Donor Immune Cells (TGFbi NK Cells) and Isatuximab for the Treatment of Relapsed or Refractory Multiple Myeloma

Inclusion Criteria:

* Patients 18 years of age or older with evidence of relapsed or refractory disease as defined by IMWG criteria and measurable disease as defined by any of the following:

  * Serum M-protein ≥ 0.5 g/dl
  * Urine monoclonal protein ≥ 200 mg/24h
  * Involved free light chain (FLC) level ≥ 10mg/dl (≥ 100mg/l) and an abnormal serum free light chain ratio (\< 0.26, or \> 1.65)
* Patients must have had at least 3 prior lines of therapy including lenalidomide, proteasome inhibitor (PI), anti-CD38 or anti-SLAMF7 directed antibody, and BCMA-targeting therapy.

  * Prior daratumumab or isatuximab is permitted but not in the immediate line prior to study entry
  * Prior autologous hematopoietic cell transplant is permitted
  * Prior allogeneic transplant is excluded
* Refractory (progressed on or within 60 days of treatment) to their last treatment

  * If chimeric antigen receptor t cell (CAR-T) therapy was the immediately prior therapy, then the definition of refractory disease will not be limited to within 60 days
  * Patients must be off last treatment for at least 2 weeks by the beginning of treatment on this protocol
* Hemoglobin ≥ 7g/dL
* Absolute neutrophil count (ANC) ≥ 1000/µL
* Platelets ≥ 70,000/µL

  * If plasma cell percentage on bone marrow biopsy core is \> 30%, platelet requirement will be adjusted to 50,000/µl
* Total bilirubin \< 2 mg/dL
* Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT)/ alkaline phosphatase \< 2.5 X the upper limit of normal (ULN)
* Calculated creatinine clearance of ≥ 30ml/min using Modification of Diet in Renal Disease (MDRD) formula
* Left ventricular ejection fraction ≥ 30%; baseline echocardiography (ECHO) is not required if ECHO was done within the preceding one year and patients do not have new signs/symptoms suggestive of heart failure
* No uncontrolled arrhythmias
* No New York Heart Association class III-IV heart failure
* 12-lead electrocardiogram (ECG) with QT interval calculated by Fridericia Formula (QTcF) interval of ≤ 470 msec
* Patients must provide informed consent
* Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of ≤ 2
* Fertility requirements:

  * Women of child bearing potential (WOCBP) must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device \[IUD\], hormonal \[birth control pills, injections, hormonal patches, vaginal rings or implants\] or partner's vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing and continue to 6 months after study treatment ending. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy.
  * Investigators shall counsel WOCBP and male participants who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy
  * A negative pregnancy test will be required for all WOCBP within 24 hours before starting treatment drugs
  * Breast feeding is not permitted
  * Male patients must agree to use an adequate method of contraception (latex or synthetic condom) for the duration of the study and up to 6 months after study treatment ending
  * Criteria also applies to azoospermic males
  * Males should refrain from sperm donation during this time and continue for 6 months after study treatment ending

Exclusion Criteria:

* Patients with active (untreated or relapsed) central nervous system (CNS) MM
* Patients with Waldenstrom macroglobulinemia, primary AL amyloidosis, primary plasma cell leukemia, or polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome

  * Patients with secondary plasma cell leukemia are permitted
* Patients receiving concurrent corticosteroids at the time protocol therapy is initiated other than for physiologic maintenance treatment
* Concurrent use of complementary or alternative medicines that would confound the interpretation of toxicities and antitumor activity of the study drugs
* Patients with contraindications or allergy to cyclophosphamide and/or daratumumab/isatuximab
* Unacceptable respiratory risk factors defined by any one of the following criteria:

  * Chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) less than 50% of predicted normal
  * Moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification
* Unacceptable cardiac risk factors defined by any of the following criteria:

  * Complete left bundle branch, bifascicular block or clinically significant abnormal electrocardiogram (EKG) finding at screening
  * Congenital long QT Syndrome
  * Myocardial infarction or unstable angina within 6 months
* Patients who have received targeted or investigational agents within 2 weeks or within 5 half-lives of the agent and active metabolites (whichever is shorter) and who have not recovered from side effects of those therapies
* Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from the side-effects of surgery
* Patients with known positivity for human immunodeficiency virus (HIV) or active hepatitis B/C

  * Patients with chronic hepatitis B infection may be enrolled but must be provided prophylaxis (ex. entecavir for one year from start of therapy)
* Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention, other than non-melanoma skin cancer and carcinoma in situ of the cervix or breast, should not be enrolled
* Patients with any significant history of non-compliance to medical regimens or unwilling or unable to comply with the instructions given to them by the study staff
* Any other medical condition, including mental illness or substance abuse, deemed by the investigator(s) to likely interfere with the patient's ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results
* Life expectancy of 6 months or less