Nivolumab Combined With Daratumumab With or Without Low-dose Cyclophosphamide

Inclusion Criteria:

1. Age \>=18 years
2. Subject must have documented multiple myeloma as defined by the criteria below:

   * Monoclonal plasma cells in the bone marrow ≥10% at some point in their disease history or presence of a biopsy proven plasmacytoma.
   * Measurable disease as defined by any of the following:

     * Serum monoclonal paraprotein (M-protein) level ≥5 g/L (0.5 g/dL); or urine M-protein level ≥200 mg/24 hours; or serum immunoglobulin free light chain ≥100 mg/L (10 mg/dL) and abnormal serum immunoglobulin kappa lambda free light chain ratio (See Appendix A)
3. Relapsed or refractory disease. Relapse is defined as progression of disease after an initial response to previous treatment, more than 60 days after cessation of treatment. Refractory disease is defined as \<25% reduction in M-protein or progression of disease during treatment or within 60 days after cessation of treatment.
4. Subject had at least 2 prior anti-myeloma regimens. (Note: Induction, bone marrow transplant with or without maintenance therapy is considered one regimen.)
5. Subject has developed lenalidomide-refractory disease during prior treatment with a lenalidomide-containing regimen. Refractory disease is defined as \<25% reduction in M-protein or progression of disease during treatment or within 60 days after cessation of treatment.
6. Subject received prior treatment with a proteasome inhibitor-containing regimen for at least 2 consecutive cycles.
7. world health organization (WHO) performance 0, 1, or 2
8. Life expectancy at least 3 months
9. Written informed consent

Exclusion Criteria:

1. Prior therapy with daratumumab or other anti-CD38 therapies
2. Non-secretory myeloma
3. Systemic amyloid light-chain (AL) amyloidosis or plasma cell leukemia (\>2.0x109/L circulating plasma cells by standard differential) or Waldenstrom's macroglobulinemia
4. Subject has known meningeal involvement of multiple myeloma
5. Subject has received anti-myeloma treatment within 2 weeks or 5 pharmacokinetic half-lives of the treatment, whichever is longer, before start of treatment. This included subjects who have received a cumulative dose of corticosteroid greater than or equal to the equivalence of 140 mg prednisone or a single dose of corticosteroid greater than or equal to the equivalence of 40 mg/day dexamethasone within the 2-week period before start of treatment.
6. Prior treatment with an anti-PD1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
7. Subject has previously received an allogeneic stem cell transplantation (at any time)
8. Inadequate marrow reserve as defined by a platelet count \<75 x 109/L (\<50 x 109/L if ≥50% of bone marrow mononucleated cells are plasma cells) or an absolute neutrophil count \<1.0 x 109/L
9. a) Subject has known chronic obstructive pulmonary disease (COPD) with an Forced Expiratory Volume in 1 second (FEV1) \< 50% of predicted normal. Note that FEV1 testing is required for patients suspected of having COPD and subjects must be excluded if FEV1 \<50% of predicted normal.

   b) Subject has known moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification. (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study).
10. Subject has clinically significant cardiac disease, including:

    * Myocardial infarction within 6 months before Cycle 1, Day 1, or unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV)
    * Cardiac arrhythmia (Common Terminology Criteria for Adverse Events \[CTCAE\] Version 4 Grade 2 or higher) or clinically significant ECG abnormalities.
    * Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) \>470 msec.
11. Significant hepatic dysfunction (total bilirubin \>1.5 times normal value (except subjects with Gilbert syndrome, who can have total bilirubin \<3.0 mg/dL) or transaminases \> 3 times normal value), unless related to myeloma
12. Creatinine clearance \<30 ml/min.
13. Known hypersensitivity to components of the investigational products or severe allergic or anaphylactic reactions to humanized products.
14. Subject has any concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, etc.) that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study.
15. Subject is known to be seropositive for human immunodeficiency virus (HIV) or known to have acquired immunodeficiency syndrome (AIDS), or any positive test for hepatitis B or hepatitis C indicating acute or chronic infection.
16. History of active malignancy during the past 3 years, except squamous cell and basal cell carcinomas of the skin and carcinoma in situ of the cervix or breast and incidental histologic finding of prostate cancer (T1a or T1b using the TNM \[tumor, nodes, metastasis\] clinical staging system) or prostate cancer that is curative, or malignancy that in the opinion of the local investigator, with concurrence with the principal investigator, is considered cured with minimal risk of recurrence within 3 years.
17. Subjects with active interstitial pneumonitis
18. Subjects with active, known or suspected autoimmune disease or inflammatory disorder (including inflammatory bowel disease \[eg, colitis, Crohn's disease\], systemic lupus erythematosus, Wegener's syndrome, myasthenia gravis, Grave's disease, rheumatoid arthritis, hypophysitis, uveitis, etc.). Subjects 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.
19. Subjects with a condition (other than MM) 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.
20. Subject is known or suspected of not being able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder) or the subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise their well-being) or that could prevent, limit, or confound the protocol-specified assessments.
21. Pregnant or lactating females
22. Women of childbearing potential not willing to use adequate contraception, defined as hormonal birth control or intrauterine device, during the trial and for 1 year after the last dose of daratumumab or nivolumab or lenalidomide. Men who are sexually active with women of childbearing potential who are not willing to use adequate contraception for the duration of treatment with the study drugs and for 1 year after the last dose of daratumumab or nivolumab or lenalidomide.
23. Peripheral neuropathy of ≥grade 2.
24. History of allergy to study drug components