A Trial of Selinexor, Ruxolitinib and Methylprednisolone

Inclusion Criteria:

Patients must meet all the following inclusion criteria to be eligible to enroll in this study:

1. Has a diagnosis of MM based on standard criteria as follows:

Myeloma criteria: Must be At least 1 of 2 1. Clonal bone marrow plasma cells >10% 2. Biopsy-proven bony or extramedullary plasmacytoma

Active Myeloma criteria: Active Myeloma criteria: Must Meet At Least ONE of the Following:

Meet at least one of the sub-criteria for #1 Evidence of End Organ Damage (a, b, c, or d), OR Meet sub-criteria #2. 60% or greater bone marrow plasma cells, OR Meet sub-criteria #3 Serum free light chain ratio, OR Meet sub-criteria #4 More than one focal lesion on MRI > 5mm in size.

1. Evidence of end organ damage that can be attributed to the underlying plasma cellproliferative disorder, specifically

2. Hypercalcemia: serum calcium >0.25 mmol/L (>1mg/dL) higher than the upper limitof normal or >2.75 mmol/L (>11mg/dL)

3. Renal insufficiency: creatinine clearance <40 mL per minute or serum creatinine >177mol/L (>2mg/dL)

4. Anemia: hemoglobin value of >20g/L below the lowest limit of normal, or ahemoglobin value <100g/L

5. Bone lesions: one or more osteolytic lesion on skeletal radiography, CT, orPET/CT. If bone marrow has <10% clonal plasma cells, more than one bone lesionis required to distinguish from solitary plasmacytoma with minimal marrowinvolvement

6. 60% or greater clonal plasma cells on bone marrow examination

7. Serum involved / uninvolved free light chain ratio of 100 or greater, provided theabsolute level of the involved light chain is at least 100 mg/L (a patient'sinvolved free light chain either kappa or lambda is the one that is above the normalreference range; the uninvolved free light chain is the one that is typically in, orbelow, the normal range)

8. More than one focal lesion on MRI that is at least 5mm or greater in size

The patient must have met the criteria for Active Myeloma at some stage following the diagnosis of Myeloma. Source documentation for both Myeloma and Active Myeloma will be required.

2. Patients with relapsed/refractory multiple myeloma with at least three prior linesof therapy 3. Received an

3. Anti-CD38 antibody

4. Immunomodulatory agent (IMiD)

5. Proteasome inhibitor (PI) 4. Currently has MM with measurable disease, defined as:

• a monoclonal immunoglobulin spike on serum electrophoresis of at least 0.5 g/dLand/or urine monoclonal protein levels of at least 200 mg/24 hours

• for patients without measurable serum and urine M-protein levels, an involvedSFLC > 100 mg/L or abnormal SFLC ratio

• for patients with IgD MM, a monoclonal immunoglobulin IgD of at least 5500 mg/Lor meet other measurable disease eligibility criteria

• for patients with IgA MM, total IgA of > 700 mg/dL 5. Currently has progressiveMM: MM patients that are relapsed or have refractory disease from at least 3regimens or lines of therapy are eligible for enrollment provided they fulfillthe other eligibility criteria:

• patients are considered relapsed, when they progress greater than 60 days fromtheir last dose of treatment

• patients are refractory when they progress while currently receiving thetreatment or within 8 weeks of its last dose 6. Adequate hepatic functionwithin 14 days prior to C1D1: Total bilirubin < 1.5 × upper limit of normal (ULN) (except patients with Gilbert's syndrome who must have a total bilirubinof < 3 × ULN), and Aspartate aminotransferase (AST) and alanineaminotransferase (ALT) normal to < 2 × ULN.

7. Adequate renal function within 14 days prior to C1D1 as determined by ORestimated CrCl of > 60 mL/min, calculated using the Cockcroft and Gaultformula (140 - Age) • Mass (kg)/ (72 • creatinine mg/dL); multiply by 0.85if female (87)(Appendix 5).
8. Adequate hematopoietic function within 14 days prior to C1D1: total WBCcount ≥1500/mm3, ANC ≥1000/mm3, hemoglobin ≥8.5 g/dL and platelet count ≥75,000/mm3 (patients for whom <50% of BM nucleated cells are plasmacells) or ≥50,000/mm3 (patients for whom ≥50% of BM nucleated cells areplasma cells).
9. Patients receiving hematopoietic growth factor support, includingerythropoietin, darbepoetin, G-CSF, GM-CSF, and platelet stimulators (e.g., eltrombopag, romiplostim, or interleukin-11) must have a 2-weekinterval between growth factor support and the Screening assessments, butthey may receive growth factor support during the study.
10. Patients must have:

• At least a 2-week interval from the last red blood cell (RBC) transfusion priorto the start of study treatment

• At least a 1-week interval from the last platelet transfusion prior to thestart of study treatment

• However, patients may receive RBC and/or platelet transfusions as clinicallyindicated per institutional guidelines during the study 11. Female patients ofchildbearing potential (FCBP) must have a negative serum pregnancy test atScreening. Female patients of childbearing potential and fertile male patientswho are sexually active must use highly effective methods of contraceptionthroughout the study and for one month following the last dose of studytreatment. Male patients must agree not to donate sperm during the studytreatment period. Specifically:

• FCBP† must have a negative serum or urine pregnancy test with a sensitivity ofat least 25 mIU/mL within 10 - 14 days prior to and again within 24 hours ofstarting treatment and must either commit to continued abstinence fromheterosexual intercourse or use acceptable methods of birth control, one highlyeffective method and one additional effective method AT THE SAME TIME, and atleast 28 days before she starts therapy. FCBP must also agree to ongoingpregnancy 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 counseledat a minimum of every 28 days about pregnancy precautions and risks of fetalexposure. † A FCBP (female of childbearing potential) is a sexually mature woman who: 1)has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not beennaturally postmenopausal for at least 24 consecutive months (i.e., has hadmenses at any time in the preceding 24 consecutive months) 12. Able to takeantiplatelet therapy if platelet count is above 30 x 109/L. Options includeaspirin (acetylsalicylic acid, ASA) at 81 or 325/mg/daily, warfarin lowmolecular weight hepairin, Pradaza, Eliquis, or Xarelto.

13. Patients with history of human immunodeficiency virus (HIV) are eligibleif they have CD4+ T cell counts ≥350 cells/µL, negative viral load perinstitutional standard, and no history of acquired immunodeficiencysyndrome (AIDS)-defining opportunistic infections in the last year.
14. Patients with untreated hepatitis C virus (HCV) are eligible if there is adocumentation of negative viral load per institutional standard.
15. Age ≥ 18 years of age. 16. Willing and able to provide written informedconsent in accordance with federal, local, and institutional guidelines.The patient must provide informed consent prior to the first screeningprocedure.
16. Able to adhere to the study visit schedule and other protocolrequirements.

Exclusion Criteria:

Patients meeting any of the following exclusion criteria are not eligible to enroll in this study:

1. Patients who had prior exposure to ruxolitinib or selinexor

2. Prior malignancy that required treatment or has shown evidence of recurrence (exceptfor non-melanoma skin cancer or adequately treated cervical carcinoma in situ)during the 3 years prior to randomization. Cancer treated with curative intent for >5 years previously and without evidence of recurrence will be allowed.

3. Have light chain amyloidosis

4. Have plasma cell leukemia

5. Have history of active tuberculosis

6. Have any concurrent medical condition or disease (e.g., uncontrolled activehypertension, uncontrolled active diabetes, active systemic infection, POEMSsyndrome [polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skinchanges], primary amyloidosis, etc.) that is likely to interfere with studyprocedures.

7. Uncontrolled active infection requiring parenteral antibiotics, antivirals, orantifungals within 1 week prior to Cycle 1 Day 1 (C1D1). Patients on prophylacticantibiotics or with a controlled infection within 1 week prior to C1D1 areacceptable.

8. Received the following prior therapy:

• Chemotherapy within 3 weeks of study drugs

• Corticosteroids (>20 mg/daily prednisone or equivalent) within 3 weeks of studydrugs to ensure that steroid dose intensity at the beginning of the treatmentis not altered by administration of steroids prior to the study. Consumption ofsteroids within 3 weeks of the treatment may interfere with efficacy and sideeffects due to differences of steroid intensity.

• Immunotherapy, immunomodulatory drugs, or proteasome inhibitors within 3 weeksbefore administration of study drugs

• 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 >200 mgdaily within 5 half-lives before study drugs. (For example, clarithromycin hashalf-life of 4 hours so washout period for clarithromycin is 20 hours.)

9. Known intolerance, hypersensitivity, or contraindication to glucocorticoids.

10. Known hypersensitivity to compounds of similar chemical or biological composition toruxolitinib or steroids.

11. Concurrent use of other anti-cancer agents or treatments.

12. Severe hypercalcemia, i.e., serum calcium ≥ 12 mg/dL (3.0 mmol/L) corrected foralbumin

13. Any condition, including the presence of laboratory abnormalities, which places thesubject at unacceptable risk if he/she were to participate in the study or confoundsthe ability to interpret data from the study.

14. Pregnant or breastfeeding females.

15. Body surface area (BSA) <1.4 m2 at baseline, calculated by the Dubois or Mostellermethod.

16. Life expectancy of less than 3 months.

17. Major surgery within 4 weeks prior to C1D1.

18. Active, unstable cardiovascular function, as indicated by the presence of:

19. Symptomatic ischemia, or

20. Uncontrolled clinically significant conduction abnormalities (e.g., patientswith ventricular tachycardia on anti-arrhythmic are excluded; patients withfirst degree atrioventricular block or asymptomatic left anterior fascicularblock/right bundle branch block will not be excluded), or

21. CHF of New York Heart Association Class ≥3 or known left ventricular ejectionfraction < 40%, or

22. Myocardial infarction (MI) within 3 months prior to C1D1 or

23. Stroke and other thrombosis, such as, pulmonary embolism (PE) or deep veinthrombosis (DVT) within 3 months prior to C1D1.

24. Any active GI dysfunction interfering with the patient's ability to swallow tablets,or any active GI dysfunction that could interfere with absorption of studytreatment.

25. Inability or unwillingness to take supportive medications such as anti-nausea andanti-anorexia agents as recommended by the National Comprehensive Cancer Network® (NCCN) Clinical Practice Guidelines in Oncology (CPGO) (NCCN CPGO) for antiemesisand anorexia/cachexia (palliative care).

26. Any active, serious psychiatric, medical, or other conditions/situations that, inthe opinion of the Investigator, could interfere with treatment, compliance, or theability to give informed consent.

27. Contraindication to any of the required concomitant drugs or supportive treatments.

28. Patients unwilling or unable to comply with the protocol.