The study drug elotuzumab, has been clinically shown to be effective in treating relapsed/refractory MM in combination with either bortezomib, or lenalidomide and dexamethasone. Elotuzumab in combination with lenalidomide and dexamethasone is currently approved by the Food and Drug Administration (FDA) for the treatment of patients with multiple myeloma. Carfilzomib is also FDA approved for treating multiple myeloma and frequently given in combination with lenalidomide and dexamethasone for treatment of relapsed/refractory MM. Based on these findings, this study will look at how subjects with relapsed/refractory MM respond to a combination treatment with the following drugs: elotuzumab, carfilzomib, lenalidomide and dexamethasone. The combination of these four drugs is not FDA approved and is experimental.

This single arm, open-label phase II study is designed with the primary objective of evaluating the efficacy of induction therapy comprised of 4 cycles of carfilzomib, lenalidomide, dexamethasone and elotuzumab (KRd+elotuzumab) in terms of very good partial response or better (VGPR+) in subjects with relapsed and/or refractory MM, and comparing to relevant historical controls. Post induction, all subjects will undergo disease evaluation for assessment of the primary endpoint. Maintenance therapy comprised of elotuzumab and lenalidomide (R+elotuzumab) will start directly after induction and continue until relapse or progression.

Inclusion Criteria

Subject must meet all of the following applicable inclusion criteria to participate in this study:

1. Written informed consent and HIPAA authorization for release of personal health information signed by the subject or his/her legally authorized representative.

2. Age >= 18 years at the time of consent.

3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 (see Appendix A, Section 18.1).

4. Documented history of relapsed and/or refractory multiple myeloma per IMWG 2016 criteria [22] as defined below (biochemical and/or clinical relapse per IMWG criteria); (NOTE: subjects refractory to bortezomib and/or lenalidomide are eligible; subjects who previously received carfilzomib are eligible provided they experienced a minimal response or better and relapsed >60 days after completion of treatment [see exclusion criteria #2]):

   1. Relapse is defined as progression of disease after an initial response to previous treatment, more than 6 months after discontinuation of treatment.
   2. Refractory is defined as lack of response to previous treatment, progression of disease during treatment, or progression of disease within 6 months of discontinuation of treatment.

5. Prior treatment with one line (and no more than one line) of systemic therapy for MM; NOTE: A new line of therapy is considered to start when a planned course of therapy is modified to include other treatment agents (alone or in combination) as a result of progressive disease (PD), relapse, or toxicity or when a planned period of observation off therapy is interrupted by a need for additional treatment for the disease. Induction therapy and stem cell transplant followed by planned maintenance therapy (provided there is no intervening PD) are considered to be a single line.

6. Subject must have recovered from any treatment-induced toxicities to ≤ grade 1 or baseline

7. Adequate washout from previous therapy:

   1. Prior chemotherapy is completed >3 weeks prior to day 1 of treatment (6 weeks for melphalan, nitrosoureas or monoclonal antibodies).
   2. Autologous transplant completed (referring to day of stem cell infusion) >12 weeks prior to day 1 of treatment; allogeneic transplant >16 weeks prior to day 1 of treatment.
   3. Prior radiotherapy completed at least 2 weeks prior to day 1 of treatment.
   4. Corticosteroid therapy at a dose equivalent to dexamethasone >4mg/day has been completed at least 2 weeks prior to day 1 of treatment.

8. Measurable disease defined as:

   1. Serum M-protein > 0.5 g/dL OR
   2. Urine M-protein ≥200 mg/24 h OR
   3. Involved free light chain (FLC) level ≥10 mg/dL provided serum FLC ratio is abnormal.

9. Demonstrate adequate organ function within 1 week of day 1 of treatment as defined in the table in Sec.tion 3.2 of protocol (#8)

10. Adequate cardiac function as defined by ≥45% Left Ventricular Ejection Fraction (LVEF) by ECHO or MUGA within 28 days prior to day 1 of treatment.

11. Females of childbearing potential (FCBP) must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to day 1 of treatment, and be willing to undergo serial serum or urine pregnancy testing. NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are postmenopausal (at least 12 consecutive months with no menses without an alternative medical cause).

12. FCBP must be willing to use a highly effective contraceptive method (i.e., achieves a failure rate of <1% per year when used consistently and correctly) plus a second contraceptive method (considered acceptable [failure rate of >1% per year] or highly effective) from the time of informed consent until 6 months after the last protocol prescribed therapy has been discontinued. NOTE: estrogens may further increase the risk of thrombosis (beyond that associated with lenalidomide) and their use should be based on a benefit-risk decision. For the highly effective contraceptive method, a method with low user dependency is preferable but not required (see tables, adapted from:

    http://www.hma.eu/fileadmin/dateien/Human\_Medicines/01-About\_HMA/Working\_Groups/CTFG/2014\_09\_HMA\_CTFG\_Contraception.pdf).

13. Male subjects (even those who have had a vasectomy) who are sexually active with a FCBP must be willing to use latex or synthetic condoms from the time of informed consent until 180 days after the last protocol prescribed therapy has been discontinued. The FCBP partner should also consider contraception recommendations (see inclusion #11).

14. As determined by the enrolling physician, ability of the subject to understand and comply with study procedures for the entire length of the study.

Exclusion Criteria

Subjects meeting any of the criteria below may not participate in the study:

1. Discontinuation of previous lenalidomide, carfilzomib or dexamethasone due to intolerance.

2. If previously treated with carfilzomib, lack of response, progression during or relapsed within 60 days after completion of treatment.

3. Any infection, at the time of screening, requiring systemic therapy (i.e. involving IV antibiotics) (NOTE: at discretion of investigator, subjects with uncomplicated urinary tract infections may be eligible).

4. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study, and any female subject must agree not to donate eggs during the study and for 4 months after the last protocol prescribed therapy has been discontinued).

5. Has a known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, carcinoma of the prostate with a current PSA value of <0.5 ng/mL or other cancer for which the subject has completed treatment, been disease-free for at least five years, and is considered by Sponsor-Investigator to be at <30% risk of relapse, or on hormonal therapy for a history of either prostate cancer or breast cancer, provided that there has been no evidence of disease progression during the previous three years.

6. Non-secretory MM.

7. Active involvement of the central nervous system by MM.

8. Prior cardiovascular cerebrovascular accident with persistent neurological deficit.

9. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).

10. Had major surgery within 4 weeks prior to day 1 of treatment.

11. Plasmapheresis within 4 weeks from day 1 of treatment.

12. Treatment with any investigational drug within 4 weeks prior to day 1 of treatment.

13. Uncontrolled clinically significant illness including, but not limited to, uncontrolled hypertension (as per the most updated Joint National Committee for the Management of Hypertension definitions), symptomatic congestive heart failure (as per New York Heart Association [NYHA] class III or IV [see Appendix C, Section 18.3], uncontrolled angina pectoris, myocardial infarction within the past 6 months, known or suspected amyloidosis, uncontrolled cardiac arrhythmia, psychiatric illness/social situations that would limit compliance with study requirements as determined by the investigator, or any other condition (including laboratory abnormalities) that would, in the opinion of the Sponsor-Investigator, place the subject at unacceptable risk if he/she were to participate in the study.

14. Known allergies, hypersensitivity, or intolerance to monoclonal antibodies or human proteins, elotuzumab or its excipients or known sensitivity to mammalian-derived products, carfilzomib or its excipients, lenalidomide or its excipients, or dexamethasone or its excipients.

15. Known human immunodeficiency virus (HIV) infection or active hepatitis A, B and/or C infection.

    1. Subjects with resolved HBV infection (i.e. subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Subjects who are PCR positive will be excluded. Exception: subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) and a known history of prior HBV vaccination do not need to be tested for HBV DNA by PCR.

Baseline, during treatment, and through 30 days after study treatment is discontinued, an average of 14 months.