Stem Cell Transplant, Chemotherapy, and Biological Therapy in Treating Patients With High-Risk or Refractory Multiple Myeloma
Condition: Multiple Myeloma and Plasma Cell Neoplasm
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Plasmacytoma
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      RATIONALE: Vaccines made from peptides may help the body build an effective immune response
      to kill tumor cells. Drugs used in chemotherapy use different ways to stop cancer cells from
      dividing so they stop growing or die. Thalidomide may stop the growth of cancer cells by
      stopping blood flow to the cancer. A stem cell transplant using stem cells from the patient
      may be able to replace immune cells that were destroyed by chemotherapy used to kill cancer
      cells. Giving an infusion of the donor's T cells after the transplant may help destroy any
      remaining cancer cells.

      PURPOSE: This phase I/II trial is studying the side effects of stem cell transplant given
      together with chemotherapy and biological therapy and to see how well it works in treating
      patients with high-risk or refractory multiple myeloma.
    

Detailed description: 
      OBJECTIVES:

      Primary

        -  To evaluate the safety of combination immunotherapy using activated T-cells and an
           hTERT/survivin multipeptide vaccine in the post-autotransplant (autologous stem cell
           transplantation) setting and whether it delays hematopoietic recovery or induces
           autoimmune events.

        -  To determine whether the strategy of infusing vaccine-primed T-cells early after
           transplant in conjunction with post-transplant booster immunizations leads to the
           induction of cellular immune responses to the putative tumor antigens hTERT ( the
           catalytic subunit of telomerase) and survivin.

        -  To determine if combination immunotherapy as delivered to arm I patients increases the
           frequency of delayed paraprotein responses between 60 days and 6 months post-transplant,
           sufficient to upgrade the maximal level of myeloma response, when compared to
           non-vaccinated (arm II) patients.

      Secondary

        -  To determine if adoptive transfer of hTERT/survivin-primed T-cells in conjunction with
           multi-peptide booster immunizations generates cytotoxic T-cell responses to autologous
           myeloma cells in vivo.

        -  To evaluate myeloma clinical responses including the frequency of complete and partial
           responses and the 1 & 2-year event-free and overall survivals.

        -  To measure antibody responses to 4 of the 7 serotypes contained in the pneumococcal
           polyvalent vaccine as well as T-cell responses to the CRM-197 carrier protein and to a
           CMV peptide antigen.

        -  To evaluate levels of hTERT and survivin expression in patient myeloma cells.

      OUTLINE: This is a multicenter study. Patients are stratified according to HLA-A2 status
      (positive vs negative). Patients are assigned to 1 of 2 treatment groups based on
      stratification.

        -  Immunization 1:

             -  Group 1 (HLA-A2 positive): Patients receive the following peptides emulsified in
                incomplete Freund's adjuvant VG: I) hTERT I540 peptide; ii) hTERT R572Y peptide;
                iii) hTERT D988Y peptide; iv) survivin Sur1M2 peptide ; and v) CMV control peptide
                N495 subcutaneously (SC). Patients also receive sargramostim (GM-CSF) SC and
                pneumococcal conjugate vaccine (PCV) intramuscularly (IM).

             -  Group 2: Patients receive PCV vaccine IM and GM-CSF SC.

        -  Steady-state T-cell harvesting:About 10 days (range 7-14) after immunization #1, all
           patients undergo a mononuclear cell apheresis procedure to collect steady-state T-cells
           that are cryopreserved for later expansion.

        -  Stem cell mobilization: After completion of the mononuclear cell apheresis procedure,
           all patients are offered DT-PACE chemotherapy for cytoreduction and stem cell
           mobilization. This regimen is as follows: dexamethasone once daily for 4 days;
           thalidomide once daily for 4 days; cisplatin IV continuously over 4 days (patients with
           serum creatinine levels ≥ 2.0 mg/dL do not receive cisplatin); doxorubicin hydrochloride
           IV continuously over 4 days; cyclophosphamide IV continuously over 4 days; etoposide IV
           continuously over 4 days. Patients also receive filgrastim (G-CSF) SC once daily
           starting on the day after completion of chemotherapy. An acceptable alternative for stem
           cell mobilization is to use cyclophosphamide IV over 12 hours or, for patients who
           require that outpatient stem cell mobilization procedures be performed, cyclophosphamide
           IV over 2 hours. The cyclophosphamide mobilization regimen should be used if the patient
           has already received DTPACE as part of the pre-transplant therapy.

        -  High-dose therapy: High-dose therapy will consist of melphalan IV over 20 minutes on day
           -1. Autologous stem cell infusion takes place on day 0, at least 18 hours after the
           administration of the high-dose melphalan. Stem cells are infused IV over 20-60 minutes.
           G-CSF SC should be administered beginning on day +5.

        -  Autologous T-cell expansion and infusion: Cryopreserved cells are expanded ex vivo for
           up to 12 days and prepared for infusion on day 2 post-transplant.

        -  Infusion of autologous T-cells: The costimulated ("activated") T-cells are infused over
           20-60 minutes on day +2 of transplant.

        -  Immunizations 2, 3, and 4:

             -  Group 1: On days 14, 42, and 90 post-transplant, patients receive peptides, PCV,
                and GM-CSF as in group I of immunization # 1.

             -  Group 2: On day 14, 42, 90 post-transplant, patients receive PCV and GM-CSF as in
                group II of immunization # 1.

        -  Maintenance therapy: At day 180 post-transplant, after completion of post-transplant
           immunological assessments, patients receive low-dose thalidomide in the absence of
           disease progression or unacceptable toxicity.

      Blood is collected at T-cell harvest and days 14, 60, 100, and 180 post-transplant. Samples
      are analyzed by quantitative CD3/CD4/CD8 studies, cellular immunoassays, antibody
      immunoassays, and gene expression.

      After completion of study treatment, patients are followed periodically.
    

Intervention name(s): CMV pp65 peptide; hTERT I540/R572Y/D988Y multipeptide vaccine; pneumococcal polyvalent vaccine; survivin Sur1M2 peptide vaccine
Intervention type(s): Biological; Biological; Biological; Biological
Intervention description(s): Given intramuscularly; Given subcutaneously; Given intramuscularly; Given subcutaneously
Intervention MeSH terms: Vaccines; Heptavalent Pneumococcal Conjugate Vaccine
Primary purpose: Treatment
Keywords: stage I multiple myeloma; stage II multiple myeloma; stage III multiple myeloma; refractory multiple myeloma