Immunomodulatory Drugs (Lenalidomide With or Without Pomalidomide) in Combination With a Corticosteroid Drug (Dexamethasone) for the Treatment of Multiple Myeloma

This phase II trial studies the effect of immunomodulatory drug(s) in combination with a corticosteroid drug in treating patients with multiple myeloma or smoldering multiple myeloma. Immunomodulatory drugs such as lenalidomide and pomalidomide work through a variety of mechanisms to affect the function of the immune system. They are widely used as treatment for multiple myeloma and remain the backbone of therapy for both newly diagnosed patients and patients that have multiple myeloma that has come back after treatment (relapsed). Corticosteroid drugs like dexamethasone are strong anti-inflammatory agents that are also widely used to treat patients with multiple myeloma. This study may help doctors find out how patients respond to one treatment cycle of immunomodulatory drug(s) in combination with dexamethasone. This may help doctors determine which combinations of drugs work best in treating patients with multiple myeloma or smoldering multiple myeloma.

PRIMARY OBJECTIVE:

I. To determine response rates (\>= partial response \[PR\]) of prospectively treated multiple myeloma (MM) patients with one cycle of therapy containing a combination of an immunomodulator and dexamethasone.

SECONDARY OBJECTIVE:

I. To identify biomarkers that predict response rates of untreated smoldering MM and MM patients to a combination of an immunomodulator and dexamethasone.

II. To compare response rates of MM among African-Americans (AA) and white patients to a combination of an immunomodulator and dexamethasone.

III. To establish correlation of biomarkers in treated MM patients with the combination of an immunomodulator and dexamethasone to the depth of hematological response observed in new or previously treated patients

OUTLINE: Patients are assigned to 1 of 4 cohorts.

COHORT A: Patients with smoldering multiple myeloma receive lenalidomide orally (PO) once daily (QD) alone on days 1-14 OR in combination with dexamethasone PO QD on days 1, 8 and 15. Treatment for cycle 1 continues for 21 days in the absence of disease progression or unacceptable toxicity. Patients then receive lenalidomide PO QD on days 1-21 alone or in combination with dexamethasone PO QD on days 1, 8, 15, and 22, or in combination with another drug. Treatment repeats every 28 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity.

COHORT B: Patients with newly diagnosed multiple myeloma receive treatment as in Cohort A.

COHORT C: Patients with relapsed or refractory multiple myeloma receive lenalidomide PO QD on days 1-14 in combination with dexamethasone PO QD on days 1, 8 and 15 OR pomalidomide PO QD on days 1-21 in combination with dexamethasone PO QD on days 1, 8 and 15. Treatment for cycle 1 continues for 21 days in the absence of disease progression or unacceptable toxicity. Patients then receive lenalidomide PO QD on days 1-21 in combination with dexamethasone PO QD on days 1, 8, 15, and 22 OR pomalidomide PO QD on days 1-21 in combination with dexamethasone PO QD on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity.

COHORT D: Patients with relapsed multiple myeloma after lenalidomide maintenance receive treatment as in Cohort C.

After completion of study treatment, patients are followed up within 7 days.

Eligibility Criteria:
Inclusion Criteria:

* Age \>= 18 years
* COHORT A: Patient must have untreated smoldering multiple myeloma which is defined by the presence of 10% or more but less than 60% clonal plasma cells in the bone marrow and the absence of any of the following myeloma related symptoms or laboratory and radiographic abnormalities: anemia, hypercalcemia, renal insufficiency, hypercalcemia, serum free light chain ratio of greater than 100 or more than one focal marrow multiple myeloma lesion on magnetic resonance imaging (MRI)
* COHORT B: Patient must have newly diagnosed myeloma requiring treatment and no prior therapies
* COHORT C: Patient must have relapsed or refractory multiple myeloma with at least one prior therapy for their multiple myeloma but not refractory to all IMiDs
* COHORT D: Patient must have relapsed or refractory multiple myeloma with lenalidomide as part of a maintenance regimen as their most recent therapy
* Measurable disease
* Provide written informed consent
* Patient must be considered for treatment with an IMiD containing regimen
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, 2 or 3
* Hemoglobin \>= 9.0 g/dL (obtained =\< 14 days prior to registration)
* Absolute neutrophil count (ANC) \>= 1500/mm\^3 (obtained =\< 14 days prior to registration)
* Platelet count \>= 100,000/mm\^3 (obtained =\< 14 days prior to registration)
* Total bilirubin =\< 1.5 x upper limit of normal (ULN) unless due to Gilbert's syndrome, in which case the direct bilirubin must be =\< 1.5 X ULN (obtained =\< 14 days prior to registration)
* Alanine aminotransferase (ALT) and aspartate transaminase (AST) 3 x ULN (=\< 5 x ULN for patients with liver involvement) (obtained =\< 14 days prior to registration)
* Prothrombin time (PT)/international normalized ratio (INR)/activated partial thromboplastin time (aPTT) =\< 1.5 x ULN OR if patient is receiving anticoagulant therapy and INR or aPTT is within target range of therapy (obtained =\< 14 days prior to registration)
* Calculated creatinine clearance \>= 45 ml/min using the Cockcroft-Gault formula (obtained =\< 14 days prior to registration)
* Negative pregnancy test done =\< 7 days prior to registration, for persons of childbearing potential only

  * NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
* Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study)
* Willingness to provide mandatory blood and bone marrow specimens for correlative research
* Willing to follow the requirements of the Pomalyst Risk Evaluation and Mitigation Strategy (REMS) program

Exclusion Criteria:

* An agent that has known genotoxic, mutagenic and teratogenic effects:

  * Pregnant persons
  * Nursing persons
  * Persons of childbearing potential who are unwilling to employ adequate contraception
* 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
* Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
* Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
* History of myocardial infarction =\< 6 months