Trial of Activated Marrow Infiltrating Lymphocytes Alone or in Conjunction With an Allogeneic Granulocyte Macrophage Colony-stimulating Factor (GM-CSF)-Based Myeloma Cellular Vaccine in the Autologous Transplant Setting in Multiple Myeloma (aMILs)

Randomized Trial of Activated Marrow Infiltrating Lymphocytes Alone or in Conjunction With an Allogeneic GM-CSF-based Myeloma Cellular Vaccine in the Autologous Transplant Setting in Multiple Myeloma

Patient Population: Patients with active myeloma (Stage II/III) that have completed induction therapy and are eligible for an autologous stem cell transplant.

Number of Patients: Will treat a total of 32 evaluable patients in a 1:1 randomization of aMILs vs aMILs plus vaccine. An evaluable patient is defined as one which has received the activated MILs and is at least 6 months post-transplant.

Study Objectives:

Disease response as determined by the Blade' criteria will be the primary endpoint of the trial at one year.

Additional study endpoints include progression free survival, parameters of T cell reconstitution, anti-tumor immune responses as well as the effect on osteoclastogenesis and clonogenic myeloma precursor cells.

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma
• Intervention / Treatment: Biological: Activated marrow infiltrating lymphocytes; Drug: Cyclophosphamide; Biological: Filgrastim; Procedure: Leukapheresis; Drug: Melphalan; Biological: Autologous stem cell transplant; Biological: Allogeneic Myeloma Vaccine

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Durie-Salmon Stage II or III multiple myeloma
• Newly diagnosed either prior to receiving treatment or having completed induction therapy
• Relapsed myeloma not previously transplanted within the past 5 years
• Measurable serum and/or urine M-protein from prior to induction therapy documented and available. A positive serum free lite assay is acceptable
• Age greater than 18 years old
• ECOG performance status of 0 - 2
• Meet all institutional requirements for autologous stem cell transplantation
• The patient must be able to comprehend and have signed the informed consent

Exclusion Criteria:

• Diagnosis of any of the following plasma cell disorders: POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein [M-protein] and skin changes) Non-secretory myeloma (no measurable protein on Serum Free Lite Assay)
• Plasma cell leukemia
• Amyloidosis
• Use of corticosteroids (glucocorticoids) within 21 days of pre-transplant vaccine or bone marrow collection
• Use of any myeloma-specific therapy other than lenalidomide within 21 days of pre-transplant vaccine
• In a complete remission at the time of bone marrow collection
• Infection requiring treatment with antibiotics, antifungal, or antiviral agents within seven days of vaccination or bone marrow collection
• Participation in any clinical trial, within four weeks prior to vaccination or bone marrow collection on this trial, which involved an investigational drug or device
• History of malignancy other than multiple myeloma within five years of vaccination or bone marrow collection, except adequately treated basal or squamous cell skin cancer
• Active autoimmune disease (e.g., rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosis) requiring systemic treatment. Hypothyroidism without evidence of Grave's Disease or Hashimoto's thyroiditis is permitted
• Evidence of spinal cord compression at time of transplant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ASCT + MILs; Cyclophosphamide and filgrastim will be given to mobilize peripheral blood stem cells. Leukapheresis will be performed to collect peripheral blood from which activated marrow infiltrating lymphocytes will be produced. A melphalan conditioning regimen will be used prior to autologous stem cell transplant, and the MILs product will be administered on Days 3 and 4.	Biological: Activated marrow infiltrating lymphocytes; Administered on Days 3 and 4.; Other Names: MILs; aMILs; Drug: Cyclophosphamide; Administered at 2.5 g/m^2.; Other Names: Cytoxan; Biological: Filgrastim; Administered post cyclophosphamide daily until leukapheresis.; Other Names: G-CSF; Procedure: Leukapheresis; Performed approximately 12 days post cyclophosphamide. Exact date depends on peripheral blood CD34+ cell counts.; Other Names: Apheresis; Drug: Melphalan; 100 mg/m^2/day given on Days -2 and -1.; Other Names: Alkeran; Biological: Autologous stem cell transplant; Infused on Day 0.; Other Names: ASCT
Experimental: ASCT + MILs + vaccine; Cyclophosphamide and filgrastim will be given to mobilize peripheral blood stem cells. Leukapheresis will be performed to collect peripheral blood from which activated marrow infiltrating lymphocytes will be produced. A melphalan conditioning regimen will be used prior to autologous stem cell transplant, and the MILs product will be administered on Days 3 and 4. The allogeneic myeloma vaccine will be administered on Days 21, 60, 180, and 300.	Biological: Activated marrow infiltrating lymphocytes; Administered on Days 3 and 4.; Other Names: MILs; aMILs; Drug: Cyclophosphamide; Administered at 2.5 g/m^2.; Other Names: Cytoxan; Biological: Filgrastim; Administered post cyclophosphamide daily until leukapheresis.; Other Names: G-CSF; Procedure: Leukapheresis; Performed approximately 12 days post cyclophosphamide. Exact date depends on peripheral blood CD34+ cell counts.; Other Names: Apheresis; Drug: Melphalan; 100 mg/m^2/day given on Days -2 and -1.; Other Names: Alkeran; Biological: Autologous stem cell transplant; Infused on Day 0.; Other Names: ASCT; Biological: Allogeneic Myeloma Vaccine; Allogeneic granulocyte macrophage colony-stimulating factor (GM-CSF)-based myeloma cellular vaccine. Administered on Days 21, 60, 180, and 300.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response Rates by Blade Criteria	Number of participants with each disease response category utilizing the Blade criteria: Complete Response (CR): Defined as negative serum and urine immunofixation and a bone marrow aspirate with < 5% plasma cells.; Near Complete Response (nCR): Defined as negative serum and urine paraprotein, positive serum and/or urine immunofixation, and a bone marrow aspirate with < 5% plasma cells.; Very Good Partial Response (VGPR): Defined as negative serum and urine paraprotein with positive serum and/or urine immunofixation; or a 90% decrease in serum paraprotein with urine paraprotein < 100 mg/24 hours.; Partial Response (PR): Defined as a 50-89% decrease in serum paraprotein.; Minimal Response (MR): Defined as a 25-49% decrease in serum paraprotein.; Stable Disease (SD): Defined as not falling into any other response category.; Overall response rate (ORR): Total of CR, nCR, VGPR, and PR.	Up to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival	Median number of months that participants were alive without disease relapse or progression (progression-free survival).	Up to 5 years
Overall Survival	Number of participants alive at 5 years (overall survival).	Up to 5 years
Feasibility as Measured by Participant Withdrawal or Removal	Number of participants who withdrew or were removed from the study for reasons other than lack of efficacy prior to completion.	Up to 1 year
Safety as Measured by Grade 3-5 Adverse Events	Number of participants who experienced at least one grade 3-5 adverse event by CTCAE 3.0 that was attributed to MILs or the myeloma vaccine.	Up to 1 year
Anti-tumor Immune Response	Evaluate tumor specific responses in blood and bone marrow; Examine T cell responses to DC-pulsed myeloma cell lines; Examine induction of novel antibody responses	Days 60, 180, and 360
The Effect of aMILs on Osteoclastogenesis as Measured by Bone Turnover (RANKL/OPG Ratio)		Days 60, 180, and 360
The Effect of aMILs on Osteoclastogenesis as Measured by Bone Turnover (Serum C Telopeptide Levels)	Serum C Telopeptide	Days 60, 180, 360
The Effect of aMILs on Osteoclastogenesis as Measured by Bone Turnover (bAlkaline Phosphatase Levels)	bAlkaline phosphatase	Days 60, 180, 360
The Effect of aMILs on Osteoclastogenesis as Measured by Bone Turnover (Osteocalcin Levels)	Osteocalcin	Days 60, 180, 360
Effect of aMILs on Clonogenic Myeloma Precursors	• Examine side population of CD19 enriched PBLs throughout study.	Days 60, 180, and 360

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Investigators: Principal Investigator: Ivan Borrello, MD, Johns Hopkins University

Study record dates

Study Major Dates

• Study Start (Actual): January 15, 2010
• Primary Completion (Actual): December 1, 2014
• Study Completion (Actual): June 1, 2020

Study Registration Dates

• First Submitted: December 14, 2009
• First Submitted That Met QC Criteria: January 7, 2010
• First Posted (Estimate): January 11, 2010

Study Record Updates

• Last Update Posted (Actual): April 9, 2021
• Last Update Submitted That Met QC Criteria: March 16, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: multiple myeloma
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Melphalan
• Other Study ID Numbers: J0997; NA_00029491 (Other Identifier: JHMIRB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No