infection or active hepatitis B or C virus infection