Pembrolizumab + Lenalidomide Post Autologous Stem Cell Transplant (ASCT) in High-risk Multiple Myeloma (MM)

Inclusion Criteria:

* Be willing and able to provide written informed consent/assent for the trial.
* Be 18 years of age on day of signing informed consent.
* Has a confirmed diagnosis of MM based on standard criteria. (See Appendix 2 for MM Diagnostic Criteria.)
* Is between 60 and 180 days from peripheral blood autologous stem cell transplant.
* At diagnosis, had MM with measurable disease, defined as:
* A monoclonal immunoglobulin spike on serum electrophoresis of at least 0.5 g/dL and/or
* Urine monoclonal levels of at least 200 mg/24 hours
* For subjects without measurable serum and urine M-protein levels, an abnormal free light chain (FLC) ratio (normal value 0.26 - 1.65) with involved FLC ≥10 mg/dL
* Radiographic evidence of disease for those without measurable M-spike or free light chains.
* Has high-risk MM, which must be present at the time of diagnosis, and defined by:

  * International Staging System (ISS) stage 3 (See Appendix 3 for ISS Staging), and/or
  * Deletion 13q by cytogenetics, and/or
  * 1q amplification, 1p deletion, p53 deletions (17p deletions), t(4;14), t(14;16), t(14;20), hypodiploidy, and/or
  * High-risk gene expression profile (GEP) scores
* Be able to provide a newly obtained bone marrow aspirate/biopsy material for biomarker analysis and disease assessment.
* Have a performance status of ≤2 on the ECOG Performance Scale (See Appendix 4).
* Demonstrate adequate organ function as defined in Table 1, all screening labs should be performed within 28 days of treatment initiation.
* All subjects must agree to follow the regional requirements for lenalidomide counseling, pregnancy testing, and birth control; and be willing and able to comply with the regional requirements (for example, periodic pregnancy tests, safety labs, etc.).
* Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 10-14 days prior to and again within 24 hours prior to receiving the first dose of pembrolizumab (MK-3475), lenalidomide and dexamethasone or pembrolizumab (MK-3475) and lenalidomide. 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 agree to ongoing pregnancy testing.
* Female subjects 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 (Reference Section 4.7.2). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 2 years.
* Male subjects must agree to use a latex condom during sexual contact with females of childbearing potential even if they have had a successful vasectomy starting with the first dose of study therapy through 120 days after the last dose of study therapy.
* Subject is able to swallow capsules and is able to take or tolerate oral medications on a continuous basis.
* 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:

* Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
* 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. The use of physiologic doses of corticosteroids may be used at the investigator's discretion.
* Has received an allogeneic stem cell transplant.
* Has received any myeloma-directed therapy after ASCT.
* Has a known history of active TB (Bacillus Tuberculosis)
* Hypersensitivity to pembrolizumab or any of its excipients.
* Progressive disease from autologous transplantation at the time of screening
* Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
* 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 known history of, or any evidence of active, non-infectious pneumonitis.
* Has an active infection requiring intravenous 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-PD-L2 agent.
* Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
* Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected).
* Has received a live vaccine within 30 days of planned start of study therapy.