Selinexor, Daratumumab, Carfilzomib and Dexamethasone for the Treatment of High-Risk, Recurrent or Refractory Multiple Myeloma

Inclusion Criteria

• Age >= 18 years
• Patients must have a documented history of relapsed or relapsed/refractory MM as defined by International Myeloma Working Group (IMWG) criteria (Rajkumar et al., 2014) * Patients must be selinexor and carfilzomib sensitive (i.e. non-refractory) * Prior daratumumab exposure is allowed, provided that it has been >= 6 months (24 weeks) from the time of registration
• High risk disease defined as 1 or more of the following: * High risk cytogenetics (any of the following) ** t(4;14), t(14;16), t(14;20) ** del(17p) ** del(1p) ** Gain 1q (>= 3 copies) * Lactate dehydrogenase (LDH) > upper limit of normal at relapse * International Staging System (ISS) stage 3 disease at relapse * Extramedullary disease at diagnosis or relapse * >= 5% circulating plasma cells at diagnosis or relapse * High risk by gene expression profiling, if known, at diagnosis or relapse * Early relapse with first-line therapy ** =< 18 months from registration for patients not undergoing autologous stem cell transplant (ASCT) ** =< 36 months from registration for patients undergoing ASCT and post-ASCT maintenance
• Measurable disease
• 1-3 prior lines of therapy
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or =< 2 (Form is available on the Academic and Community Cancer Research United [ACCRU] website)
• Absolute neutrophil count (ANC) >= 1,000 cells/mm^3 without filgrastim (lab draw must be >= 7 days from completion of growth factor therapy) or peg- filgrastim or its equivalent (lab draw must be >= 14 days from completion of growth factor therapy) or its equivalent within 1 week of the initiation of treatment or pegfilgrastim or its equivalent within 2 weeks of the initiation of treatment (obtained =< 28 days prior to registration)
• Platelet count of >= 100,000 cells/mm^3 for patients who have bone marrow plasmacytosis of < 50%, or >= 50,000 cells/mm^3 for patients who have bone marrow plasmacytosis of > 50%, both without platelet transfusion support (lab draw must be ≥ 7 days from completion of platelet transfusion) or the use of TPO mimetics (obtained =< 28 days prior to registration) * NOTE: If your site laboratory reports use different units of measurements than what is required by the protocol eligibility requirements, please use the “Lab Test Unit Conversion Worksheet” available on the ACCRU website under “General Forms"
• Total bilirubin =< 2.0 times the upper limit of the institutional normal values except in subjects with congenital bilirubinemia, such as Gilbert syndrome (in which case a direct bilirubin =< 1.5 x upper limit of normal [ULN] is required) (obtained =< 28 days prior to registration)
• Total aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 times the upper limit of the institutional normal values (obtained =< 28 days prior to registration)
• Patients must have adequate cardiac function defined as left ventricular ejection fraction (LVEF) >= 45% by echocardiogram, magnetic resonance imaging (MRI) or multigated acquisition (MUGA) scan
• For those with symptomatic pulmonary disease (e.g. chronic obstructive pulmonary disease [COPD], asthma) or other signs/symptoms of pulmonary disease, adequate pulmonary function as defined by a forced expiratory volume in one second (FEV1) >= 50% of predicted and diffusing capacity for carbon monoxide (DLCO)/alveolar volume (VA) >= 50% of predicted =< 28 days prior to registration * Note: Baseline pulmonary function tests are only required on an as needed basis
• Patients must have evidence of adequate renal function, as defined by the following: creatinine clearance (CrCl) >= 30 mL/min., as measured by a 24-hour urine collection, or estimated by the Cockcroft and Gault formula (obtained =< 28 days prior to registration) * Calculated creatinine clearance must be >= 30 ml/min using the Cockcroft-Gault formula
• Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only
• Female patients of childbearing potential must have a negative serum pregnancy test at screening and agree to use highly effective (dual methods of) contraception throughout the study and for 6 months following the last dose of study drug; and male patients must use an effective barrier method of contraception throughout the study and for 3 months following the last dose of study drug if sexually active
• Ability to complete questionnaire(s) by themselves or with assistance
• Provide informed written consent =< 28 days prior to registration
• Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
• Willing to provide mandatory bone marrow aspirate biopsies for research purposes

Exclusion Criteria

• Prior treatment with daratumumab =< 24 weeks prior to registration
• Patient with carfilzomib-refractory disease defined as disease progression =< 60 days of last carfilzomib dose * Exception: If carfilzomib was dosed at or below 36 mg/m^2 weekly, or if carfilzomib was dosed at or below 45 mg/m^2 every other week maintenance dosing
• Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects: * Pregnant women * Nursing women * Men or women of childbearing potential who are unwilling to employ adequate contraception
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
• Uncontrolled hypertension, defined as a systolic blood pressure of >= 160 mmHg or a diastolic blood pressure of >= 90 mmHg
• Significant cardiac disease, including any of the following: * >= class 3 New York Heart Association (NYHA) congestive heart failure * Electrocardiogram (EKG) evidence of acute ischemia * Unstable angina * Myocardial infarction =< 6 months prior to registration * Clinically significant arrhythmias or conduction block (premature atrial contractions [PACs], premature ventricular contractions [PVCs], rate controlled atrial fibrillation, sinus arrhythmia, asymptomatic sinus bradycardia or sinus tachycardia and 1st degree heart block are not considered clinically significant) * >= grade 2 QT interval by Fridericia (QTcF) prolongation (i.e. > 480 ms) * Note: Prior to registration, any EKG abnormality at screening not felt to put the patient at risk must be documented by the investigator as not medically significant
• A diagnosis of human immunodeficiency virus (HIV) does not exclude the patient from participation. However, the viral load must be < 50 copies/mm^3 and CD4 count >= 200 on anti-HIV therapy within 28 days prior to cycle 1, day 1 of treatment
• Positive hepatitis C antibody test result or positive hepatitis C ribonucleic acid (RNA) test result 28 days prior to registration * NOTE: Patients with positive hepatitis C antibody due to prior eradicated disease can be enrolled if a confirmatory negative hepatitis C RNA test is obtained
• Is seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg] =< 28 days prior to registration). Patients with resolved 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) deoxyribonucleic acid (DNA) levels. Patients who are PCR positive will be excluded. Exception: Patients with serologic findings suggestive of HBV vaccination
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements
• Discontinuation of prior carfilzomib or daratumumab due to treatment toxicity
• Radiation =<14 days prior to registration. Note: Palliative radiation therapy (XRT) to < 5% of the total marrow volume as assessed by the treating investigator is allowed =< 14 days days of registration
• Major surgery =< 4 weeks (28 days) prior to registration
• Any multiple myeloma therapy =<14 days prior to registration
• Receiving any other investigational agent which would be considered a treatment for the primary neoplasm
• Active central nervous system (CNS) involvement
• Concomitant amyloid light-chain (AL) amyloidosis or polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome
• Patients cannot have other prior or concomitant malignancies except for: * Non-melanoma skin cancer * In situ malignancy * Low-risk prostate cancer after curative therapy * Prostate cancer Gleason grade 6 AND with stable prostate specific antigen (PSA) levels off treatment * Other cancer for which the patient has been treated with curative intent or disease free for >= 3 years