UARK 2010-35, A Study of Expanded Natural Killer Cell Therapy for Multiple Myeloma
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Bortezomib
Intervention description: bortezomib to be given days -9, -6, and -2 at 1.0mg/m2, i.v.
Intervention MeSH terms: Bortezomib
Phase: Phase 2
Study type: Interventional
Primary purpose: Prevention
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 10.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Multiple Myeloma

Summary:

      The purpose of this study is to determine the therapeutic efficacy of the exp-NK cell therapy
      in research participants with relapsed high risk MM [defined as gene expression profile (GEP)
      70 gene score ≥0.66 and/or metaphase chromosomal abnormalities and/or high LDH ≥ 360U/L] by
      establishing the (near) complete response rate. Response rate will be compared to case
      matched historical controls (patients who relapsed on Total Therapy 2 or 3 with high-risk MM
      defined as above). Disease-free survival and overall survival will be captured but are not
      primary or secondary endpoints.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patient (Recipient of NK Cells) Inclusion Criteria

          -  Relapsed patients must have high risk disease as defined by GEP risk score of ≥ 0.66
             or metaphase cytogenetic abnormalities or LDH ≥ 360 U/L (Rule out hemolysis, infection
             and contact PI for clarification if any doubt) Patients must have had at least 1 line
             of prior chemotherapy and/or have relapsed after auto- PBSCT.

          -  For subjects who have had a prior transplant, ≥2 months must have relapsed after the
             last transplant prior to enrollment.

          -  Zubrod ≤ 2, unless solely due to symptoms of MM-related (bone) disease.

          -  Patients must have a platelet count of ≥ 50,000/µL within 35 days of registration,
             unless lower levels are explained by extensive bone marrow plasmacytosis or extensive
             prior therapy.

          -  Patients must be at least 18 years of age and not older than 75 years of age at the
             time of registration.

          -  Participants must have preserved renal function as defined by a serum creatinine level
             of ≤ 3 mg/dL within 35 days of registration.

          -  Participants must have an ejection fraction by ECHO or MUGA scan ≥ 40% within 90 days
             prior to registration.

          -  Patients must have adequate pulmonary function studies > 50% of predicted on
             mechanical aspects (FEV1, FVC, etc) and diffusion capacity (DLCO) > 50% of predicted
             within 90 days prior to registration. If the patient is unable to complete pulmonary
             function tests due to MM related pain or condition, exception may be granted if the
             principal investigator documents that the patient is a candidate for high dose
             therapy.

          -  Patients must have signed an IRB-approved informed consent and HIPAA authorization
             form.

          -  Either a haploidentical family donor fit to undergo leukapheresis is available or the
             recipient is fit to undergo leukapheresis for exp-NK cell generation (see donor
             selection).

          -  Patient (Recipient of NK Cells) Exclusion criteria

          -  History of poorly controlled hypertension, diabetes mellitus, or any other serious
             medical illness or psychiatric illness that could potentially interfere with the
             completion of treatment according to this protocol or could be considered to be an
             exclusion criterion deemed by the PI.

          -  Patients must not have prior malignancy, except for adequately treated basal cell or
             squamous cell skin cancer, in situ cervical cancer, or other cancer for which the
             patient has not received treatment for one year prior to enrollment. Other cancers
             will only be acceptable if the patient's life expectancy exceeds three years as
             determined by the PI.

          -  Pregnant or nursing women may not participate. Women of childbearing potential must
             have a negative pregnancy documented within one week of registration. Women/men of
             reproductive potential may not participate unless they have agreed to use an effective
             contraceptive method.

          -  Donor Inclusion Criteria

          -  The source of the NK cells will be either A) a family member who is HLA haploidentical
             to the recipient, or B) if a suitable haploidentical donor is not available, the
             recipient may be the source of the NK cells.

          -  HLA typing will be performed by the Arkansas Children's Hospital clinical laboratory.

          -  If the recipient expresses HLA-C group I, HLA-C group II, and Bw4 KIR ligands, then a
             KIR-ligand mismatched haploidentical donor cannot be found, and the recipient will be
             the source of the NK cells.

          -  If the recipient fails to express one or more of the primary KIR ligands (HLA-C group
             I, HLA-C group II, and Bw4) then family member donors will be HLA typed in an effort
             to find a haploidentical donor. If multiple haploidentical donors are available, KIR
             phenotyping will be performed in Dr. van Rhee's research laboratory to select a KIR
             mismatched donor whenever possible.

          -  Donor selection will be performed by the PI or one of the MD co-investigators if Dr.
             van Rhee is not available.

          -  Signed IRB approved consent and HIPAA authorization form.

          -  Donor is not HIV I/II (+).

          -  Donor is not HTLV-I/II (+).

          -  Donor is not Hepatitis B or C (+) unless positive due to previous vaccination or has
             received therapy and is negative for Hepatitis B or C by RT-PCR.

          -  Donor is a suitable candidate for insertion of apheresis catheter. Donors with unusual
             anatomy or vascular anomalies preventing insertion of a pheresis catheter will be
             rejected.

          -  Age 18 years or greater or has signed an Assent and be age ≥16 years.

          -  Donor has a negative pregnancy test by serum or urine test.

          -  In preparation for the peripheral blood mononuclear cell donation, the donor will
             undergo a detailed medical history and physical examination. Clinical studies will
             include blood chemistries (electrolytes, liver function and CRP) CBC with differential
             and platelets, PT/PTT, viral panel, EKG (age over 40 yrs), and chest x-ray (age over
             40yrs). Fitness to donate cells for NK expansion will be evaluated by a physician not
             involved in the initial assessment of the exp-NK cell recipient for enrollment onto
             the protocol.

          -  Serologic evaluation will be used to assess exposure to syphilis, West Nile Virus,
             Chagas, CMV IgG, hepatitis B, and C, HIV I and II, and HTLV I/II. An HIV-I/II[+] and
             HTLV-1/II (+) donor will be rejected on medical grounds. Donors who been vaccinated
             against hepatitis B and who have antibodies against hepatitis B surface antigen are
             allowed.

          -  Haplo-identical donor must not have prior malignancy, except for adequately treated
             basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for
             which the patient has not received treatment for one year prior to donation.

        Exclusion Criteria:

          -  Patient (Recipient of NK Cells) Exclusion criteria

          -  History of poorly controlled hypertension, diabetes mellitus, or any other serious
             medical illness or psychiatric illness that could potentially interfere with the
             completion of treatment according to this protocol or could be considered to be an
             exclusion criterion deemed by the PI.

          -  Patients must not have prior malignancy, except for adequately treated basal cell or
             squamous cell skin cancer, in situ cervical cancer, or other cancer for which the
             patient has not received treatment for one year prior to enrollment. Other cancers
             will only be acceptable if the patient's life expectancy exceeds three years as
             determined by the PI.

          -  Pregnant or nursing women may not participate. Women of childbearing potential must
             have a negative pregnancy documented within one week of registration. Women/men of
             reproductive potential may not participate unless they have agreed to use an effective
             contraceptive method.