Inclusion Criteria - Registration:

• Age ≥ 18 years.
• Actively relapsing multiple myeloma.
• Measurable disease of multiple myeloma as defined by at least ONE of the following:
  • Serum monoclonal protein ≥ 0.5 g/dL;
    • If IgA isotype, then IgA quantification > upper limit of normal.
  • ≥ 200 mg of monoclonal protein in the urine on 24-hour electrophoresis
  • Serum immunoglobulin free light chain ≥ 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio.
  • Monoclonal bone marrow plasmacytosis ≥ 10% (evaluable disease).
• Patients must have received at least 2 prior regimens and patients should have been exposed to a PI, an IMiD and an anti-CD38 antibody.
  • NOTE: Induction therapy followed by an ASCT and maintenance therapy without any relapse counts as 1 regimen.
• ECOG Performance Status (PS) 0, 1 or 2.
• The following laboratory values obtained ≤14 days prior to registration:
  • Hemoglobin ≥ 8.0 g/dL (No red cell transfusion should have been administered within 4 days of registration);
  • Absolute neutrophil count (ANC) ≥ 1000/mm^3;
  • Platelet count 50,000/mm^3 or > 30,000/mm^3 if bone marrow plasma cells percentage > 50% by morphology. (No platelet transfusion should have been administered within 7 days of registration);
  • Total bilirubin ≤ 1.5 x ULN;
  • Alanine aminotransferase (ALT) and Aspartate transaminase (AST) 3 x ULN (≤ 5 x ULN for patients with liver involvement);
  • Calculated creatinine clearance ≥ 45 ml/min using the Cockcroft-Gault formula below:
  • Cockcroft-Gault Equation:
  • Creatinine clearance for males =  (140 - age)(weight in kg)
  •                                                           (72)(serum creatinine in mg/dL)
  • Creatinine clearance for females =  (140 - age)(weight in kg)(0.85)
  •                                                              (72)(serum creatinine in mg/dL)
• Negative pregnancy test done ≤7 days prior to registration, for persons of childbearing potential only.
  • NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Provide written informed consent.
• Able to swallow Metformin and Nelfinavir tablets.
• Willingness to provide mandatory blood sample and bone marrow aspirate for research purposes.
• Willingness to return to Mayo Clinic for follow-up (during the Active Monitoring Phase of the study).

Exclusion Criteria - Registration:

• Pregnant persons.
• Nursing persons.
• Persons of childbearing potential who are unwilling to employ adequate contraception.
• Major surgery ≤ 14 days before study registration.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• Another active malignancy requiring therapy such as radiation, chemotherapy, or immunotherapy.
  • NOTE: Patients on hormonal therapy for treated breast or prostate cancer are permitted if they meet other eligibility criteria.
• History of myocardial infarction ≤6 months prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
• Known allergy to any of the study medications, their analogues or excipients in the various formulations.
• Subjects must not have conditions associated with increased risk of metformin associated lactic acidosis, including New York Heart Association Class III or IV congestive heart failure, history of acidosis of any type, alcoholic liver disease, or habitual intake of 3 or more alcoholic beverages per day.
• Clinical history of Type I or Type II diabetes.
• Currently on either metformin or a HIV-PI or both.
• Elevated baseline lactate level > ULN (2.3 mmol/L).
• Any of the following recent prior anti-myeloma therapy:
• Alkylators (e.g., melaphalan, cyclophosphamide) and anthracyclines ≤ 14 days prior to registration.
• High dose corticosteroids (equivalent to > 10 mg of predisone/day) and immunomodulatory drugs (thalidomide or lenalidomide) ≤ 7 days prior to registration.
• Monoclonoal antibodies ≤ 14 days prior to registration.
• Currently receiving any of the medications listed in Appendix III that cannot be discontinued 7 days prior to starting study and throughout study therapy.