Inclusion Criteria:

• Capable of giving signed informed consent.
• Male or female, 18 years or older (at the time consent is obtained).
• Have confirmed diagnosis of Multiple Myeloma (MM) as defined by the IMWG.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 for Arm A and 0 to 2 for Arm B.
• Have undergone stem cell transplant (SCT), or are considered transplant ineligible.
• Have been previously treated with at least 1 prior line of MM therapy, and must have documented disease progression during or after their most recent therapy according to the IMWG criteria.
• Must have at least ONE aspect of measurable disease, defined as one the following: Urine M-protein excretion >=200 milligram (mg)/24 hours, or; Serum M-protein concentration >=0.5 gram (g)/deciliter (dL) (>=5.0 g/Liter), or; Serum free light chain (FLC) assay: involved FLC level >=10 mg/dL (>=100 mg/L) and an abnormal serum FLC ratio (<0.26 or >1.65).
• Participants with a history of autologous SCT, are eligible for study participation provided the following eligibility criteria are met: Autologous SCT was >100 days prior to study enrollment; No active bacterial, viral, or fungal infection(s) present; Participant meets the remainder of the eligibility criteria.
• All prior treatment-related toxicities (defined by National Cancer Institute Common Toxicity Criteria for Adverse Events [NCI-CTCAE], Version 4.03, 2010) must be <= Grade 1 at the time of enrollment, except for alopecia. Participants with Grade 2 neuropathy can be enrolled into Len/Dex treatment arm, but not into Bor/Dex treatment arm.
• Adequate organ system functions as defined by the laboratory assessments.
• The contraception's used by female participant's be consistent with local regulations, regarding methods of contraception for those participating in clinical studies. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: is not a woman of child bearing potential (WOCBP) or Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency, during the intervention period and for at least 120 days after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. WOCBP must have 2 negative highly sensitive serum pregnancy tests, as required by local regulations (first within 14 days of Cycle 1 Day 1 and the second one within 24 hours of dosing on Cycle1 Day1) and agree to use effective contraception during the study and for 120 days after the last dose of study medication; Additional requirements for pregnancy testing during and after study intervention (i.e., REMS program for WOCBP taking lenalidomide).The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
• Male participant's using contraception should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Male participants must agree to refrain from donating sperm and either be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent from the time of first dose of study until 140 days after the last dose of study treatment to allow for clearance of any altered sperm: OR Agree to use a male condom and female partner to use an additional highly effective contraceptive method with a failure rate of <1% per year when having sexual intercourse with a WOCBP who is not currently pregnant. If the female partner of the male participant is pregnant at the time of enrollment, or becomes pregnant during the trial, the male participant must agree to remain abstinent (if it is consistent with their preferred and usual lifestyle) or use a male condom. Additional criteria WOCBP participants in Arm A: Due to lenalidomide being a thalidomide analogue with risk for embryofetal toxicity and prescribed under a restricted distribution program called the REVLIMID (Lenalidomide) REMS program, WOCBP participants will be eligible if they commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with lenalidomide, during therapy, during dose interruptions and continuing for 120 days following discontinuation of treatment.

Exclusion Criteria:

• Systemic anti-myeloma therapy (including systemic steroids) within 14 days, or plasmapheresis within 7 days prior to the first dose of study drug.
• Use of an investigational drug within 14 days or five half-lives (whichever is longer) preceding the first dose of study drug.
• Prior treatment with a monoclonal antibody within 30 days of receiving the first dose of study drugs.
• Prior allogenic stem cell transplant. Note: participants who have undergone syngeneic transplant will be allowed only if they have no history and no currently active, graft versus host disease (GvHD) - Evidence of active mucosal or internal bleeding.
• Any major surgery within the last four weeks.
• Presence of active renal condition (infection, requirement for dialysis or any other condition that could affect participant's safety). Participants with isolated proteinuria resulting from MM are eligible, provided they fulfill criteria.
• Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions (including lab abnormalities) that could interfere with participant's safety, obtaining informed consent or compliance to the study procedures.
• Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, or otherwise stable chronic liver disease per investigator's assessment).
• Participants with invasive malignancies other than multiple myeloma are excluded, unless the second malignancy has been considered medically stable for at least 2 years. The participant must not be receiving active therapy, other than hormonal therapy for this disease.Note: Participants with curatively treated non-melanoma skin cancer are allowed without a 2-year restriction.
• Evidence of cardiovascular risk including any of the following: a. Corrected QT (QTc) interval >=480 millisecond (msec); Evidence of current clinically significant uncontrolled arrhythmias, including clinically significant ECG abnormalities including 2nd degree (Type II) or 3rd degree atrioventricular (AV) block; History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within 3 months of Screening; Class III or IV heart failure as defined by the New York Heart Association functional classification system; Uncontrolled hypertension.
• Known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to drugs chemically related to GSK2857916, or any of the components of the study treatment.
• Pregnant or lactating female.
• Active infection requiring treatment.
• Known HIV infection.
• Presence of hepatitis B surface antigen (HBsAg), or hepatitis B core antibody (HBcAb at Screening or within 3 months prior to first dose of study treatment).
• Current corneal disease except for mild punctuate keratopathy.
• Positive hepatitis C antibody test result or positive hepatitis C RNA test result at Screening or within 3 months prior to first dose of study treatment. NOTE: Participants with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C ribonucleic acid (RNA) test is obtained.
• Current corneal disease except for mild punctuate keratopathy.
• Additional Exclusion Criteria for participants Assigned to Treatment A: Participants unable to tolerate antithrombotic prophylaxis must be excluded; Discontinuation of prior treatment with lenalidomide due to intolerable AEs.
• Additional Exclusion Criteria for Participants Assigned to Treatment B: Unacceptable AEs from previous bortezomib treatment; Ongoing Grade 2 or higher peripheral neuropathy or neuropathic pain from previous bortezomib treatment; Intolerance or contraindications to anti-viral prophylaxis.