The primary objective of this Phase Ib/II trial is to study the safety and tolerability of the combination of selinexor, carfilzomib, isatuximab-OBDS (on body delivery system) and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma, who have received at least one line of therapy. The phase Ib portion comprises the safety run-in with 6-12 patients, with the option to reduce the selinexor dose from 40 mg to 20 mg if the higher dose reaches the prescribed toxicity threshold. The Phase II portion of the trial will test the Recommended Phase 2 Dose (RP2D) in an expansion cohort of up to 50 patients.

Inclusion Criteria:

1. Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.

2. Age ≥ 18 years at the time of consent.

3. ECOG Performance Status of ≤2 within 28 days prior to registration. A performance status of >2 will be allowed only if it is related to bone pain that is expected to improve with treatment.

4. Patients with a diagnosis of relapsed or relapsed/refractory MM who have received at least 1 line of prior therapy. In the phase 2 component, we will specifically enrich for patients with 1q gain or amplification as well as other IMWG high-risk features with the aim of including ≥50% of the enrolled population (a minimum of 25 patients) with high risk disease. High risk disease is defined as the presence of:

   • del(17p), with a cutoff of >20% clonal fraction, and/or TP53 mutation
   • an IgH translocation including t(4;14), t(14;16), or t(14;20) along with 1q+ and/or del(1p32)
   • monoallelic del(1p32) along with 1q+ or biallelic del(1p32)
   • β2 microglobulin ≥5.5 mg/L with normal creatinine (<1.2 mg/dL) For purposes of the study, patients with 2 or more of these high risk cytogenetic abnormalities. Patients known to carry such abnormalities on previous FISH analysis and/or cytogenetic testing will also be eligible, if results from on-study marrow are unavailable or not obtainable. Therefore, enrollment of patients without these feature(s) will halt once 25 standard risk, non-mutated patients are enrolled and treated. Refractory is defined as patients relapsing on or within 60 days of therapy, per IMWG.

5. Patients must have measurable disease as defined by at least one of the following:

   1. A monoclonal protein (M-protein): ≥ 0.5g/dL on serum protein electrophoresis or ≥ 200 mg of monoclonal protein on a 24-hour urine protein or involved serum light chain ≥ 10 mg/dl at time of relapse, or
   2. Biopsy proven plasmacytoma that can be assessed by physical exam or imaging, or
   3. If non- or oligo secretory, ≥10% plasma cells on BM biopsy/aspirate at time of relapse or plasmacytoma as described and/or evaluable disease by positron emission tomography, either MR or CT. Patients must be willing to undergo repeat BM aspirate and biopsy to assess response.
   4. Due to the difficulty of quantitation using conventional SPEP of IgA and IgD monoclonal proteins, an absolute increase of > 25 % over previous nadir of the total values in mg/dl (or adjusted units) will meet eligibility requirements for progression and study eligibility.

   NOTE: Urine protein electrophoresis (UPEP) (on a 24-h collection) is required at baseline; no substitute method is acceptable. Urine must be assessed to establish response if the baseline urine M-spike is ≥ 200 mg/24 h. Please note that if both serum and urine M-components are present at the time of enrollment, both should be assessed in order to evaluate response for CR but monthly 24 hour urine tests outside of this response testing are not necessary. For patients without a monoclonal urine protein ≥200mg/24 hours, the test only needs to be repeated to corroborate CR.

6. Patients may have received any number and type of previous treatments for myeloma including carfilzomib and an anti-CD38 antibody but cannot be refractory to the combination of daratumumab and carfilzomib.

7. Patients may not have received any anti-CD38 therapy within 6 months of start of study treatment (not enrollment).

8. Previous allogeneic transplant is allowed provided the patient is not receiving ongoing systemic therapy for graft-versus-host disease (GVHD).

9. Previous B-cell maturation antigen (BCMA)-directed therapy, including chimeric antigen receptor T-cell therapy (CAR-T) transplantation, antibody drug conjugates, or bispecific engagers is also allowed, provided there is no evidence of residual cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. In addition, other T cell redirecting therapy exposure is permitted as well.

10. Demonstrate adequate organ function as defined below; all screening labs to be obtained within 28 days prior to registration.

    • White blood cell (WBC): ≥ 1,500/mm3
    • Absolute Neutrophil Count (ANC): ≥ 1,000/mm3 a (For subjects with known Duffy null phenotype (benign ethnic neutropenia), the lowest acceptable ANC will be 750/mm3)
    • Platelet Count: ≥75,000/mm3
    • Hemoglobin (Hgb): ≥ 8 g/dL
    • Calculated creatinine clearance: ≥ 20 cc/min using the Cockcroft-Gault formula
    • Total Bilirubin: ≤ 2 × upper limit of normal (ULN) (except patients with suspected Gilbert's syndrome [hereditary indirect hyperbilirubinemia] who must have a total bilirubin of ≤ 3x ULN)
    • Aspartate aminotransferase (AST): ≤ 3 × ULN
    • Alanine aminotransferase (ALT): ≤ 3 × ULN

11. Females of childbearing potential who are sexually active with a male able to father a child must have a negative pregnancy test (serum or urine) within 7 days prior to registration.

12. Females of childbearing potential who are sexually active with a male able to father a child must be willing to abstain from heterosexual activity or use an effective method(s) of contraception from the time of informed consent, during the study and for 6 months after the last dose of study drug(s). Males able to father a child must be willing to abstain from heterosexual activity or to use an effective method(s) of contraception from initiation of treatment, during the study and for 3 months after the last dose of study drug(s). Male participants must agree not to donate sperm during this same time period.

13. As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study

14. Patients with known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) may be enrolled if the viral load by polymerase chain reaction (PCR) is undetectable with/without active treatment and absolute lymphocyte count is ≥ 350/ul. Such subjects may stay on antiviral therapy during study treatment.

15. Patients with a positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection may be enrolled if the viral load by PCR is undetectable with/without active treatment. Such patients may stay on viral therapy while on treatment. Due to a potential HBV and HepC reactivation risk with carfilzomib, the subjects are required to have HBs Ag and HBc Ab screening.

16. Subject willing to provide mandatory bone marrow biopsy and peripheral blood laboratory testing for research purposes only.

Exclusion Criteria:

1. Active infection requiring systemic therapy (Note: subjects can be enrolled if they will be completing antibiotic therapy by the time of actual start date of treatment)
2. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).
3. Known additional malignancy that is active and/or progressive, requiring urgent or new treatment. Exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, prostate cancer on stable hormonal therapy, DCIS or other cancer for which the subject has been disease-free for at least three years. Patients who have undergone a curative procedure for another malignancy are eligible.
4. Active central nervous system (CNS) metastases. NOTE: Subjects who are symptomatic and have not undergone prior brain imaging must undergo a head computed tomography (CT) scan or brain MRI within 28 days prior to registration to exclude brain metastases.
5. History of severe hypersensitivity reaction (grade 3 or more) to an anti-CD38 antibody that in the opinion of the investigator excludes the use of these drugs.
6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (NYHA Class III and IV), unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
7. Treatment with any investigational drug within 14 days prior to registration.
8. Any previously active gastrointestinal dysfunction that prevents the patient from swallowing tablets or interferes with absorption of study treatment. This is likely to be a rare occurrence.
9. Treatment with moderate or strong inhibitors/inducers of CYP3A within 7 days prior to Day 1 of Cycle 1. Potent inhibitors of CYP3A4 include clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal and grapefruit. Inducers of CYP3A4 include phenobarbital, phenytoin, rifampicin, and St. John's Wort. For patients receiving diltiazem or verapamil, alternative therapy will need to be substituted, if necessary, if the drug cannot otherwise be safely discontinued.
10. Currently receiving a strong CYP3A4 inhibitor/inducer and unable to discontinue such medications.
11. Prior exposure to a SINE compound, including selinexor.
12. Exposure to anti-CD38 directed therapy (ex. daratumumab; isatuximab; daratumumab/hyaluronidase) within 6 months of study registration.
13. Patients with an echocardiogram or other cardiac imaging study showing a LVEF of <40% within 60 days of study registration.
14. Presence of plasma cell leukemia at time of registration
15. Patients with a history of POEMS syndrome or primary AL amyloidosis are excluded