Selinexor in Combination with Carfilzomib, Daratumumab or Pomalidomide, and Dexamethasone for the Treatment of Patients with Multiple Myeloma Relapsing on Current Therapy

Inclusion Criteria

• Age >= 18 years at time of informed consent
• Histologically confirmed multiple myeloma (MM) and evidence of disease progression while on one of the below MM regimens: * Arm 1: Refractory to or disease progression while on a carfilzomib-containing regimen * Arm 2: Refractory to or disease progression while on a pomalidomide-containing regimen * Exploratory Arm: Refractory to or disease progression while on a daratumumab containing regimen
• > 1 prior line of therapy
• Measurable disease as defined: Serum M-protein >= 0.5 g/dL; urine M-protein excretion at least 200 mg/24 hours; serum free light chain (FLC) >= 100 mg/L, provided that FLC ratio is abnormal; if serum protein electrophoresis is felt to be unreliable for routine M-protein measurement (i.e. immunoglobulin [Ig]A MM) then quantitative Ig levels by nephelometry or turbidometry are acceptable; for non-secretory disease, bone marrow plasma cells > 10% or a biopsy-proven plasmacytoma by PET/CT or MRI is acceptable. This allows for the inclusion of patients that are excluded from most other trials in which serum or urine parameters of disease are required. Response in the non-secretory disease subset will be monitored by either of the following: bone marrow biopsy, target lesion biopsy, or PET Scan every three months depending on how the patient came on study
• Documented evidence of disease progression or refractory disease on the current treatment as defined as: * Achieving SD or less for >= 1 cycle during treatment with regimens stated (i.e. relapsed) OR * < 25% response (i.e. never achieved MR) or PD during or within 60 days from the endof most recent MM regimen as listed in #2 (i.e. refractory)
• Any non-hematological toxicities (except for peripheral neuropathy) that patients experienced from treatments in previous regimens must resolve to grade 2 or less by cycle 1 day 1
• Eastern Cooperative Oncology Group (ECOG) 2 or less
• Total bilirubin < 1.5 × upper limit of normal (ULN) (except patients with Gilbert’s syndrome who must have a total bilirubin of < 3 × ULN) (within 28 days prior to cycle 1 day 1 [C1D1])
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) normal to < 2 × ULN (within 28 days prior to C1D1)
• Serum creatinine =< 2.0 mg/dL or estimated creatinine clearance of >= 30 mL/min (within 28 days prior to C1D1), calculated using the Cockcroft and Gault formula (140 – age) * mass (kilograms)/ (72 * creatinine mg/dL); multiply by 0.85 if female
• Total white blood cell (WBC) count >= 1500/mm^3 (within 14 days prior to C1D1) * Patients receiving hematopoietic growth factor support, including erythropoietin, darbepoetin, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), and platelet stimulators (eg, eltrombopag, romiplostim, or interleukin-11) must have a 2-week interval between growth factor support and the screening assessments, but they may receive growth factor support during the study * Patients must have: ** At least a 2-week interval from the last red blood cell (RBC) transfusion prior to the screening hemoglobin assessment, and ** At least a 1-week interval from the last platelet transfusion prior to the screening platelet assessment *** However, patients may receive RBC and/or platelet transfusions as clinically indicated per institutional guidelines during the study
• Absolute neutrophil count >= 1000/mm^3 (within 14 days prior to C1D1) * Patients receiving hematopoietic growth factor support, including erythropoietin, darbepoetin, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), and platelet stimulators (eg, eltrombopag, romiplostim, or interleukin-11) must have a 2-week interval between growth factor support and the screening assessments, but they may receive growth factor support during the study * Patients must have: ** At least a 2-week interval from the last red blood cell (RBC) transfusion prior to the screening hemoglobin assessment, and ** At least a 1-week interval from the last platelet transfusion prior to the screening platelet assessment *** However, patients may receive RBC and/or platelet transfusions as clinically indicated per institutional guidelines during the study
• Hemoglobin >= 8.5 g/dL (within 14 days prior to C1D1) * Patients receiving hematopoietic growth factor support, including erythropoietin, darbepoetin, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), and platelet stimulators (eg, eltrombopag, romiplostim, or interleukin-11) must have a 2-week interval between growth factor support and the screening assessments, but they may receive growth factor support during the study * Patients must have: ** At least a 2-week interval from the last red blood cell (RBC) transfusion prior to the screening hemoglobin assessment, and ** At least a 1-week interval from the last platelet transfusion prior to the screening platelet assessment *** However, patients may receive RBC and/or platelet transfusions as clinically indicated per institutional guidelines during the study
• Platelet count >= 75,000/mm^3 (patients for whom < 50% of bone marrow nucleated cells are plasma cells) or >= 50,000/mm^3 (patients for whom >= 50% of bone marrow nucleated cells are plasma cells) (within 14 days prior to C1D1) * Patients receiving hematopoietic growth factor support, including erythropoietin, darbepoetin, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), and platelet stimulators (eg, eltrombopag, romiplostim, or interleukin-11) must have a 2-week interval between growth factor support and the screening assessments, but they may receive growth factor support during the study * Patients must have: ** At least a 2-week interval from the last red blood cell (RBC) transfusion prior to the screening hemoglobin assessment, and ** At least a 1-week interval from the last platelet transfusion prior to the screening platelet assessment *** However, patients may receive RBC and/or platelet transfusions as clinically indicated per institutional guidelines during the study
• Female patients of childbearing potential must have a negative serum pregnancy test at screening. Female patients of childbearing potential and fertile male patients who are sexually active with a female of childbearing potential must use highly effective methods of contraception throughout the study and for 6 months following the last dose of study treatment

Exclusion Criteria

• Smoldering MM
• Radiation therapy (RT), chemotherapy or immunotherapy other than above stated regimens in =< 2 weeks prior to C1D1. Patients on long-term glucocorticosteroids during screening do not require a washout period. Prior RT is permitted for treatment of fractures or to prevent fractures as well as for pain management
• Active graft versus host disease after allogeneic stem cell transplant
• Life expectancy < 3 months
• Known active hepatitis A, B, or C infection
• Unresolved grade >= 3 toxicity with prior carfilzomib, daratumumab and pomalidomide containing regimen(s)
• Unresolved grade >= 2 neuropathy
• History of uncontrolled hypertension, chronic advanced chronic obstructive pulmonary disease (COPD), or New York Heart Association (NYHA) Class III (and above)
• Has any concurrent medical condition or disease (eg, uncontrolled active hypertension, uncontrolled active diabetes, active systemic infection, etc.) that is likely to interfere with study procedures
• Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within 1 week prior to C1D1. Patients on prophylactic antibiotics or with a controlled infection within 1 week prior to C1D1 are eligible
• Known intolerance, hypersensitivity, or contraindication to glucocorticoids
• Pregnant or breastfeeding females
• Body surface area (BSA) < 1.4 m^2 at baseline, calculated by the Dubois (Dubois 1916) or Mosteller (Mosteller 1987) method as selinexor can cause significant weight loss
• Any active gastrointestinal dysfunction interfering with the patient’s ability to swallow tablets, or any active gastrointestinal dysfunction that could interfere with absorption of study treatment
• Inability or unwillingness to take supportive medications such as anti-nausea and anti-anorexia agents as recommended by the National Comprehensive Cancer Network (registered trademark) (NCCN) Clinical Practice Guidelines in Oncology (CPGO) (NCCN CPGO) for antiemesis and anorexia/cachexia (palliative care)
• Any active, serious psychiatric, medical, or other conditions/situations that, in the opinion of the Investigator, could interfere with treatment, compliance, or the ability to give informed consent
• Contraindication to any of the required concomitant drugs or supportive treatments
• Patients unwilling or unable to comply with the protocol