A Phase 1 Study of Ruxolitinib, Steroids and Lenalidomide for Relapsed/Refractory Multiple Myeloma (RRMM) Patients

Inclusion Criteria: Subjects must meet all of the following inclusion criteria to be eligible to enroll in thisstudy.

1. Has a diagnosis of MM based on standard criteria as follows: Major criteria:
2. Plasmacytomas on tissue biopsy.
3. Bone marrow plasmacytosis (greater than 30% plasma cells).
4. Monoclonal immunoglobulin spike on serum electrophoresis IgG greater than 3.5 g/dL orIgA greater than 2.0 g/dL or kappa or lambda light chain excretion greater than 1g/day on 24 hour urine protein electrophoresis. Minor criteria:
5. bone marrow plasmacytosis (10% to 30% plasma cells)
6. monoclonal immunoglobulin present but of lesser magnitude than given under majorcriteria
7. lytic bone lesions
8. normal IgM less than 50 mg/dL, IgA less than 100 mg/dL, or IgG less than 600 mg/dL Any of the following sets of criteria will confirm the diagnosis of multiple myeloma:

• any 2 of the major criteria
• major criterion 1 plus minor criterion 2, 3, or 4
• major criterion 3 plus minor criterion 1 or 3
• minor criteria 1, 2, and 3, or 1, 2, and 4

2. Currently has MM with measurable disease, defined as:

• a monoclonal immunoglobulin spike on serum electrophoresis of at least 0.5 g/dL and/or
• urine monoclonal protein levels of at least 200mg/24 hours
• for patients without measurable serum and urine M-protein levels, an involved SFLC > 100 mg/L or abnormal SFLC ratio
• for patients with IgD MM, a monoclonal immunoglobulin IgD of at least 1500 mg/L ormeet other measurable disease eligibility criteria

3. Currently has progressive MM MM patients that are relapsed or have refractory disease from at least 2 regimens or linesof therapy including an IMID and a proteasome inhibitor, are eligible for enrollmentprovided they fulfill the other eligibility criteria:

• Patients are considered relapsed, when they progress greater than 8 weeks from theirlast dose of treatment.
• Patients are refractory when they progress while currently receiving the treatment orwithin 8 weeks of its last dose.

4. Previous exposure to lenalidomide independent of the response
5. The patient is not a candidate for a transplant
6. Understand and voluntarily sign an informed consent form before receiving anystudy-related procedure that is not part of normal medical care, with theunderstanding that consent may be withdrawn at any time without prejudice to theirfuture medical care.
7. Able to adhere to the study visit schedule and other protocol requirements
8. ECOG performance status of ≤ 2 at study entry
9. Life-expectancy of greater than 3 months
10. Laboratory test results within these ranges at Screening and confirmed atenrollment prior to drug dosing on Cycle 1, Day 1:

• Absolute neutrophil count ≥ 1.5 x 10E9/L; if the bone marrow is extensivelyinfiltrated ( ≥ 70% plasma cells) then ≥ 1.0 x 10E9/L
• Platelet count ≥ 75 x 10E9/L; if the bone marrow is extensively infiltrated ( ≥ 70%plasma cells) then ≥ 50 x 10E9/L patients must not have received platelet transfusionfor at least 7 days prior to receiving screening platelet count. If patient havecreatinine clearance of less than 60mL/min, patient's platelet count must be greaterthan 150 x 10E9/L.
• Hemoglobin ≥ 8.0 g/dL within 21 days prior to enrollment. Use of erythropoieticstimulating factors and red blood cell (RBC) transfusions per institutional guidelinesis allowed; however, most recent RBC transfusion must have been at least 7 days priorto obtaining screening hemoglobin.
• Calculated or measured creatinine clearance (CrCl) of > 60 mL/minute (Study Part 1,2,3(2), and 4) or 30 to ≤ 60 mL/minute (Part 3(1)) as calculated by Cockcroft-Gaultmethod (Appendix 3).
• Total bilirubin levels ≤ 2.0 mg/dL (normal levels)
• AST (SGOT) and ALT (SGPT) ≤ 2 x ULN
• Serum potassium 3.0 - 5.5 mEq/L

11. Patients must be registered into the mandatory REVLIMID REMS™ program, and bewilling and able to comply with the requirements of the REVLIMID REMS™ program
12. FCBP† must have a negative serum or urine pregnancy test with a sensitivity of atleast 25 mIU/mL within 10 - 14 days prior to and again within 24 hours of startingruxolitinib and must either commit to continued abstinence from heterosexualintercourse or use acceptable methods of birth control, one highly effective methodand one additional effective method AT THE SAME TIME, and at least 28 days before shestarts taking ruxolitinib with or without lenalidomide. FCBP must also agree toongoing pregnancy testing. Men must agree to use a latex condom during sexual contactwith a FCBP even if they have had a vasectomy. All subjects must be counseled at aminimum of every 28 days about pregnancy precautions and risks of fetal exposure. † A FCBP (female of childbearing potential) is a sexually mature woman who: 1) has notundergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturallypostmenopausal for at least 24 consecutive months (i.e., has had menses at any time inthe preceding 24 consecutive months)
13. Able to take aspirin (acetylsalicylic acid, ASA) at 81 or 325 mg/daily asantiplatelet therapy if platelet count is above 30 x 10E9/L (subjects intolerant toASA may use warfarin or low molecular weight heparin)

Exclusion Criteria:

• Subjects meeting any of the following exclusion criteria are not to be enrolled in thestudy:

1. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein,and skin changes)
2. Plasma cell leukemia (> 2.0 × 10E9/L circulating plasma cells by standarddifferential)
3. Primary amyloidosis
4. Non-hematologic malignancy within the past 5 years with the exception of a)adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroidcancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer ofGleason Grade 6 or less with stable prostate-specific antigen levels; or d)cancer considered cured by surgical resection or unlikely to impact survivalduring the duration of the study, such as localized transitional cell carcinomaof the bladder or benign tumors of the adrenal or pancreas
5. Impaired cardiac function or clinically significant cardiac diseases, includingany one of the following:

• Myocardial infarction within 6 months prior to enrollment
• New York Heart Association (NYHA) Class II or greater heart failure oruncontrolled angina
• Clinically significant pericardial disease
• Severe uncontrolled ventricular arrhythmias
• Echocardiogram or MUGA evidence of LVEF below institutional normal within 28days prior to enrollment
• Electrocardiographic evidence of acute ischemia or active conduction systemabnormalities. Prior to study entry, any ECG abnormality at Screening has tobe documented by the investigator as not medically relevant.

6. Severe hypercalcemia, i.e., serum calcium ≥ 12 mg/dL (3.0 mmol/L) corrected foralbumin
7. Any serious medical condition, laboratory abnormality, or psychiatric illnessthat would prevent the subject from signing the informed consent form
8. Any condition, including the presence of laboratory abnormalities, which placesthe subject at unacceptable risk if he/she were to participate in the study orconfounds the ability to interpret data from the study
9. Undergone major surgery within 28 days prior enrollment or has not recovered fromside effects of such therapy (vertebroplasty or kyphoplasty is not considered tobe a major surgery; however, the investigator is to discuss enrollment of asubject with a recent history of kyphoplasty with the medical monitor).
10. Pregnant or breast feeding females (lactating females must agree not to breastfeed while taking lenalidomide)
11. Received the following prior therapy:

• Chemotherapy within 3 weeks of study drugs
• Corticosteroids (>20 mg/daily prednisone or equivalent) within 3 weeks ofstudy drugs to ensure that steroid dose intensity at the beginning of thetreatment is not altered by administration of steroids prior to the study.Consumption of steroids within 3 weeks of the treatment may interfere withefficacy and side effects due to differences of steroid intensity.
• Immunotherapy or antibody therapy as well as thalidomide, arsenic trioxide,or bortezomib within 21 days before study drugs
• Lenalidomide within 7 days before study drugs
• Lenalidomide within 21 days before study drugs (Part 4 only)
• Extensive radiation therapy within 28 days before study drugs. Receipt oflocalized radiation therapy does not preclude enrollment.
• Use of any other experimental drug or therapy within 28 days of study drugs
• Strong CYP3A4 inhibitors, strong CYP3A4 inducers and fluconazole doses >200mg daily within 5 half-lives before study drugs. (For example,clarithromycin has half-life of 4 hours so washout period for clarithromycinis 20 hours.)

12. Known hypersensitivity to compounds of similar chemical or biological compositionto thalidomide and lenalidomide or steroids.
13. Concurrent use of other anti-cancer agents or treatments
14. The development of erythema nodosum if characterized by a desquamating rash whiletaking thalidomide or similar drugs
15. Known positivity for human immunodeficiency virus (HIV), hepatitis B or C, and /or active tuberculosis (TB) including subjects with latent TB or with the riskfactor for activation of latent TB.