Selinexor, Pomalidomide, and Dexamethasone with or Without Carfilzomib for the Treatment of Patients with Relapsed Refractory Multiple Myeloma, the SCOPE Trial

Inclusion Criteria:

• Age >= 18 years

• Diagnosis of RRMM with progressive disease at study entry as per the InternationalMyeloma Working Group (IMWG) uniform criteria

• Measurable disease by IMWG criteria as defined by at least one of the following:

• Serum M-protein >= 0.5 g/dL

• Urine M-protein >= 200 mg in a 24-hour collection

• Serum free light chain level >= 10 mg/dL provided the free light chain ratio isabnormal

• For patients with extramedullary measurable disease (EMD) by CT or MRI or theCT portion of the PET/CT: Must have at least one lesion that has a singlediameter of >= 2 cm. Skin lesions can be used if the area is >= 2cm in at leastone diameter and measured with a ruler

• Bone marrow plasma cells >= 30%

• Patients with IgA myeloma in whom serum protein electrophoresis is deemedunreliable, due to co-migration of normal serum proteins with the para proteinin the beta region, may be considered eligible as long as total serum IgA levelis elevated above normal range

• Prior treatment:

• Arm A: At least one of the following must be true: (1) Subjects must have beenpreviously treated with at least 3 prior lines of therapy, including aproteasome inhibitor and an immunomodulatory drug (IMiD) (2) Subjects who arerefractory to carfilzomib and/or pomalidomide may enroll in Arm A using thequadruplet regimen, SKPd, provided carfilzomib, pomalidomide and dexamethasone (KPd) triplet is not the most recent line of prior therapy and that they havebeen previously treated with at least 3 prior lines of therapy, including aproteasome inhibitor and an IMiD. Carfilzomib/Pomalidomide refractory status isdefined by the IMWG criteria: disease that is nonresponsive (stable disease [SD] or progressive disease [PD]) while on therapy, or progresses within 60days of last therapy in patients who have achieved minimal response (MR) orbetter at some point previously before then progressing in their diseasecourse.

• Arm B: Subjects must have progressive disease and been exposed to up to 2 priorlines of therapy, including a proteasome inhibitor and lenalidomide

• Provide written informed consent

• Willing to return to enrolling institution for follow-up (during the activemonitoring phase of the study) and ability to adhere with the study visit scheduleand other protocol procedures

• Willingness to provide mandatory tissue specimens for correlative research

• Willingness to use fixed-duration therapy (up to 18 cycles) for relapsed refractorymultiple myeloma

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2

• Ability to complete questionnaire(s) by themselves or with assistance

• Willingness to provide mandatory blood specimens for correlative research

• Calculated creatinine clearance (using Cockcroft-Gault equation) >= 15 mL/min (obtained =< 14 days prior to registration)

• Absolute neutrophil count (ANC) >= 1500/uL(without growth factor support for >= 7days ( obtained =< 14 days prior to registration)

• Un-transfused Platelet count >= 100,000/uL (without platelet transfusion for >= 14days) for SKPd and >= 100,000 (without platelet transfusion for >= 7 days) for SPdis permitted. Additionally, for both Arms A and B platelet count of >= 75,000/uL ispermitted if thrombocytopenia is deemed by the investigator to be secondary tosevere bone marrow infiltration (>= 50%) by myeloma as determined

• Hemoglobin >= 8.0 g/dL Note: Screening hemoglobin should be independent of red bloodcell transfusion for at least 3 days prior to screening

• Total bilirubin =< 2.0 x upper limit of normal (ULN). Note: Patients with Gilbert'ssyndrome who must have a total bilirubin of < 3 times ULN

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN

• Prothrombin time (PT)/international normalized ratio (INR)/activated partialthromboplastin time (aPTT) =< 1.5 x ULN

• Note: If patient is receiving warfarin and INR should be within 2-3

• Negative serum pregnancy test done =<7 days prior to registration, for persons ofchildbearing potential only

• Willingness to follow strict birth control measures as suggested by the study:Female subjects of childbearing potential should be willing to use 2 methods ofbirth control or be surgically sterile, or abstain from heterosexual activity for 28days prior to starting pomalidomide, during the course of the study, during any doseinterruptions, and through 30 days after last dose of pomalidomide and carfilzomib.Female subjects of child bearing potential are those who 1) have achieved menarcheat some point, 2) have not undergone a hysterectomy or bilateral oophorectomy or 3)have not been naturally postmenopausal (amenorrhea following cancer therapy does notrule out childbearing potential) for at least 24 consecutive months (i.e., has hadmenses at any time in the preceding 24 consecutive months). Note: Abstinence isacceptable if this is the usual lifestyle and preferred contraception for thesubject. Male subjects must agree to practice abstinence or use an effective barriermethod of contraception starting with the first dose of carfilzomib or pomalidomidethrough 6 months after last dose of pomalidomide and carfilzomib if sexually activewith a female of childbearing potential. Note: Abstinence is acceptable if this isthe usual lifestyle and preferred contraception for the subject. Other acceptablemethods of contraception are condoms with contraceptive foam, oral, implantable orinjectable contraceptives, contraceptive patch, intrauterine device, diaphragm withspermicidal gel, or a sexual partner who is surgically sterilized orpost-menopausal. All subjects must agree to follow the local requirements forpomalidomide counseling, pregnancy testing, and birth control; and be willing andable to comply with the local requirements (for example, periodic pregnancy tests,safety labs, etc.)

• Willingness to follow the requirements of the Pomalyst Risk Evaluation andMitigation Strategy (REMS) program

• Able to swallow capsules and able to take and tolerate oral medications on acontinuous basis

Exclusion Criteria:

• History of myocardial infarction =< 6 months prior to pre-registration, orcongestive heart failure requiring use of ongoing maintenance therapy for lifethreatening ventricular arrhythmias. Unstable angina within 4 months prior torandomization, New York Heart Association (NYHA) class III or IV heart failure, leftventricular ejection fraction (LVEF) < 40%, uncontrolled angina, corrected QT (QTc)interval >= 470 msec, History of severe coronary artery disease, severe uncontrolledventricular arrhythmias including uncontrolled chronic atrial fibrillation/atrialflutter, history of torsades de pointe, sick sinus syndrome, or electrocardiographicevidence of acute ischemia or grade 3 conduction system abnormalities unless subjecthas a pacemaker

• Failure to recover from acute, reversible effects of prior therapy regardless ofinterval since last treatment.

EXCEPTION: Grade 1 peripheral (sensory) neuropathy that has been stable for at least 1 month since completion of prior treatment

• Uncontrolled intercurrent non-cardiac illness including, but not limited to:

• Ongoing or active infection. Uncontrolled infection requiring parenteralantibiotics, antivirals, or antifungals =< 14 days prior to registration;patients with controlled infection or on prophylactic antibiotics are permittedin the study

• Psychiatric illness/social situations

• Dyspnea at rest due to complications of advanced malignancy or other diseasethat requires continuous oxygen therapy

• Any other conditions that would limit compliance with study requirements

• Patients known to be human immunodeficiency virus (HIV) positive and/or currentlyreceiving antiretroviral therapy

• Currently receiving any other investigational agent which would be considered as atreatment for RRMM

• Non investigational radiation, chemotherapy, or immunotherapy or any otheranticancer therapy =< 14 days or five half-lives, whichever is shorter prior toregistration. Note: (localized radiation to a single site =< 7 days prior toregistration is allowed)

• Participation in an investigational anti-cancer study =< 21 days or five half-liveswhichever is shorter prior to registration

• Major Surgery =< 21 days prior to registration

• Co-morbid systemic illnesses or other severe concurrent disease which, in thejudgment of the investigator, would make the patient inappropriate for entry intothis study or interfere significantly with the proper assessment of safety andtoxicity of the prescribed regimens

• Other active malignancy =< 5 years prior to registration. EXCEPTIONS: Non-melanoticskin cancer or carcinoma-in-situ of the cervix that has undergone potentiallycurative therapy. NOTE: If there is a history of prior malignancy, they must not bereceiving other specific treatment for their cancer

• Uncontrolled hypertension or uncontrolled diabetes =< 14 days prior to registration

• Known active hepatitis A, B, or C infection; or known to be positive for hepatitis Cvirus (HCV) ribonucleic acid (RNA) or hepatitis B surface antigen (HBsAg) [hepatitisB virus (HBV) surface antigen]

• Significant neuropathy (grades 3-4, or grade 2 with pain) =< 14 days prior toregistration

• Known history of allergy to Captisol (a cyclodextrin derivative used to solubilizecarfilzomib)

• Any underlying condition that would significantly interfere with the absorption ofan oral medication

• Contraindication to any of the required concomitant drugs or supportive treatments,including hypersensitivity to all anticoagulation and antiplatelet options,antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiacimpairment

• Subjects with pleural effusions requiring thoracentesis or ascites requiringparacentesis =< 14 days prior to registration

• Patients with coagulation problems and active bleeding in the last month (e.g,peptic ulcer, epistaxis, spontaneous bleeding)

• Subjects with smoldering multiple myeloma (SMM), monoclonal gammopathy ofundetermined significance (MGUS) or Waldenström's macroglobulinemia or ALamyloidosis

• History of repeated infections, hyperviscosity or POEMS syndrome (plasma celldyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, andskin changes)

• Has a known history of immunosuppression or is receiving systemic steroid therapy orany other form of systemic immunosuppressive therapy =< 7 days prior registration.The use of physiologic doses of corticosteroids may be approved after consultationwith the study chair

• Note: A short course of 40 mg dexamethasone (=< 4 days) or equivalent foremergency use is allowed after previous consultation with the study chair. Inthese cases, baseline m-protein values from serum and urine should be obtainedbefore the short steroid course and be repeated prior to study drugsadministration on cycle 1 day 1

• Treatment with plasmapheresis =< 28 days prior to registration

• Known hypersensitivity to thalidomide, lenalidomide or dexamethasone

• Unable or unwilling to undergo thromboembolic prophylaxis including, as clinicallyindicated, aspirin, Coumadin (warfarin) or low-molecular weight heparin

• Evidence of active, non-infectious pneumonitis

• Received a live vaccine =< 30 days prior to registration

• Pomalidomide and carfilzomib (for arm A) or pomalidomide (for Arm B) commerciallyunavailable to the patient

• Prior exposure to Selinexor

• Pregnant persons

• Nursing persons

• Persons of childbearing potential who are unwilling to employ adequatecontraception (applies to both male and female participants as written)