Umbilical Cord Blood-Derived Natural Killer Cells, Elotuzumab, Lenalidomide, and High Dose Melphalan, Followed by Stem Cell Transplant in Treating Patients With Multiple Myeloma

This phase II trial studies the side effects and best dose of umbilical cord blood-derived natural killer cells when given together with elotuzumab, lenalidomide, and high dose melphalan before autologous stem cell transplant and to see how well they work in treating patients with multiple myeloma. Before transplant, stem cells are taken from patients and stored. Immunotherapy with monoclonal antibodies, such as elotuzumab, may induce changes in the body's immune system and may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as lenalidomide and melphalan, may work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before a stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. Giving natural killer cells from donor umbilical cord blood before transplant may also kill myeloma cells that remain in the body after the last chemotherapy treatment. After treatment, stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy.

PRIMARY OBJECTIVES:

I. To find the maximum tolerated dose (MTD) of umbilical cord blood (UCB)-derived natural killer (NK) cells.

II. To determine efficacy by the percent of patients achieving very good partial remission (VGPR) + complete remission (CR) at 3 months post-transplant.

III. To assess the minimal residual disease rate 100 days post-transplant in high-risk patients.

SECONDARY OBJECTIVE:

I. To quantify duration of infused allogeneic donor UCB-derived NK cells in the recipient.

OUTLINE: This is a dose-escalation study of UCB-derived NK cells.

Patients receive elotuzumab intravenously (IV) over 2-5 hours on day -15 and -8, lenalidomide orally (PO) once daily (QD) on days -8 to -2, high-dose melphalan IV over 30 minutes on day -7, and UCB-derived NK cells IV over 1 hour on day -5. Patients undergo autologous stem cell transplant on day 0.

After completion of study treatment, patients are followed up at 30, 60 and 100 days and 6 and 12 months.

Eligibility Criteria:
Inclusion Criteria:

* Patients with high risk multiple myeloma who are transplant candidates, in partial response (PR) or better; high risk will be defined as patients with any of the following:

  * Fluorescence in situ hybridization showing t(4:14), t(14:16), t(14:20), gain (amp) 1q; deletion (Del) 17/17p \[or tp53 gene mutation/deletion by next generation sequencing (NGS), or by conventional cytogenetics\];
  * Deletion 13 by conventional cytogenetic analysis;
  * High risk signatures as determined by the GEP-70 or EMC-92 gene expression profiles;
  * Relapsed disease within 18 months of prior autologous stem cell transplant (ASCT)
* Patients with plasma cell leukemia who are transplant candidates
* Performance score of at least 70% by Karnofsky or 0 to 2 Eastern Cooperative Oncology Group (ECOG)
* Left ventricular ejection fraction greater than 40%
* Pulmonary function test (PFT) demonstrating a diffusion capacity of least 40% predicted
* Estimated serum creatinine clearance \>= 60 ml/min (using the Cockcroft-Gault formula and/or serum creatinine =\< 1.6 mg/dL
* Serum glutamate pyruvate transaminase (SGPT) less than 3 x upper limit of normal
* Total bilirubin less than 2 x upper limit of normal
* All study participants must be registered into the mandatory Revlimid Risk Evaluation and Mitigation Strategy (REMS) program, and be willing and able to comply with the requirements of the Revlimid REMS program
* Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS program
* Men must agree to use a latex condom during sexual contact with females of child bearing potential even if they have had a successful vasectomy
* Patients must have a cord blood (CB) unit available which is matched with the patient at 4, 5, or 6/6 human leukocyte antigen (HLA) class I (serological) and II (molecular) antigens
* Patient or legally authorized representative able to sign informed consent

Exclusion Criteria:

* Patients receiving any other investigational agents
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to melphalan
* Known hypersensitivity or desquamating rash to either thalidomide or lenalidomide
* Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, uncontrolled hypertension (systolic \> 160, diastolic \> 100 despite antihypertensive therapy, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
* Human immunodeficiency virus (HIV)-positive patients are excluded due to increased risk of lethal infections when treated with myeloablative chemotherapy