Selinexor Maintenance Post CAR-T Cell Therapy for Multiple Myeloma

Inclusion Criteria:

* Diagnosis of triple-class exposed or refractory multiple myeloma (MM). Diagnosis must be histologically confirmed. Patients with multiple myeloma with local amyloid deposition in the bone marrow are eligible. Only the following risk categories will be enrolled:

  * High risk myeloma, defined by the presence of at least one of the following features:

    * Deletion 17p and/or TP53 alteration:

      * Deletion of 17p with a cancer clonal fraction (CCF) ≥20%, assessed on CD138-positive/purified plasma cells, AND/OR
      * TP53 mutation identified using a validated next-generation sequencing (NGS)-based assay.
    * High-risk IgH translocation with chromosome 1 abnormality:

      * Presence of t(4;14), t(14;16), or t(14;20) in combination with either gain/amplification of 1q (1q+) and/or deletion of 1p32.
    * Chromosome 1p32 deletion patterns:

      * Monoallelic deletion of 1p32 occurring with gain/amplification of 1q, OR
      * Biallelic deletion of 1p32.
    * Elevated β2-microglobulin without renal dysfunction:

      * Serum β2-microglobulin ≥5.5 mg/L in the setting of normal renal function, defined as serum creatinine \<1.2 mg/dL.
    * Presence of extramedullary disease prior to receiving CAR-T OR
  * Standard risk myeloma with MRD-positive (MRD+) disease at MRD draw around Day 58-60 post CAR-T.
* Received standard of care ciltacabtagene autoleucel (cilta-cel; Carvykti).
* Able to monitor disease response by ClonoSEQ MRD testing.
* At least 18 years of age.
* ECOG performance status ≤ 2.
* Adequate bone marrow and organ function as defined below:

  * Absolute neutrophil count ≥ 1.0 K/cumm
  * Platelets ≥ 50 K/cumm
  * Hemoglobin ≥ 8.5 g/dL without blood transfusion within 7 days before C1D1.
  * Total bilirubin ≤ 1.5 x IULN; patients with Gilbert's syndrome must have a total bilirubin \< 3 x IULN.
  * AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN
  * Calculated creatinine clearance ≥ 15 mL/min by Cockcroft-Gault
* The effects of selinexor on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception prior to C1D1 of selinexor, for the duration of study participation, and for 90 days after completion of selinexor. Should a woman become pregnant or suspect she is pregnant while participating in this study or should a man suspect he has fathered a child, s/he must inform her treating physician immediately.
* Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Exclusion Criteria:

* MM with active CNS involvement.
* Confirmed progressive disease by IMWG after CAR-T administration.
* Unresolved cytokine release syndrome (CRS) or CAR-T neurologic toxicity.
* Any unresolved non-hematologic grade ≥ 3 treatment-related toxicity from CAR-T.
* Administration or planned administration of any other concomitant chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy which would be considered a treatment of multiple myeloma from Day 28 post-CAR-T cell therapy through discontinuation from study treatment. Note: patients may be on corticosteroids if they are being given for disorders other than multiple myeloma (e.g., adrenal insufficiency, rheumatoid arthritis)
* Has received selinexor or another XPO1 inhibitor post-CART.
* Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
* Prior organ transplant requiring immunosuppressive therapy.
* Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial
* Currently receiving any other investigational agents.
* A history of allergic reactions attributed to compounds of similar chemical or biologic composition to selinexor or other agents used in the study.
* 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.
* Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection requiring parenteral antibiotics, antivirals, or antifungals within 1 week prior to C1D1 of selinexor (patients on prophylactic antibiotics or with a controlled infection within 1 week prior to C1D1 of selinexor may enroll); active, unstable cardiovascular function, as indicated by the presence of symptomatic ischemia, uncontrolled clinically significant conduction abnormalities (e.g. patients with ventricular or atrial tachycardia on anti-arrhythmics are excluded; patients with first degree atrioventricular block or asymptomatic left anterior fascicular block/right bundle branch block will not be excluded), congestive heart failure of NYHA class ≥ 3 or known left ventricular ejection fraction of \< 40%, or myocardial infraction within 3 months prior to C1D1 of selinexor therapy.
* Major surgery within 28 days prior to C1D1 of selinexor
* Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 7 days of C1D1 of selinexor.
* HIV-infected if not on effective anti-retroviral therapy with undetectable viral load for 6 months. Patients with HIV who are receiving effective anti-retroviral therapy and have had an undetectable viral load for at least 6 months are eligible. HIV testing not required in the absence of known history of infection.
* Evidence of chronic hepatitis B virus (HBV) that is detectable on suppressive therapy. Patients with evidence of chronic HBV infection with undetectable HBV viral load on suppressive therapy are eligible. HBV testing not required in the absence of known history of infection.
* History of hepatitis C virus (HCV) infection that has not been cured or that has a detectable viral load. Patients with a history of HCV that has been treated and cured are eligible. Patients with HCV infection who are currently on treatment and have an undetectable HCV viral load are eligible. HCV testing not required in the absence of known history of infection.