Study of Lenalidomide/Dexamethasone With Nivolumab and Ipilimumab in Patients With Newly Diagnosed Multiple Myeloma

Inclusion Criteria:

1. Patients must have been previously diagnosed with histologically or cytologically confirmed multiple myeloma
2. Patients must have measurable disease, as defined by at least one of the following: \* Serum monoclonal protein level \>/=0.5 g/dL for IgG, IgA, or IgM disease \* Monoclonal protein or total serum IgD \>/=0.5 g/dL for IgD disease \* Urinary M-protein excretion of \>/=200 mg over a 24-hour period \* Involved free light chain level \>/=10 mg/dL, along with an abnormal free light chain ratio
3. Patients must be age 18 or older, and must be willing and able to provide voluntary written informed consent, with the understanding that consent may be withdrawn by the subject at any time without prejudice to their future medical care
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 Karnofsky \>/=60%.
5. Patients must have evidence of adequate bone marrow reserves, as defined by the following: \* Absolute neutrophil count (ANC) \>/= 1,000 cells/mm\^3 \* Hemoglobin \>/= 9 g/dL, independent of blood transfusions \* Platelet counts of \>/= 100,000 cells/mm\^3 for patients who have bone marrow plasmacytosis of \<50%, or \>/= 50,000 cells/mm\^3 for patients who have bone marrow plasmacytosis of \>/= 50%
6. Patients must have evidence of adequate hepatic function, as defined by the following: \* Total bilirubin \</= 1.5 times the upper limit of the institutional normal values (except in subjects with Gilbert Syndrome, who can have a total bilirubin \< 3.0 mg/dL) \* Total AST (SGOT) and ALT (SGPT) \</= 3 times the upper limit of the institutional normal values
7. Patients must have evidence of adequate renal function, as defined by the following: \* Serum creatinine within the institutional normal limits, OR if the creatinine is elevated \* Creatinine clearance (CrCl) \>/= 40 mL/min., as measured by a 24-hour urine collection, or estimated by the Cockcroft and Gault formula: Female CrCl = (140 - age in years) x weight in kg x 0.85 / 72 x serum creatinine in mg/dL Male CrCl = (140 - age in years) x weight in kg x 1.00 / 72 x serum creatinine in mg/dL
8. Patients must have evidence of adequate cardiac function, as defined by the following: \* Absence of New York Heart Association (NYHA) class II, III, or IV congestive heart failure \* Absence of uncontrolled angina or hypertension \* Absence of myocardial infarction in the previous 6 months \* Absence of clinically significant bradycardia, or other uncontrolled cardiac arrhythmia defined as grade 3 or 4 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0
9. Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab/ipilimumab to undergo five half-lives) after the last dose of investigational drug. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab/ipilimumab. Additionally WOCBP must use adequate methods of contraception for the duration of the study consistent with the standard requirements for lenalidomide.
10. WOCBP is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL.
11. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab/ipilimumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product. Women who are not of childbearing potential (i.e. who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception)
12. Patients must be newly diagnosed and must not have received prior treatment directed to multiple myeloma.

Exclusion Criteria:

1. Patients who have known central nervous system involvement with multiple myeloma will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
2. Patients with a known history of allergic reactions attributed to any compounds of similar chemical or biologic composition to be used on this study.
3. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring intravenous antibiotics, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, in the opinion of the Principal Investigator.
4. Pregnant or lactating women.
5. Patients with known active hepatitis A, B, and/or C infection are excluded. This is due to the difficulty that would be faced in assessing the attribution of any events of hepatic toxicity while on therapy.
6. Ongoing graft-versus-host (GVHD) due to prior allogeneic hematopoietic stem cell transplantation. Patients with prior history of acute GVHD or extensive chronic GVHD requiring a minimum of 6 months or longer treatment since allogeneic hematopoietic stem cell transplantation are also excluded.
7. Patients should be excluded if they have an active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
8. Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Additionally, patients will be excluded if they have required therapy for control of GVHD within 4 weeks of study treatment.
9. Patients should be excluded if they have had prior systemic treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
10. Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).