Selinexor and Lenalidomide for Consolidation and Maintenance Treatment in Multiple Myeloma Post-transplant

Inclusion Criteria:

* Patients ≥18 years of age at time of enrollment.
* Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).
* Histologically confirmed diagnosis of multiple myeloma that is symptomatic. Patients with multiple myeloma with local amyloid deposition in the bone marrow are eligible.
* Patients must have undergone lenalidomide-based induction regimen.
* Patient must have undergone AHCT within 80 to 140 days prior to C1D1 for MM.
* Patient must be MRD-positive (per 10\^-5 threshold) using clonoSEQ MRD® assay on bone marrow biopsy prior to study enrollment.
* Patient must have achieved very good partial response or better per IMWG response criteria prior to study enrollment.
* Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance status 0, 1, or 2.
* Adequate organ function as defined below:

  * Absolute neutrophil count (ANC) ≥ 1.5 K/cumm.
  * Platelet count ≥ 100 K/cumm (patients for whom \<50% of bone marrow nucleated cells are plasma cells) or ≥50 K/cumm (patients for whom ≥50% of bone marrow nucleated cells are plasma cells).; platelet transfusions to help patients meet eligibility criteria are not allowed within 7 days before C1D1.
  * Hemoglobin ≥ 8.5 g/dL without blood transfusion within 7 days before C1D1.
  * Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN), patients with Gilbert's syndrome must have a total bilirubin of \< 3 x ULN.
  * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN.
  * Calculated creatinine clearance ≥ 15 mL/min per Cockcroft and Gault formula.
* Women of childbearing potential must follow pregnancy testing requirements as outlined in the Revlimid REMS® program material. This is defined as either committing to continued abstinence from heterosexual intercourse or beginning TWO acceptable methods of contraception (one highly effective method and one additional effective method AT THE SAME TIME) at least 28 days prior to the start of lenalidomide, for the duration of study participation, and for 28 days following the last dose of lenalidomide. Women of childbearing potential must also agree to ongoing pregnancy testing.
* Men must agree to use a latex condom during sexual contact with a woman of childbearing potential even if they have had a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
* All study participants must be registered into the mandatory Revlimid REMS® program and be willing to comply with its requirements. Per standard Revlimid REMS® program requirements, all physicians who prescribe lenalidomide for research subjects enrolled into this trial, must be registered in, and must comply with, all requirements of the Revlimid REMS® program.

Exclusion Criteria:

* Patients with lenalidomide-refractory disease during induction.
* Prior receipt of selinexor or another XPO1 inhibitor previously.
* Female patients who are lactating or have a positive serum pregnancy test during the screening period.
* Evidence of MM disease progression any time prior to enrollment. Progression from smoldering/asymptomatic MM to symptomatic MM is not exclusionary.
* Tandem autologous transplantation.
* History of plasma cell leukemia or MM CNS involvement.
* 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-transplant through discontinuation from study. Patients may be on corticosteroids if they are being given for disorders other than multiple myeloma (e.g., adrenal insufficiency, rheumatoid arthritis, etc.).
* 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.
* Subjects with active hepatitis B virus (Hep B) are allowed if antiviral therapy for hepatitis B has been given for \>8 weeks and viral load is \<100 IU/ml prior to first dose of trial treatment. Subjects with untreated hepatitis C virus (HCV) are allowed. Subjects with Human Immunodeficiency Virus (HIV) who have CD4+ T-cell counts ≥ 350 cells/µL and no history of AIDS-defining opportunistic infections in the last year are allowed.
* Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
* Known intolerance, hypersensitivity, or contraindication to glucocorticoids.
* 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.
* Concurrent hematologic or non-hematologic malignancy requiring treatment (other than multiple myeloma with local amyloid deposition in the bone marrow).
* Active, unstable cardiovascular function, as indicated by the presence of:

  * Symptomatic ischemia, or
  * Uncontrolled clinically significant conduction abnormalities (e.g. patients with ventricular 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), or
  * Congestive heart failure of NYHA Class ≥3 or known left ventricular ejection fraction of \<40%, or
  * Myocardial infarction within 3 months prior to C1D1.
* Grade \> 3 peripheral neuropathy, or Grade 2 with pain on clinical examination during the screening period.
* Major surgery within 14 days prior to C1D1.
* 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 acceptable.
* Participation in other clinical trials, including those with other investigational agents not included in this trial, within 30 days prior to C1D1 and throughout the duration of this trial.