Pembrolizumab in Treating Patients With Intermediate or High-Risk Smoldering Multiple Myeloma

Inclusion Criteria:

* Adult patients with intermediate or high-risk smoldering multiple myeloma (SMM) are eligible; patients need to have clonal bone marrow plasma cells \>= 10% and/or monoclonal spike in blood of \>= 3 g/dL and/or monoclonal urine component (Bence jones proteinuria) \>= 500 mg/24 hours and need to meet subject inclusion criteria and exclusion criteria as per below
* Patients must have histologically confirmed SMM based on the following criteria:

  * (A) Mayo clinic criteria (patient must have at least 2 risk factors present):

    * 1\. Bone marrow core biopsy plasma cell involvement by cluster of differentiation (CD)138 immunohistochemistry \>= 10%
    * 2\. Monoclonal spike \>= 3 g/dL
    * 3\. Free light chain ratio in serum \< 0.125 or \> 8; \*2 of 3 risk factors: intermediate risk for progression at a rate of 51% at 5 years, \*3 of 3 risk factors: high risk for progression at a rate of 76% at 5 years
  * OR (B) Programa para el Tratamiento de Hemopatias Malignas (PETHEMA) criteria (patient must have at least 1 risk factor present)

    * 1\. \>= 95% abnormal plasma cells/total plasma cells in bone marrow compartment
    * 2\. Immunoparesis \*1 of 2 risk factors: intermediate risk for progression at a rate of 46% at 5 years, \*2 of 2 risk factors: high risk for progression at a rate of 72% at 5 years
  * OR (C) Southwestern Oncology Group (SWOG) criteria (patient must have 2 risk factors present or one risk factor if this risk factor is a 70-gene signature (GEP70) score of \> 37.2)

    * 1\. Monoclonal spike \>= 3 g/dL
    * 2\. Involved free light chain \>= 25 mg/dL
    * 3\. GEP70 risk score \> 37.2 \*\>= 2 risk factors: high risk of progression at a rate of 70% at 2 years\*; we would also include patients with 1 risk factor as long as this risk factor is GEP70 risk score \> 37.2 since patients with this risk factor have an intermediate risk of progression at a rate of 50% at 2 years
* Creatinine clearance \>= 50 ml/min; creatinine clearance (CrCl) will be calculated by Cockcroft-Gault method
* Eastern Cooperative Oncology Group (ECOG) performance status 0-1
* Absolute neutrophil count (ANC) \>= 1.0 x 10\^9 /L
* Hemoglobin \>= 10 g/dL
* Platelet count \>= 50 x 10\^9/L
* Bilirubin \< 1.5 x the upper limit of normal (ULN)
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 3.0 x ULN
* Subjects must be able to give informed consent
* Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
* Female subjects of childbearing potential should 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; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year
* Male subjects should 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

Exclusion Criteria:

* Evidence of myeloma defining events or biomarkers of malignancy due to underlying plasma cell proliferative disorder meeting at least one of the following

  * 1\) Hypercalcemia: serum calcium \> 0.25 mmol/L (\> 1 mg/dL) higher than the upper limit of normal or \> 2.75 mmol/L (\> 11 mg/dL)
  * 2\) Renal insufficiency: creatinine clearance \< 40 ml/min or serum creatinine \> 2 mg/dL
  * 3\) Anemia: hemoglobin value \< 10 g/dL or 2 g/dL \< normal reference
  * 4\) Bone lesions: one or more osteolytic lesions on skeletal radiography, computerized tomography (CT) or 2-deoxy-2\[F-18\] fluoro-D-glucose positron emission tomography CT (PET-CT)
  * 5\) Clonal bone marrow plasma cell percentage \>= 60%
  * 6\) Involved: uninvolved serum free light chain ratio \>= 100 measured by Freelite assay (The Binding Site Group, Birmingham, United Kingdom \[UK\])
  * 7\) \> 1 focal lesions on magnetic resonance imaging (MRI) studies (each focal lesion must be 5 mm or more in size), if clinically indicated
* Prior or concurrent systemic treatment for SMM; a) bisphosphonates are permitted; b) treatment with corticosteroids is not permitted; c) radiotherapy is not permitted; d) prior treatment for smoldering multiple myeloma with chemotherapy agents approved for the treatment of multiple myeloma is not permitted
* Plasma cell leukemia
* Pregnant or lactating females; breastfeeding should be discontinued if the mother is treated with pembrolizumab
* Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
* Has a known history of active TB (bacillus tuberculosis)
* Hypersensitivity to pembrolizumab or any of its excipients
* Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =\< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
* Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
* Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
* Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
* Has an active infection requiring systemic therapy
* Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
* Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
* Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
* Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-programmed death ligand 2 (PD-L2) agent
* Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
* Has known active hepatitis B (e.g., hepatitis B surface antigen \[HBsAg\] reactive) or hepatitis C (e.g., hepatitis C virus \[HCV\] ribonucleic acid \[RNA\] \[qualitative\] is detected)
* Has received a live vaccine within 30 days of planned start of study therapy; Note: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
* Evidence of interstitial lung disease