Pembrolizumab as Salvage Therapy for the Treatment of Multiple Myeloma in Patients Progressing on CAR-T Cell Therapy

Inclusion Criteria:

* Subject is, in the investigator's opinion, willing and able to comply with the protocol requirements
* Subject has given voluntary signed written informed consent before performance of any study-related procedure that is not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to their future medical care
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
* Have documented multiple myeloma as defined by the International Myeloma Working Group (IMWG) 2014 criteria including: Clonal bone marrow plasma cells \>= 10% (If bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement). In addition, the patient must meet one of the criteria in c1 or c2:

  * Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically (one or more of the following):

    * Hypercalcemia: serum calcium \> 0.25 mmol/L (\> 1 mg/dL) higher than the upper limit of normal (ULN) or \> 2.75 mmol/L (\> 11 mg/dL)
    * Renal insufficiency: Creatinine clearance (CrCl) \< 40 mL/min (measured or estimated by validated equations) or serum creatinine \> 177 umol/L (\> 2 mg/dL)
    * Anemia: hemoglobin value of \> 20 g/L below the lower limit of normal, or a hemoglobin value \< 100 g/L
    * Bone lesions: 1 or more osteolytic lesions on skeletal radiography, computed tomography (CT), or magnetic resonance imaging (MRI) (Clonality should be established by showing kappa/lambda-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used)
  * Any one or more of the following:

    * Clonal bone marrow plasma cell percentage \>= 60% (Clonality should be established by showing kappa/lambda-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used)
    * Involved: uninvolved serum free light chain (FLC) ratio \> 100 (These values are based on the serum Freelite assay. The involved FLC must be \>= 100 mg/L
    * \> 1 focal lesions on MRI studies; Each focal lesion must be 5 mm or more in size
* Measurable disease as defined by any of the following:

  * Serum M-protein level \>= 1.0 g/dL or urine M-protein level \>= 200 mg/24 hours
  * IgA, IgD, IgE, or IgM multiple myeloma: serum M-protein level \>= 0.5 g/dL or urine M-protein level \>= 200 mg/24 hours; or
  * Light chain multiple myeloma without measurable disease in the urine: serum Ig free light chain (FLC) \>= 10 mg/dL and abnormal serum Ig kappa/lambda FLC ratio
* Must have undergone BCMA-directed CART cell therapy and have evidence of progression per IMWG criteria upon response assessment
* Must have at least 4-week washout period for all the investigational monoclonal antibodies
* Men and women, age \>= 18 years or legal age of consent per local regulations (whichever is greater)
* Female patients who:

  * Are postmenopausal for at least 1 year before the screening visit, OR
  * Are surgically sterile, OR
  * If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, OR
  * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception.)
  * Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours of starting study drugs
* Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree to one of the following:

  * Agree to practice effective barrier contraception during the entire study treatment period and through 4 weeks after the last dose of study drug, OR
  * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception.)

Exclusion Criteria:

* Renal insufficiency, defined as creatinine clearance =\< 30 mL/min (either actual or calculated value), within 21 days of initiation of protocol therapy. The Cockcroft - Gault formula should be used for calculating creatinine clearance values
* Platelet count =\< 75,000 cells/mm\^3 at time of screening evaluation. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrollment
* Participants with an absolute neutrophil count (ANC) =\< 1000 cells/mm\^3 at time of screening evaluation. Growth factors may not be used to meet ANC eligibility criteria within 14 days of obtaining screening evaluation
* Participants with hemoglobin level \< 7.5 g/dL, at time of screening. Transfusion may not be used to meet eligibility criteria within 7 days of obtaining screening evaluation
* Participant had undergone ACT \> 12 weeks from study enrollment
* Participants with hepatic impairment, defined as bilirubin \>= 1.5 x institutional upper limit of normal (ULN) or aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\]), alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]), or alkaline phosphatase \>= 3x institutional ULN
* Patients may be receiving concomitant therapy with bisphosphonates and low dose corticosteroids (e.g., prednisone up to but no more than 10 mg orally \[p.o.\] once daily \[q.d.\] or its equivalent) for other rheumatological manifestations. Doses of corticosteroid should be stable for at least 7 days prior to study treatment.)
* Known significant cardiac abnormalities including:

  * Congestive heart failure, New York Heart Association (NYHA) class III or IV
  * Uncontrolled angina, arrhythmia or hypertension
  * Myocardial infarction within the past six months
  * Any other uncontrolled or severe cardiovascular condition
* Prior cerebrovascular event with residual neurologic deficit
* Serious, intercurrent illness including, but not limited to, clinically relevant active infection, known active hepatitis B or C viral infection, known human immunodeficiency virus (HIV) infection, uncontrolled diabetes mellitus, or serious co-morbid medical conditions such as chronic restrictive pulmonary disease, and cirrhosis
* Any condition, including laboratory abnormalities, that in the opinion of the investigator places the subject at unacceptable risk if he/she were to participate in the study
* Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection
* Known hypersensitivity to acyclovir or similar anti-viral drug
* Participants with known central nervous system (CNS) involvement
* Female participants pregnant or breast-feeding
* Participants who have undergone major surgery =\< 4 weeks prior to starting study drug or who have not recovered from side effects of the surgery
* Participants with any significant history of non-compliance to medical regimens or unwilling or unable to comply with the instructions given to him/her by the study staff
* Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol
* Participation in other clinical trials, including those with other investigational agents not included in this trial, within 30 days of the start of this trial and throughout the duration of this trial
* Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
* Has severe hypersensitivity to (grade \>= 3) to pembrolizumab and/or any of its excipients
* Subjects that have undergone prior allogeneic stem cell transplant