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
Prior daratumumab exposure is allowed, provided that it has been 6 months or more from the time of cycle 1 day 1 (C1D1) of protocol therapy

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 cycle 1 day 1 for patients not undergoing autologous stem cell transplant (ASCT)
=< 36 months from cycle 1 day 1 for patients undergoing ASCT and post-ASCT maintenance
Measurable disease
1-3 prior lines of therapy
Eastern Cooperative Oncology Group (ECOG) performance status (PS) =< 2 (Form is available on the Academic and Community Cancer Research United [ACCRU] website)

Patients must have evidence of adequate bone marrow reserves, as defined by the following:

Absolute neutrophil count (ANC) >= 1,000 cells/mm^3 without filgrastim or its equivalent within 1 week of the initiation of treatment or pegfilgrastim or its equivalent within 2 weeks of the initiation of treatment
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 within 1 week of the initiation of treatment or the use of TPO mimetics
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)
Total aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 times the upper limit of the institutional normal values
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 within 28 days prior to day 1 of treatment

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

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)

Exclusion Criteria:

Prior treatment with daratumumab within 6 months from cycle 1 day1
Patient with carfilzomib-refractory disease defined as disease progression on or within 60 days of last carfilzomib dose

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 within 6 months prior to day 1 of treatment
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 study entry, 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 at screening

NOTE: Subjects 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]). Subjects 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. Subjects 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 within 14 days prior to day 1 of treatment. Note: palliative radiation therapy (XRT) to < 5% of the total marrow volume as assessed by the treating investigator is allowed within 14 days
Major surgery within 4 weeks prior to day 1 of treatment
Any multiple myeloma therapy within 14 days prior to cycle 1, day 1
Receiving any other investigational agent which would be considered as 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
Prior exposure to daratumumab within 24 weeks from cycle 1, day 1