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 diseasehistory 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 urineM-protein level ≥200 mg/24 hours; or serum immunoglobulin free light chain ≥100 mg/L (10 mg/dL) and abnormal serum immunoglobulin kappa lambda freelight chain ratio (See Appendix A)

3. Relapsed or refractory disease. Relapse is defined as progression of disease afteran initial response to previous treatment, more than 60 days after cessation oftreatment. Refractory disease is defined as <25% reduction in M-protein orprogression of disease during treatment or within 60 days after cessation oftreatment.

4. Subject had at least 2 prior anti-myeloma regimens. (Note: Induction, bone marrowtransplant with or without maintenance therapy is considered one regimen.)

5. Subject has developed lenalidomide-refractory disease during prior treatment with alenalidomide-containing regimen. Refractory disease is defined as <25% reduction inM-protein or progression of disease during treatment or within 60 days aftercessation of treatment.

6. Subject received prior treatment with a proteasome inhibitor-containing regimen forat 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/Lcirculating plasma cells by standard differential) or Waldenstrom'smacroglobulinemia

4. Subject has known meningeal involvement of multiple myeloma

5. Subject has received anti-myeloma treatment within 2 weeks or 5 pharmacokinetichalf-lives of the treatment, whichever is longer, before start of treatment. Thisincluded subjects who have received a cumulative dose of corticosteroid greater thanor equal to the equivalence of 140 mg prednisone or a single dose of corticosteroidgreater 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-4antibody (including ipilimumab or any other antibody or drug specifically targetingT-cell co-stimulation or checkpoint pathways).

7. Subject has previously received an allogeneic stem cell transplantation (at anytime)

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 neutrophilcount <1.0 x 109/L

9. a) Subject has known chronic obstructive pulmonary disease (COPD) with an ForcedExpiratory Volume in 1 second (FEV1) < 50% of predicted normal. Note that FEV1testing is required for patients suspected of having COPD and subjects must beexcluded 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 whocurrently have controlled intermittent asthma or controlled mild persistent asthmaare allowed in the study).

10. Subject has clinically significant cardiac disease, including:

• Myocardial infarction within 6 months before Cycle 1, Day 1, or unstable oruncontrolled disease/condition related to or affecting cardiac function (eg,unstable angina, congestive heart failure, New York Heart Association ClassIII-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 byFridericia's formula (QTcF) >470 msec.

11. Significant hepatic dysfunction (total bilirubin >1.5 times normal value (exceptsubjects with Gilbert syndrome, who can have total bilirubin <3.0 mg/dL) ortransaminases > 3 times normal value), unless related to myeloma

12. Creatinine clearance <30 ml/min.

13. Known hypersensitivity to components of the investigational products or severeallergic 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 interferewith study procedures or results, or that in the opinion of the investigator wouldconstitute a hazard for participating in this study.

15. Subject is known to be seropositive for human immunodeficiency virus (HIV) or knownto have acquired immunodeficiency syndrome (AIDS), or any positive test forhepatitis B or hepatitis C indicating acute or chronic infection.

16. History of active malignancy during the past 3 years, except squamous cell and basalcell carcinomas of the skin and carcinoma in situ of the cervix or breast andincidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor,nodes, metastasis] clinical staging system) or prostate cancer that is curative, ormalignancy that in the opinion of the local investigator, with concurrence with theprincipal investigator, is considered cured with minimal risk of recurrence within 3years.

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 lupuserythematosus, Wegener's syndrome, myasthenia gravis, Grave's disease, rheumatoidarthritis, hypophysitis, uveitis, etc.). Subjects with vitiligo, type I diabetesmellitus, residual hypothyroidism due to autoimmune condition only requiring hormonereplacement, psoriasis not requiring systemic treatment, or conditions not expectedto recur in the absence of an external trigger are permitted to enroll.

19. Subjects with a condition (other than MM) requiring systemic treatment with eithercorticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressivemedications within 14 days of study drug administration. Inhaled or topicalsteroids, and adrenal replacement doses > 10 mg daily prednisone equivalents arepermitted 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 thesubject has any condition for which, in the opinion of the investigator,participation would not be in the best interest of the subject (eg, compromise theirwell-being) or that could prevent, limit, or confound the protocol-specifiedassessments.

21. Pregnant or lactating females

22. Women of childbearing potential not willing to use adequate contraception, definedas hormonal birth control or intrauterine device, during the trial and for 1 yearafter the last dose of daratumumab or nivolumab or lenalidomide. Men who aresexually active with women of childbearing potential who are not willing to useadequate contraception for the duration of treatment with the study drugs and for 1year after the last dose of daratumumab or nivolumab or lenalidomide.

23. Peripheral neuropathy of ≥grade 2.

24. History of allergy to study drug components