An Exploratory Study to Evaluate the Combination of Elotuzumab and Nivolumab With and Without Pomalidomide in Relapsed Refractory Multiple Myeloma

This research study is studying a combination of targeted therapies as a possible treatment for multiple myeloma (MM).

The drugs involved in this study are:

* Elotuzumab
* Nivolumab
* Pomalidomide
* Dexamethasone

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug combination to learn whether the combination works in treating a specific disease. "Investigational" means that the drug combination is being studied.

This study has two parts. Each part tests a different combination of drugs.

* In Part 1 participants will be given elotuzumab and nivolumab.
* In Part 2 participants will be given elotuzumab, nivolumab, pomalidomide, and dexamethasone.

Each of these drugs works in a different way to help the body fight multiple myeloma. The drugs are being tested in different combinations to see if they are more effective when taken together.

Elotuzumab is an antibody, that stimulates the immune system to fight your disease. The FDA (the U.S. Food and Drug Administration) has approved elotuzumab in combination with lenalidomide as a treatment option for this disease.

In this research study, the participant will receive pomalidomide which is an immunomodulatory drug. This means that pomalidomide modulates the immune system to help fight the disease. The FDA has approved pomalidomide as a treatment option for this disease after receiving two other therapies.

Dexamethasone, also FDA approved, is a type of steroid and is usually combined with other chemotherapy for the treatment of blood cancers, such as myeloma and leukemias.

The FDA has not approved nivolumab for this specific disease but it has been approved for other uses, specifically lung cancer. Nivolumab works by blocking an inhibitory signal within immune cells, potentially allowing the immune system to fight the cancer.

In this research study the investigators are looking to see if the combination of elotuzumab, nivolumab, pomalidomide, and dexamethasone is effective in fighting the cancer.

Eligibility Criteria:
Inclusion Criteria:

* Male or female patient ≥ age 18 years
* Patient is able to understand and has given voluntary written informed consent before performance of any study-related procedures not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care
* Patient has been previously diagnosed with MM based on standard International Myeloma Working Group (IMWG) criteria and currently requires treatment.
* Patient must have received at least two previous lines of therapy for multiple myeloma including lenalidomide or thalidomide and a proteasome inhibitor (bortezomib, carfilzomib or ixazomib).
* Patient must have demonstrated disease progression on or within 60 days of completion of the last therapy. Patient has measurable disease defined as at least one of the following:

  * Serum M protein ≥ 0.5 g/dL (≥5 g/L)
  * Urine M protein ≥200 mg/24 hours
  * Serum free light chain (FLC) assay: Involved FLC assay ≥10 mg/dL (≥100 mg/L) and an abnormal serum FLC ratio (\<0.26 or \>1.65)
* Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (Appendix A)
* Negative serum or urine pregnancy test for women of child-bearing potential
* Screening Laboratory parameters:
* Absolute neutrophil count (ANC) ≥ 1,000 cells/dL (1.0 x 109/L). Granulocyte colony-stimulating factor (GCSF) is not permitted during screening to meet eligibility criteria and within 14 days of initiation of therapy

  * Platelet count ≥ 75,000 cells/dL (75 x 109/L) Platelet transfusion is not permitted during screening to meet eligibility criteria and within 14 days of initiation of therapy
  * Hemoglobin ≥ 8.0 g/dl ( red blood cell (RBC) transfusions are permitted during the screening period)
  * Total Bilirubin ≤ 1.5 X upper limit of normal (ULN) (Patients with known Gilbert Syndrome are allowed to have total bilirubin \< 3.0 mg/dL)
  * Aspartate transaminase (AST, or SGOT) and alanine transaminase (ALT, or SGPT) ≤ 3.0x ULN
  * Estimated creatinine clearance by Cockcroft-Gault formula ≥ 40 mL/min
  * Serum creatinine \< 1.5 X ULN. (Appendix C)

Exclusion Criteria:

* Diagnosed or treated for another malignancy within 3 years prior to enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low risk prostate cancer after curative therapy.
* Prior therapy with pomalidomide
* Prior treatment with monoclonal antibodies including elotuzumab
* Prior therapy with anti-programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1) agents.
* Received any investigational drug within 14 days or 5 half-lives of the investigational drug, whichever is longer.
* Prior anti-cancer therapy within 14 days.
* Patient has any Grade 3 or \> unresolved adverse reaction from previous treatment. Previous allogeneic stem cell transplantation with active graft-versus-host disease (GVHD) or being under immunosuppressive therapy in the last 2 months prior to inclusion in the trial.
* Autologous stem cell transplant if \< 12 weeks from enrollment.
* Daily requirement for oral corticosteroids (equivalent to \> 10 mg/day prednisone daily) Inhaled or topical corticosteroids are allowed.
* Patient is human immunodeficiency virus (HIV) positive,.
* Patient is Hepatitis B Surface antigen-positive.
* Patient has active hepatitis C infection.
* Patient has an 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).
* Any clinically significant, uncontrolled medical conditions that, in the treating Investigator's opinion, would impose excessive risk to the patient or may interfere with compliance or interpretation of the study results. Uncontrolled intercurrent illness may include, but is not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia, or psychiatric illness/social situations as determined by treating investigator that would limit compliance with study requirements.
* History of erythema multiforme or severe hypersensitivity to prior IMiD's®
* Inability to tolerate thromboprophylaxis
* Known severe intolerance to prior steroid therapy (Grade 3 or above adverse event which was unresponsive to a dose reduction)