Nivolumab, Ixazomib, Cyclophosphamide, and Dexamethasone in Relapsed/Refractory Myeloma

Inclusion Criteria: * Previously treated relapsed and refractory multiple myeloma per International Myeloma Working Group consensus criteria (Rajkumar et al., 2011). * Patients must have received at least three prior lines of therapy, including an immunomodulatory drug (e.g. lenalidomide, pomalidomide), a proteasome inhibitor (e.g. bortezomib, carfilzomib), and anti-CD38 monoclonal antibody (e.g. daratumumab) * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (see Appendix A). * Age ≥ 18 years * All laboratory assessments for eligibility should be performed within 21 days of initiation of protocol therapy unless otherwise specified. * Measurable disease of multiple myeloma as defined by at least one of the following (IgD and IgA with monoclonal protein \< 0.5 g/dL may be permitted after discussion with PI): * Serum monoclonal protein ≥ 0.5 g/dL (or quantitative IgA ≥ 1000 mg/dL), or * ≥ 200 mg of monoclonal protein in the urine on 24-hour urine protein electrophoresis, and/or * Serum free light chain ≥ 100 mg/L (10 mg/dL) and abnormal serum free kappa to serum free kappa light chain ratio * ANC ≥ 1000/μL. G-CSF is not permitted within 14 days of screening. * Platelet count ≥ 75,000/µL. Platelet transfusions are not permitted within 7 days of screening. * Hemoglobin ≥ 8 g/dL. Red blood cell transfusions are permitted to meet eligibility criteria. * Calculated creatinine clearance of ≥ 30 mL/min according to Cockroft-Gault equation. * Adequate hepatic function, as evidenced by each of the following: * Serum aspartate transaminase (ALT) and/or aspartate transaminase (AST) values \< 3 × the institutional upper limit of normal (ULN). * Serum bilirubin values \< 1.5 mg/dL. Patients with elevated bilirubin due to Gilbert's syndrome may be permitted with PI approval. * Able to swallow capsules whole (ixazomib capsules should not be crushed, dissolved or broken). * Women of childbearing potential (WOCBP)\* must agree to follow instructions for methods of contraception for the duration of study treatment with nivolumab and for five months after the last dose of study treatment. If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through five months after the last dose of study drug OR agree to practice true abstinence when it in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. \-- Women of child bearing potential are women who are not postmenopausal for at least one year and who are not surgically sterile. * Males who are sexually active (even if surgically sterilized, i.e. vasectomy) with WOBCP must agree to follow instructions for methods of contraception for the duration of study treatment with nivolumab and 7 months after the last dose of study treatment. Agree to practice effective barrier contraception during the entire study treatment period and through 7 months after the last dose of study drug, or agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. * Patient has given voluntary, signed written informed consent before performance of any study-related procedure that is not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care Exclusion Criteria: * Prior therapy with ixazomib * Prior therapy with any anti-PD1 antibody (e.g. nivolumab, pembrolizumab) or anti-PDL1 antibody (e.g. atezolizumab, avelumab, durvalumab) * Participants who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) or with monoclonal antibodies 3 weeks of C1D1 or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier. Patients may have received dexamethasone within 2 weeks prior to C1D1. * Participation in other clinical trials, including those with other investigational agents, within five half-lives prior to C1D1and throughout the duration of this trial. Prior treatment with an investigational agent within five half lives prior to C1D1 may be permitted after discussion with the PI. * Concomitant high-dose corticosteroid use except chronic steroids (maximum dose 10 mg/day prednisone equivalent) if they are being given for disorders other than myeloma, e.g. adrenal insufficiency, rheumatoid arthritis, etc. * Female patients who are lactating or have a positive serum pregnancy test during the screening period (within 21 days of C1D1). * Prior history of malignancies, other than MM, unless the patient has been free of the disease for ≥ 3 years. Exceptions include the following if the patient has undergone complete resection: * Basal or squamous cell carcinoma of the skin * Carcinoma in situ of the cervix * Ductal carcinoma in situ of the breast * Incidental histologic finding of prostate cancer (T1a or T1b) * Patients with another malignancy undergoing active treatment with the exception of non-melanoma skin cancer or in situ cervical cancer. * Patients with plasma cell leukemia, POEMS syndrome, or amyloidosis are excluded from this trial. * HIV infection. * Active hepatitis B infection or active hepatitis C infection. Participants who have prior hepatitis C infection and who have received an antiviral treatment and show no detectable viral RNA for 6 months prior to screening are eligible. * Peripheral neuropathy ≥ grade 2 despite supportive therapy. * Prior allogeneic stem cell transplant within five years prior to study registration. Patients who have had an allogeneic stem cell transplant within five years prior to study registration may participate as long as there are no symptoms of graft versus host disease. * Patient has a history of significant cardiovascular, neurological, endocrine, gastrointestinal, respiratory, or inflammatory illness that could preclude study participation, pose an undue medical hazard, or interfere with the interpretation of the study results, including, but not limited to, patients with congestive heart failure (New York Heart Association \[NYHA\] Class 3 or 4); unstable angina; cardiac arrhythmia; recent (within the preceding 6 months) myocardial infarction or stroke; hypertension requiring \> 2 medications for adequate control; diabetes mellitus with \> 2 episodes of ketoacidosis in the preceding 12 months; or chronic obstructive pulmonary disease (COPD) requiring \> 2 hospitalizations in the preceding 12 months. 3.2.15 Autoimmune disease: patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's disease, are excluded from this study, as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis \[scleroderma\], systemic lupus erythematosus, autoimmune pneumonitis, autoimmune vasculitis (e.g., Wegener's granulomatosis) and motor neuropathy considered of autoimmune origin (e.g. Guillain-Barré syndrome and myasthenia gravis). Patients with 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 are permitted to enroll. * Patients with history of interstitial lung disease and/or pneumonitis, or pulmonary hypertension. * Major surgery within 14 days prior to study registration. * Central nervous system involvement. * Infection requiring systemic antibiotic therapy or other serious infection within 14 days prior to study registration * Systemic treatment with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John's wort within 14 days prior to C1D1. * Receipt of a live or attenuated vaccine within 30 days of C1D1. * Any serious medical of psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol. * Known allergy to any study medications, their analogs, or excipients in the various formulations of any agent.