Bortezomib and Pembrolizumab With or Without Pelareorep for the Treatment of Relapsed or Refractory Multiple Myeloma, AMBUSH Trial

A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

* Note: in the event that 72 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for subject to start receiving study medication.

Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).

Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to allocation.

* Note: Participants must have recovered from all AEs due to previous therapies to =\< grade 1 or baseline. Participants with =\< grade 2 neuropathy may be eligible. Participants with endocrine -related AEs grade =\< 2 requiring treatment or hormone replacement may be eligible.

* Note: If the participant had major surgery, the participant must have recovered adequately from the procedure and/or any complications from the surgery prior to starting study intervention.

Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (=\< 2 weeks of radiotherapy) to non-central nervous system (CNS) disease. Palliative radiotherapy is allowed while on study treatment for treatment of symptomatic lesions.

Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, bacillus calmette-guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed.

Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention.

* Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.

Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.

Known additional malignancy that is progressing or has required active treatment within the past 5 years.

* Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) or other noninvasive or indolent hat have undergone potentially curative therapy are not excluded.

Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.

Has severe hypersensitivity (\>= grade 3) to pembrolizumab and/or any of its excipients.

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 and is allowed.

Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.

Has an active infection requiring systemic therapy.

Has a known history of Human Immunodeficiency Virus (HIV) infection.

* Note: No HIV testing is required unless mandated by local health authority.

Concurrent active hepatitis B (defined as HBsAg positive and/or detectable HBV deoxyribonucleic acid \[DNA\]) and hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV ribonucleic acid \[RNA\]) infection.

* Note: Hepatitis B and C screening tests are not required unless:

* Known history of HBV and HCV infection.

* As mandated by local health authority.

Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant 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 study, starting with the screening visit through 120 days after the last dose of trial treatment.

Has had an allogenic tissue/solid organ transplant.

History or prior allogenic stem cell transplant.

Receipt of concurrent immunosuppressive therapy.

Clinically significant cardiac disease (New York Heart Association, Class III or IV) including pre-existing arrhythmia, uncontrolled angina pectoris, myocardial infarction 1 year prior to study entry, or a known history of grade 2 or higher compromised left ventricular ejection fraction.

Dementia or altered mental status that would prohibit informed consent.

Has a history of or current evidence of any other severe, acute or chronic medical or psychiatric condition, therapy or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the principal investigator, would make the patient inappropriate for this study.

History of allergic (anaphylactic) sensitivity to bortezomib, boron or mannitol.

Grade 2 or greater neuropathy at the time of screening.

Has a known history of active TB (Bacillus tuberculosis).

What this study is about