Phase II Study of Lenalidomide and Eltrombopag in Patients With Symptomatic Anemia

Inclusion Criteria:

* Patient must have a documented diagnosis of myelodysplastic syndrome (MDS) of at least three months duration (MDS duration \>= 3 months) according to World Health Organization (WHO) criteria or non-proliferative chronic myelomonocytic leukemia (CMML) (white blood cells \[WBC\] =\< 12,000/L)
* Patients must have International Prognostic Scoring System (IPSS) categories of low- or intermediate-1-risk disease
* Patients must have symptomatic anemia untransfused with hemoglobin =\< 9.5 g/dL within 8 weeks of registration or with red blood cell (RBC) transfusion-dependence (i.e., \>= 2 units/month) confirmed for a minimum of 8 weeks before randomization
* Patients must have IPSS score determined by cytogenetic analysis prior to randomization; patients with cytogenetic failure and =\< 10% marrow blasts will be eligible
* Patients must be off all disease modifying therapy for MDS for 28 days prior to initiation of study treatment; patients may receive hydrocortisone prophylactically to prevent transfusion reactions
* Patients must not have documented iron deficiency; all patients must have documented marrow iron stores; if marrow iron stain is not available, the transferrin saturation must be \>= 20% or a serum ferritin \>= 100 ng/100 mL or soluble transferring receptor \< 5 mg/L.
* Women must not be pregnant or breastfeeding; females of childbearing potential should have 2 negative pregnancy tests (sensitivity of at least 50 mIU/mL); the first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing lenalidomide
* Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS® program; able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to acetylsalicylic acid \[ASA\] may use warfarin or low molecular weight heparin)
* Women of childbearing potential and sexually active males must agree to use 2 methods of an accepted and effective method of contraception and counseled on the potential teratogenic effects of lenalidomide; effective contraception must be used by patients for at least 4 weeks before beginning lenalidomide therapy, during lenalidomide therapy, during dose interruptions and for 4 weeks following discontinuation of lenalidomide therapy; reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or because the patient has been postmenopausal naturally for at least 24 consecutive months; two reliable forms of contraception must be used simultaneously unless continuous abstinence from heterosexual sexual contact is the chosen method; females of childbearing potential should be referred to a qualified provider of contraceptive methods, if needed; sexually mature females who have not undergone a hysterectomy or who have not been postmenopausal naturally for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months) are considered to be females of childbearing potential; it is not known whether CC-5013 (lenalidomide) is present in the semen of patients receiving the drug; therefore, males receiving CC-5013 (lenalidomide) must always use a latex condom during any sexual contact with females of childbearing potential even if they have undergone a successful vasectomy
* Patients must not have received prior therapy with lenalidomide (for more than 2 months) nor eltrombopag
* Patients must not have uncontrolled hypertension
* Patients must have absolute neutrophil count (ANC) \>= 500 cells/L (0.5 x 10\^9/L)
* Eastern Cooperative Oncology Group (ECOG) performance 0-3
* Subject is able to understand and comply with protocol requirements and instructions
* Patient has signed and dated informed consent
* Prothrombin time (PT/international normalized ratio \[INR\]) and activated partial thromboplastin time (aPTT) must be within 80 to 120% of the normal range at baseline

Exclusion Criteria:

* Pre-existing cardiovascular disease (including congestive heart failure, New York Heart Association \[NYHA\] grade III/IV), or arrhythmia known to increase the risk of thromboembolic events (e.g. atrial fibrillation), or subjects with a corrected QT interval (QTc) \> 450 msec
* Patients determined to be at increased risk of arterial or venous thrombosis by the investigator
* Bone marrow fibrosis that leads to a dry tap
* Female subjects who are nursing or pregnant (positive serum or urine beta-human chorionic gonadotropin (beta-hCG) pregnancy test) at screening or pre-dose on day 1
* Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication
* Patients with documented liver cirrhosis
* Patients with splenomegaly with a spleen size \> 16 cm